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【结 构 式】

【分子编号】11463

【品名】3-Bromo-1-propene; 3-Bromopropene；allyl bromide

【CA登记号】106-95-6

【 分 子 式 】C3H5Br

【 分 子 量 】120.9767

【元素组成】C 29.79% H 4.17% Br 66.05%
与该中间体有关的原料药合成路线共 100 条
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合成路线1

该中间体在本合成路线中的序号：(B)

The metal-ammonia reduction of 4,6-dimethoxy-m-xylene (I) gives 1,5-dimethyl-2,4-dimethoxy-1,4-cyclohexadiene (II), which by treatment with potassium tert-butoxide in DMSO is converted into the conjugated diene (III). The Dies-Alder reaction of (III) with dimethyl acetylenedicarboxylate (A), and subsequent elimination of the bridge affords dimethyl 3-methyl-4,6-dimethoxyphthalate (IV), which is selectively monodemethylated with BCl3 yielding the o-hydroxyphthalic ester (V). The hydrolysis and anhydrization of (V) gives 3-hydroxy-5-methoxy-6-methylphthalic anhydride (VI), which is reduced with Zn and HCl in acetic acid affording 4-methyl-5-methoxy-7-hydroxyphthalide (VII). The reaction of (VII) with allyl bromide (B) by means of K2CO3 in ether gives the allylic ether (VIII), which undergoes thermal rearrangement into 4-methyl-5-methoxy-7-hydroxy-6-allyl-phthalide (IX). The ozonolysis of (IX) affords the aldehyde (X), which by a Wittig condensation with 1-formylethylydenetriphenylphosphorane (XI) is converted into the new aldehyde (XII). A new Wittig reaction of (XII) with the phosphorane (XIII) gives the ethyl ester (XIV), which is finally hydrolyzed and partially reduced with diimide.

参考文献 中间体
合成目标
【1】 Castaner, J.; Hillier, K.; Mycophenolic acid. Drugs Fut 1978, 3, 8, 594.
【2】 Wright, J.J.; Birch, A.J.; A total synthesis of mycophenolic acid. J Chem Soc 1969, 14, 788-789.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(A) 24551 Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester 762-42-5 C6H6O4 详情 详情
(I) 39930 1,5-dimethoxy-2,4-dimethylbenzene; 5-methoxy-2,4-dimethylphenyl methyl ether C10H14O2 详情 详情
(II) 39931 1,5-dimethoxy-2,4-dimethyl-1,4-cyclohexadiene; 5-methoxy-2,4-dimethyl-1,4-cyclohexadien-1-yl methyl ether C10H16O2 详情 详情
(III) 39932 3-methoxy-4,6-dimethyl-1,3-cyclohexadien-1-yl methyl ether; 2,4-dimethoxy-1,5-dimethyl-1,3-cyclohexadiene C10H16O2 详情 详情
(IV) 39933 dimethyl 4,6-dimethoxy-3-methylphthalate C13H16O6 详情 详情
(V) 39934 dimethyl 6-hydroxy-4-methoxy-3-methylphthalate C12H14O6 详情 详情
(VI) 39935 7-hydroxy-5-methoxy-4-methyl-2-benzofuran-1,3-dione C10H8O5 详情 详情
(VII) 39936 7-hydroxy-5-methoxy-4-methyl-2-benzofuran-1(3H)-one C10H10O4 详情 详情
(VIII) 39937 7-(allyloxy)-5-methoxy-4-methyl-2-benzofuran-1(3H)-one C13H14O4 详情 详情
(IX) 39938 6-allyl-7-hydroxy-5-methoxy-4-methyl-2-benzofuran-1(3H)-one C13H14O4 详情 详情
(X) 39939 2-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde C12H12O5 详情 详情
(XI) 39940 2-(triphenylphosphoranylidene)propanal C21H19OP 详情 详情
(XII) 39941 (E)-4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-2-methyl-2-butenal C15H16O5 详情 详情
(XIII) 39942 ethyl 2-(triethylphosphoranylidene)acetate C10H21O2P 详情 详情
(XIV) 39943 ethyl (2E,4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methyl-2,4-hexadienoate C19H22O6 详情 详情

合成路线2

该中间体在本合成路线中的序号：(II)

By condensation of 2'-hydroxy-5,9-dimethyl-6,7-benzomorphan (I) with allyl bromide (II) by means of NaHCO3 in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Gordon, M.; Lafferty, J.J. (SmithKline Beecham Corp.); Novel N-allyl and N-propargyl benzmorphan derivs.. US 4048178 .
【2】 Serradell, M.N.; Castaner, J.; Paton, D.M.; Blancafort, P.; SKF-10,047. Drugs Fut 1983, 8, 5, 439.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 36016 (1R,9R,13R)-1,13-dimethyl-10-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-trien-4-ol C14H19NO 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

The alkylation of 4-(N-acetyl-N-ethylamino)-2-hydroxyacetophenone (I) with allyl bromide (II) by means of K2CO3 in DMF gives the allyl ether (III), which is isomerized by refluxing in diethylaniline to 4-(N-acetyl-N-ethylamino)-3-allyl-2-hydroxyacetophenone (IV) The reduction of (IV) with H2 over Pd/C in ethanol affords the corresponding propyl derivative (V), which is deacetylated with HBr in refluxing acetic acid water to 4-(ethylamino)-3-propyl-2-hydroxyacetophenone (VI). The addition of (VI) dimethyl acetylenedicarboxylate (VII) in refluxing ethanol affords the aminomaleate (VIII), which by cyclization witn polyphosphoric acid at 100 C gives methyl 1-ethyl-6-acetyl-7-hydroxy-4 oxo-8-propyl-4H-quinoline-2-carboxylate (IX). The condensation of (IX) with diethyl oxalate in DMF by means of NaH results in the ester of the final product (X), which is then hydrolyzed with NaHCO3 iin refluxing ethanol.

参考文献 中间体
合成目标
【1】 Wilkinson, D.J.; Lockley, W.J.S.; Synthesis of nedocromil sodium labelled with tritium, deuterium and carbon-14. J Label Compd Radiopharm 1985, 22, 9, 883.
【2】 Caims, H.; Cox, D. (Rhone-Poulenc Rorer Ltd.); Nouvelles pyranoquinoleinones et leurs compositions pharmaceutiques. DE 2819215; ES 469391; JP 1199909; JP 53137969 .
【3】 Cairns, H.; Cox, D. (Rhone-Poulenc Rorer Ltd.); 4,6-Dioxo-4H,6H-pyrano[3,2-g]quinoline-2,8-dicarbocyclic acids. GB 2022078 .
【4】 Prous, J.; Castaner, J.; Nedocromil sodium. Drugs Fut 1986, 11, 9, 756.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(I) 24545 N-(4-acetyl-3-hydroxyphenyl)-N-ethylacetamide C12H15NO3 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 24547 3-[4-acetyl-3-(allyloxy)phenyl]-2-pentanone C16H20O3 详情 详情
(IV) 24548 N-(4-acetyl-2-allyl-3-hydroxyphenyl)-N-ethylacetamide 69049-64-5 C15H19NO3 详情 详情
(V) 24549 N-(4-acetyl-3-hydroxy-2-propylphenyl)-N-ethylacetamide C15H21NO3 详情 详情
(VI) 24550 1-[4-(ethylamino)-2-hydroxy-3-propylphenyl]-1-ethanone 69049-68-9 C13H19NO2 详情 详情
(VII) 24551 Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester 762-42-5 C6H6O4 详情 详情
(VIII) 24552 dimethyl (Z)-2-[4-acetyl(ethyl)-3-hydroxy-2-propylanilino]-2-butenedioate 77941-04-9 C19H25NO6 详情 详情
(IX) 24553 methyl 6-acetyl-1-ethyl-7-hydroxy-4-oxo-8-propyl-1,4-dihydro-2-quinolinecarboxylate 69049-70-3 C18H21NO5 详情 详情
(X) 24554 diethyl 9-ethyl-4,6-dioxo-10-propyl-6,9-dihydro-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate 69049-72-5 C23H25NO7 详情 详情

合成路线4

该中间体在本合成路线中的序号：(II)

By condensation of 2-(2,6-dichloroanilino)-2-imidazoline (I) with allyl bromide (II) by means of pyridine in refluxing methanol.

参考文献 中间体
合成目标
【1】 Staehle, H.; et al.; US 3708485 .
【2】 Castaner, J.; Hopkins, S.J.; Alinidine. Drugs Fut 1980, 5, 1, 11.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 39118 N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine; N-(2,6-dichlorophenyl)-N-(4,5-dihydro-1H-imidazol-2-yl)amine C9H9Cl2N3 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情

合成路线5

该中间体在本合成路线中的序号：(VII)

The condensation of 7-amino-3-bromomethyl-3-cephem-4-carboxylic acid tert-butyl ester 1-oxide (I) with 2-(2-tritylamino-4-thiazolyl)-2-[2-(tert-butoxycarbonyl)-2-propyloxyimino]acetic acid (II) by means of dicyclohexylcarbodiimide in CH2Cl2 gives the corresponding amide (III), which is treated with N-allyl-pyridine-2-thione (IV) in dimethylacetamide yielding the pyridinium salt (V). Finally, this compound is deprotected by a treatment with HCl in formic acid. The thione (IV) is prepared as follows: The reaction of 2-bromopyridine (VI) with allyl bromide (VII) in acetone gives N-allyl-2-bromopyridinium bromide (VIII), which is then treated with potassium hydrosulfide in water.

参考文献 中间体
合成目标
【1】 Labeeuw, B.; Salhi, A. (Sanofi-Synthelabo); Derivatives of pyridinium thiomethyl cephalosporins. EP 0088853; FR 2516515; JP 58090590; US 4593022 .
【2】 Serradell, M.N.; Matthews, R.; Castaner, J.; Burnie, J.; CM-40874. Drugs Fut 1985, 10, 3, 193.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 29048 tert-butyl 7-amino-3-(bromomethyl)-5,8-dioxo-5lambda(4)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C12H17BrN2O4S 详情 详情
(II) 29047 2-[[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid C32H33N3O5S 详情 详情
(III) 29049 tert-butyl 3-(bromomethyl)-7-([2-[[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-5,8-dioxo-5lambda(4)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C44H48BrN5O8S2 详情 详情
(IV) 29050 1-allyl-2(1H)-pyridinethione C8H9NS 详情 详情
(V) 29051 1-allyl-2-([[2-(tert-butoxycarbonyl)-7-([2-[[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]imino]-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-5,8-dioxo-5lambda(4)-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]sulfanyl)pyridinium bromide C52H57BrN6O8S3 详情 详情
(VI) 29052 2-Bromopyridine；α-bromopyridine;α-bromoazine 109-04-6 C5H4BrN 详情 详情
(VII) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VIII) 29053 1-allyl-2-bromopyridinium bromide C8H9Br2N 详情 详情

合成路线6

该中间体在本合成路线中的序号：(II)

The Keck's enantioselective allylation of dodecanal (I) with allyl bromide (II) employing a catalytic amount of (R)-BINOL and titanium tetraisopropoxide furnishes the chiral alcohol (III), which is esterified with acryloyl chloride (IV), TEA and DMAP to give the acrylate (V). The olefin metathesis of (V) by means of Grubbs' catalyst and Ti(O-iPr)4 in refluxing dichloromethane yields the dihydropyranone (VI), which is epoxidized with H2O2 and NaOH to afford the chiral epoxide (VII). The reductive cleavage of (VII) with diphenyl diselenide and NaBH4 gives the chiral tetrahydropyranone (VIII), which is silylated with Tbdms-Cl and DIEA, yielding the silyl ether (IX). Opening of the lactone ring of (IX) with TEA and methanol affords the hydroxyester (X), which is treated with dihydropyran and PPTS to provide the tetrahydropyranyl ether (XI). The desilylation of (XI) with TBAF in THF gives the beta-hydroxyester (XII), which is alkylated with hexyl iodide and LDA in THF, yielding the adduct (XIII). The cyclization of (XIII) by hydrolysis with LiOH, followed by treatment with Ph-SO2-Cl, affords the beta-lactone (XIV), which is treated with PPTS to eliminate the tetrahydropyranyl-protecting group and yield the secondary alcohol (XV). The esterification of (XV) with N-(benzyloxycarbonyl)-L-leucine (XVI) by means of DCC and DMAP affords the leucinate (XVII), which is deprotected with H2 over Pd/C, affording (XVIII) with a free amino group that is formylated with acetic formic mixed anhydride to furnish the target (-)-tetrahydrolipstatin.

参考文献 中间体
合成目标
【1】 Ghosh, A.K.; Liu, C.; A stereoselective synthesis of (-)-tetrahydrolipstatin. Chem Commun (London) 1999, 1743.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11082 Lauraldehyde; Dodecanal 112-54-9 C12H24O 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 11089 (4S)-1-Pentadecen-4-ol C15H30O 详情 详情
(IV) 11577 Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride 814-68-6 C3H3ClO 详情 详情
(V) 49595 (1S)-1-undecyl-3-butenyl acrylate C18H32O2 详情 详情
(VI) 49596 (6S)-6-undecyl-5,6-dihydro-2H-pyran-2-one C16H28O2 详情 详情
(VII) 49597 (1S,4S,6S)-4-undecyl-3,7-dioxabicyclo[4.1.0]heptan-2-one C16H28O3 详情 详情
(VIII) 49598 (4S,6S)-4-hydroxy-6-undecyltetrahydro-2H-pyran-2-one C16H30O3 详情 详情
(IX) 49599 (4S,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-undecyltetrahydro-2H-pyran-2-one C22H44O3Si 详情 详情
(X) 49600 methyl (3S,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxyhexadecanoate C23H48O4Si 详情 详情
(XI) 49601 methyl (3S,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-(tetrahydro-2H-pyran-2-yloxy)hexadecanoate C28H56O5Si 详情 详情
(XII) 49602 methyl (3S,5S)-3-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)hexadecanoate C22H42O5 详情 详情
(XIII) 49603 methyl (2S,3S,5S)-2-hexyl-3-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)hexadecanoate C28H54O5 详情 详情
(XIV) 49604 (3S,4S)-3-hexyl-4-[(2S)-2-(tetrahydro-2H-pyran-2-yloxy)tridecyl]-2-oxetanone C27H50O4 详情 详情
(XV) 49605 (3S,4S)-3-hexyl-4-[(2S)-2-hydroxytridecyl]-2-oxetanone C22H42O3 详情 详情
(XVI) 22838 (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid C14H19NO4 详情 详情
(XVII) 49606 (1S)-1-[[(2S,3S)-3-hexyl-4-oxooxetanyl]methyl]dodecyl (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoate C36H59NO6 详情 详情
(XVIII) 49607 (1S)-1-[[(2S,3S)-3-hexyl-4-oxooxetanyl]methyl]dodecyl (2S)-2-amino-4-methylpentanoate C28H53NO4 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

The chiral amine intermediate (XV) has been obtained as follows: The alkylation of 4-fluorophenol (I) with allyl bromide (II) and K2CO3 gives the allyl ether (III), which by thermal rearrangement at 210 C yields 2-allyl-4-fluorophenol (IV). The silylation of (IV) with TBDMS-Cl and imidazole affords the silyl ether (V), which is submitted to hydroboration with BH3 and H2O2 to provide the propanol (VI). The oxidation of (VI) with Dess Martin periodinane (DMP) gives the aldehyde (VII), which is condensed with the phosphorane (VIII) to yield the pentenoic ester (IX). The reduction of (IX) with DIBAL affords the unsaturated alcohol, which is desilylated with TBAF in THF furnishing the diol (XI). The treatment of (XI) under the Sharpless asymmetric epoxidation conditions ((-)-DET and titanium tetraisopropoxide) gives, after cyclization with NaOH, 1(R)-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2(S)-yl)-1,2-ethanediol (XII), which is selectively tosylated with TsCl and pyridine yielding the monotosylate (XIII). The reaction of (XIII) with sodium azide in DMF affords the azide (XIV), which is reduced to the corresponding amine (XV) with H2 over Pd/C in ethanol.

参考文献 中间体
合成目标
【1】 Chandrasekhar, S.; Reddy, M.V.; Enantioselective total synthesis of the antihypertensive agent (S,R,R,R)-nebivolol. Tetrahedron 2000, 56, 34, 6339.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 19639 4-fluorophenol 371-41-5 C6H5FO 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 40848 1-(allyloxy)-4-fluorobenzene; allyl 4-fluorophenyl ether C9H9FO 详情 详情
(IV) 40849 2-allyl-4-fluorophenol C9H9FO 详情 详情
(V) 40850 (2-allyl-4-fluorophenoxy)(tert-butyl)dimethylsilane; 2-allyl-4-fluorophenyl tert-butyl(dimethyl)silyl ether C15H23FOSi 详情 详情
(VI) 40851 3-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)-1-propanol C15H25FO2Si 详情 详情
(VII) 40852 3-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)propanal C15H23FO2Si 详情 详情
(VIII) 14182 ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane 1099-45-2 C22H21O2P 详情 详情
(IX) 40853 ethyl (E)-5-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)-2-pentenoate C19H29FO3Si 详情 详情
(X) 40854 (E)-5-(2-[[tert-butyl(dimethyl)silyl]oxy]-5-fluorophenyl)-2-penten-1-ol C17H27FO2Si 详情 详情
(XI) 40855 4-fluoro-2-[(E)-5-hydroxy-3-pentenyl]phenol C11H13FO2 详情 详情
(XII) 40856 (1R)-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1,2-ethanediol C11H13FO3 详情 详情
(XIII) 40857 (2R)-2-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl 4-methylbenzenesulfonate C18H19FO5S 详情 详情
(XIV) 40858 (1R)-2-azido-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1-ethanol C11H12FN3O2 详情 详情
(XV) 40859 (1R)-2-amino-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-1-ethanol C11H14FNO2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(XIX)

Synthesis of the aromatic intermediate (XXXIII): The esterification of the 5-hydroxyisophthalic acid (XVII) with SOCl2 and methanol gives the dimethyl ester (XVIII), which is treated with allyl bromide (XIX) and K2CO3 in refluxing acetone to yield the allyl ether (XX). The thermal isomerization of (XX) affords 4-allyl-5-hydroxyisophthalic acid dimethyl ester (XXI), which is treated with Bn-Br and K2CO3 in refluxing acetone to provide the benzyl ether (XXII). The hydrolysis of the ester groups of (XXII) with NaOH in THF gives the isophthalic acid (XXIII), which by reaction with Br2 and NaHCO3 yields the lactone (XXIV). The reduction of the carboxyl group of (XXIV) with isopropyl chloroformate and NaBH4 in THF/water affords the carbinol (XXV), which is protected with Bom-Cl and DIEA, providing compound (XXVI). The debromination of (XXVI) with Zn and NH4Cl in ethanol/water gives the 2-allylbenzoic acid (XXVII), which by a Curtius rearrangement with DPPA and TEA in refluxing tert-butanol yields the aryl carbamate (XXVIII). The reaction of (XXVIII) with OsO4 and NaIO4 in dioxane/water affords the indoline derivative (XXIX), which is treated with NaBH4 in EtOH to afford the 2-phenylethanol derivative (XXX). The reaction of (XXX) with Tbdms-Cl, TEA and DMAP provides the silyl ether (XXXI), which is treated with Tbdms-OTf and pyridine to give the aniline derivative (XXXII). Finally, this amine is reprotected with Alloc-Cl and NaHCO3 to yield the desired intermediate (XXXIII).

参考文献 中间体
合成目标
【1】 Katoh, T.; Terashima, S.; Total synthesis of antitumor antibiotic FR900482. Yuki Gosei Kagaku Kyokaishi 1997, 55, 11, 946.
【2】 Yoshino, T.; et al.; Total synthesis of an enantiomeric pair of FR900482. 2. Syntheses of the aromatic and the optically active aliphatic segments. Tetrahedron 1997, 53, 30, 10239.
【3】 Yoshino, T.; et al.; Total synthesis of natural (+)-FR900482. 2. Efficient syntheses of the aromatic and the optically active aliphatic fragments. Tetrahedron Lett 1996, 37, 20, 3475.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVII) 47387 5-hydroxyisophthalic acid 618-83-7 C8H6O5 详情 详情
(XVIII) 31197 dimethyl 5-hydroxyisophthalate 13036-02-7 C10H10O5 详情 详情
(XIX) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XX) 47388 dimethyl 5-(allyloxy)isophthalate C13H14O5 详情 详情
(XXI) 47389 dimethyl 4-allyl-5-hydroxyisophthalate C13H14O5 详情 详情
(XXII) 47390 dimethyl 4-allyl-5-(benzyloxy)isophthalate C20H20O5 详情 详情
(XXIII) 47391 4-allyl-5-(benzyloxy)isophthalic acid C18H16O5 详情 详情
(XXIV) 47392 5-(benzyloxy)-3-(bromomethyl)-1-oxo-3,4-dihydro-1H-isochromene-7-carboxylic acid C18H15BrO5 详情 详情
(XXV) 47393 5-(benzyloxy)-3-(bromomethyl)-7-(hydroxymethyl)-3,4-dihydro-1H-isochromen-1-one C18H17BrO4 详情 详情
(XXVI) 47394 5-(benzyloxy)-7-[[(benzyloxy)methoxy]methyl]-3-(bromomethyl)-3,4-dihydro-1H-isochromen-1-one C26H25BrO5 详情 详情
(XXVII) 47395 2-allyl-3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]benzoic acid C26H26O5 详情 详情
(XXVIII) 47396 tert-butyl 2-allyl-3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]phenylcarbamate C30H35NO5 详情 详情
(XXIX) 47397 tert-butyl 4-(benzyloxy)-6-[[(benzyloxy)methoxy]methyl]-2-hydroxy-1-indolinecarboxylate C29H33NO6 详情 详情
(XXX) 47398 tert-butyl 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-hydroxyethyl)phenylcarbamate C29H35NO6 详情 详情
(XXXI) 47399 tert-butyl 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenylcarbamate C35H49NO6Si 详情 详情
(XXXII) 47400 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenylamine; 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)aniline C30H41NO4Si 详情 详情
(XXXIII) 47401 allyl 3-(benzyloxy)-5-[[(benzyloxy)methoxy]methyl]-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenylcarbamate C34H45NO6Si 详情 详情

合成路线9

该中间体在本合成路线中的序号：(II)

The reaction of N-isopropylethanolamine (I) with allyl bromide (II) in THF gives the secondary amine (III), which is treated with SOCl2 in dichloromethane to yield the chloroethylamine (IV). The condensation of (IV) with 2-(2-chlorophenyl)-4-(1-piperidinyl)butyronitrile (V) by means of KOH in DMSO affords the adduct (VI), whose nitrile group is hydrolyzed with H2SO4 to provide the corresponding amide (VII). The elimination of the allyl group of (VII) by means of a Rh catalyst and 1,4-diazabicyclo[2,2,2]octane (DABCO) in refluxing aqueous ethanol gives the secondary amine (VIII), which is finally acetylated with Ac2O in ethyl acetate to yield the target diamide.

参考文献 中间体
合成目标
【1】 Awasthi, A.K.; Paul, K.; A new and improved synthesis of bidisomide. Org Process Res Dev 2001, 5, 5, 528.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 51925 2-(Isopropylamino)ethanol; 2-(iso-Propylamino)ethanol; N-Isopropylethanolamine 109-56-8 C5H13NO 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 51926 2-[allyl(isopropyl)amino]-1-ethanol C8H17NO 详情 详情
(IV) 51927 N-(2-chloroethyl)-N-isopropyl-2-propen-1-amine; N-allyl-N-(2-chloroethyl)-N-isopropylamine C8H16ClN 详情 详情
(V) 11434 2-(2-Chlorophenyl)-4-piperidinobutanenitrile C15H19ClN2 详情 详情
(VI) 51928 4-[allyl(isopropyl)amino]-2-(2-chlorophenyl)-2-[2-(1-piperidinyl)ethyl]butanenitrile C23H34ClN3 详情 详情
(VII) 51929 4-[allyl(isopropyl)amino]-2-(2-chlorophenyl)-2-[2-(1-piperidinyl)ethyl]butanamide C23H36ClN3O 详情 详情
(VIII) 11438 2-(2-Chlorophenyl)-4-(isopropylamino)-2-(2-piperidinoethyl)butanamide C20H32ClN3O 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XXIII)

2) (2R,3S,5S(2'S,4'R))-5-(2-(iodomethyl)tetrahydrofuran-4-yl)-5-(4-methoxy benzyloxy)-2-methyl-3-(triisopropylsilyloxy)pentanal (XXXII). The regioselective reduction of methyl 5-(4-methoxybenzyloxy)-3-oxopentanoate (XXI) with H2 over Ru2Cl4((S)-BINAP)2(C2H5)3N in methanol gives the 3(S)-hydroxy derivative (XXII), which is condensed with ally bromide (XXIII) by means of lithium diisopropylamide THF-HMPA to yield the ally derivative (XXIV). The reduction of (XXIV) with LiAlH4 in THF affords the diol (XXV), which is cyclized to the ketal (XXVI) by means of DDQ in dichloromethane. The reaction of (XXVI) first with N-iodosuccinimide (NIS) and then with diisobutylaluminum hydride affords (3S(2'S,4'R))-3-(2-iodomethyl)tetrahydrofuran-4-yl)-3-(4-methoxybenzyl)-1-propanol (XXVII), which is oxidized to the corresponding aldehyde (XXVIII) by means of oxalyl chloride in dichloromethane. The condensation of (XXVIII) with 2(E)-butenyltriphenylstannane (XXIX) by means of boron trifluoride ethearate in dichloromethane gives the alcohol (XXX), which is protected with TIPS trifluoromethanesulfonate in dichloromethane yielding the fully protected diol (XXXI). Finally, the double bond of (XXXI) is oxidized with ozone in methanol - dichloromethane yielding the second building fragment (XXXII).

参考文献 中间体
合成目标
【1】 Smith, D.B.; Schreiber, S.L.; Ragan, J.A.; Uehling, D.E.; Nakatsuka, M.; Sammakia, T.; Total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK5. J Am Chem Soc 1990, 112, 14, 5583.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXI) 11461 methyl 6-(4-methoxyphenyl)-3-oxohexanoate C14H18O4 详情 详情
(XXII) 11462 methyl (3S)-3-hydroxy-6-(4-methoxyphenyl)hexanoate C14H20O4 详情 详情
(XXIII) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XXIV) 11464 methyl (2S)-2-[(1S)-1-hydroxy-4-(4-methoxyphenyl)butyl]-4-pentenoate C17H24O4 详情 详情
(XXV) 11465 (2R,3S)-2-Allyl-5-[(4-methoxybenzyl)oxy]-1,3-pentanediol C16H24O4 详情 详情
(XXVI) 11466 (2R)-2-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-4-penten-1-ol C16H22O4 详情 详情
(XXVII) 11467 (3S)-3-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-4-(4-methoxyphenyl)-1-butanol C16H23IO3 详情 详情
(XXVIII) 11468 (3S)-3-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-4-(4-methoxyphenyl)butanal C16H21IO3 详情 详情
(XXIX) 11469 (E)-2-Butenyl(triphenyl)stannane C22H22Sn 详情 详情
(XXX) 11470 (3S,4S,6S)-6-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-7-(4-methoxyphenyl)-3-methyl-1-hepten-4-ol C20H29IO3 详情 详情
(XXXI) 11481 ([(1S,2S)-1-[(2S)-2-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-3-(4-methoxyphenyl)propyl]-2-methyl-3-butenyl]oxy)(triisopropyl)silane; (1S,2S)-1-[(2S)-2-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-3-(4-methoxyphenyl)propyl]-2-methyl-3-butenyl triisopropylsilyl ether C29H49IO3Si 详情 详情
(XXXIII) 11471 1,4-Pentadien-3-ol 922-65-6 C5H8O 详情 详情
(XXXIV) 11472 (1S)-1-[(2R)Oxiranyl]-2-propen-1-ol C5H8O2 详情 详情
(XXXV) 11473 (2S)-2-[(1S)-1-(4-Methoxybenzyl)-2-propenyl]oxirane; Methyl 4-[(2S)-2-[(2S)oxiranyl]-3-butenyl]phenyl ether C13H16O2 详情 详情
(XXXVI) 11474 (3S,4R)-7-Ethoxy-4-methoxy-3-(4-methoxybenzyl)-1-hepten-6-yne; 4-[(2S,3R)-6-Ethoxy-3-methoxy-2-vinyl-5-hexynyl]phenyl methyl ether C18H24O3 详情 详情
(XXXVII) 11475 ethyl (4R,5S)-5-hydroxy-4-methoxy-6-heptenoate C10H18O4 详情 详情
(XXXVIII) 11476 (5R,6S)-5-Methoxy-6-vinyltetrahydro-2H-pyran-2-one C8H12O3 详情 详情
(XXXIX) 11585 methyl (1R,5R)-5-methoxy-3-cyclohexene-1-carboxylate C9H14O3 详情 详情
(XL) 11586 methyl (1R,3R,4R)-4-hydroxy-3-methoxycyclohexanecarboxylate C9H16O4 详情 详情
(XLI) 11588 methyl (1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarboxylate C18H36O4Si 详情 详情
(XLII) 11480 [(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]methanol C17H36O3Si 详情 详情
(XLIII) 11532 (1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarbaldehyde C17H34O3Si 详情 详情

合成路线11

该中间体在本合成路线中的序号：(XXXV)

The asymmetric reduction of 5-(4-methoxybenzyloxy)-3-oxopentanoic acid methyl ester (XXXIII) with H2 over a chiral Ru catalyst gives the chiral hydroxyester (XXXIV), which is alkylated by means of allyl bromide (XXXV) and LDA to yield the chiral 2-allyl-3-hydroxypentanoic ester (XXXVI). The reduction of (XXXVI) with LiAlH4, and then with DDQ affords the 1,3-dioxan-4-ylethanol (XXXVII), which is treated with NIS, NaHCO3 and reduced with DIBAL to afford the iodomethyl tetrahydrofuran (XXXVIII). The oxidation of the primary OH group of (XXXVIII) with oxalyl chloride provides the carbaldehyde (XXXIX), which is condensed with the propenylstannane (XL) by means of BF3/Et2O in dichloromethane to give the unsaturated alcohol (XLI). The protection of the OH group of (XLI) with TipsOTf yields the unsaturated silyl ether (XLII), which is ozonolyzed by means of O3, pyridine and Me2S to afford the carbaldehyde (XLIII). The condensation of (XLIII) with the chiral intermediate 2-bromovinyl cyclohexane (XVIII) by means of tBuLi and MgBr2 provides the alcohol (XLIV), which is esterified with 1-(tert-butoxycarbonyl)piperidine-2(S)-carboxylic acid (XLV) by means of DCC to give the expected ester (XLVI). The reaction of (XLVI) with Zn and NH4Cl yields the chiral alpha-allyl alcohol (XLVII), which is oxidized by means of oxalyl chloride to afford the corresponding carbaldehyde (XLVIII).

参考文献 中间体
合成目标
【1】 Ragan, J.A.; The total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK506. Diss Abstr Int B - Sci Eng 1991, 51, 8, 3849.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVIII) 11485 ([(1R,2R,4R)-4-[(E)-2-Bromo-1-propenyl]-2-methoxycyclohexyl]oxy)(triisopropyl)silane; (1R,2R,4R)-4-[(E)-2-Bromo-1-propenyl]-2-methoxycyclohexyl triisopropylsilyl ether C19H37BrO2Si 详情 详情
(XXXIII) 57260 methyl 5-[(4-methoxybenzyl)oxy]-3-oxopentanoate C14H18O5 详情 详情
(XXXIV) 57261 methyl (3S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]pentanoate C14H20O5 详情 详情
(XXXV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XXXVI) 57262 methyl (2S)-2-{(1S)-1-hydroxy-3-[(4-methoxybenzyl)oxy]propyl}-4-pentenoate C17H24O5 详情 详情
(XXXVII) 11466 (2R)-2-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-4-penten-1-ol C16H22O4 详情 详情
(XXXVIII) 57263 (3S)-3-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-3-[(4-methoxybenzyl)oxy]-1-propanol C16H23IO4 详情 详情
(XXXIX) 57264 (3S)-3-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-3-[(4-methoxybenzyl)oxy]propanal C16H21IO4 详情 详情
(XL) 11469 (E)-2-Butenyl(triphenyl)stannane C22H22Sn 详情 详情
(XLI) 57265 (1S,3S,4S)-1-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-1-[(4-methoxybenzyl)oxy]-4-methyl-5-hexen-3-ol C20H29IO4 详情 详情
(XLII) 57266 (1S,2S)-1-{(2S)-2-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-2-[(4-methoxybenzyl)oxy]ethyl}-2-methyl-3-butenyl triisopropylsilyl ether; [((1S,2S)-1-{(2S)-2-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-2-[(4-methoxybenzyl)oxy]ethyl}-2-methyl-3-butenyl)oxy](triisopropyl)silane C29H49IO4Si 详情 详情
(XLIII) 57267 (2R,3S,5S)-5-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-5-[(4-methoxybenzyl)oxy]-2-methyl-3-[(triisopropylsilyl)oxy]pentanal C28H47IO5Si 详情 详情
(XLIV) 57268 (E,3S,4S,5S,7S)-7-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-7-[(4-methoxybenzyl)oxy]-1-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4-dimethyl-5-[(triisopropylsilyl)oxy]-1-hepten-3-ol C47H85IO7Si2 详情 详情
(XLV) 11487 (2S)-1-(tert-Butoxycarbonyl)hexahydro-2-pyridinecarboxylic acid C11H19NO4 详情 详情
(XLVI) 57269 1-(tert-butyl) 2-((1S,2E)-1-{(1S,2S,4S)-4-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-4-[(4-methoxybenzyl)oxy]-1-methyl-2-[(triisopropylsilyl)oxy]butyl}-3-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate C58H102INO10Si2 详情 详情
(XLVII) 57270 1-(tert-butyl) 2-{(1S,2S,3S,5S,6R)-6-(hydroxymethyl)-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl} (2S)-1,2-piperidinedicarboxylate C58H103NO10Si2 详情 详情
(XLVIII) 57271 1-(tert-butyl) 2-{(1S,2S,3S,5S,6S)-6-formyl-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl} (2S)-1,2-piperidinedicarboxylate C58H101NO10Si2 详情 详情

合成路线12

该中间体在本合成路线中的序号：(IV)

A formal total synthesis of vancomycin has been reported. The known aglycon of vancomycin (I) was protected at the amino group as the allyloxy- carbonyl derivative (III) using allyloxycarbonyl succinimide (II). Then, carboxylate group was converted to allyl ester (V) with allyl bromide (IV) and KHCO3.

参考文献 中间体
合成目标
【1】 Thompson, C.; et al.; Synthesis of vancomycin from the aglycon. J Am Chem Soc 1999, 121, 6, 1237.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 25729 (1S,2R,18R,19R,22S,25R,28R,40R)-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18,32,35,37,50-hexahydroxy-19-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6).2(14,17).1(8,12).1(29,33).0(10,25).0(34,39)]pentaconta-3,5,8(50),9,11,14,16,29(49),30,32,34,36,38,45,47-pentadecaene-40-carboxylic acid C53H52Cl2N8O17 详情 详情
(II) 25730 allyl 2,5-dioxo-1-pyrrolidinecarboxylate C8H9NO4 详情 详情
(III) 25731 (1S,2R,18R,19R,22S,25R,28R,40R)-19-([(2R)-2-[[(allyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18,32,35,37,50-hexahydroxy-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6).2(14,17).1(8,12).1(29,33).0(10,25).0(34,39)]pentaconta-3,5,8(50),9,11,14,16,29(49),30,32,34,36,38,45,47-pentadecaene-40-carboxylic acid C57H56Cl2N8O19 详情 详情
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 25732 allyl (1S,2R,18R,19R,22S,25R,28R,40R)-19-([(2R)-2-[[(allyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18,32,35,37,50-hexahydroxy-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6).2(14,17).1(8,12).1(29,33).0(10,25).0(34,39)]pentaconta-3,5,8(50),9,11,14,16,29(49),30,32,34,36,38,45,47-pentadecaene-40-carboxylate C60H60Cl2N8O19 详情 详情

合成路线13

该中间体在本合成路线中的序号：(IV)

Selective protection of the phenol group of (V) with p-methoxybenzyl chloride (VI) gave benzyl ether (VII), and the remaining phenol groups of (VII) were further alkylated with allyl bromide to afford (VIII).

参考文献 中间体
合成目标
【1】 Thompson, C.; et al.; Synthesis of vancomycin from the aglycon. J Am Chem Soc 1999, 121, 6, 1237.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 25732 allyl (1S,2R,18R,19R,22S,25R,28R,40R)-19-([(2R)-2-[[(allyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18,32,35,37,50-hexahydroxy-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6).2(14,17).1(8,12).1(29,33).0(10,25).0(34,39)]pentaconta-3,5,8(50),9,11,14,16,29(49),30,32,34,36,38,45,47-pentadecaene-40-carboxylate C60H60Cl2N8O19 详情 详情
(VI) 11910 4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether 824-94-2 C8H9ClO 详情 详情
(VII) 25733 allyl (1S,2R,18R,19R,22S,25R,28R,40R)-19-([(2R)-2-[[(allyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18,32,35,37-pentahydroxy-50-[(4-methoxybenzyl)oxy]-20,23,26,42,44-pentaoxo-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6).2(14,17).1(8,12).1(29,33).0(10,25).0(34,39)]pentaconta-3,5,8(50),9,11,14,16,29(49),30,32,34,36,38,45,47-pentadecaene-40-carboxylate C68H68Cl2N8O20 详情 详情
(VIII) 25734 allyl (1S,2R,18R,19R,22S,25R,28R,40R)-32,37-bis(allyloxy)-19-([(2R)-2-[[(allyloxy)carbonyl](methyl)amino]-4-methylpentanoyl]amino)-22-(2-amino-2-oxoethyl)-5,15-dichloro-2,18-dihydroxy-50-[(4-methoxybenzyl)oxy]-20,23,26,42,44-pentaoxo-35-(vinyloxy)-7,13-dioxa-21,24,27,41,43-pentaazaoctacyclo[26.14.2.2(3,6).2(14,17).1(8,12).1(29,33).0(10,25).0(34,39)]pentaconta-3,5,8(50),9,11,14,16,29(49),30,32,34,36,38,45,47-pentadecaene-40-carboxylate C76H78Cl2N8O20 详情 详情

合成路线14

该中间体在本合成路线中的序号：(V)

Several related syntheses for AA-193 have been reported: 1) The Friedel-Crafts' condensation of 2,5-dichlorophenol (I) with benzoyl chloride (II) by means of AlCl3 gives 2,5-dichloro-4-hydroxybenzophenone (III), which by reaction with hydroxylamine and KOH is converted to 5-chloro-6-hydroxy-3-phenylbenzisoxazole (IV). The condensation of (IV) with allyl bromide (V) by means of K2CO3 affords the 7-allyl derivative (VI), which is cyclized by means of N-bromosuccinimide and NaOH to 5-chloro-7-(hydroxymethyl)-3-phenyl-7,8-dihydrofuro[2,3-g]-1,2-benzisox azole (VII). Finally, this compound is oxidized to the final product with KMnO4 in refluxing dichloromethane. 2) The chlorination of 1,3-dimethoxybenzene (VIII) with SO2Cl2 gives 1-chloro-2,4-dimethoxybenzene (IX), which is condensed with benzoyl chloride (II) as before, yielding 5-chloro-2,4-dihydroxybenzophenone (X). Tosylation of (X) with tosyl chloride gives the corresponding ditosyl derivative (XI), which by reaction with hydroxylamine is converted to the oxime (XII). Finally, this compound is treated with KOH in order to cyclize to the benzisoxazole (IV). 3) The reaction of the benzisoxazole (IV) with formaldehyde and dimethylamine gives 5-chloro-7-(dimethylaminomethyl)-6-hydroxy-3-phenylbenzisoxazole (XIII), which is condensed and cyclized with the ylide (XIV) to yield the ethyl ester of the desired product (XV). Finally, this compound is hydrolyzed with NaOH.

参考文献 中间体
合成目标
【1】 Koga, H.; Kuromaru, K.; Ishizawa, T.; Aoki, B.; Sato, H.; Studies on uricosuric diuretics. V. Convenient and efficient synthesis of 2,3-dihydrobenzofuran derivatives. Chem Pharm Bull 1992, 40, 10, 2597.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11953 2,5-Dichlorophenol 583-78-8 C6H4Cl2O 详情 详情
(II) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(III) 11955 (2,5-Dichloro-4-hydroxyphenyl)(phenyl)methanone C13H8Cl2O2 详情 详情
(IV) 11945 5-Chloro-3-phenyl-1,2-benzisoxazol-6-ol C13H8ClNO2 详情 详情
(V) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VI) 11950 7-Allyl-5-chloro-3-phenyl-1,2-benzisoxazol-6-ol C16H12ClNO2 详情 详情
(VII) 11941 (5-Chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazol-7-yl)methanol C16H12ClNO3 详情 详情
(VIII) 11934 m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether 151-10-0 C8H10O2 详情 详情
(IX) 11942 1-Chloro-2,4-dimethoxybenzene; 2-Chloro-5-methoxyphenyl methyl ether 7051-13-0 C8H9ClO2 详情 详情
(X) 11962 (5-Chloro-2,4-dihydroxyphenyl)(phenyl)methanone C13H9ClO3 详情 详情
(XI) 11963 2-benzoyl-4-chloro-5-[[(4-methylphenyl)sulfonyl]oxy]phenyl 4-methylbenzenesulfonate C27H21ClO7S2 详情 详情
(XII) 11964 4-chloro-2-[(hydroxyimino)(phenyl)methyl]-5-[[(4-methylphenyl)sulfonyl]oxy]phenyl 4-methylbenzenesulfonate C27H22ClNO7S2 详情 详情
(XIII) 11946 5-Chloro-7-[(dimethylamino)methyl]-3-phenyl-1,2-benzisoxazol-6-ol C16H15ClN2O2 详情 详情
(XIV) 11966 2-(Dimethylsulfonium)acetic acid ethyl ester inner salt C6H12O2S 详情 详情
(XV) 11948 ethyl 5-chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazole-7-carboxylate C18H14ClNO4 详情 详情

合成路线15

该中间体在本合成路线中的序号：

The condensation of benzaldehyde (I) with malonic ester (II) by means of piperidine and acetic acid in benzene gives the unsaturated malonate (III), which by a selective ester cleavage and a Curtius rearrangement by means of N3-PO(OPh)2 and Et3N in toluene yields the unsaturated aminoester (IV). The reduction of (IV) with a chiral rhodium catalyst affords the chiral protected aminoester (V), which is cyclized to the bridged lactone (VI) by means of BF3 ethearate in dichloromethane. Reductive cleavage of the benzyloxycarbonyl benzyl ether groups of (VI) with H2 over Pd/C affords the free aminophenol (VII). The condensation of (VII) with aldehyde (VIII) (obtained by reduction of ester (IX) with DIBAL in dichloromethane) by means of KCN and AcOH, and after allylation of the aromatic OH group with allyl bromide, the intermediate (X) is obtained. The reduction of the lactone group of (X) with DIBAL, followed by desilylation with KF and cyclization with CH3SO3H affords the polycyclic compound (XI).

参考文献 中间体
合成目标
【1】 Gin, D.Y.; Corey, E.J.; Kania, R.S.; Enantioselective total synthesis of Ecteinascidin 743. J Am Chem Soc 1996, 118, 38, 9202-03.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(I) 36449 6-(benzyloxy)-7-methyl-1,3-benzodioxole-5-carbaldehyde C16H14O4 详情 详情
(II) 36450 1-(2,2-dimethoxyethyl) 3-isobutyl malonate C10H16O6 详情 详情
(III) 36451 1-(2,2-dimethoxyethyl) 3-isobutyl 2-[(E)-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-5-yl]methylidene]malonate C26H28O9 详情 详情
(IV) 36452 2,2-dimethoxyethyl (Z)-2-[[(benzyloxy)carbonyl]amino]-3-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-5-yl]-2-propenoate C30H31NO9 详情 详情
(V) 36453 2,2-dimethoxyethyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-5-yl]propanoate C30H33NO9 详情 详情
(VI) 35454 2-phenyl-1H-imidazole-4-carbaldehyde C10H8N2O 详情 详情
(VII) 36455 (1R,12S)-9-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-13-one C13H13NO5 详情 详情
(VIII) 36456 allyl (1S)-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-oxoethylcarbamate C26H45NO6Si2 详情 详情
(IX) 36457 methyl (2S)-2-[[(allyloxy)carbonyl]amino]-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)propanoate C27H47NO7Si2 详情 详情
(X) 36458 allyl (1S,2R)-2-[(1R,12S)-9-(allyloxy)-8-methyl-13-oxo-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-16-yl]-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-cyanoethylcarbamate C43H61N3O10Si2 详情 详情
(XI) 36459 allyl (1R,2S,13R,15R,16S)-5-(allyloxy)-15-cyano-20,22-dihydroxy-13-(hydroxymethyl)-21-methoxy-6-methyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaene-24-carboxylate C31H33N3O9 详情 详情

合成路线16

该中间体在本合成路线中的序号：(XLIV)

The previously reported synthesis of 139221 (scheme 13922101a) has been investigated in order to find a more efficient, reproducible and economical route to work in the mutikilogram scale. Herein it is reported a new process which is simpler and proceeds with an overall yield of 54% (the original process, 35%). The condensation of intermediate aminolactone (I) (scheme 13922101a, intermediate (VII)) with acid (XLII) (the acid derived from scheme 13922101a, intermediate ester (IX)) by means of 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP), and 1-hydroxy-7-azabenzotriazole (HOAt) in THF/dichloromethane gives the coupling product (XLIII), which is allylated with allyl bromide (XLIV) and Cs2CO3 in DMF yielding the allyl ether (XLV). The reduction of the lactone group of (XLV) with LiAlH2(OEt)2 in ethyl ether affords the lactol (XLVI), which is desilylated with KF in methanol to provide the phenolic compound (XLVII). The opening of the lactol ring of (XLVII) with simultaneous cyclization by means of Tf-OH in water/trifluoroethanol gives the hexacyclic intermediate (XLVIII), which is finally reductocondensed with KCN by means of LiAlH2(OEt)2 in THF to furnish the previously reported pentacyclic intermediate (XI) (scheme 13922101a, intermediate (XI)).

参考文献 中间体
合成目标
【1】 Martinez, E.J.; Corey, E.J.; A new, more efficient, and effective process for the synthesis of a key pentacyclic intermediate for production of ecteinascidin and phthalascidin antitumor agents. Org Lett 2000, 2, 7, 993.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 36455 (1R,12S)-9-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-13-one C13H13NO5 详情 详情
(XI) 36459 allyl (1R,2S,13R,15R,16S)-5-(allyloxy)-15-cyano-20,22-dihydroxy-13-(hydroxymethyl)-21-methoxy-6-methyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaene-24-carboxylate C31H33N3O9 详情 详情
(XLII) 38116 (2S)-2-[[(allyloxy)carbonyl]amino]-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)propionic acid C26H45NO7Si2 详情 详情
(XLIII) 38117 allyl (1S)-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-[(1R,12S)-9-hydroxy-8-methyl-13-oxo-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-16-yl]-2-oxoethylcarbamate C39H56N2O11Si2 详情 详情
(XLIV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XLV) 38118 allyl (1S)-2-[(1R,12S)-9-(allyloxy)-8-methyl-13-oxo-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-16-yl]-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-oxoethylcarbamate C42H60N2O11Si2 详情 详情
(XLVI) 38119 allyl (1S)-2-[(1R,12S,13S)-9-(allyloxy)-13-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-16-yl]-1-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)-2-oxoethylcarbamate C42H62N2O11Si2 详情 详情
(XLVII) 38120 allyl (1S)-2-[(1R,12S,13S)-9-(allyloxy)-13-hydroxy-8-methyl-4,6,14-trioxa-16-azatetracyclo[10.3.1.0(2,10).0(3,7)]hexadeca-2,7,9-trien-16-yl]-1-(3,5-dihydroxy-4-methoxybenzyl)-2-oxoethylcarbamate C30H34N2O11 详情 详情
(XLVIII) 38121 allyl (1R,2S,13R,16S)-5-(allyloxy)-20,22-dihydroxy-13-(hydroxymethyl)-21-methoxy-6-methyl-15-oxo-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaene-24-carboxylate C30H32N2O10 详情 详情

合成路线17

该中间体在本合成路线中的序号：(VI)

Reaction of cyanosafracin B (I) with Boc2O in ethanol gives the amino-protected compound (II), which is treated with methoxymethyl bromide (MOM-Br), DIEA and DMAP in acetonitrile yielding the O-protected compound (III). The demethylation of (III) with NaOH in methanol affords the hydroxyquinone (IV), which is reduced with H2 over Pd/C and cyclized with bromochloromethane and Cs2CO3 in hot DMF to provide compound (V). Reaction of (V) with allyl bromide (VI) and Cs2CO3 in DMF gives the allyl ether (VII), which first is treated with TFA, phenyl isothiocyanate and HCl to yield the primary amine (VIII) and then protected at the free NH2 group with Troc-Cl and pyridine, to afford the amino protected compound (IX).

参考文献 中间体
合成目标
【1】 Cuevas, C.; Martin, M.J.; Perez, M.; et al.; Synthesis of ecteinascidin ET-743 and phathalascidin Pt-650 from cyanosafracin B. Org Lett 2000, 2, 16, 2545.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 41775 (2S)-2-amino-N-[[(1S,2S,10R,12R,13R)-12-cyano-19-hydroxy-7,18-dimethoxy-6,17,21-trimethyl-5,8-dioxo-11,21-diazapentacyclo[11.7.1.0(2,11).0(4,9).0(15,20)]henicosa-4(9),6,15,17,19-pentaen-10-yl]methyl]propanamide C29H35N5O6 详情 详情
(II) 41776 tert-butyl (1S)-2-([[(1S,2S,10R,12R,13R)-12-cyano-19-hydroxy-7,18-dimethoxy-6,17,21-trimethyl-5,8-dioxo-11,21-diazapentacyclo[11.7.1.0(2,11).0(4,9).0(15,20)]henicosa-4(9),6,15,17,19-pentaen-10-yl]methyl]amino)-1-methyl-2-oxoethylcarbamate C34H43N5O8 详情 详情
(III) 41777 tert-butyl (1S)-2-([[(1S,2S,10R,12R,13R)-12-cyano-7,18-dimethoxy-19-(methoxymethoxy)-6,17,21-trimethyl-5,8-dioxo-11,21-diazapentacyclo[11.7.1.0(2,11).0(4,9).0(15,20)]henicosa-4(9),6,15,17,19-pentaen-10-yl]methyl]amino)-1-methyl-2-oxoethylcarbamate C36H47N5O9 详情 详情
(IV) 41778 tert-butyl (1S)-2-([[(1S,2S,10R,12R,13R)-12-cyano-7-hydroxy-18-methoxy-19-(methoxymethoxy)-6,17,21-trimethyl-5,8-dioxo-11,21-diazapentacyclo[11.7.1.0(2,11).0(4,9).0(15,20)]henicosa-4(9),6,15,17,19-pentaen-10-yl]methyl]amino)-1-methyl-2-oxoethylcarba C35H45N5O9 详情 详情
(V) 41779 tert-butyl (1S)-2-([[(1S,2S,13R,15R,16R)-15-cyano-5-hydroxy-21-methoxy-22-(methoxymethoxy)-6,20,24-trimethyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaen-13-yl]methyl]amino)-1-methyl-2-oxoe C36H47N5O9 详情 详情
(VI) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VII) 41780 tert-butyl (1S)-2-([[(1S,2S,13R,15R,16R)-5-(allyloxy)-15-cyano-21-methoxy-22-(methoxymethoxy)-6,20,24-trimethyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaen-13-yl]methyl]amino)-1-methyl-2-o C39H51N5O9 详情 详情
(VIII) 41781 (1S,2S,13R,15R,16R)-5-(allyloxy)-13-(aminomethyl)-22-hydroxy-21-methoxy-6,20,24-trimethyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaene-15-carbonitrile C29H34N4O5 详情 详情
(IX) 41782 2,2,2-trichloroethyl [(1S,2S,13R,15R,16R)-5-(allyloxy)-15-cyano-22-hydroxy-21-methoxy-6,20,24-trimethyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0(2,14).0(4,12).0(7,11).0(18,23)]tetracosa-4,6,11,18,20,22-hexaen-13-yl]methylcarbamate C32H35Cl3N4O7 详情 详情

合成路线18

该中间体在本合成路线中的序号：(XL)

The selective protection of the phenolic OH of (XXXIII) by means of benzyl bromide and K2CO3 in refluxing acetonitrile gives the benzyl ether (XXXIV), which is reductocyclized by means of Red-Al in THF to yield the oxazolidine (XXXV). The cleavage of the oxazolidine ring of (XXXV) by means of Tms-CN and BF3/Et2O in dichloromethane affords the hydroxy nitrile (XXXVI), which is treated with Ac2O and pyridine to provide the acetate (XXXVII). The desilylation of (XXXVII) with HF in acetonitrile, followed by oxidation with DMP gives the carbaldehyde (XXXVIII), which is submitted to hydrogenolysis of the benzyl ethers by means of H2 over Pd/C in THF, performing a simultaneous cyclization to yield the pentacyclic compound (XXXIX). The reaction of (XXXIX) with allyl bromide (XL) and DIEA affords the allyl ether (XLI), which is treated with K2CO3 in methanol to provide the carbinol (XLII). The reaction of (XLII) with L-cysteine derivative (XLIII) by means of WSCD and DMAP in dichloromethane gives the corresponding ester (XLIV).

参考文献 中间体
合成目标
【1】 Abe, M.; Yanagisawa, A.; Tohma, S.; Kan, T.; Fukuyama, T.; Endo, A.; Total synthesis of ecteinascidin 743. J Am Chem Soc 2002, 124, 23, 6552.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIX) 58637 2,2,2-trichloroethyl (1R,2R,3S,13R,15R,16S)-13-[(acetyloxy)methyl]-15-cyano-3,5,22-trihydroxy-21-methoxy-6,20-dimethyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0~2,14~.0~4,12~.0~7,11~.0~18,23~]tetracosa-4,6,11,18,20,22-hexaene-24-carboxylate C30H30Cl3N3O10 详情 详情
(XXXIII) 58631 2,2,2-trichloroethyl (1R,9S,12R)-3-(benzyloxy)-12-({[tert-butyl(dimethyl)silyl]oxy}methyl)-11-[(1R)-2-hydroxy-1-(6-hydroxy-7-methyl-1,3-benzodioxol-4-yl)ethyl]-4-methoxy-5-methyl-10-oxo-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene-13-carbox C40H49Cl3N2O10Si 详情 详情
(XXXIV) 58632 2,2,2-trichloroethyl (1R,9S,12R)-3-(benzyloxy)-11-{(1R)-1-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-4-yl]-2-hydroxyethyl}-12-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methoxy-5-methyl-10-oxo-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene-13-ca C47H55Cl3N2O10Si 详情 详情
(XXXV) 58633 2,2,2-trichloroethyl (1R,9S,10S,13R,15R)-3-(benzyloxy)-13-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-4-yl]-15-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-methoxy-5-methyl-11-oxa-14,16-diazatetracyclo[7.6.1.0~2,7~.0~10,14~]hexadeca-2,4,6-triene-16-carbox C47H55Cl3N2O9Si 详情 详情
(XXXVI) 58634 2,2,2-trichloroethyl (1R,9S,10R,12R)-3-(benzyloxy)-11-{(1R)-1-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-4-yl]-2-hydroxyethyl}-12-({[tert-butyl(dimethyl)silyl]oxy}methyl)-10-cyano-4-methoxy-5-methyl-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene C48H56Cl3N3O9Si 详情 详情
(XXXVII) 58635 2,2,2-trichloroethyl (1R,9S,10R,12R)-11-{(1R)-2-(acetyloxy)-1-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-4-yl]ethyl}-3-(benzyloxy)-12-({[tert-butyl(dimethyl)silyl]oxy}methyl)-10-cyano-4-methoxy-5-methyl-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-tr C50H58Cl3N3O10Si 详情 详情
(XXXVIII) 58636 2,2,2-trichloroethyl (1R,9S,10R,12R)-11-{(1R)-2-(acetyloxy)-1-[6-(benzyloxy)-7-methyl-1,3-benzodioxol-4-yl]ethyl}-3-(benzyloxy)-10-cyano-12-formyl-4-methoxy-5-methyl-11,13-diazatricyclo[7.3.1.0~2,7~]trideca-2,4,6-triene-13-carboxylate C44H42Cl3N3O10 详情 详情
(XL) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XLI) 58638 2,2,2-trichloroethyl (1R,2R,3S,13R,15R,16S)-13-[(acetyloxy)methyl]-22-(allyloxy)-15-cyano-3,5-dihydroxy-21-methoxy-6,20-dimethyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0~2,14~.0~4,12~.0~7,11~.0~18,23~]tetracosa-4,6,11,18,20,22-hexaene-24-carboxylate C33H34Cl3N3O10 详情 详情
(XLII) 58639 2,2,2-trichloroethyl (1R,2R,3S,13R,15R,16S)-22-(allyloxy)-15-cyano-3,5-dihydroxy-13-(hydroxymethyl)-21-methoxy-6,20-dimethyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0~2,14~.0~4,12~.0~7,11~.0~18,23~]tetracosa-4,6,11,18,20,22-hexaene-24-carboxylate C31H32Cl3N3O9 详情 详情
(XLIII) 58640 (2R)-3-(acetylsulfanyl)-2-{[(allyloxy)carbonyl]amino}propanoic acid C9H13NO5S 详情 详情
(XLIV) 58641 2,2,2-trichloroethyl (1R,2R,3S,13R,15R,16S)-13-{[((2R)-3-(acetylsulfanyl)-2-{[(allyloxy)carbonyl]amino}propanoyl)oxy]methyl}-22-(allyloxy)-15-cyano-3,5-dihydroxy-21-methoxy-6,20-dimethyl-8,10-dioxa-14,24-diazahexacyclo[14.7.1.0~2,14~.0~4,12~.0~7,11~ C40H43Cl3N4O13S 详情 详情

合成路线19

该中间体在本合成路线中的序号：(XXXI)

Reaction of 3-methoxybenzyl alcohol (XXIX) with TBDMS-Cl and imidazole in dichloromethane gives the silyl ether (XXX), which is condensed with allyl bromide (XXXI) by means of BuLi in hexane to yield the 2-allyl derivative (XXXII). Deprotection of (XXXII) by means of TBAF in THF affords the benzyl alcohol (XXXIII), which is oxidized with oxalyl chloride and TEA in DMSO/dichloromethane to provide 2-allyl-3-methoxybenzaldehyde (XXXIV). Condensation of compound (XXXIV) with the chiral 1-decyne (XXXV) by means of ethylmagnesium bromide in THF gives the secondary alcohol (XXXVI), which is oxidized with pyridinium chlorochromate (PCC) in dichloromethane yielding ketone (XXXVII). The enantioselective reduction of ketone (XXXVII) by means of trimethylboroxine (TMBO), BH3/Me2S and (R)-(2-pyrrolidinyl)diphenylmethanol in toluene affords the chiral secondary alcohol (XXXVIII) as a single diastereomer. Silylation of alcohol (XXXVIII) with TBDMS-Cl and imidazole yields the corresponding ether (XXXIX), which is submitted to cyclization catalyzed by Co2(CO)8 in refluxing acetonitrile affording the tricyclic ketone (XL). Hydrogenation of the conjugated double bond of (XL) with H2 over Pd/C in ethanol provides the saturated ketone (XLI), which is reduced with NaBH4 in ethanol to give the tricyclic alcohol (XLII). Elimination of the tetrahydropyranyl-protecting group of (XLII) with p-toluensulfonic acid in methanol provides diol (XXV) already described.

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Castaner, J.; Rabasseda, X.; UT-15. Drugs Fut 2001, 26, 4, 364.
【2】 Rao, M.S.; Staszewski, J.P.; Guo, L.; Penmasta, R.; Moriarty, R.M. (United Therapeutics Corp.); Process for stereoselective synthesis of prostacyclin derivs.. WO 9921830 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
20632 diphenyl[(2R)pyrrolidinyl]methanol C17H19NO 详情 详情
(XXV) 46571 (1R,2R,3aS,9aS)-1-[(3S)-3-hydroxyoctyl]-5-methoxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol C22H34O3 详情 详情
(XXIX) 46574 3-Anisylalcohol; (3-methoxyphenyl)methanol; m-Anisyl alcohol; m-methoxybenzyl alcohol; 3-Anisic alcohol; 3-Anise Alcohol; 3-methoxybenzyl alcohol; 3-methoxybenzene methanol 6971-51-3 C8H10O2 详情 详情
(XXX) 46575 tert-butyl(dimethyl)silyl 3-methoxybenzyl ether; tert-butyl[(3-methoxybenzyl)oxy]dimethylsilane C14H24O2Si 详情 详情
(XXXI) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XXXII) 46576 2-allyl-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)phenyl methyl ether; [(2-allyl-3-methoxybenzyl)oxy](tert-butyl)dimethylsilane C17H28O2Si 详情 详情
(XXXIII) 46577 (2-allyl-3-methoxyphenyl)methanol C11H14O2 详情 详情
(XXXIV) 46578 2-allyl-3-methoxybenzaldehyde C11H12O2 详情 详情
(XXXV) 46579 (1S)-1-pentyl-4-pentynyl tetrahydro-2H-pyran-2-yl ether; 2-[[(1S)-1-pentyl-4-pentynyl]oxy]tetrahydro-2H-pyran C15H26O2 详情 详情
(XXXVI) 46580 (6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-ol C26H38O4 详情 详情
(XXXVII) 46581 (6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-one C26H36O4 详情 详情
(XXXVIII) 46582 (1S,6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecyn-1-ol C26H38O4 详情 详情
(XXXIX) 46583 [[(1S,6S)-1-(2-allyl-3-methoxyphenyl)-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecynyl]oxy](tert-butyl)dimethylsilane; 2-allyl-3-[(1S,6S)-1-[[tert-butyl(dimethyl)silyl]oxy]-6-(tetrahydro-2H-pyran-2-yloxy)-2-undecynyl]phenyl methyl ether C32H52O4Si 详情 详情
(XL) 46584 (4R,9aS)-4-[[tert-butyl(dimethyl)silyl]oxy]-8-methoxy-3-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,4,9,9a-tetrahydro-2H-cyclopenta[b]naphthalen-2-one C33H52O5Si 详情 详情
(XLI) 46570 (1R,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-1,3,3a,4,9,9a-hexahydro-2H-cyclopenta[b]naphthalen-2-one C27H40O4 详情 详情
(XLII) 46585 (1R,2R,3aS,9aS)-5-methoxy-1-[(3S)-3-(tetrahydro-2H-pyran-2-yloxy)octyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-2-ol C27H42O4 详情 详情

合成路线20

该中间体在本合成路线中的序号：(XXVII)

Reduction of the ester function of (XXIV) by means of DIBAL afforded alcohol (XXV), which was further protected as the tetrahydropyranyl ether (XXVI). The free secondary hydroxyl of (XXVI) was then alkylated with allyl bromide (XXVII) and NaH to produce the allyl ether (XXVIII). Selective olefin hydroboration at the allyl ether moiety of (XXVIII), followed by oxidative work-up gave rise to the primary alcohol (XXIX). After silylation of (XXIX), the tetrahydropyranyl ether was hydrolyzed with ethanolic HCl providing the tris-O-silylated compound (XXX)

参考文献 中间体
合成目标
【1】 Takahashi, T.; Shiono, M. (Kuraray Co., Ltd.); Cyclohexanetriol derivs.. EP 0503630 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXIV) 59871 ethyl 2-((3R,4R,5R)-3,5-bis{[tert-butyl(diphenyl)silyl]oxy}-4-hydroxy-2-methylenecyclohexylidene)acetate C43H52O5Si2 详情 详情
(XXV) 59872 (1R,2R,6R)-2,6-bis{[tert-butyl(diphenyl)silyl]oxy}-4-[(Z)-2-hydroxyethylidene]-3-methylenecyclohexanol C41H50O4Si2 详情 详情
(XXVI) 59873 (1R,2R,6R)-2,6-bis{[tert-butyl(diphenyl)silyl]oxy}-3-methylene-4-[(Z)-2-(tetrahydro-2H-pyran-2-yloxy)ethylidene]cyclohexanol C46H58O5Si2 详情 详情
(XXVII) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XXVIII) 59874 ({(1R,2R,3R)-2-(allyloxy)-3-{[tert-butyl(diphenyl)silyl]oxy}-4-methylene-5-[(Z)-2-(tetrahydro-2H-pyran-2-yloxy)ethylidene]cyclohexyl}oxy)(tert-butyl)diphenylsilane; allyl (1R,2R,6R)-2,6-bis{[tert-butyl(diphenyl)silyl]oxy}-3-methylene-4-[(Z)-2-(tetrahydro-2H-pyran-2-yloxy)ethylidene]cyclohexyl ether C49H62O5Si2 详情 详情
(XXIX) 59875 3-({(1R,2R,6R)-2,6-bis{[tert-butyl(diphenyl)silyl]oxy}-3-methylene-4-[(Z)-2-(tetrahydro-2H-pyran-2-yloxy)ethylidene]cyclohexyl}oxy)-1-propanol C49H64O6Si2 详情 详情
(XXX) 59876 2-[(3R,4R,5R)-3,5-bis{[tert-butyl(diphenyl)silyl]oxy}-4-(3-{[tert-butyl(diphenyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]-1-ethanol C60H74O5Si3 详情 详情

合成路线21

该中间体在本合成路线中的序号：(VII)

The condensation of (2alpha,3alpha,5alpha,16alpha,17alpha)-2,3:16,17-diepoxyandrostan-17-ol acetate (I) with pyrrolidine (II) by means of NaOH in methanol, followed by reduction with NaBH4 in the same solvent gives (2alpha,3alpha,5alpha,16beta,17beta)-2,3-epoxy-16-(1-pyrrolidinyl) androstan-17-ol (III), which is further condensed with morpholine (IV) in refluxing water yielding (2beta,3alpha,5alpha,16beta,17beta)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstane-3,17-diol (V). Partial acetylation of (V) with acetyl chloride in dichloromethane at room temperature affords the corresponding 17-acetoxy derivative (VI), which is finally quaternized with allyl bromide (VII) in dichloromethane.

参考文献 中间体
合成目标
【1】 Savage, D.S.; Sleig, T.; Carlyle, I.G. (Akzo Nobel N.V.); Novel 2beta-morpholino-androstane derivs. and process for their preparation. AU 8814570; EP 0287150; JP 1988277693; US 4894369 .
【2】 Pento, J.T.; Castaner, J.; Rocuronium Bromide. Drugs Fut 1994, 19, 9, 841.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13647 (1aR,2aS,2bS,4aS,5aR,6aS,6bR,8aS,9aS)-2a,4a-dimethylhexadecahydro-4bH-oxireno[2'',3'':4',5']cyclopenta[1',2':7,8]phenanthro[2,3-b]oxiren-4-yl acetate C21H30O4 详情 详情
(II) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(III) 13649 (1R,2S,3aS,3bR,5aS,6aS,7aR,8aS,8bS,10aS)-8a,10a-Dimethyl-2-(1-pyrrolidinyl)hexadecahydro-1H-cyclopenta[7,8]phenanthro[2,3-b]oxiren-1-ol C23H37NO2 详情 详情
(IV) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(V) 13651 (2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-10,13-Dimethyl-2-(4-morpholinyl)-16-(1-pyrrolidinyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-3,17-diol C27H46N2O3 详情 详情
(VI) 13652 (2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-3-hydroxy-10,13-dimethyl-2-(4-morpholinyl)-16-(1-pyrrolidinyl)hexadecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate C29H48N2O4 详情 详情
(VII) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情

合成路线22

该中间体在本合成路线中的序号：(XX)

In a different procedure, 3,4-dichlorophenylacetic acid (XIV) was condensed with the lithiated chiral oxazolidinone (XV), via activation as the mixed anhydride with pivaloyl chloride, to afford the N-acyl oxazolidinone (XVI). Diastereoselective alkylation of the sodium enolate of (XVI) with allyl iodide (XVII) afforded the (S)-pentenyl oxazolidinone (XVIII), which was further hydrolyzed to the chiral acid (XIX) by means of lithium peroxide. Alternatively, acid (XIX) was obtained by alkylation of the lithium dianion of 3,4-dichlorophenylacetic acid (XIV) with allyl bromide (XX), followed by resolution of the resultant racemic acid (XXI) with (S)-1-phenylethylamine. Acid (XIX) was converted to the amide (XXII) via the corresponding acid chloride. Reduction of amide (XXII) with DIBAL gave the secondary amine (XXIII), which was subsequently acylated with benzoyl chloride, yielding benzamide (XXIV). Dihydroxylation of the olefin double bond with N-methylmorpholine-N-oxide in the presence of OsO4, followed by oxidative cleavage of the resultant diol (XXV) with sodium periodate furnished aldehyde (XXVI). Finally, reductive amination of aldehyde (XXVI) with piperidine (III) in the presence of NaBH3CN provided the title compound

参考文献 中间体
合成目标
【1】 Hale, J.J.; Finke, P.E.; MacCross, M.; A facile synthesis of the novel neurokinin A antagonist SR 48968. Bioorg Med Chem Lett 1993, 3, 2, 319.
【2】 Finke, P.E.; Mills, S.G.; Hale, J.J.; MacCoss, M. (Merck & Co., Inc.); Process of making chiral 2-aryl-1,4-butanediamine derivs.. WO 9407839 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 59283 N-(4-phenyl-4-piperidinyl)acetamide C13H18N2O 详情 详情
(XIV) 30414 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid 5807-30-7 C8H6Cl2O2 详情 详情
(XV) 58942 　 C10H10LiNO2 详情 详情
(XVI) 62381 (4S)-4-benzyl-3-[2-(3,4-dichlorophenyl)acetyl]-1,3-oxazolidin-2-one C18H15Cl2NO3 详情 详情
(XVII) 32112 3-iodo-1-propene;3-iodo-propen;allyl iodide 556-56-9 C3H5I 详情 详情
(XVIII) 62382 (4S)-4-benzyl-3-[(2S)-2-(3,4-dichlorophenyl)-4-pentenoyl]-1,3-oxazolidin-2-one C21H19Cl2NO3 详情 详情
(XIX) 62383 (2S)-2-(3,4-dichlorophenyl)-4-pentenoic acid C11H10Cl2O2 详情 详情
(XX) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XXI) 50421 2-(3,4-dichlorophenyl)-4-pentenoic acid C11H10Cl2O2 详情 详情
(XXII) 62384 (2S)-2-(3,4-dichlorophenyl)-N-methyl-4-pentenamide C12H13Cl2NO 详情 详情
(XXIII) 62385 (2S)-2-(3,4-dichlorophenyl)-N-methyl-4-penten-1-amine; N-[(2S)-2-(3,4-dichlorophenyl)-4-pentenyl]-N-methylamine C12H15Cl2N 详情 详情
(XXIV) 62386 N-[(2S)-2-(3,4-dichlorophenyl)-4-pentenyl]-N-methylbenzamide C19H19Cl2NO 详情 详情
(XXV) 62387 N-[(2S)-2-(3,4-dichlorophenyl)-4,5-dihydroxypentyl]-N-methylbenzamide C19H21Cl2NO3 详情 详情
(XXVI) 26943 N-[(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide C18H17Cl2NO2 详情 详情

合成路线23

该中间体在本合成路线中的序号：

1) The reaction of cis-(1S,2R)-indanediol (I) with acetonitrile and concentrated H2SO4 gives cis-(1S,2R)-1-aminoindan-2-ol (II), which is cyclocondensed with 3-phenylpropionyl chloride (III), isopropenyl methyl ether and triethylamine to yield the acetonide amide (IV). The condensation of amide (IV) with (S)-(+)-glycidyl p-toluenesulfonate (V) in the presence of lithium hexamethyldisylazide (LHS) affords the chiral epoxide (VI), which is condensed with 4-(tert-butoxycarbonyl)-N-tert-butylpiperazine-2(S)-carboxamide (VII) in refluxing isopropyl acetate and deprotected with aqueous HCl to give the dihydroxy-diamide (VIII). Finally, this compound is condensed with 3-(chloromethyl)pyridine (IX) by means of triethylamine in DMF. 2) The amide (IV) can also be alkylated with allyl bromide and butyllithium to the pentenyl amide (X), which is diastereoselectively converted to the chiral iodohydrine (XI) by means of N-iodosuccinimide (NIS). Finally, this compound is cyclized in basic medium, yielding the epoxide (VI), already obtained.

参考文献 中间体
合成目标
【1】 Maligres, P.E.; Upadhyay, V.; Rossen, K.; Cianciosi, S.J.; Purick, R.M.; Eng, K.K.; Reamer, R.A.; Askin, D.; Volante, R.P.; Reider, P.J.; Diastereoselective syn-epoxidation of 2-alkyl-4-enamides to epoxyamides: Synthesis of the Merck HIV-1 protease inhibitor epoxide intermediate. Tetrahedron Lett 1995, 36, 13, 2195-8.
【2】 Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600.
【3】 Askin, D.; Volante, R.P.; Eng, K.K. (Merck & Co., Inc.); Process for making HIV protease inhibitors. WO 9502584 .
【4】 Verhoeven, T.R.; Roberts, E.F.; Senanayake, C.H.; Ryan, K.M. (Merck & Co., Inc.); Regiospecific processes to make cis-1-amino-2-alkanol from diol or halohydrin. US 5449830 .
【5】 Askin, D.; Eng, K.K.; Rossen, K.; Purick, R.M.; Wells, K.M.; Volante, R.P.; Reider, P.J.; Highly diastereoselective reaction of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate. Synthesis of the orally active HIV-1 protease inhibitor L-735,524. Tetrahedron Lett 1994, 35, 5, 673-6.
【6】 Dorsey, B.D.; Levin, R.B.; McDaniel, S.L.; et al.; L-735,524: The design of a potent and orally bioavailable HIV protease inhibitor. J Med Chem 1994, 37, 21, 3443-51.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(I) 16238 (1S,2R)-2,3-dihydro-1H-indene-1,2-diol 67528-22-7 C9H10O2 详情 详情
(II) 16239 (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol 126456-43-7 C9H11NO 详情 详情
(III) 16240 3-phenylpropanoyl chloride; Hydrocinnamoylchloride 645-45-4 C9H9ClO 详情 详情
(IV) 16241 1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-phenyl-1-propanone C21H23NO2 详情 详情
(V) 16242 (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate 113826-06-5 C10H12O4S 详情 详情
(VI) 16243 (2R)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone C24H27NO3 详情 详情
(VII) 16244 tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate 150323-35-6 C14H27N3O3 详情 详情
(VIII) 16245 (2S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-N-(tert-butyl)-2-piperazinecarboxamide C30H42N4O4 详情 详情
(IX) 15793 3-(Chloromethyl)pyridine 3099-31-8 C6H6ClN 详情 详情
(X) 16247 (2S)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-4-penten-1-one C24H27NO2 详情 详情
(XI) 16248 (2R,4S)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-4-hydroxy-5-iodo-1-pentanone C24H28INO3 详情 详情

合成路线24

该中间体在本合成路线中的序号：(II)

Reaction of the Grignard reagent derived from 4-chlorobenzyl bromide (I) with allyl bromide (II) gives 4-(4-chlorophenyl)but-1-ene (III), which is epoxidized with peracetic acid in dichloromethane to yield 4-(4-chlorophenyl)-1,2-epoxybutane (IV). Opening of (IV) with the anion of imidazole (V) gives 1-[4-(4-chlorophenyl)-2-hydroxybutyl]imidazole (VI), which is oxidized under Swern conditions to 4-(4-chlorophenyl)-1-(1-imidazolyl)-2-butanone (VII). Ketone (VII) is then reacted with (S)-solketal tosylate [(S)-1,2-O-isopropylideneglycerol-3-O-tosylate] (VIII) in the presence of p-toluenesulfonic acid in toluene to give a mixture of stereoisomers, and (2S,4S)-cis-2-[2-(4-chlorophenyl)ethyl]-2-(imidazol-1-ylmethyl)-4-(p-toluenesulfonyloxy)methyl-1,3-dioxolane (IX) is then separated by crystallization. Finally, (IX) is treated with 4-aminothiophenol (X) in the presence of potassium carbonate in acetone.

参考文献 中间体
合成目标
【1】 Dyson, N.H.; Gardner, J.O.; Prince, A.; Kertesz, D.J. (Syntex (USA), Inc.); Process for preparing 1,3-dioxolane derivs. JP 1995508002; US 5208331 .
【2】 Walker, K.A.; Burton, P.M.; Swinney, D.C. (Syntex (USA), Inc.); 1,3-Dioxolane derivs. as cholesterol lowering agents. JP 1992308588; US 5158949 .
【3】 Walker, K.A.M.; Rotstein, D.M.; Kertesz, D.J.; et al.; Selective inhibition of mammalian lanosterol 14alpha-demethylase: A possible strategy for cholesterol lowering. J Med Chem 1993, 36, 15, 2235-7.
【4】 Prous, J.; Mealy, N.; Castañer, J.; RS-21607-197. Drugs Fut 1994, 19, 2, 125.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 16481 1-(bromomethyl)-4-chlorobenzene 622-95-7 C7H6BrCl 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 16483 1-(3-butenyl)-4-chlorobenzene C10H11Cl 详情 详情
(IV) 16484 2-(4-chlorophenethyl)oxirane C10H11ClO 详情 详情
(V) 10255 Imidazole; 1H-Imidazole 288-32-4 C3H4N2 详情 详情
(VI) 16486 4-(4-chlorophenyl)-1-(1H-imidazol-1-yl)-2-butanol C13H15ClN2O 详情 详情
(VII) 16487 4-(4-chlorophenyl)-1-(1H-imidazol-1-yl)-2-butanone C13H13ClN2O 详情 详情
(VIII) 16488 (2S)-2,3-dihydroxypropyl 4-methylbenzenesulfonate C10H14O5S 详情 详情
(IX) 16489 [(2S,4S)-2-(4-chlorophenethyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate C23H25ClN2O5S 详情 详情
(X) 16490 4-aminophenylhydrosulfide; 4-aminothiophenol; 4-aminobenzenethiol 1193-02-8 C6H7NS 详情 详情

合成路线25

该中间体在本合成路线中的序号：

The Western fragment (VI) of SC-53228 was derived from methyl 2,4-dihydroxybenzoate (I). Allylation of this material under standard conditions (allyl bromide, potassium carbonate, DMF) afforded the 4-allyl ether as the predominant product along with a smaller quantity (approx. 5%) of the 2-allyl ether. This mixture was subjected to thermally induced Claisen rearrangement (neat, 190 C) to access the requisite tetrasubstituted aromatic nucleus (II). The yield for these two steps was approx. 55%. Cyclopropanation of the allyl group was best effected by the Denmark modification of Simmons Smith reaction (Et2Zn, Cl(CH2)2Cl, ClCH2l). This process proved to be somewhat capricious in that, as a general rule, some starting material was always recovered from the reaction mixture regardless of the stoichiometry of the reagents used. This unreacted olefin could be removed by treating the crude reaction mixture with palladium (II) salts (palladium trifluoroacetate, tetrabutylammonium chloride in acetone/water). Yields of the cyclopropane product (III) resulting from this 2-step sequence ranged between 50 and 90%. This diol ester was converted, uneventfully, to the monomethyl amide (IV) (CH3NH2, NH4Cl, 77%) and the linker attached under standard conditions (Cl(CH2)3Br, DMF, K2CO3) (V). This reaction proved to be nonselective and low yielding (approx. 45% yield). Methylation (dimethyl sufate, KOH, THF) followed by Finkelstein reaction (NaI, MEK) provided the key Western fragment (VI) in approximately 10% overall yield from methyl 2,4-dihydroxybenzoate.

参考文献 中间体
合成目标
【1】 Smith, P.F.; Paulson, S.K.; Tsai, B.S.; Fretland, D.J.; Dygos, J.H.; Yu, S.S.; Djuric, S.W.; SC-53228. Drugs Fut 1994, 19, 12, 1093.
【2】 Yu, S.; Docter, S.; Djuric, S.; et al.; Synthesis and pharmacological activity of SC-53228, a leukotriene B4 receptor antagonist with high intrinsic potency and selectivity. Bioorg Med Chem Lett 1994, 4, 6, 811-6.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(I) 16623 methyl 2,4-dihydroxybenzoate 2150-47-2 C8H8O4 详情 详情
(II) 16624 methyl 3-allyl-2,4-dihydroxybenzoate C11H12O4 详情 详情
(III) 16625 methyl 3-(cyclopropylmethyl)-2,4-dihydroxybenzoate C12H14O4 详情 详情
(IV) 16626 3-(cyclopropylmethyl)-2,4-dihydroxy-N-methylbenzamide C12H15NO3 详情 详情
(V) 16627 4-(3-chloropropoxy)-3-(cyclopropylmethyl)-2-hydroxy-N-methylbenzamide C15H20ClNO3 详情 详情
(VI) 16628 3-(cyclopropylmethyl)-4-(3-iodopropoxy)-2-methoxy-N-methylbenzamide C16H22INO3 详情 详情

合成路线26

该中间体在本合成路线中的序号：(IX)

The esterification of L-phenylglycine (I) with AcCl and methanol gives the methyl ester (II), which is N-protected by means of Boc2O and TEA to yield the N-Boc derivative (III). The reduction of (III) with NaBH4 in ethanol/THF affords the alcohol (IV), which is oxidized by means of (COCl)2 and DMSO to provide the carbaldehyde (V). The reaction of (V) with vinylmagnesium bromide (VI) in THF gives the allyl alcohol (VII), which is protected with Tbdms-Cl and imidazole to yield the silyl ether (VIII). The alkylation of (VIII) with allyl bromide (IX) and NaH in DMF affords the N-allyl derivative (X), which is desilylated by means of TBAF and AcOH in THF to provide the allyl alcohol (XI). The ring closing metathesis reaction of (XI) with a Grubbs' catalyst in dichloromethane gives the tetrahydropyridine (XII), which is treated with H2 over Pd/C in ethanol to yield the chiral protected piperidine (XIII). The condensation of (XIII) with 3,5-bis(trifluoromethyl)benzyl bromide (XIV) by means of NaH in DMF affords the benzyl ether (XV), which is finally deprotected with TFA to provide the target piperidine.

参考文献 中间体
合成目标
【1】 Bhaskar, G.; Rao, B.V.; Stereoselective synthesis of L-733,060. Tetrahedron Lett 2003, 44, 5, 915.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 10716 (2S)-2-Amino-2-phenylethanoic acid; L-(+)-alpha-Phenylglycine 2935-35-5 C8H9NO2 详情 详情
(II) 10717 methyl (2S)-2-amino-2-phenylethanoate C9H11NO2 详情 详情
(III) 12485 methyl (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoate C14H19NO4 详情 详情
(IV) 59225 (R)-N-(tert-Butoxycarbonyl)-phenylglycinol; N-t-BOC-D-phenylglycinol 102089-74-7 C13H19NO3 详情 详情
(V) 45428 tert-butyl (1S)-2-oxo-1-phenylethylcarbamate C13H17NO3 详情 详情
(VI) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(VII) 64501 tert-butyl (1S,2S)-2-hydroxy-1-phenyl-3-butenylcarbamate C15H21NO3 详情 详情
(VIII) 64502 tert-butyl (1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenyl-3-butenylcarbamate C21H35NO3Si 详情 详情
(IX) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(X) 64503 tert-butyl allyl((1S,2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenyl-3-butenyl)carbamate C24H39NO3Si 详情 详情
(XI) 64504 tert-butyl allyl[(1S,2S)-2-hydroxy-1-phenyl-3-butenyl]carbamate C18H25NO3 详情 详情
(XII) 64505 tert-butyl (2S,3S)-3-hydroxy-2-phenyl-3,6-dihydro-1(2H)-pyridinecarboxylate C16H21NO3 详情 详情
(XIII) 64499 tert-butyl (2S,3S)-3-hydroxy-2-phenyl-1-piperidinecarboxylate C16H23NO3 详情 详情
(XIV) 27677 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene 32247-96-4 C9H5BrF6 详情 详情
(XV) 64500 tert-butyl (2S,3S)-3-{[3,5-bis(trifluoromethyl)benzyl]oxy}-2-phenyl-1-piperidinecarboxylate C25H27F6NO3 详情 详情

合成路线27

该中间体在本合成路线中的序号：(X)

Synthesis of undecenoic ester intermediate (XXI): The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, TsOH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and Me-Li in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and Raney-Ni in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and TsOH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).

参考文献 中间体
合成目标
【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12641 Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol 126-30-7 C5H12O2 详情 详情
(II) 44529 3-(benzyloxy)-2,2-dimethyl-1-propanol C12H18O2 详情 详情
(III) 44504 3-(benzyloxy)-2,2-dimethylpropanal C12H16O2 详情 详情
(IV) 33891 Methyl ethyl ketone; 2-Butanone 78-93-3 C4H8O 详情 详情
(V) 44505 (E)-7-(benzyloxy)-6,6-dimethyl-4-hepten-3-one C16H22O2 详情 详情
(VI) 44506 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone C16H22O3 详情 详情
(VII) 44507 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone O-methyloxime C17H25NO3 详情 详情
(VIII) 44508 (4R,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone O-methyloxime C18H29NO3 详情 详情
(IX) 44509 (4S,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone C17H26O3 详情 详情
(X) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XI) 44510 (4S,6S,7R)-9-(benzyloxy)-7-hydroxy-4,6,8,8-tetramethyl-1-nonen-5-one C20H30O3 详情 详情
(XII) 44511 (3R,4R,5S,6S)-1-(benzyloxy)-2,2,4,6-tetramethyl-8-nonene-3,5-diol C20H32O3 详情 详情
(XIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XIV) 44512 benzyl 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propyl ether; (4R,5S,6S)-4-[2-(benzyloxy)-1,1-dimethylethyl]-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxane C23H36O3 详情 详情
(XV) 44513 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]-1-propanol C16H30O3 详情 详情
(XVI) 44514 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propanal C16H28O3 详情 详情

合成路线28

该中间体在本合成路线中的序号：(XV)

The oxidation of the lactol (XIII) with Br2 and BaCO3 gives the lactone (XIV), which is stereoselectively alkylated with allyl bromide (XV) by means of LDA in HMPA to yield lactone (XVI). The opening of the lactone ring of (XVI) with MeONa affords the dihydroxyester (XVII), which is protected by reaction with anisaldehyde dimethylacetal (XVIII) and CSA to provide the benzylidene derivative (XIX). The reduction of the ester group of (XIX) with LiAlH4 gives the corresponding carbinol (XX), which is acylated with Ms-Cl and TEA to yield the mesylate (XXI). The reduction of the mesyloxy group of (XXI) with LiAlH4 affords the dimethyl compound (XXII), which is submitted to a regioselective cleavage of the Pmp protecting group by means of DIBAL in toluene to provide the primary alcohol (XXIII). The oxidation of (XXIII) with DMP gives the corresponding aldehyde (XXIV), which is condensed with tert-butyl isobutyrylacetate (XXV) by means of NaH and BuLi to yield the unsaturated ketoester (XXVI). Stereoselective reduction of the beta-oxo group of (XXVI) by means of Me4NBH(OAc)3 affords the desired diol (XXVII), which is regioselectively silylated at the beta-hydroxy group by means of Tbdms-OTf to provide the monosilyl ether (XXVIII). The oxidation of the remaining hydroxy group of (XXVIII) by means of DMP gives the unsaturated ketoester (XXIX).

参考文献 中间体
合成目标
【1】 Wong, C.-H.; Liu, J.; Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones. Angew Chem. Int Ed 2002, 41, 8, 1404.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 54267 (4S,5S)-5-methyltetrahydro-2H-pyran-2,4-diol C6H12O3 详情 详情
(XIV) 54268 (4S,5S)-4-hydroxy-5-methyltetrahydro-2H-pyran-2-one C6H10O3 详情 详情
(XV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XVI) 54269 (3S,4R,5S)-3-allyl-4-hydroxy-5-methyltetrahydro-2H-pyran-2-one C9H14O3 详情 详情
(XVII) 54270 methyl (2S)-2-[(1R,2S)-1,3-dihydroxy-2-methylpropyl]-4-pentenoate C10H18O4 详情 详情
(XVIII) 26485 1-(dimethoxymethyl)-4-methoxybenzene 2186-92-7 C10H14O3 详情 详情
(XIX) 54271 methyl (2S)-2-[(4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-pentenoate n/a C18H24O5 详情 详情
(XX) 54272 (2R)-2-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-penten-1-ol n/a C17H24O4 详情 详情
(XXI) 54273 (2R)-2-[(4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-pentenyl methanesulfonate n/a C18H26O6S 详情 详情
(XXII) 54274 (4S,5S)-2-(4-methoxyphenyl)-5-methyl-4-[(1S)-1-methyl-3-butenyl]-1,3-dioxane; methyl 4-{(4S,5S)-5-methyl-4-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-2-yl}phenyl ether n/a C17H24O3 详情 详情
(XXIII) 54275 (2S,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-6-hepten-1-ol n/a C17H26O3 详情 详情
(XXIV) 54276 (2R,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-6-heptenal n/a C17H24O3 详情 详情
(XXV) 54277 tert-butyl 4-methyl-3-oxopentanoate 94250-54-1 C10H18O3 详情 详情
(XXVI) 54278 tert-butyl (5S,6S,7S,8S)-5-hydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-3-oxo-10-undecenoate n/a C27H42O6 详情 详情
(XXVII) 54279 tert-butyl (3S,5S,6S,7S,8S)-3,5-dihydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-10-undecenoate n/a C27H44O6 详情 详情
(XXVIII) 54280 tert-butyl (3S,5S,6S,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-10-undecenoate n/a C33H58O6Si 详情 详情
(XXIX) 54281 tert-butyl (3S,6R,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate n/a C33H56O6Si 详情 详情

合成路线29

该中间体在本合成路线中的序号：(X)

The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, Ts-OH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and MeLi in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and Raney-Ni in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and Ts-OH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).

参考文献 中间体
合成目标
【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12641 Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol 126-30-7 C5H12O2 详情 详情
(II) 44529 3-(benzyloxy)-2,2-dimethyl-1-propanol C12H18O2 详情 详情
(III) 44504 3-(benzyloxy)-2,2-dimethylpropanal C12H16O2 详情 详情
(IV) 33891 Methyl ethyl ketone; 2-Butanone 78-93-3 C4H8O 详情 详情
(V) 44505 (E)-7-(benzyloxy)-6,6-dimethyl-4-hepten-3-one C16H22O2 详情 详情
(VI) 44506 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone C16H22O3 详情 详情
(VII) 44507 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone O-methyloxime C17H25NO3 详情 详情
(VIII) 44508 (4R,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone O-methyloxime C18H29NO3 详情 详情
(IX) 44509 (4S,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone C17H26O3 详情 详情
(X) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XI) 44510 (4S,6S,7R)-9-(benzyloxy)-7-hydroxy-4,6,8,8-tetramethyl-1-nonen-5-one C20H30O3 详情 详情
(XII) 44511 (3R,4R,5S,6S)-1-(benzyloxy)-2,2,4,6-tetramethyl-8-nonene-3,5-diol C20H32O3 详情 详情
(XIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XIV) 44512 benzyl 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propyl ether; (4R,5S,6S)-4-[2-(benzyloxy)-1,1-dimethylethyl]-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxane C23H36O3 详情 详情
(XV) 44513 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]-1-propanol C16H30O3 详情 详情
(XVI) 44514 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propanal C16H28O3 详情 详情

合成路线30

该中间体在本合成路线中的序号：(VII)

Treatment of (R)-1-chloro-2,3-propanediol (I) with either K2CO3 or Cs2CO3 in CH2Cl2, followed by O-protection with Trt-Cl and Et3N in CH2Cl2, yields (S)-trityl glycidol (II). Alternatively, derivative (II) can also be obtained either by direct O-protection of (R)-glycidol (III) by means of Trt-Cl and Et3N in refluxing CH2Cl2 or by cyclization of protected propanediol derivative (IV)--obtained from treatment of compound (I) with Trt-Cl and Et3N in CH2Cl2--by means of KOH in EtOH. Reaction of (S)-trityl glycidol (II) with vinyl magnesium bromide (V) by means of CuI in THF provides (S)-1-(triphenylmethoxy)-4-penten-2-ol (VI), which is then condensed with allyl bromide (VII) with KOtBu or NaH in THF to afford compound (VIII). Ozonolysis of (VIII) in CH2Cl2/MeOH, followed by reductive quench with NaBH4 in NaOH, gives (S)-3-(2-hydroxyethoxy)-4-(triphenylmethoxy)-1-butanol (IX), which is then treated with MsCl/Et3N in CH2Cl2 to yield bismesylate (X). Coupling of compound (X) with 2,3-bis(1H-indol-3-yl)-N-methylmaleimide (XI) [obtained by treatment of dichloromaleic anhydride (XII) with methylamine hydrochloride by means of NaOMe in HOAc to furnish dichloro-N-methylmaleimide (XIII), followed by Grignard reaction of (XIII) with indole (XIV) in toluene/THF by means of EtMgBr in Et2O] by means of Cs2CO3 in DMF gives the 14-membered macrocycle (XV).

参考文献 中间体
合成目标
【1】 Faul, M.M.; Sullivan, K.A.; Neel, D.A.; Krumrich, C.A.; Jirousek, M.R.; Winneroski, L.L.; Gillig, J.R.; Rito, C.J.; Macrocyclic bisindolylmaleimides: Synthesis by inter- and intramolecular alkylation. J Org Chem 1998, 63, 6, 1961.
【2】 Engel, G.L.; Farid, N.A.; Faul, M.M.; Jirousek, M.R.; Richardson, L.A.; Winneroski, L.L. Jr. (Eli Lilly and Company); Protein kinase C inhibitor. EP 0776895; JP 1999500149; US 5710145; WO 9718809 .
【3】 Faul, M.M.; Winneroski, L.L. Jr.; Krumrich, C.A. (Eli Lilly and Company); Intermediates and their use to prepare N,N'-bridged bisindolylmaleimides. US 5721272 .
【4】 Rito, C.J.; Mcdonald, J.H. III; Jirousek, M.R.; Winneroski, L.L. Jr.; Heath, W.F. Jr.; Faul, M.M. (Eli Lilly and Company); Improved synthesis of bisindolylmaleimides. EP 0657411; US 5541347 .
【5】 Faul, M.M.; Winneroski, L.L. Jr.; Krumrich, C.A. (Eli Lilly and Company); Intermediates and their use to prepare N,N'-bridged bisindolylmaleimides. EP 0776899 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 49696 (S)-(+)-Alpha-Chlorohydrin; (S)-(+)-3-Chloro-1,2-propanediol; (S)-3-Chloro-1,2-propanediol 60827-45-4 C3H7ClO2 详情 详情
(II) 41006 (2S)-oxiranylmethyl trityl ether; (2S)-2-[(trityloxy)methyl]oxirane C22H20O2 详情 详情
(III) 19241 (2S)oxiranylmethanol 60456-23-7 C3H6O2 详情 详情
(IV) 51942 (2R)-1-chloro-3-(trityloxy)-2-propanol C22H21ClO2 详情 详情
(V) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(VI) 41007 (2S)-1-(trityloxy)-4-penten-2-ol C24H24O2 详情 详情
(VII) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VIII) 41008 1-[[[(2S)-2-(allyloxy)-4-pentenyl]oxy](diphenyl)methyl]benzene; allyl (1S)-1-[(trityloxy)methyl]-3-butenyl ether C27H28O2 详情 详情
(IX) 41010 (3S)-3-(2-hydroxyethoxy)-4-(trityloxy)-1-butanol C25H28O4 详情 详情
(X) 51943 (7S)-2,11-dimethyl-2,11-dimethylene-7-[(trityloxy)methyl]-3,6,10-trioxa-2lambda(6),11lambda(6)-dithia-1,11-dodecadiene; 2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]ethyl (1S)-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-[(trityloxy)methyl]propyl ether C31H40O4S2 详情 详情
(XI) 51012 5-(tert-butyl) 1-(2,3,5,6-tetrafluorophenyl) (2S)-2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]pentanedioate C32H38F4N2O9 详情 详情
(XII) 21947 3,4-dichloro-2,5-furandione 1122-17-4 C4Cl2O3 详情 详情
(XIII) 41029 3,4-dichloro-1-methyl-1H-pyrrole-2,5-dione C5H3Cl2NO2 详情 详情
(XIV) 15292 Indole; 1H-indole 120-72-9 C8H7N 详情 详情
(XV) 41016 (18S)-4-methyl-18-[(trityloxy)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione C46H39N3O4 详情 详情

合成路线31

该中间体在本合成路线中的序号：(IV)

The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X).The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with Pmb-Cl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3/pyridine to the corresponding aldehyde (XV). The condensation of (XV) with 4-(triisopropylsilyloxy)-1(E)-butenyl iodide (XVI) by means of BuLi in THF, followed by oxidation of the intermediate alcohol with SO3/pyridine provides the unsaturated ketone (XVII).

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(I) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(II) 35676 tert-butyl(3-iodopropoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-iodopropyl ether C9H21IOSi 详情 详情
(III) 35677 dimethyl 2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C14H28O5Si 详情 详情
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 35678 dimethyl 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C17H32O5Si 详情 详情
(VI) 35679 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,3-propanediol C15H32O3Si 详情 详情
(VII) 35680 3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propyl tert-butyl(dimethyl)silyl ether; [3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propoxy](tert-butyl)dimethylsilane C18H36O3Si 详情 详情
(VIII) 35681 2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]acetaldehyde C17H34O4Si 详情 详情
(IX) 17966 cyclohexanamine; cyclohexyl amine; cyclohexylamine 108-91-8 C6H13N 详情 详情
(X) 35682 N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]-N-cyclohexylamine; N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]cyclohexanamine C23H45NO3Si 详情 详情
(XI) 35683 (E)-8-decenal C10H18O 详情 详情
(XII) 35684 (2Z,10E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]-2,10-dodecadienal C27H50O4Si 详情 详情
(XIII) 35685 tert-butyl[3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propoxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propyl ether C35H58O4Si 详情 详情
(XIV) 35686 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-1-propanol C29H44O4 详情 详情
(XV) 35687 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal C29H42O4 详情 详情
(XVI) 35688 (E)-4-iodo-3-butenyl triisopropylsilyl ether; [[(E)-4-iodo-3-butenyl]oxy](triisopropyl)silane C13H27IOSi 详情 详情
(XVII) 35689 (E)-1-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-7-[(triisopropylsilyl)oxy]-4-hepten-3-one C42H68O5Si 详情 详情

合成路线32

该中间体在本合成路线中的序号：(IV)

The intermediate aldehyde (XV) has been obtained as follows: The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X). The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with PmbCl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3.Pyr to the corresponding aldehyde (XV).

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(II) 35676 tert-butyl(3-iodopropoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-iodopropyl ether C9H21IOSi 详情 详情
(III) 35677 dimethyl 2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C14H28O5Si 详情 详情
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 35678 dimethyl 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C17H32O5Si 详情 详情
(VI) 35679 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,3-propanediol C15H32O3Si 详情 详情
(VII) 35680 3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propyl tert-butyl(dimethyl)silyl ether; [3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propoxy](tert-butyl)dimethylsilane C18H36O3Si 详情 详情
(VIII) 35681 2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]acetaldehyde C17H34O4Si 详情 详情
(IX) 17966 cyclohexanamine; cyclohexyl amine; cyclohexylamine 108-91-8 C6H13N 详情 详情
(X) 35682 N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]-N-cyclohexylamine; N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]cyclohexanamine C23H45NO3Si 详情 详情
(XI) 35683 (E)-8-decenal C10H18O 详情 详情
(XII) 35684 (2Z,10E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]-2,10-dodecadienal C27H50O4Si 详情 详情
(XIII) 35685 tert-butyl[3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propoxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propyl ether C35H58O4Si 详情 详情
(XIV) 35686 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-1-propanol C29H44O4 详情 详情
(XV) 35687 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal C29H42O4 详情 详情

合成路线33

该中间体在本合成路线中的序号：(VIII)

The reaction of 2(R)-(acetoxymethyl)-5-methyl-3(E)-hexen-1-ol (I) with MsCl and TEA in dichloromethane gives the mesylate (II), which is treated with NaN3 in hot DMF to yield the azido derivative (III). The hydrolysis of (III) catalyzed by Pseudomonas cepacia affords the azido alcohol (IV), which is reduced with PPh3 in THF/water to provide the aminoalcohol (V). The N-protection of (V) by means of Boc-ON and Et3N gives the carbamate (VI), which is O-protected by means of Tips-Cl and imidazole yielding the silyl ether (VII). The alkylation of the carbamate (VII) with allyl bromide (VIII) and NaH in DMF affords the allyl carbamate (IX), which is submitted to a ring closure metathesis reaction catalyzed by Grubb's catalyst to provide the chiral tetrahydropyridine (X). The desilylation of (X) by means of TBAF in THF gives N-(tert-butoxycarbonyl)-3(R)-(hydroxymethyl)-1,2,3,6-tetrahydropyridine (XI), which is treated with mCPBA in dichloromethane to yield an inseparable diastereomeric mixture of epoxides (XII) + (XIII). Finally, this mixture is treated with either HClO4 in acetone, HCl in ethyl acetate or with refluxing aq. KOH to afford separable mixtures of the target isofagomine and (XIV), one of its diastereomers.

参考文献 中间体
合成目标
【1】 Guanti, G.; Riva, R.; Asymmetrized tris(hydroxymethyl)methane as precursor of iminosugars: Application to the synthesis of isofagomine. Tetrahedron Lett 2003, 44, 2, 357.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 61784 (2R,3E)-2-(hydroxymethyl)-5-methyl-3-hexenyl acetate C10H18O3 详情 详情
(II) 61785 (2S,3E)-5-methyl-2-{[(methylsulfonyl)oxy]methyl}-3-hexenyl acetate C11H20O5S 详情 详情
(III) 61786 (2R,3E)-2-(azidomethyl)-5-methyl-3-hexenyl acetate C10H17N3O2 详情 详情
(IV) 61787 (2R,3E)-2-(azidomethyl)-5-methyl-3-hexen-1-ol C8H15N3O 详情 详情
(V) 61788 (2R,3E)-2-(aminomethyl)-5-methyl-3-hexen-1-ol C8H17NO 详情 详情
(VI) 61789 tert-butyl (2R,3E)-2-(hydroxymethyl)-5-methyl-3-hexenylcarbamate C13H25NO3 详情 详情
(VII) 61790 tert-butyl (2R,3E)-5-methyl-2-{[(triisopropylsilyl)oxy]methyl}-3-hexenylcarbamate C22H45NO3Si 详情 详情
(VIII) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(IX) 61791 tert-butyl allyl((2R,3E)-5-methyl-2-{[(triisopropylsilyl)oxy]methyl}-3-hexenyl)carbamate C25H49NO3Si 详情 详情
(X) 61792 tert-butyl (3R)-3-{[(triisopropylsilyl)oxy]methyl}-3,6-dihydro-1(2H)-pyridinecarboxylate C20H39NO3Si 详情 详情
(XI) 61793 tert-butyl (3R)-3-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate C11H19NO3 详情 详情
(XII) 61794 tert-butyl (1R,5R,6S)-5-(hydroxymethyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate C11H19NO4 详情 详情
(XIII) 61795 tert-butyl (1S,5R,6R)-5-(hydroxymethyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate C11H19NO4 详情 详情
(XIV) 61796 (3S,4S,5R)-5-(hydroxymethyl)-3,4-piperidinediol C6H13NO3 详情 详情

合成路线34

该中间体在本合成路线中的序号：

The alkylation of diosmetin (I) with allyl bromide in the presence of NaH in DMF furnished the triallyl ether (II). Claisen rearrangement of (II) in refluxing trichlorobenzene then gave the title compound.

参考文献 中间体
合成目标
【1】 Wierzbicki, M.; Boussard, M.-F.; Verbeuren, T.; Vallez, M.-O.; Canet, E.; Rolland, Y. (ADIR et Cie.); Diosmetin derivs., process for their preparation and pharmaceutical compsns. containing them. CA 2161297; EP 0709383; FR 2726273; JP 1996225563; US 5629339 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(I) 30012 5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-chromen-4-one 520-34-3 C16H12O6 详情 详情
(II) 32941 5,7-bis(allyloxy)-2-[3-(allyloxy)-4-methoxyphenyl]-4H-chromen-4-one C25H24O6 详情 详情

合成路线35

该中间体在本合成路线中的序号：

Condensation of L-phenylalanine methyl ester (I) with benzaldehyde gave aldimine (II). Then, alkylation of (II) with allyl bromide in the presence of LDA, and subsequent imine hydrolysis afforded the racemic alpha-allylphenylalanine methyl ester (III), which was protected as the N-Boc derivative (IV) upon treatment with Boc2O. Ozonolysis of the olefin group of (IV), followed by reductive workup with Me2S yielded the aldehyde ester (V). This was cyclized with hydrazine, affording pyridazinone (VI), which was further hydrogenated over PtO2 to give (VII). The 1,3-dipolar cycloaddition of the iminium ion (VIII), formed by treatment of (VII) with formaldehyde, with boiling ethyl acrylate furnished a mixture of pyrazolopyridazines (IXa-b). After chromatographic isolation of the racemic cis amino ester, hydrolysis with LiOH yielded carboxylic acid (X), which was activated as the mixed anhydride (XI) with isobutyl chloroformate. Coupling of racemic anhydride (XI) with the L-arginine analogue (XII) provided a diastereomeric mixture of amides, from which the desired isomer (XIII) was isolated by column chromatography. Finally, deprotection of (XIII) by means of trifluoroacetic acid furnished the title compound.

参考文献 中间体
合成目标
【1】 Nakanishi, H.; Ogbu, C.O.; Shea, J.P.; Cao, B.; Kahn, M.; Boatman, P.D.; Kim, H.-O.; Eguchi, M.; Secondary structure peptide mimetics: Design, synthesis, and evaluation of beta-strand mimetic thrombin inhibitors. J Med Chem 1999, 42, 8, 1367.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(IXa) 36777 methyl (1S,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylate C21H29N3O5 详情 详情
(IXb) 36778 methyl (1R,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylate C21H29N3O5 详情 详情
(I) 12324 methyl (2R)-2-amino-3-phenylpropanoate 21685-51-8 C10H13NO2 详情 详情
(II) 36770 methyl (2S)-3-phenyl-2-[[(E)-benzylidene]amino]propanoate C17H17NO2 详情 详情
(III) 36771 methyl 2-amino-2-benzyl-4-pentenoate C13H17NO2 详情 详情
(IV) 36772 methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-pentenoate C18H25NO4 详情 详情
(V) 36773 methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoate C17H23NO5 详情 详情
(VI) 36774 tert-butyl 4-benzyl-3-oxo-2,3,4,5-tetrahydro-4-pyridazinylcarbamate C16H21N3O3 详情 详情
(VII) 36775 tert-butyl 4-benzyl-3-oxohexahydro-4-pyridazinylcarbamate C16H23N3O3 详情 详情
(VIII) 36776 4-benzyl-4-[(tert-butoxycarbonyl)amino]-1-methylene-3-oxohexahydropyridazin-1-ium C17H24N3O3 详情 详情
(X) 36779 (1S,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylic acid C20H27N3O5 详情 详情
(XI) 36780 　 C25H35N3O7 详情 详情
(XII) 36781 [[[[(4S)-4-amino-6-chloro-5-oxohexyl]amino](imino)methyl]amino](4-methoxy-2,3,6-trimethylphenyl)dioxo-lambda(6)-sulfane C17H27ClN4O4S 详情 详情
(XIII) 36782 　 C38H52ClN7O10S 详情 详情

合成路线36

该中间体在本合成路线中的序号：(IV)

The reaction of phenylalanine methyl ester (I) with benzaldehyde (II) and TEA in dichloromethane gives the aldimine (III), which is condensed with allyl bromide (IV) by means of n-BuLi in THF yielding the adduct (V). Treatment of (V) with HCl in methanol cleaves the benzylidene protecting group to afford the alpha-allylphenylalanine methyl ester (VI), which is reprotected with Boc2O and NaHCO3 in THF providing the carbamate (VII). The ozonolysis of (VII) with O3 in MeOH/CH2Cl2 gives the aldehyde (VIII), which is cyclized with hydrazine in refluxing THF yielding the tetrahydropyridazinone (IX). Hydrogenation of (IX) with H2 over PtO2 in methanol affords the hexahydropyridazinone (X), which is cyclocondensed with ethyl acrylate (XI) and formaldehyde to furnish the pyrazolopyridazine (XII). Hydrolysis of the ester group of (XII) with LiOH in THF/water gives the acid (XIII), which is finally condensed with N-omega(4-methoxytrityl)-L-arginylchloromethane (XIV) by means of isobutyl chloroformate and NMM in THF yielding, after working up, a diastereomeric mixture of amides, from which the target diastereomer is obtained by column chromatography.

参考文献 中间体
合成目标
【1】 Nakanishi, H.; Ogbu, C.O.; Shea, J.P.; Cao, B.; Kahn, M.; Boatman, P.D.; Kim, H.-O.; Eguchi, M.; Secondary structure peptide mimetics: Design, synthesis, and evaluation of beta-strand mimetic thrombin inhibitors. J Med Chem 1999, 42, 8, 1367.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 40419 methyl 2-amino-3-phenylpropanoate 5619-07-8 C10H13NO2 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 40420 methyl 3-phenyl-2-[[(E)-benzylidene]amino]propanoate C17H17NO2 详情 详情
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 40416 methyl 2-benzyl-2-[[(E)-benzylidene]amino]-4-pentenoate C20H21NO2 详情 详情
(VI) 36771 methyl 2-amino-2-benzyl-4-pentenoate C13H17NO2 详情 详情
(VII) 36772 methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-pentenoate C18H25NO4 详情 详情
(VIII) 36773 methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoate C17H23NO5 详情 详情
(IX) 36774 tert-butyl 4-benzyl-3-oxo-2,3,4,5-tetrahydro-4-pyridazinylcarbamate C16H21N3O3 详情 详情
(X) 36775 tert-butyl 4-benzyl-3-oxohexahydro-4-pyridazinylcarbamate C16H23N3O3 详情 详情
(XI) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(XII) 40417 ethyl (1S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylate C22H31N3O5 详情 详情
(XIII) 36779 (1S,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylic acid C20H27N3O5 详情 详情
(XIV) 40418 N-[(4S)-4-amino-6-chloro-5-oxohexyl]-N'-[(4-methoxyphenyl)(diphenyl)methyl]guanidine C27H31ClN4O2 详情 详情

合成路线37

该中间体在本合成路线中的序号：

Condensation of L-phenylalanine methyl ester (V) with benzaldehyde gave aldimine (VI). Then, alkylation of (VI) with allyl bromide in the presence of LDA, and subsequent imine hydrolysis afforded the racemic alpha-allylphenylalanine methyl ester (VII), which was protected as the N-Boc derivative (VIII) upon treatment with Boc2O. Ozonolysis of the olefin group of (VIII), followed by reductive workup with Me2S yielded the aldehyde ester (IX). This was cyclized with hydrazine, affording pyridazinone (X), which was further hydrogenated over PtO2 to give (XI). The 1,3-dipolar cycloaddition of the iminium ion (XII), formed by treatment of (XI) with formaldehyde, and boiling ethyl acrylate furnished a mixture of pyrazolopyridazines (XIIIa-b). After chromatographic isolation of the racemic cis amino ester, its hydrolysis with LiOH yielded carboxylic acid (XIV). Coupling of (XIV) with aminoalcohol (IVa-b) using EDC and HOBt provided the corresponding amide (XVa-d) as a mixture of 4 diastereomers. Oxidation of the secondary alcohol of (XVa-d) with Dess-Martin periodinane gave the diastereomeric ketones (XVIa-b). Then, deprotection of (XVIa-b) by means of trifluoroacetic acid, followed by separation of the isomers by HPLC furnished the title compound.

参考文献 中间体
合成目标
【1】 Nakanishi, H.; Ogbu, C.O.; Shea, J.P.; Cao, B.; Kahn, M.; Boatman, P.D.; Kim, H.-O.; Eguchi, M.; Secondary structure peptide mimetics: Design, synthesis, and evaluation of beta-strand mimetic thrombin inhibitors. J Med Chem 1999, 42, 8, 1367.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XIIIa) 36777 methyl (1S,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylate C21H29N3O5 详情 详情
(XIIIb) 36778 methyl (1R,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylate C21H29N3O5 详情 详情
(IVa) 36787 2-[(1S,2S)-2-amino-1-hydroxy-5-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]pentyl]-1,3-benzothiazole C23H31N5O4S2 详情 详情
(IVb) 36788 2-[(1R,2S)-2-amino-1-hydroxy-5-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]pentyl]-1,3-benzothiazole C23H31N5O4S2 详情 详情
(XVa) 36789 tert-butyl (3S,6S)-3-[([(1S)-1-[(S)-1,3-benzothiazol-2-yl(hydroxy)methyl]-4-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-ylcarbamate C43H56N8O8S2 详情 详情
(XVb) 36790 tert-butyl (3S,6S)-3-[([(1S)-1-[(R)-1,3-benzothiazol-2-yl(hydroxy)methyl]-4-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-ylcarbamate C43H56N8O8S2 详情 详情
(XVc) 36791 tert-butyl (3S,6S)-3-[([(1R)-1-[(R)-1,3-benzothiazol-2-yl(hydroxy)methyl]-4-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-ylcarbamate C43H56N8O8S2 详情 详情
(XVd) 36792 tert-butyl (3S,6S)-3-[([(1R)-1-[(S)-1,3-benzothiazol-2-yl(hydroxy)methyl]-4-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-ylcarbamate C43H56N8O8S2 详情 详情
(XVIa) 36793 tert-butyl (3S,6S)-3-[([(1S)-1-(1,3-benzothiazol-2-ylcarbonyl)-4-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-ylcarbamate C43H54N8O8S2 详情 详情
(XVIb) 36794 tert-butyl (3R,6S)-3-[([(1S)-1-(1,3-benzothiazol-2-ylcarbonyl)-4-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-ylcarbamate C43H54N8O8S2 详情 详情
(V) 12324 methyl (2R)-2-amino-3-phenylpropanoate 21685-51-8 C10H13NO2 详情 详情
(VI) 36770 methyl (2S)-3-phenyl-2-[[(E)-benzylidene]amino]propanoate C17H17NO2 详情 详情
(VII) 36771 methyl 2-amino-2-benzyl-4-pentenoate C13H17NO2 详情 详情
(VIII) 36772 methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-pentenoate C18H25NO4 详情 详情
(IX) 36773 methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoate C17H23NO5 详情 详情
(X) 36774 tert-butyl 4-benzyl-3-oxo-2,3,4,5-tetrahydro-4-pyridazinylcarbamate C16H21N3O3 详情 详情
(XI) 36775 tert-butyl 4-benzyl-3-oxohexahydro-4-pyridazinylcarbamate C16H23N3O3 详情 详情
(XII) 36776 4-benzyl-4-[(tert-butoxycarbonyl)amino]-1-methylene-3-oxohexahydropyridazin-1-ium C17H24N3O3 详情 详情
(XIV) 36779 (1S,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylic acid C20H27N3O5 详情 详情

合成路线38

该中间体在本合成路线中的序号：(IV)

The reaction of phenylalanine methyl ester (I) with benzaldehyde (II) and TEA in dichloromethane gives the aldimine (III), which is condensed with allyl bromide (IV) by means of n-BuLi in THF yielding the adduct (V). Treatment of (V) with HCl in methanol cleaves the benzylidene protecting group to afford the alpha-allylphenylalanine methyl ester (VI), which is reprotected with Boc2O and NaHCO3 in THF providing the carbamate (VII). The ozonolysis of (VII) with O3 in MeOH/CH2Cl2 gives the aldehyde (VIII), which is cyclized with hydrazine in refluxing THF yielding the tetrahydropyridazinone (IX). Hydrogenation of (IX) with H2 over PtO2 in methanol affords the hexahydropyridazinone (X), which is cyclocondensed with ethyl acrylate (XI) and formaldehyde to furnish the pyrazolopyridazine (XII). Hydrolysis of the ester group of (XII) with LiOH in THF/water gives the acid (XIII), which is finally condensed with the argininol derivative (XIV) by means of EDC, HOBT and DIEA in THF yielding the corresponding amide (XV). Finally, the secondary alcohol of (XV) is oxidized with Dess Martin periodinane (DMP) to afford, after working up, a diastereomeric mixture of amides, from which the target diastereomer is obtained by HPLC chromatography.

参考文献 中间体
合成目标
【1】 Nakanishi, H.; Ogbu, C.O.; Shea, J.P.; Cao, B.; Kahn, M.; Boatman, P.D.; Kim, H.-O.; Eguchi, M.; Secondary structure peptide mimetics: Design, synthesis, and evaluation of beta-strand mimetic thrombin inhibitors. J Med Chem 1999, 42, 8, 1367.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 40419 methyl 2-amino-3-phenylpropanoate 5619-07-8 C10H13NO2 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 40420 methyl 3-phenyl-2-[[(E)-benzylidene]amino]propanoate C17H17NO2 详情 详情
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 40416 methyl 2-benzyl-2-[[(E)-benzylidene]amino]-4-pentenoate C20H21NO2 详情 详情
(VI) 36771 methyl 2-amino-2-benzyl-4-pentenoate C13H17NO2 详情 详情
(VII) 36772 methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-pentenoate C18H25NO4 详情 详情
(VIII) 36773 methyl 2-benzyl-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoate C17H23NO5 详情 详情
(IX) 36774 tert-butyl 4-benzyl-3-oxo-2,3,4,5-tetrahydro-4-pyridazinylcarbamate C16H21N3O3 详情 详情
(X) 36775 tert-butyl 4-benzyl-3-oxohexahydro-4-pyridazinylcarbamate C16H23N3O3 详情 详情
(XI) 10164 ethyl acrylate 140-88-5 C5H8O2 详情 详情
(XII) 40417 ethyl (1S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylate C22H31N3O5 详情 详情
(XIII) 36779 (1S,7S)-7-benzyl-7-[(tert-butoxycarbonyl)amino]-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxylic acid C20H27N3O5 详情 详情
(XIV) 40421 N-[(4S)-4-amino-5-(1,3-benzothiazol-2-yl)-5-hydroxypentyl]-N'-[(4-methoxyphenyl)(diphenyl)methyl]guanidine C33H35N5O2S 详情 详情
(XV) 40422 (1S)-7-amino-N-[(1S)-4-[[amino(imino)methyl]amino]-1-[1,3-benzothiazol-2-yl(hydroxy)methyl]butyl]-7-benzyl-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxamide C28H36N8O3S 详情 详情

合成路线39

该中间体在本合成路线中的序号：(X)

The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, Ts-OH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and MeLi in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and Raney-Ni in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and Ts-OH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).

参考文献 中间体
合成目标
【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12641 Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol 126-30-7 C5H12O2 详情 详情
(II) 44529 3-(benzyloxy)-2,2-dimethyl-1-propanol C12H18O2 详情 详情
(III) 44504 3-(benzyloxy)-2,2-dimethylpropanal C12H16O2 详情 详情
(IV) 33891 Methyl ethyl ketone; 2-Butanone 78-93-3 C4H8O 详情 详情
(V) 44505 (E)-7-(benzyloxy)-6,6-dimethyl-4-hepten-3-one C16H22O2 详情 详情
(VI) 44506 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone C16H22O3 详情 详情
(VII) 44507 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone O-methyloxime C17H25NO3 详情 详情
(VIII) 44508 (4R,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone O-methyloxime C18H29NO3 详情 详情
(IX) 44509 (4S,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone C17H26O3 详情 详情
(X) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XI) 44510 (4S,6S,7R)-9-(benzyloxy)-7-hydroxy-4,6,8,8-tetramethyl-1-nonen-5-one C20H30O3 详情 详情
(XII) 44511 (3R,4R,5S,6S)-1-(benzyloxy)-2,2,4,6-tetramethyl-8-nonene-3,5-diol C20H32O3 详情 详情
(XIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XIV) 44512 benzyl 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propyl ether; (4R,5S,6S)-4-[2-(benzyloxy)-1,1-dimethylethyl]-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxane C23H36O3 详情 详情
(XV) 44513 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]-1-propanol C16H30O3 详情 详情
(XVI) 44514 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propanal C16H28O3 详情 详情

合成路线40

该中间体在本合成路线中的序号：(VI)

Protection of (R)-glycidol (I) with trityl chloride (II) and TEA in dichloromethane gives the trityl ether (III), which is condensed with vinylmagnesium bromide (IV) in THF to yield the pentenol (V). The alkylation of (V) with allyl bromide (VI) by means of NaH in THF affords the allyl ether (VII), which is oxidized with O3 in methanol/dichloromethane, giving dialdehyde (VIII). Reduction of (VIII) with NaBH4 in ethanol provides diol (IX), which is treated with mesyl chloride and TEA in dichloromethane to afford the fully protected alcohol (X). Cyclization of (X) with 3,4-bis(3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione (XI) by means of Cs2CO3 in DMF yields the hexacyclic compound (XII), which is N-demethylated by reaction with KOH in refluxing ethanol to give the hexacyclic furan derivative (XIII), which is then treated with hexamethyldisilazane (HMDS) in hot methanol to afford the hexacyclic demethylated pyrrole (XIV). Elimination of the trityl protecting group of (XIV) with HCl in dichloromethane gives the methanol derivative (XV), which is treated with Br2, pyridine and triphenyl phosphite in dichloromethane to yield the bromomethyl derivative (XVI). Finally, this compound is treated with dimethylamine in DMF to provide LY-333531. Alternatively, compound (XV) is treated with methanesulfonic anhydride and pyridine in THF, giving the mesylate (XVII), which is then treated with dimethylamine as before.

参考文献 中间体
合成目标
【1】 Faul, M.M.; Sullivan, K.A.; Neel, D.A.; Krumrich, C.A.; Jirousek, M.R.; Winneroski, L.L.; Gillig, J.R.; Rito, C.J.; Macrocyclic bisindolylmaleimides: Synthesis by inter- and intramolecular alkylation. J Org Chem 1998, 63, 6, 1961.
【2】 Sorbera, L.A.; Rabasseda, X.; Silvestre, J.S.; Castañer, J.; LY-333531 Mesylate Hydrate. Drugs Fut 2000, 25, 10, 1017-1026.
【3】 Engel, G.L.; Farid, N.A.; Faul, M.M.; Jirousek, M.R.; Richardson, L.A.; Winneroski, L.L. Jr. (Eli Lilly and Company); Protein kinase C inhibitor. EP 0776895; JP 1999500149; US 5710145; WO 9718809 .
【4】 Faul, M.M.; Winneroski, L.L. Jr.; Krumrich, C.A. (Eli Lilly and Company); Intermediates and their use to prepare N,N'-bridged bisindolylmaleimides. US 5721272 .
【5】 Rito, C.J.; Mcdonald, J.H. III; Jirousek, M.R.; Winneroski, L.L. Jr.; Heath, W.F. Jr.; Faul, M.M. (Eli Lilly and Company); Improved synthesis of bisindolylmaleimides. EP 0657411; US 5541347 .
【6】 Faul, M.M.; Winneroski, L.L. Jr.; Krumrich, C.A. (Eli Lilly and Company); Intermediates and their use to prepare N,N'-bridged bisindolylmaleimides. EP 0776899 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 16260 (R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol 57044-25-4 C3H6O2 详情 详情
(II) 28630 Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride 76-83-5 C19H15Cl 详情 详情
(III) 41006 (2S)-oxiranylmethyl trityl ether; (2S)-2-[(trityloxy)methyl]oxirane C22H20O2 详情 详情
(IV) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(V) 41007 (2S)-1-(trityloxy)-4-penten-2-ol C24H24O2 详情 详情
(VI) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VII) 41008 1-[[[(2S)-2-(allyloxy)-4-pentenyl]oxy](diphenyl)methyl]benzene; allyl (1S)-1-[(trityloxy)methyl]-3-butenyl ether C27H28O2 详情 详情
(VIII) 41009 (3S)-3-(2-oxoethoxy)-4-(trityloxy)butanal C25H24O4 详情 详情
(IX) 41010 (3S)-3-(2-hydroxyethoxy)-4-(trityloxy)-1-butanol C25H28O4 详情 详情
(X) 41011 (3S)-3-[2-[(methylsulfonyl)oxy]ethoxy]-4-(trityloxy)butyl methanesulfonate C27H32O8S2 详情 详情
(XI) 41012 3,4-di(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione 113963-68-1 C21H15N3O2 详情 详情
(XII) 41016 (18S)-4-methyl-18-[(trityloxy)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione C46H39N3O4 详情 详情
(XIII) 41017 (18S)-18-[(trityloxy)methyl]-4,17-dioxa-14,21-diazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione C45H36N2O5 详情 详情
(XIV) 41014 (18S)-18-[(trityloxy)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione C45H37N3O4 详情 详情
(XV) 41013 (18S)-18-(hydroxymethyl)-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione C26H23N3O4 详情 详情
(XVI) 41018 (18S)-18-(bromomethyl)-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione C26H22BrN3O3 详情 详情
(XVII) 41015 [(18S)-3,5-dioxo-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaen-18-yl]methyl methanesulfonate C27H25N3O6S 详情 详情

合成路线41

该中间体在本合成路线中的序号：(II)

Alkylation of the sodium salt of 5-nitroguaiacol (I) with allyl bromide (II) gave the allyl ether (III). The methoxy group of (III) was then displaced by NaOH in hot DMSO to produce 2-(allyloxy)-4-nitrophenol (IV), which was further alkylated with (R)-glycidyl tosylate (V), yielding the chiral oxirane (VI). Claisen rearrangement of the allyl ether function of (VI), followed by intramolecular cyclization between the phenol and epoxide groups in hot mesitylene furnished the benzodioxane derivative (VII). Treatment of (VII) with p-toluenesulfonyl chloride afforded tosylate (VIII). Oxidative cleavage of the allyl group of (VIII) with KMnO4 under phase-transfer conditions gave rise to the carboxylic acid (IX). Catalytic hydrogenation of the nitro group of (IX), followed by lactamization of the resultant aminoacid (X) under acidic conditions produced the dioxinoindolone system (XI). Then, nucleophilic displacement of the tosylate group of (XI) with benzylamine (XII) yielded the desired amine, which was finally converted to the corresponding fumarate salt.

参考文献 中间体
合成目标
【1】 Stack, G.P.; Mewshaw, R.E.; Bravo, B.A.; Kang, Y.H. (Wyeth); Dioxino derivs. and their use as dopamine agonists. EP 0771800; JP 1997249671; US 5756532 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 56181 sodium 2-methoxy-5-nitrobenzenolate C7H6NNaO4 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 56182 allyl 2-methoxy-5-nitrophenyl ether; 2-(allyloxy)-1-methoxy-4-nitrobenzene C10H11NO4 详情 详情
(IV) 56183 2-(allyloxy)-4-nitrophenol C9H9NO4 详情 详情
(V) 16242 (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate 113826-06-5 C10H12O4S 详情 详情
(VI) 56184 (2R)-2-{[2-(allyloxy)-4-nitrophenoxy]methyl}oxirane; allyl 5-nitro-2-[(2R)oxiranylmethoxy]phenyl ether C12H13NO5 详情 详情
(VII) 56185 [(2S)-8-allyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methanol C12H13NO5 详情 详情
(VIII) 56186 [(2R)-8-allyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate C19H19NO7S 详情 详情
(IX) 56187 2-[(3R)-3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-6-nitro-2,3-dihydro-1,4-benzodioxin-5-yl]acetic acid C18H17NO9S 详情 详情
(X) 56188 2-[(3R)-6-amino-3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2,3-dihydro-1,4-benzodioxin-5-yl]acetic acid C18H19NO7S 详情 详情
(XI) 56189 [(2R)-8-oxo-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-e]indol-2-yl]methyl 4-methylbenzenesulfonate C18H17NO6S 详情 详情
(XII) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情

合成路线42

该中间体在本合成路线中的序号：(X)

The condensation of 6-methoxyindan-1-one (I) with phosphonate (II) by means of NaH in THF gives 2-(6-methoxyindan-1-ylidene)acetonitrile (III), which is hydrogenated with h2 over Raney Co in ethanol/NH3 to yield 2-(6-methoxyindan-1-ylidene)ethylamine (IV). The acylation of (IV) with propionyl chloride (V) and TEA in THF affords the corresponding amide (VI), which is submitted to an asymmetric reduction with H2 and a chiral Ru catalyst to provide N-[2-(6-methoxyindan-1(S)-yl)ethyl]propionamide (VII). The bromination of (VII) with Br2 and NaOAc in methanol gives the 5-bromo derivative (VIII), which is demethylated by means of BBr3 in dichloromethane to yield the hydroxy compound (IX). The reaction of (IX) with allyl bromide (X) by means of NaH in DMF affords the allyl ether (XI), which is submitted to a Claisen rearrangement in N,N-diethylaniline at 200 C to provide the 7-allyl derivative (XII).The reaction of (XII) with ozone in methanol gives the acetaldehyde derivative (XIII), which is reduced with NaBH4 in methanol to yield the ethanol derivative (XIV). The hydrogenolysis of the Br substituent of (XIV) by means of H2 over Pd/C in methanol/TEA affords the dihydroxy compound (XV), which is treated with MsCl and pyridine to provide the mesylate (XVI). Finally, this compound is cyclized by means of TEA in refluxing ethyl acetate to furnish the target indeno[5,4-b]furan derivative.

参考文献 中间体
合成目标
【1】 Chilman-Blair, K.; Castaner, J.; Silvestre, J.S.; Bayes, M.; TAK-375. Drugs Fut 2003, 28, 10, 950.
【2】 Uchikawa, O.; Fukatsu, K.; Tokunoh, R.; et al.; Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists. J Med Chem 2002, 45, 19, 4222.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 34515 6-methoxy-1-phenyl-1-indanol C16H16O2 详情 详情
(II) 10045 Diethyl cyanomethylphosphonate 2537-48-6 C6H12NO3P 详情 详情
(III) 62218 2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)acetonitrile C12H11NO 详情 详情
(IV) 62219 2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)ethylamine; 2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)-1-ethanamine C12H15NO 详情 详情
(V) 15967 propanoyl chloride; propionyl chloride 79-03-8 C3H5ClO 详情 详情
(VI) 62220 N-[2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)ethyl]propanamide C15H19NO2 详情 详情
(VII) 62221 N-{2-[(1S)-6-methoxy-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C15H21NO2 详情 详情
(VIII) 62222 N-{2-[(1S)-5-bromo-6-methoxy-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C15H20BrNO2 详情 详情
(IX) 62223 N-{2-[(1S)-5-bromo-6-hydroxy-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C14H18BrNO2 详情 详情
(X) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XI) 62224 N-{2-[(1S)-6-(allyloxy)-5-bromo-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C17H22BrNO2 详情 详情
(XII) 62225 N-{2-[(1S)-7-allyl-5-bromo-6-hydroxy-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C17H22BrNO2 详情 详情
(XIII) 62226 N-{2-[(1S)-5-bromo-6-hydroxy-7-(2-oxoethyl)-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C16H20BrNO3 详情 详情
(XIV) 62227 N-{2-[(1S)-5-bromo-6-hydroxy-7-(2-hydroxyethyl)-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C16H22BrNO3 详情 详情
(XV) 62228 N-{2-[(1S)-6-hydroxy-7-(2-hydroxyethyl)-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide C16H23NO3 详情 详情
(XVI) 62229 2-{(3S)-5-hydroxy-3-[2-(propionylamino)ethyl]-2,3-dihydro-1H-inden-4-yl}ethyl methanesulfonate C17H25NO5S 详情 详情

合成路线43

该中间体在本合成路线中的序号：(IV)

The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X).The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with Pmb-Cl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3/pyridine to the corresponding aldehyde (XV). The condensation of (XV) with 4-(triisopropylsilyloxy)-1(E)-butenyl iodide (XVI) by means of BuLi in THF, followed by oxidation of the intermediate alcohol with SO3/pyridine provides the unsaturated ketone (XVII).

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(I) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(II) 35676 tert-butyl(3-iodopropoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-iodopropyl ether C9H21IOSi 详情 详情
(III) 35677 dimethyl 2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C14H28O5Si 详情 详情
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 35678 dimethyl 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C17H32O5Si 详情 详情
(VI) 35679 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,3-propanediol C15H32O3Si 详情 详情
(VII) 35680 3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propyl tert-butyl(dimethyl)silyl ether; [3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propoxy](tert-butyl)dimethylsilane C18H36O3Si 详情 详情
(VIII) 35681 2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]acetaldehyde C17H34O4Si 详情 详情
(IX) 17966 cyclohexanamine; cyclohexyl amine; cyclohexylamine 108-91-8 C6H13N 详情 详情
(X) 35682 N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]-N-cyclohexylamine; N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]cyclohexanamine C23H45NO3Si 详情 详情
(XI) 35683 (E)-8-decenal C10H18O 详情 详情
(XII) 35684 (2Z,10E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]-2,10-dodecadienal C27H50O4Si 详情 详情
(XIII) 35685 tert-butyl[3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propoxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propyl ether C35H58O4Si 详情 详情
(XIV) 35686 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-1-propanol C29H44O4 详情 详情
(XV) 35687 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal C29H42O4 详情 详情
(XVI) 35688 (E)-4-iodo-3-butenyl triisopropylsilyl ether; [[(E)-4-iodo-3-butenyl]oxy](triisopropyl)silane C13H27IOSi 详情 详情
(XVII) 35689 (E)-1-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-7-[(triisopropylsilyl)oxy]-4-hepten-3-one C42H68O5Si 详情 详情

合成路线44

该中间体在本合成路线中的序号：(IV)

The intermediate aldehyde (XV) has been obtained as follows: The reaction of dimethyl malonate (I) with 3-(tert-butyldimethylsilyloxy)propyl iodide (II) by means of NaH in THF gives the alkylmalonate (III), which by a new alkylation with allyl bromide (IV) and NaH in DME affords the dialkylmalonate (V). The reduction of (V) with LiBH4 in THF yields the 1,3-propanediol (VI), which is cyclized with 2,2-dimethoxypropane and CSA in dichloromethane giving the 1,3-dioxane (VII). The ozonolysis of the double bond of (VII) with O3 in dichloromethane yields the aldehyde (VIII), which is protected by heating with cyclohexylamine (IX) to afford the imine (X).The condensation of (X) with 8(E)-decenal (XI) by means of LDA in ethyl ether gives the unsaturated aldehyde (XII), which is treated with Pmb-Cl and KH in DME/HMPA to yield the enol ether (XIII). The desilylation of (XIII) with TBAF in THF gives the propanol derivative (XIV), which is oxidized with SO3.Pyr to the corresponding aldehyde (XV).

参考文献 中间体
合成目标
【1】 Nicolaou, K.C.; et al.; Total synthesis of the CP molecules CP-263,114 and CP-225,917 - Part 1: Synthesis of key intermediates and intelligence gathering. Angew Chem. Int Ed Engl 1999, 38, 11, 1669.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(II) 35676 tert-butyl(3-iodopropoxy)dimethylsilane; tert-butyl(dimethyl)silyl 3-iodopropyl ether C9H21IOSi 详情 详情
(III) 35677 dimethyl 2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C14H28O5Si 详情 详情
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 35678 dimethyl 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)malonate C17H32O5Si 详情 详情
(VI) 35679 2-allyl-2-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-1,3-propanediol C15H32O3Si 详情 详情
(VII) 35680 3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propyl tert-butyl(dimethyl)silyl ether; [3-(5-allyl-2,2-dimethyl-1,3-dioxan-5-yl)propoxy](tert-butyl)dimethylsilane C18H36O3Si 详情 详情
(VIII) 35681 2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]acetaldehyde C17H34O4Si 详情 详情
(IX) 17966 cyclohexanamine; cyclohexyl amine; cyclohexylamine 108-91-8 C6H13N 详情 详情
(X) 35682 N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]-N-cyclohexylamine; N-[(E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]ethylidene]cyclohexanamine C23H45NO3Si 详情 详情
(XI) 35683 (E)-8-decenal C10H18O 详情 详情
(XII) 35684 (2Z,10E)-2-[5-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,2-dimethyl-1,3-dioxan-5-yl]-2,10-dodecadienal C27H50O4Si 详情 详情
(XIII) 35685 tert-butyl[3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propoxy]dimethylsilane; tert-butyl(dimethyl)silyl 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propyl ether C35H58O4Si 详情 详情
(XIV) 35686 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)-1-propanol C29H44O4 详情 详情
(XV) 35687 3-(5-[(2E,9E)-1-[(E)-2-(4-methoxyphenyl)ethylidene]-2,9-undecadienyl]-2,2-dimethyl-1,3-dioxan-5-yl)propanal C29H42O4 详情 详情

合成路线45

该中间体在本合成路线中的序号：(IV)

The acylation of (-)-2,10-camphorsultam (II) with octanoyl chloride (I) provides the N-octanoyl sultam (III). Diastereoselective alkylation of the lithium enolate of (III) with allyl bromide (IV) gives rise to the (2S)-2-propenoyloctanoyl sultam (V). Hydrolysis of the N-acyl sultam (V) to furnish acid (VI) is then effected by treatment with hydrogen peroxide-tetrabutylammonium hydroxide. Finally, catalytic hydrogenation of the unsaturated acid (VI) in the presence of either Pd/C or Pt/C yields the required (R)-2-propyloctanoic acid. Alternatively, the title compound is obtained by hydrogenation of the N-acyl sultam (V) to the saturated derivative (VII), followed by hydrolytic removal of the camphorsultam moiety.

参考文献 中间体
合成目标
【1】 Hasegawa, T.; Kawanaka, Y.; Kasamatsu, E.; Iguchi, Y.; Yonekawa, Y.; Okamoto, M.; Ohta, C.; Hashimoto, S.; Ohuchida, S.; Process development of ONO-2506: A therapeutic agent for stroke and Alzheimer's disease. Org Process Res Dev 2003, 7, 2, 168.
【2】 Hasegawa, T.; Yamamoto, H.; A practical synthesis of optically active (R)-2-propyloctanoic acid: Therapeutic agent for Alzheimer's disease. Bull Chem Soc Jpn 2000, 73, 2, 423.
【3】 Hasegawa, T.; Yamamoto, H.; A practical removal method of camphorsultam. Synlett 1998, 8, 882.
【4】 Yamamoto, H. (Ono Pharmaceutical Co., Ltd.); Novel intermediates and processes for the preparation of optically active octanoic acid derivs.. EP 1078921; US 6333415; WO 9958513 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11123 Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride 111-64-8 C8H15ClO 详情 详情
(II) 58242 (1S,5R,7R)-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione C10H17NO2S 详情 详情
(III) 58243 (1S,5R,7R)-10,10-dimethyl-4-octanoyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione C18H31NO3S 详情 详情
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 58244 (1S,5R,7R)-4-[(2S)-2-hexyl-4-pentenoyl]-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione C21H35NO3S 详情 详情
(VI) 58245 (1S,5R,7R)-10,10-dimethyl-4-[(2R)-2-propyloctanoyl]-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione C21H37NO3S 详情 详情
(VII) 58246 (2S)-2-hexyl-4-pentenoic acid C11H20O2 详情 详情

合成路线46

该中间体在本合成路线中的序号：(II)

The alkylation of 4(S)-benzyl-3-nonanoyloxazolidin-2-one (I) with allyl bromide (II) by means of lithium diisopropylamide (LDA), followed by hydrolysis with LiOOH gives the chiral pentenoic acid (III), which is treated with dimethylamine and cyanophosphonic acid diethyl ester yielding the dimethylamide (IV). The iodination of (IV) with I2/dimethoxyethane (DME) with simultaneous cyclization yields 3(R)-heptyl-5(S)-(iodomethyl)tetrahydrofuran-2-one (V). The condensation of (V) with thioacetic acid by means of NaH, followed by a reductive cleavage and tritylation with triphenylmethanol and trifluoroacetic acid (TFA) affords 3(R)-heptyl-5(S)-(tritylsulfanylmethyl)tetrahydrofuran-2-one (VI). The ring opening of (VI) with NaOH, follwed by silylation with tert-butyldimethylsilyl chloride gives 4(S)-(tert-butyldimethyl-silyloxy)-2(R)-heptyl-5-(tritylsulfanyl)pentanoic acid (VII), which is condensed with 2(S)-amino-N,3,3-trimethylbutyramide (VIII) by means of cyanophosphonic acid diethyl ester and desilylated with tetrabutylammonium fluoride to yield 2(S)-[2(R)-heptyl-4-(S)-hydroxy-5-(tritylsulfanyl)pentanamido]-N,3,3-trimethylbutyramide (IX). Finally, this compound is detritylated with trifluoroacetic acid (TFA) to afford the target compound (X).

参考文献 中间体
合成目标
【1】 Levin, J.I.; DiJoseph, J.F.; Killar, L.M.; Sharr, M.A.; Skotnicki, J.S.; Patel, D.V.; Xiao, X.-Y.; Shi, L.; Navre, M.; Campbell, D.A.; The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1998, 8, 10, 1163.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
42235 Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC 2942-58-7 C5H10NO3P 详情 详情
(I) 27010 (4S)-4-benzyl-3-nonanoyl-1,3-oxazolidin-2-one C19H27NO3 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 27011 (2R)-2-hexyl-4-pentenoic acid C11H20O2 详情 详情
(IV) 27012 (2R)-2-hexyl-N,N-dimethyl-4-pentenamide C13H25NO 详情 详情
(V) 27013 (3R,5S)-3-heptyl-5-(iodomethyl)dihydro-2(3H)-furanone C12H21IO2 详情 详情
(VI) 27014 (3R,5S)-3-heptyl-5-[(tritylsulfanyl)methyl]dihydro-2(3H)-furanone C31H36O2S 详情 详情
(VII) 27015 (2R)-2-[(2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-(tritylsulfanyl)propyl]nonanoic acid C37H52O3SSi 详情 详情
(VIII) 18843 (2S)-2-amino-N,3,3-trimethylbutanamide 89226-12-0 C7H16N2O 详情 详情
(IX) 27016 (2R)-2-[(2S)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-(tritylsulfanyl)propyl]-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]nonanamide C44H66N2O3SSi 详情 详情

合成路线47

该中间体在本合成路线中的序号：(II)

The alkylation of 4(S)-benzyl-3-(4-methylpentanoyl)oxazolidin-2-one (I) with allyl bromide (II) by means of lithium diisopro-pylamide (LDA), followed by hydrolysis with LiOOH gives the chiral pentenoic acid (III), which is iodinated with I2, KI, KHCO3 with simultaneous cyclization yielding (R,R)-5-(iodomethyl)-3-isobutyltetrahydrofuran-2-one (IV). The condensation of (IV) with thioacetic acid by means of NaH, followed by a reductive cleavage and tritylation with triphenylmethanol and trifluoroacetic acid gives (R,R)-3-isobutyl-5-(tritylsulfanylmethyl)tetrahydrofuran-2-one (V). The ring opening of (V) with NaOH, follwed by silylation with tert-butyldimethylsilyl chloride gives (R,R)-4-(tert-butyldimethylsilyloxy)-2-isobutyl-5-(tritylsulfanyl)pentanoic acid (VI), which is condensed with 2(S)-amino-N,3,3-trimethylbutyramide (VII) by means of cyanophosphonic acid diethyl ester and desilylated with tetrabutylammonium fluoride to yield 2(S)-[2(R)-isobutyl-4-(R)-hydroxy-5-(triphenylmethylsulfanyl)pen-tanamido]-N,3,3-trimethylbutyramide (VIII). Finally, this compound is detritylated with trifluoroacetic acid (TFA) to afford the target compound.

参考文献 中间体
合成目标
【1】 Levin, J.I.; DiJoseph, J.F.; Killar, L.M.; Sharr, M.A.; Skotnicki, J.S.; Patel, D.V.; Xiao, X.-Y.; Shi, L.; Navre, M.; Campbell, D.A.; The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1998, 8, 10, 1163.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
42235 Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC 2942-58-7 C5H10NO3P 详情 详情
(I) 25391 (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one C16H21NO3 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 26985 (2R)-2-isobutyl-4-pentenoic acid C9H16O2 详情 详情
(IV) 27021 (3R,5R)-5-(iodomethyl)-3-isobutyldihydro-2(3H)-furanone C9H15IO2 详情 详情
(V) 27022 (3R,5R)-3-isobutyl-5-[(tritylsulfanyl)methyl]dihydro-2(3H)-furanone C28H30O2S 详情 详情
(VI) 27023 (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-5-(tritylsulfanyl)pentanoic acid C34H46O3SSi 详情 详情
(VII) 18843 (2S)-2-amino-N,3,3-trimethylbutanamide 89226-12-0 C7H16N2O 详情 详情
(VIII) 27024 (2R,4R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-4-hydroxy-2-isobutyl-5-(tritylsulfanyl)pentanamide C35H46N2O3S 详情 详情

合成路线48

该中间体在本合成路线中的序号：(II)

The alkylation of 4(S)-benzyl-3-(4-methylpentanoyl)oxazolidin-2-one (I) with allyl bromide (II) by means of lithium diisopro-pylamide (LDA), followed by hydrolysis with LiOOH gives the chiral pentenoic acid (III), which is treated with dimethylamine and cyanophosphonic acid diethyl ester yielding the dimethylamide (IV). The iodination of (IV) with I2/dimethoxyethane (DME) with simultaneous cyclization yields 5(S)-(iodomethyl)-3(R)-isobutyltetrahydrofuran-2-one (V). The condensation of (V) with thioacetic acid by means of NaH, followed by a reductive cleavage and tritylation with triphenylmethanol and TFA affords 3(R)-isobutyl-5(S)-(triphenylmethylsulfanylmethyl)tetrahydrofuran-2-one (VI). The ring opening of (VI) with NaOH, follwed by silylation with tert-butyldimethylsilyl chloride gives 4(S)-(tert-butyldimethylsilyloxy)-2(R)-isobutyl-5-(tritylsulfanyl)pentanoic acid (VII), which is condensed with 2(S)-amino-N,3,3-trimethylbutyramide (VIII) by means of cyanophosphonic acid diethyl ester and desilylated with tetrabutylammonium fluoride to yield 2(S)-[2(R)-isobutyl-4-(S)-hydroxy-5-(tritylsulfanyl)pentanamido]-N,3,3-trimethylbutyramide (IX). Finally, this compound is detritylated with trifluoroacetic acid (TFA) to afford the target campound (X).

参考文献 中间体
合成目标
【1】 Levin, J.I.; DiJoseph, J.F.; Killar, L.M.; Sharr, M.A.; Skotnicki, J.S.; Patel, D.V.; Xiao, X.-Y.; Shi, L.; Navre, M.; Campbell, D.A.; The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1998, 8, 10, 1163.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
42235 Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC 2942-58-7 C5H10NO3P 详情 详情
(I) 25391 (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one C16H21NO3 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 26985 (2R)-2-isobutyl-4-pentenoic acid C9H16O2 详情 详情
(IV) 26986 (2R)-2-isobutyl-N,N-dimethyl-4-pentenamide C11H21NO 详情 详情
(V) 26987 (3R,5S)-5-(iodomethyl)-3-isobutyldihydro-2(3H)-furanone C9H15IO2 详情 详情
(VI) 26988 (3R,5S)-3-isobutyl-5-[(tritylsulfanyl)methyl]dihydro-2(3H)-furanone C28H30O2S 详情 详情
(VII) 26989 (2R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-5-(tritylsulfanyl)pentanoic acid C34H46O3SSi 详情 详情
(VIII) 18843 (2S)-2-amino-N,3,3-trimethylbutanamide 89226-12-0 C7H16N2O 详情 详情
(IX) 26990 (2R,4S)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-4-hydroxy-2-isobutyl-5-(tritylsulfanyl)pentanamide C35H46N2O3S 详情 详情

合成路线49

该中间体在本合成路线中的序号：(II)

The alkylation of 4(S)-benzyl-3-nonanoyloxazolidin-2-one (I) with allyl bromide (II) by means of lithium diisopropylamide (LDA), followed by hydrolysis with LiOOH gives the chiral pentenoic acid (III), which is iodinated with I2, KI, KHCO3 with simultaneous cyclization yielding (R,R)-3-heptyl-5-(iodomethyl)tetrahydrofuran-2-one (IV). The condensation of (IV) with thioacetic acid by means of NaH, followed by a reductive cleavage and tritylation with triphenylmethanol and trifluoroacetic acid (TFA) affords (R,R)-3-heptyl-5-(triphenylmethyl-sulfanylmethyl)tetrahydrofuran-2-one (V). The ring opening of (V) with NaOH, follwed by silylation with tert-butyldimethylsilyl chloride gives (R,R)-4-(tert-butyldimethylsilyloxy)-2-heptyl-5-(tritylsulfanyl)pentanoic acid (VI), which is condensed with 2(S)-amino-N,3,3-trimethylbutyramide (VII) by means of cyanophosphonic acid diethyl ester and desilylated with tetrabutylammonium fluoride to yield 2(S)-[2(R)-heptyl-4(R)-hydroxy-5-(tritylsulfanyl)pentanamido]-N,3,3-trimethylbutyramide (VIII). Finally, compound (VIII) is oxidized with TFA, pyridine, DMSO and EDC, and detritylated with TFA to give the target compound.

参考文献 中间体
合成目标
【1】 Levin, J.I.; DiJoseph, J.F.; Killar, L.M.; Sharr, M.A.; Skotnicki, J.S.; Patel, D.V.; Xiao, X.-Y.; Shi, L.; Navre, M.; Campbell, D.A.; The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1998, 8, 10, 1163.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
42235 Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC 2942-58-7 C5H10NO3P 详情 详情
(I) 27010 (4S)-4-benzyl-3-nonanoyl-1,3-oxazolidin-2-one C19H27NO3 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 27011 (2R)-2-hexyl-4-pentenoic acid C11H20O2 详情 详情
(IV) 27017 (3R,5R)-3-heptyl-5-(iodomethyl)dihydro-2(3H)-furanone C12H21IO2 详情 详情
(V) 27018 (3R,5R)-3-heptyl-5-[(tritylsulfanyl)methyl]dihydro-2(3H)-furanone C31H36O2S 详情 详情
(VI) 27019 (2R)-2-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-(tritylsulfanyl)propyl]nonanoic acid C37H52O3SSi 详情 详情
(VII) 18843 (2S)-2-amino-N,3,3-trimethylbutanamide 89226-12-0 C7H16N2O 详情 详情
(VIII) 27020 (2R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-[(2R)-2-hydroxy-3-(tritylsulfanyl)propyl]nonanamide C38H52N2O3S 详情 详情

合成路线50

该中间体在本合成路线中的序号：(II)

The alkylation of 4(S)-benzyl-3-(4-methylpentanoyl)oxazolidin-2-one (I) with allyl bromide (II) by means of lithium diisopro-pylamide (LDA), followed by hydrolysis with LiOOH gives the chiral pentenoic acid (III), which is iodinated with I2, KI, KHCO3 with simultaneous cyclization yielding (R,R)-5-(iodomethyl)-3-isobutyltetrahydrofuran-2-one (IV). The condensation of (IV) with thioacetic acid by means of NaH, followed by a reductive cleavage and tritylation with triphenylmethanol and trifluoroacetic acid gives (R,R)-3-isobutyl-5-(tritylsulfanylmethyl)tetrahydrofuran-2-one (V). The ring opening of (V) with NaOH, follwed by silylation with tert-butyldimethylsilyl chloride gives (R,R)-4-(tert-butyldimethylsilyloxy)-2-isobutyl-5-(tritylsulfanyl)pentanoic acid (VI), which is condensed with 2(S)-amino-N,3,3-trimethylbutyramide (VII) by means of cyanophosphonic acid diethyl ester and desilylated with tetrabutylammonium fluoride to yield 2(S)-[2(R)-isobutyl-4-(R)-hydroxy-5-(triphenylmethylsulfanyl)pen-tanamido]-N,3,3-trimethylbutyramide (VIII). Finally, compound (VIII) is oxidized with TFA, pyridine, DMSO and EDC, and detritylated with TFA to give the target compound.

参考文献 中间体
合成目标
【1】 Levin, J.I.; DiJoseph, J.F.; Killar, L.M.; Sharr, M.A.; Skotnicki, J.S.; Patel, D.V.; Xiao, X.-Y.; Shi, L.; Navre, M.; Campbell, D.A.; The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1998, 8, 10, 1163.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
42235 Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC 2942-58-7 C5H10NO3P 详情 详情
(I) 25391 (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one C16H21NO3 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 26985 (2R)-2-isobutyl-4-pentenoic acid C9H16O2 详情 详情
(IV) 27021 (3R,5R)-5-(iodomethyl)-3-isobutyldihydro-2(3H)-furanone C9H15IO2 详情 详情
(V) 27022 (3R,5R)-3-isobutyl-5-[(tritylsulfanyl)methyl]dihydro-2(3H)-furanone C28H30O2S 详情 详情
(VI) 27023 (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-5-(tritylsulfanyl)pentanoic acid C34H46O3SSi 详情 详情
(VII) 18843 (2S)-2-amino-N,3,3-trimethylbutanamide 89226-12-0 C7H16N2O 详情 详情
(VIII) 27024 (2R,4R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-4-hydroxy-2-isobutyl-5-(tritylsulfanyl)pentanamide C35H46N2O3S 详情 详情

合成路线51

该中间体在本合成路线中的序号：(IX)

Orcinol (I) was acetylated with Ac2O in pyridine to give diacetate (II), which was submitted to a Fries rearrangement in the presence of AlCl3 in chlorobenzene at 90 C to afford acetophenone (III). Subsequent condensation of (III) with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (IV) was effected either in the presence of CdCO3 in boiling toluene or K2CO3 and tributyl benzylammonium chloride in CH2Cl2 at r.t. The resulting (glucopyranosyloxy)acetophenone (V) was condensed with 5-formylbenzofuran (VI) in the presence of KOH to give chalcone (VII). Hydrogenation of (VII) over Pt/C then yielded the (benzofuranyl)propiophenone (VIII). After protection of the 6'-hydroxyl group of (VIII) as the allyl ether (X) with allyl bromide (IX) and K2CO3, the primary alcohol of (X) was acylated with ClCOOMe to furnish carbonate ester (XI). Finally, the O-allyl group of (XI) was cleaved with palladium catalyst and ammonium formate.

参考文献 中间体
合成目标
【1】 Doggrell, S.A.; Castañer, J.; T-1095. Drugs Fut 2001, 26, 8, 750.
【2】 Tsujihara, K.; et al.; Na+-glucose contransporter (SGLT) inhibitors as antidiabetic agents. 4. Synthesis and pharmacological properties of 4'-dehydroxyphlorizin derivatives substituted on the B ring. J Med Chem 1999, 42, 26, 5311.
【3】 Hongu, M.; Matsumoto, M.; Oku, A.; Saito, K.; Tsujihara, K. (Tanabe Seiyaku Co., Ltd.); Propiophenone derivs. and process for preparing the same. EP 0850948; JP 1998237089; US 6048842 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16993 methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate 79-22-1 C2H3ClO2 详情 详情
(I) 27257 5-Methyl-1,3-benzenediol; Orcinol 505-15-4 C7H8O2 详情 详情
(II) 27258 3-(acetoxy)-5-methylphenyl acetate C11H12O4 详情 详情
(III) 27259 1-(2,6-dihydroxy-4-methylphenyl)-1-ethanone C9H10O3 详情 详情
(IV) 27260 (2R,3R,4S,5S,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-bromotetrahydro-2H-pyran-3-yl acetate 572-09-8 C14H19BrO9 详情 详情
(V) 27261 (2R,3R,4S,5R,6S)-6-(2-acetyl-3-hydroxy-5-methylphenoxy)-4,5-bis(acetoxy)-2-[(acetoxy)methyl]tetrahydro-2H-pyran-3-yl acetate C23H28O12 详情 详情
(VI) 27262 1-benzofuran-5-carbaldehyde C9H6O2 详情 详情
(VII) 27263 (E)-3-(1-benzofuran-5-yl)-1-(2-hydroxy-4-methyl-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-2-propen-1-one C24H24O9 详情 详情
(VIII) 27264 3-(1-benzofuran-5-yl)-1-(2-hydroxy-4-methyl-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-1-propanone C24H26O9 详情 详情
(IX) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(X) 27265 1-(2-(allyloxy)-4-methyl-6-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]phenyl)-3-(1-benzofuran-5-yl)-1-propanone C27H30O9 详情 详情
(XI) 27266 ((2R,3S,4S,5R,6S)-6-[3-(allyloxy)-2-[3-(1-benzofuran-5-yl)propanoyl]-5-methylphenoxy]-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl methyl carbonate C29H32O11 详情 详情

合成路线52

该中间体在本合成路线中的序号：

The cyclization of L-serine (I) with pivalaldehyde (II) by means of LDA in THF gives the oxazolidine (III), which is acylated with formic and acetic anhydride yielding the N-formyloxazolidine (IV). The reaction of (IV) with LDA affords the chiral enol (V), which is treated with allyl bromide in THF to give the chiral 4-allyloxazolidine (VI). Cleavage of the oxazolidine ring with acetyl chloride and treatment with benzyl chloroformate yields the protected chiral 2-allylserine (VII), which is oxidized with oxalyl chloride to the corresponding aldehyde (VIII). The Wittig condensation of (VIII) with triphenylphosphoranylideneacetic acid methyl ester (IX) affords the intermediate (X), which is submitted to UV irradiation with an Hanovia medium pressure mercury lamp through a Pyrex filter in benzene containing benzophenone. A mixture of isomeric bicyclic compounds from which the desired compound (XI) is isolated by column chromatography. The hydrogenation of (IX) with H2 over Pd/C in methanol provides the bicyclic aminoester (XII), which is finally hydrolyzed with 6N HCl.

参考文献 中间体
合成目标
【1】 von Diester, S.; et al.; Stereoselektive Alkylierung an C(alpha) von Serin, Glycerinsaure, Threonin und Weinsaure uber heterocyclische Enolate mit exocyclischer Doppelbindung. Helv Chim Acta 1987, 70, 1194-1216.
【2】 Kozikowski, A.P.; et al.; Synthesis and biology of the conformationally restricted ACPD analogue, 2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic acid-I, a potent mGluR agonist. J Med Chem 1998, 41, 10, 1641.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(I) 20915 methyl (2S)-2-amino-3-hydroxypropanoate 5680-80-8 C4H9NO3 详情 详情
(II) 19797 Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal 630-19-3 C5H10O 详情 详情
(III) 36839 methyl (4S)-2-(tert-butyl)-1,3-oxazolidine-4-carboxylate C9H17NO3 详情 详情
(IV) 36840 methyl (4S)-2-(tert-butyl)-3-formyl-1,3-oxazolidine-4-carboxylate C10H17NO4 详情 详情
(V) 36841 lithium [(2R)-2-(tert-butyl)-3-formyl-1,3-oxazolidin-4-ylidene](methoxy)methanolate C10H16LiNO4 详情 详情
(VI) 36842 methyl (2R,4S)-4-allyl-2-(tert-butyl)-3-formyl-1,3-oxazolidine-4-carboxylate C13H21NO4 详情 详情
(VII) 36843 methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-2-(hydroxymethyl)-4-pentenoate C15H19NO5 详情 详情
(VIII) 36844 methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-2-(2-oxoethyl)-4-pentenoate C16H19NO5 详情 详情
(IX) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(X) 36845 dimethyl (E,4S)-4-allyl-4-[[(benzyloxy)carbonyl]amino]-2-pentenedioate C18H21NO6 详情 详情
(XI) 36846 dimethyl (1R,2S,4R,5S)-2-[[(benzyloxy)carbonyl]amino]bicyclo[2.1.1]hexane-2,5-dicarboxylate C18H21NO6 详情 详情
(XII) 36847 dimethyl (1R,2S,4R,5S)-2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylate C10H15NO4 详情 详情

合成路线53

该中间体在本合成路线中的序号：(II)

The alkylation of 2',4''-di-O-(trimethylsilyl)erythromycin A 9-O-(1-isopropoxycyclohexyl)oxime (I) with allyl bromide (II) by means of potassium tert-butoxide in DMSO/THF, followed first by acidification with acetic acid and then by treatment with NaHSO3/HCO2H, gives 6-O-allylerythromycin A (III), which is acylated with acetic anhydride in acetonitrile, yielding the diacetate (IV). Reaction of (IV) with either carbonyldiimidazole (CDI) and LiH or CDI and sodium hexamethyldisilazane (NaHMDS) in THF affords the 12-O-(imidazolylcarbonyl)erythromycin derivative (V), which is cyclized with NH4OH in acetonitrile / THF, giving the cyclic carbamate (VI). Elimination of the cladinose group of (VI) by treatment with HCl in ethanol/water followed by reaction with N-chlorosuccinimide (NCS) and dimethyl sulfide in dichloromethane provides the ketolide (VII), which is condensed with 3-bromoquinoline (VIII) under Heck coupling conditions, palladium acetate, tris(o-tolyl)phosphine and Et3N in acetonitrile, and finally deprotected with MeOH 60-80%.

参考文献 中间体
合成目标
【1】 Ma, Z.; et al.; Novel erythromycin derivatives with aryl groups tethered to the C-6 position are potent protein synthesis inhibitors and active against multidrug-resistant respiratory pathogens. J Med Chem 2001, 44, 24, 4137.
【2】 Or, Y.; Clark, R.F.; Ma, Z.; Design, synthesis, and characterization of ABT-773: A novel ketolide highly active against multidrug-resistant pathogens. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F2133.
【3】 Ewing, P.; Or, Y.S.; Nilius, A.M.; Wang, S.; Clark, R.F.; Alder, J.; Chu, D.T.W.; Mitten, M.; Flamm, R.K.; Ma, Z.; Design, synthesis, and antimicrobial activity of 6-O-substituted ketolides active against resistant respiratory tract pathogens. J Med Chem 2000, 43, 6, 1045-49.
【4】 Rabasseda, X.; Sorbera, L.A.; Castañer, J.; ABT-773. Drugs Fut 2000, 25, 5, 445.
【5】 Adachi, T.; Sekiguchi, K.; Sota, K.; Asaka, T.; Matsunaga, T.; Morimoto, S.; Watanabe, Y.; Kashimura, M. (Taisho Pharmaceutical Co., Ltd.); Erythromycin A derivs.. EP 0272110; US 4990602 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 35291 　 C52H100N2O14Si2 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 28391 (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-12,13-dihydroxy-4-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione C40H71NO13 详情 详情
(IV) 35292 　 C44H75NO15 详情 详情
(V) 35293 　 C48H75N3O15 详情 详情
(VI) 35294 　 C45H74N2O15 详情 详情
(VII) 35295 　 C35H56N2O11 详情 详情
(VIII) 28432 3-bromoquinoline 5332-24-1 C9H6BrN 详情 详情

合成路线54

该中间体在本合成路线中的序号：(XXI)

The intermediate gamma-butyrolactone (XXVIII) has been obtained as follows: Allylation of the imidazolidinone intermediate (V) with allyl bromide (XXI) and LiHMDS in THF gives the chiral intermediate (XXII), which by dihydroxylation and cleavage of the chiral auxiliary with OsO4 and NMMO in tert-butanol/acetone/water yields the lactone alcohol (XXIII). Oxidation of (XXIII) with NaIO4 and RuCl3 in CCl4/acetonitrile/water affords the carboxylic acid (XXIV), which by treatment with (COCl)2 in toluene provides the acyl chloride (XXV). Esterification of (XXV) with benzyl alcohol gives the corresponding benzyl ester as a diastereomeric mixture, from which the desired isomer (XXVI) is separated by flash chromatography. Hydrogenolysis of the benzyl ester (XXVI) with H2 over Pd/C in ethyl acetate yields the carboxylic acid (XXVII), which is treated with oxalyl chloride in toluene to afford the desired gamma-butyrolactone intermediate (XXVIII).

参考文献 中间体
合成目标
【1】 Mealy, N.E.; Castañer, R.M.; Silvestre, J.S.; Castañer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139.
【2】 Rüeger, H.; Maibaum, J.; Stutz, S.; Spindler, F.; Göschke, R.; A convergent synthesis approach towards CGP60536B, a non-peptide orally potent renin inhibitor, via an enantiomerically pure ketolactone intermediate. Tetrahedron Lett 2000, 41, 51, 10085.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 28131 (4S)-4-benzyl-3-(3-methylbutanoyl)-1,3-oxazolidin-2-one C15H19NO3 详情 详情
(XXI) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XXII) 50566 (4S)-4-benzyl-3-[(2S)-2-isopropyl-4-pentenoyl]-1,3-oxazolidin-2-one C18H23NO3 详情 详情
(XXIII) 50567 (3S)-5-(hydroxymethyl)-3-isopropyldihydro-2(3H)-furanone C8H14O3 详情 详情
(XXIV) 50568 (4S)-4-isopropyl-5-oxotetrahydro-2-furancarboxylic acid C8H12O4 详情 详情
(XXV) 50569 (4S)-4-isopropyl-5-oxotetrahydro-2-furancarbonyl chloride C8H11ClO3 详情 详情
(XXVI) 50570 benzyl (2S,4S)-4-isopropyl-5-oxotetrahydro-2-furancarboxylate C15H18O4 详情 详情
(XXVII) 50571 (2S,4S)-4-isopropyl-5-oxotetrahydro-2-furancarboxylic acid C8H12O4 详情 详情
(XXVIII) 50572 (2S,4S)-4-isopropyl-5-oxotetrahydro-2-furancarbonyl chloride C8H11ClO3 详情 详情

合成路线55

该中间体在本合成路线中的序号：(XXI)

The chiral azido intermediate (XXXIV) can also be obtained as follows: Reaction of (+)-pseudoephedrine isovaleramide (XLIII) with allyl bromide (XXI) by means of LDA in THF gives the pentenoyl amide (XLIV), which is treated with NBS in DME/water to yield the spiro compound (XLV). Hydrolysis of the bromomethyl group of (XLV) with tetrabutylammonium acetate and K2CO3 affords the carbinol (XLVI), which is oxidized to aldehyde (XLVII) with SO3/pyridine and TEA in DMSO/dichloromethane. Condensation of (XLVII) with the propyl chloride intermediate (XXX) by means of Mg, dibromoethane and CeCl3 in refluxing THF provides the already reported chiral hydroxylactone (XXXII), which is treated first with 4-bromobenzenesulfonyl chloride and then with NaN3 to give the desired azido derivative (XXXIV).

参考文献 中间体
合成目标
【1】 Mealy, N.E.; Castañer, R.M.; Silvestre, J.S.; Castañer, J.; Aliskiren Fumarate. Drugs Fut 2001, 26, 12, 1139.
【2】 Carey, J.S.; Sandham, D.A.; Taylor, R.J.; Fassler, A.; A convergent synthesis of the renin inhibitor CGP60536B. Tetrahedron Lett 2000, 41, 51, 10091.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXI) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XXX) 50574 4-[(2R)-2-(chloromethyl)-3-methylbutyl]-1-methoxy-2-(3-methoxypropoxy)benzene; 3-[5-[(2R)-2-(chloromethyl)-3-methylbutyl]-2-methoxyphenoxy]propyl methyl ether 324763-39-5 C17H27ClO3 详情 详情
(XXXII) 50576 (3S,5S)-5-[(1R,3S)-1-hydroxy-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-3-isopropyldihydro-2(3H)-furanone C25H40O6 详情 详情
(XXXIV) 50578 (3S,5S)-5-[(1S,3S)-1-azido-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl]-3-isopropyldihydro-2(3H)-furanone C25H39N3O5 详情 详情
(XLIII) 50585 N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N,3-dimethylbutanamide C15H23NO2 详情 详情
(XLIV) 50586 (2S)-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-2-isopropyl-N-methyl-4-pentenamide C18H27NO2 详情 详情
(XLV) 50587 (2S,3S,5R,7S,9S)-7-(bromomethyl)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]nonane C18H26BrNO2 详情 详情
(XLVI) 50588 [(2S,3S,5R,7S,9S)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]non-7-yl]methanol C18H27NO3 详情 详情
(XLVII) 50589 (2S,3S,5R,7S,9S)-9-isopropyl-3,4-dimethyl-2-phenyl-1,6-dioxa-4-azaspiro[4.4]nonane-7-carbaldehyde C18H25NO3 详情 详情

合成路线56

该中间体在本合成路线中的序号：(I)

The hydroboration of allyl bromide (I) with diisopinocampheylborane gives the 3-bromopropylboronic ester (II), which by treatment with acetaldehyde and water yields the boronic acid (III). The reaction of (III) with NaN3 and ethanol affords 3-azidoboronic acid ethyl ester (IV), which is transesterified with optically active pipanediol (V) giving the cyclic ester (VI). The homologation of (VI) with LDA, ZnCl2 and dichloromethane in THF yields the alpha-chlorobutylboronic ester (VII), which is aminated with hexamethyldisylazane (HMDS) and BuLi to provide the silylated alpha-aminoboronic ester (VIII). The desilylation of (VIII) with methanol, and its protection with benzyl chloroformate gives the protected alpha-aminoboronic ester (IX). The hydrogenation of the azido group of (IX) with H2 over PtO2 affords the 4-aminobutylboronic ester (X), which is treated with N,N'-bis(tert-butoxycarbonyl)thiourea (XI), HgCl2 and TEA in DMF to give the guanidine derivative (XII). Finally, this compound is hydrolyzed and deprotected with refluxing 6N HCl.

参考文献 中间体
合成目标
【1】 Lebarbier, C.; Carreaux, F.; Carboni, B.; Boucher, J.L.; Synthesis of boronic acid analogs of L-arginine as alternate substrates or inhibitors of nitric oxide synthase. Bioorg Med Chem Lett 1998, 8, 18, 2573.
【2】 Lebarbier, C.; et al.; Synthesis of a boronic acid analogue of L-ornithine. Synthesis 1996, 1371.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(II) 36654 bis[[(1R,2S,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]methyl] 3-bromopropylboronate C25H44BBrO2 详情 详情
(III) 36655 3-bromopropylboronic acid C3H8BBrO2 详情 详情
(IV) 36656 diethyl 3-azidopropylboronate C7H16BN3O2 详情 详情
(V) 32535 (1R,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol C10H18O2 详情 详情
(VI) 36657 3-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]propyl azide; (1S,2R,6S,8S)-4-(3-azidopropyl)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]decane C13H22BN3O2 详情 详情
(VII) 36658 (4S)-4-chloro-4-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butyl azide; (1S,2R,6S,8S)-4-[(1S)-4-azido-1-chlorobutyl]-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]decane C14H23BClN3O2 详情 详情
(VIII) 36659 N-[(1R)-4-azido-1-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butyl](trimethyl)-N-(trimethylsilyl)silanamine; N-[(1R)-4-azido-1-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butyl]-N,N-bis(trimethylsilyl)amine C20H41BN4O2Si2 详情 详情
(IX) 36660 benzyl (1R)-4-azido-1-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butylcarbamate C22H31BN4O4 详情 详情
(X) 36661 benzyl (1R)-4-amino-1-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butylcarbamate C22H33BN2O4 详情 详情
(XI) 21843 tert-butyl [(tert-butoxycarbonyl)amino]carbothioylcarbamate 145013-05-4 C11H20N2O4S 详情 详情
(XII) 36662 benzyl (1R)-4-([[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl]amino)-1-[(1S,2R,6S,8S)-6,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butylcarbamate C33H51BN4O8 详情 详情

合成路线57

该中间体在本合成路线中的序号：(V)

The sodium salt of L-phenylalanine (I) was condensed with pivalaldehyde (II) in boiling pentane to afford imine (III). Subsequent reaction of (III) with benzyl chloroformate generated oxazolidinone (IV) as a 9:1 mixture of diastereoisomers, which were separated chromatographically. The required cis compound was treated with allyl bromide (V) in the presence of potassium hexamethyldisilazide in THF at -78 C to provide (VI) as the major isomer. Aldehyde (VII) was then obtained by ozonolysis of (VI) at -78 C. Reductive amination of (VII) with L-homophenylalanine methyl ester (VIII) using NaBH3CN yielded the corresponding amine (IX) which, upon heating in toluene in the presence of 1-hydroxybenzotriazole, afforded pyrrolidinone (X). Reduction of the ester function of (X) with Ca(BH4)2 gave alcohol (XI), which was finally oxidized under Swern conditions to the target aldehyde.

参考文献 中间体
合成目标
【1】 Scheidt, K.A.; Roush, W.R.; McKerrow, J.H.; Selzer, P.M.; Hansell, E.; Rosenthal, P.J.; Structure-based design, synthesis and evaluation of conformationally constrained cysteine protease inhibitors. Bioorg Med Chem 1998, 6, 12, 2477.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13952 (S)-(-)-Phenylalanine; L-Phenylalanine 63-91-2 C9H11NO2 详情 详情
(II) 19797 Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal 630-19-3 C5H10O 详情 详情
(III) 24385 sodium (2S)-2-[[(E)-2,2-dimethylpropylidene]amino]-3-phenylpropanoate C14H18NNaO2 详情 详情
(IV) 24386 benzyl (4S)-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate C22H25NO4 详情 详情
(V) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VI) 24388 benzyl (2S,4S)-4-allyl-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate C25H29NO4 详情 详情
(VII) 24389 benzyl (2S,4R)-4-benzyl-2-(tert-butyl)-5-oxo-4-(2-oxoethyl)-1,3-oxazolidine-3-carboxylate C24H27NO5 详情 详情
(VIII) 24390 methyl (2S)-2-amino-4-phenylbutanoate C11H15NO2 详情 详情
(IX) 24391 benzyl (2S,4R)-4-benzyl-2-(tert-butyl)-4-(2-[[(1S)-1-(methoxycarbonyl)-3-phenylpropyl]amino]ethyl)-5-oxo-1,3-oxazolidine-3-carboxylate C35H42N2O6 详情 详情
(X) 24392 methyl (2S)-2-((3R)-3-benzyl-3-[[(benzyloxy)carbonyl]amino]-2-oxopyrrolidinyl)-4-phenylbutanoate C30H32N2O5 详情 详情
(XI) 24393 benzyl (3R)-3-benzyl-1-[(1S)-1-(hydroxymethyl)-3-phenylpropyl]-2-oxopyrrolidinylcarbamate C29H32N2O4 详情 详情

合成路线58

该中间体在本合成路线中的序号：(V)

The sodium salt of L-phenylalanine (I) was condensed with pivalaldehyde (II) in boiling pentane to afford imine (III). Subsequent reaction of (III) with benzyl chloroformate generated oxazolidinone (IV) as a 9:1 mixture of diastereoisomers, which were separated chromatographically. The required cis compound was treated with allyl bromide (V) in the presence of potassium hexamethyldisilazide in THF at -78 C to provide (VI) as the major isomer. Aldehyde (VII) was then obtained by ozonolysis of (VI) at -78 C. Reductive amination of (VII) with L-homophenylalanine methyl ester (VIII) using NaBH3CN yielded the corresponding amine (IX) which, upon heating in toluene in the presence of 1-hydroxybenzotriazole, afforded pyrrolidinone (X). The carbobenzoxy group of (X) was then removed by hydrogenolysis over Pd/C, and the resulting amine was acylated with benzenesulfonyl chloride to produce sulfonamide (XI). Finally, the target aldehyde was obtained by the sequence of ester reduction of (XI) with Ca(BH4)2, followed by Swern oxidation of the resulting alcohol.

参考文献 中间体
合成目标
【1】 Scheidt, K.A.; Roush, W.R.; McKerrow, J.H.; Selzer, P.M.; Hansell, E.; Rosenthal, P.J.; Structure-based design, synthesis and evaluation of conformationally constrained cysteine protease inhibitors. Bioorg Med Chem 1998, 6, 12, 2477.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13952 (S)-(-)-Phenylalanine; L-Phenylalanine 63-91-2 C9H11NO2 详情 详情
(II) 19797 Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal 630-19-3 C5H10O 详情 详情
(III) 24385 sodium (2S)-2-[[(E)-2,2-dimethylpropylidene]amino]-3-phenylpropanoate C14H18NNaO2 详情 详情
(IV) 24386 benzyl (4S)-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate C22H25NO4 详情 详情
(V) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VI) 24388 benzyl (2S,4S)-4-allyl-4-benzyl-2-(tert-butyl)-5-oxo-1,3-oxazolidine-3-carboxylate C25H29NO4 详情 详情
(VII) 24389 benzyl (2S,4R)-4-benzyl-2-(tert-butyl)-5-oxo-4-(2-oxoethyl)-1,3-oxazolidine-3-carboxylate C24H27NO5 详情 详情
(VIII) 24390 methyl (2S)-2-amino-4-phenylbutanoate C11H15NO2 详情 详情
(IX) 24391 benzyl (2S,4R)-4-benzyl-2-(tert-butyl)-4-(2-[[(1S)-1-(methoxycarbonyl)-3-phenylpropyl]amino]ethyl)-5-oxo-1,3-oxazolidine-3-carboxylate C35H42N2O6 详情 详情
(X) 24392 methyl (2S)-2-((3R)-3-benzyl-3-[[(benzyloxy)carbonyl]amino]-2-oxopyrrolidinyl)-4-phenylbutanoate C30H32N2O5 详情 详情
(XI) 24394 methyl (2S)-2-[(3R)-3-benzyl-2-oxo-3-[(phenylsulfonyl)amino]pyrrolidinyl]-4-phenylbutanoate C28H30N2O5S 详情 详情

合成路线59

该中间体在本合成路线中的序号：(II)

The alkylation of the prochiral trans-2,5-dimethylpiperazine (I) with allyl bromide (II) produced a racemic mixture of N-allyl piperazines. After separation of the (+)-isomer by precipitation with (+)-camphoric acid, the desired (-)-piperazine (III) was isolated from the remaining enriched mixture by crystallization as the di-p-toluoyl-D-tartrate salt.

参考文献 中间体
合成目标
【1】 Maw, G.N. (Pfizer Inc.); Anti-inflammatory piperazinyl-benzyl-tetrazole derivs. and intermediates thereof. EP 0983251; JP 2000513024; WO 9852929 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 20687 (2R,5S)-2,5-dimethylpiperazine C6H14N2 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 20690 (2R,5S)-1-allyl-2,5-dimethylpiperazine C9H18N2 详情 详情

合成路线60

该中间体在本合成路线中的序号：(XV)

The reaction of the chiral epoxide (I) with 4-methoxybenzaldehyde (II) by means of NaAl(OMe)3H in THF gives the 1,3-dioxane (III), which is opened by reduction with DIBAL in dichloromethane to yield the chiral benzyl ether (IV). The oxidation of the primary alcohol of (IV) with DMP in dichloromethane affords the corresponding aldehyde (V), which is condensed with the boronate (VI) and S,S-diisopropyl tartrate in toluene to provide the unsaturated alcohol (VII).The protection of (VII) with Tbdps-Cl and imidazole yields the fully protected triol (VIII), which is oxidized at the terminal double bond with 9-BBN in THF to give the primary alcohol (IX). The oxidation of (IX) with DMP in dichloromethane affords the aldehyde (X), which is condensed with methylenetriphenylphosphorane (XI) in THF to provide the terminal olefin (XII). Elimination of the Pmb protecting group of (XII) with DDQ in dichloromethane gives the alcohol (XIII), which is esterified with 2-allyl-6-methoxybenzoic acid (XIV)(obtained by allylation of 2-methoxybenzoic acid (XV) with allyl bromide (XVI), BuLi and MgBr2) by means of DEAD and PPh3 yielding the ester (XVII). The cyclization of (XVII) by means of a metathesis reaction catalyzed by a ruthenium catalyst in refluxing dichloromethane affords the bicyclic lactone (XVIII), which is treated with BBr3 in dichloromethane to provide the dihydroxylated lactone (XIX).

参考文献 中间体
合成目标
【1】 Labrecque, D.; et al.; Enantioselective total synthesis of salicylihalamides A and B. Tetrahedron Lett 2001, 42, 14, 2645.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 47480 [(2R,3R)-3-[3-(benzyloxy)propyl]oxiranyl]methanol C13H18O3 详情 详情
(II) 27251 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde 123-11-5 C8H8O2 详情 详情
(III) 47481 (4R)-4-[3-(benzyloxy)propyl]-2-(4-methoxyphenyl)-1,3-dioxane; benzyl 3-[(4R)-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]propyl ether C21H26O4 详情 详情
(IV) 47482 (3R)-6-(benzyloxy)-3-[(4-methoxybenzyl)oxy]-1-hexanol C21H28O4 详情 详情
(V) 47483 (3R)-6-(benzyloxy)-3-[(4-methoxybenzyl)oxy]hexanal C21H26O4 详情 详情
(VI) 47484 dimethyl (E)-2-butenylboronate C6H13BO2 详情 详情
(VII) 47485 (3S,4R,6R)-9-(benzyloxy)-6-[(4-methoxybenzyl)oxy]-3-methyl-1-nonen-4-ol C25H34O4 详情 详情
(VIII) 47486 [((1R,2S)-1-[(2R)-5-(benzyloxy)-2-[(4-methoxybenzyl)oxy]pentyl]-2-methyl-3-butenyl)oxy](tert-butyl)diphenylsilane; benzyl (4R,6R,7S)-6-[[tert-butyl(diphenyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]-7-methyl-8-nonenyl ether C41H52O4Si 详情 详情
(IX) 47487 (3S,4R,6R)-9-(benzyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-6-[(4-methoxybenzyl)oxy]-3-methyl-1-nonanol C41H54O5Si 详情 详情
(X) 47488 (3S,4R,6R)-9-(benzyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-6-[(4-methoxybenzyl)oxy]-3-methylnonanal C41H52O5Si 详情 详情
(XI) 27301 methylene(triphenyl)phosphorane C19H17P 详情 详情
(XII) 47489 [((1R,2S)-1-[(2R)-5-(benzyloxy)-2-[(4-methoxybenzyl)oxy]pentyl]-2-methyl-4-pentenyl)oxy](tert-butyl)diphenylsilane; benzyl (4R,6R,7S)-6-[[tert-butyl(diphenyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]-7-methyl-9-decenyl ether C42H54O4Si 详情 详情
(XIII) 47490 (4R,6R,7S)-1-(benzyloxy)-6-[[tert-butyl(diphenyl)silyl]oxy]-7-methyl-9-decen-4-ol C34H46O3Si 详情 详情
(XIV) 13926 2-Methoxybenzoic acid; o-Methoxybenzoic Acid 579-75-9 C8H8O3 详情 详情
(XV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XVI) 47491 2-allyl-6-methoxybenzoic acid C11H12O3 详情 详情
(XVII) 47492 (1S,3R,4S)-1-[3-(benzyloxy)propyl]-3-[[tert-butyl(diphenyl)silyl]oxy]-4-methyl-6-heptenyl 2-allyl-6-methoxybenzoate C45H56O5Si 详情 详情
(XVIII) 47493 (3S,5R,6S)-3-[3-(benzyloxy)propyl]-5-[[tert-butyl(diphenyl)silyl]oxy]-14-methoxy-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one C43H52O5Si 详情 详情
(XIX) 47494 (3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-3-(3-hydroxypropyl)-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one C35H44O5Si 详情 详情

合成路线61

该中间体在本合成路线中的序号：(II)

The chiral tetrahydropyran intermediate (XI) has been obtained as follows. The reaction of (-)-pseudoephedrine propionamide (I) with the allyl bromide (II) by the Myers' method gives pentenamide (III), which is reduced with LiNH2BH3 in THF to yield 2(S)-methyl-4-penten-1-ol (IV). Swern oxidation of (IV) affords the corresponding aldehyde (V), which is submitted to an asymmetric aldol condensation with the silyl enol ether (VI) catalyzed by Cu(OTf)2, (S)-Tol-BINAP and (Bu4N)Ph3SiF2 in THF to provide the adduct (VII). The methanolysis of (VII) with Me-OH in refluxing toluene gives the beta-keto ester (VIII), which is treated with Et2BOMe, NaBH4 and HF to yield the chiral hydroxy lactone (IX). The reduction of (IX) with DIBAL in THF affords the lactol (X), which is finally methylated with Ts-OH in refluxing methanol to provide the target tetrahydropyran intermediate (XI).

参考文献 中间体
合成目标
【1】 Bauer, M.; Maier, M.E.; Synthesis of the core structure of salicylihalamide A by intramolecular Suzuki reaction. Org Lett 2002, 4, 13, 2205.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 56935 N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N-methylpropanamide C13H19NO2 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 56936 (2S)-N-[(1R,2R)-2-hydroxy-1-methyl-2-phenylethyl]-N,2-dimethyl-4-pentenamide C16H23NO2 详情 详情
(IV) 56937 (2S)-2-methyl-4-penten-1-ol C6H12O 详情 详情
(V) 26241 (2S)-2-methyl-4-pentenal C6H10O 详情 详情
(VI) 53651 [(2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl)oxy](trimethyl)silane; 2,2-dimethyl-4-methylene-4H-1,3-dioxin-6-yl trimethylsilyl ether n/a C10H18O3Si 详情 详情
(VII) 56938 6-[(2R,3S)-2-hydroxy-3-methyl-5-hexenyl]-2,2-dimethyl-4H-1,3-dioxin-4-one C13H20O4 详情 详情
(VIII) 56939 methyl (5R,6S)-5-hydroxy-6-methyl-3-oxo-8-nonenoate C11H18O4 详情 详情
(IX) 56940 (4S,6R)-4-hydroxy-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-2-one C10H16O3 详情 详情
(X) 56941 (4S,6R)-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-2,4-diol C10H18O3 详情 详情
(XI) 56942 (4S,6R)-2-methoxy-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-4-ol C11H20O3 详情 详情

合成路线62

该中间体在本合成路线中的序号：(XV)

The reaction of the chiral epoxide (I) with 4-methoxybenzaldehyde (II) by means of NaAl(OMe)3H in THF gives the 1,3-dioxane (III), which is opened by reduction with DIBAL in dichloromethane to yield the chiral benzyl ether (IV). The oxidation of the primary alcohol of (IV) with DMP in dichloromethane affords the corresponding aldehyde (V), which is condensed with the boronate (VI) and S,S-diisopropyl tartrate in toluene to provide the unsaturated alcohol (VII).The protection of (VII) with Tbdps-Cl and imidazole yields the fully protected triol (VIII), which is oxidized at the terminal double bond with 9-BBN in THF to give the primary alcohol (IX). The oxidation of (IX) with DMP in dichloromethane affords the aldehyde (X), which is condensed with methylenetriphenylphosphorane (XI) in THF to provide the terminal olefin (XII). Elimination of the Pmb protecting group of (XII) with DDQ in dichloromethane gives the alcohol (XIII), which is esterified with 2-allyl-6-methoxybenzoic acid (XIV)(obtained by allylation of 2-methoxybenzoic acid (XV) with allyl bromide (XVI), BuLi and MgBr2) by means of DEAD and PPh3 yielding the ester (XVII). The cyclization of (XVII) by means of a metathesis reaction catalyzed by a ruthenium catalyst in refluxing dichloromethane affords the bicyclic lactone (XVIII), which is treated with BBr3 in dichloromethane to provide the dihydroxylated lactone (XIX).

参考文献 中间体
合成目标
【1】 Labrecque, D.; et al.; Enantioselective total synthesis of salicylihalamides A and B. Tetrahedron Lett 2001, 42, 14, 2645.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 47480 [(2R,3R)-3-[3-(benzyloxy)propyl]oxiranyl]methanol C13H18O3 详情 详情
(II) 27251 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde 123-11-5 C8H8O2 详情 详情
(III) 47481 (4R)-4-[3-(benzyloxy)propyl]-2-(4-methoxyphenyl)-1,3-dioxane; benzyl 3-[(4R)-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]propyl ether C21H26O4 详情 详情
(IV) 47482 (3R)-6-(benzyloxy)-3-[(4-methoxybenzyl)oxy]-1-hexanol C21H28O4 详情 详情
(V) 47483 (3R)-6-(benzyloxy)-3-[(4-methoxybenzyl)oxy]hexanal C21H26O4 详情 详情
(VI) 47484 dimethyl (E)-2-butenylboronate C6H13BO2 详情 详情
(VII) 47485 (3S,4R,6R)-9-(benzyloxy)-6-[(4-methoxybenzyl)oxy]-3-methyl-1-nonen-4-ol C25H34O4 详情 详情
(VIII) 47486 [((1R,2S)-1-[(2R)-5-(benzyloxy)-2-[(4-methoxybenzyl)oxy]pentyl]-2-methyl-3-butenyl)oxy](tert-butyl)diphenylsilane; benzyl (4R,6R,7S)-6-[[tert-butyl(diphenyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]-7-methyl-8-nonenyl ether C41H52O4Si 详情 详情
(IX) 47487 (3S,4R,6R)-9-(benzyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-6-[(4-methoxybenzyl)oxy]-3-methyl-1-nonanol C41H54O5Si 详情 详情
(X) 47488 (3S,4R,6R)-9-(benzyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-6-[(4-methoxybenzyl)oxy]-3-methylnonanal C41H52O5Si 详情 详情
(XI) 27301 methylene(triphenyl)phosphorane C19H17P 详情 详情
(XII) 47489 [((1R,2S)-1-[(2R)-5-(benzyloxy)-2-[(4-methoxybenzyl)oxy]pentyl]-2-methyl-4-pentenyl)oxy](tert-butyl)diphenylsilane; benzyl (4R,6R,7S)-6-[[tert-butyl(diphenyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]-7-methyl-9-decenyl ether C42H54O4Si 详情 详情
(XIII) 47490 (4R,6R,7S)-1-(benzyloxy)-6-[[tert-butyl(diphenyl)silyl]oxy]-7-methyl-9-decen-4-ol C34H46O3Si 详情 详情
(XIV) 13926 2-Methoxybenzoic acid; o-Methoxybenzoic Acid 579-75-9 C8H8O3 详情 详情
(XV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XVI) 47491 2-allyl-6-methoxybenzoic acid C11H12O3 详情 详情
(XVII) 47492 (1S,3R,4S)-1-[3-(benzyloxy)propyl]-3-[[tert-butyl(diphenyl)silyl]oxy]-4-methyl-6-heptenyl 2-allyl-6-methoxybenzoate C45H56O5Si 详情 详情
(XVIII) 47493 (3S,5R,6S)-3-[3-(benzyloxy)propyl]-5-[[tert-butyl(diphenyl)silyl]oxy]-14-methoxy-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one C43H52O5Si 详情 详情
(XIX) 47494 (3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-3-(3-hydroxypropyl)-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one C35H44O5Si 详情 详情

合成路线63

该中间体在本合成路线中的序号：(II)

The reaction of 2-fluoro-5-(trifluoromethyl)phenol (I) with allyl bromide (II) by means of K2CO3 in DMF gives the phenol ether (III), which is submitted to an allylic rearrangement by heating at 190 C to yield 2-allyl-6-fluoro-3-(trifluoromethyl)phenol (IV). The cyclization of (IV) by means of MCPBA and KOH affords the dihydrobenzofuran (V), which is treated with Ac2O and pyridine to provide the acetate (VI). The dehydrogenation of (VI) by means of NBS and AIBN, followed by a treatment with tBu-OK and K2CO3 in methanol, gives 1-[7-fluoro-4-(trifluoromethyl)benzofuran-2-yl]methanol (VII), which is oxidized with oxalyl chloride and TEA in DMSO to yield the corresponding carbaldehyde (VIII). The condensation of (VIII) with 4-acryloylbenzoic acid methyl ester (IX) by means of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (BHMT) and TEA in DMF affords the 1,4-butanedione derivative (X), which is submitted to a pyrrole synthesis by cyclization with AcONH4 in refluxing ethanol to provide the disubstituted pyrrole (XI). Finally, the ester group of (XI) is hydrolyzed with NaOH in ethanol to furnish the target carboxylic acid.

参考文献 中间体
合成目标
【1】 Yoshimura, H.; et al.; Discovery of novel and potent retinoic acid receptor alpha agonists: Syntheses and evaluation of benzofuranyl-pyrrole and benzothiophenyl-pyrrole derivatives. J Med Chem 2000, 43, 15, 2929.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 50315 2-Fluoro-5-(trifluoromethyl)phenol 141483-15-0 C7H4F4O 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 50316 2-(allyloxy)-1-fluoro-4-(trifluoromethyl)benzene; allyl 2-fluoro-5-(trifluoromethyl)phenyl ether C10H8F4O 详情 详情
(IV) 50317 2-allyl-6-fluoro-3-(trifluoromethyl)phenol C10H8F4O 详情 详情
(V) 50318 [7-fluoro-4-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methanol C10H8F4O2 详情 详情
(VI) 50319 [7-fluoro-4-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl acetate C12H10F4O3 详情 详情
(VII) 50320 [7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]methanol C10H6F4O2 详情 详情
(VIII) 35847 7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-carbaldehyde C10H4F4O2 详情 详情
(IX) 35857 methyl 4-acryloylbenzoate C11H10O3 详情 详情
(X) 35850 methyl 4-[4-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-4-oxobutanoyl]benzoate C21H14F4O5 详情 详情
(XI) 35851 methyl 4-[5-[7-fluoro-4-(trifluoromethyl)-1-benzofuran-2-yl]-1H-pyrrol-2-yl]benzoate C21H13F4NO3 详情 详情

合成路线64

该中间体在本合成路线中的序号：(XII)

The intermediate phenyl sulfone (XXIII) has been obtained as follows. The reaction of tetrahydropyranyl glycidol (I) with isopropenyl bromide (X) by means of CuCN in THF gives the secondary alcohol (XI), which is treated with allyl bromide (XII) and KH in THF to yield the allyl ether (XIII). A ring closing metathesis reaction with (XIII) catalyzed by a Ru catalyst yields the protected dihydropyran derivative (XIV), which is treated with CSA in methanol to afford the carbinol (XV). The oxidation of (XV) with (COCl)2 and DMSO in dichloromethane provides the carbaldehyde (XVI), which is treated with CBr4 and PPh3 in dichloromethane to give the dibromovinyl derivative (XVII). The condensation of (XVII) with the intermediate aldehyde (VI) by means of BuLi in THF yields the propargyl alcohol derivative (XVIII), which is oxidized with DMP to the corresponding acetylenic ketone (XIX). Alternatively, acetylenic ketone (XIX) can also be obtained by condensation of dibromovinyl derivative (XVII) with the intermediate Weinreb amide (IX) by means of BuLi in THF. The enantioselective reduction of ketone (XIX) with L-Selectride in THF affords the chiral propargyl alcohol (XX), which is reduced with Red-Al and treated with TFA to provide the trans-allylic alcohol (XXI). The reaction of the diol (XXI) with Pmp-CH(OEt)2 and CSA gives the acetal (XXII), which is finally reduced with DIBAL in dichloromethane to yield the intermediate Pmb-protected phenyl sulfone (XXIII).

参考文献 中间体
合成目标
【1】 Ghosh, A.K.; Wang, Y.; Kim, J.T.; Total synthesis of microtubule-stabilizing agent (-)-laulimalide. J Org Chem 2001, 66, 26, 8973.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 63105 2-[(2R)oxiranyloxy]tetrahydro-2H-pyran; (2R)oxiranyl tetrahydro-2H-pyran-2-yl ether C7H12O3 详情 详情
(VI) 63109 (2S)-2-[(4-methoxybenzyl)oxy]-4-(phenylsulfonyl)butanal C18H20O5S 详情 详情
(IX) 63111 (2S)-N-methoxy-2-[(4-methoxybenzyl)oxy]-N-methyl-4-(phenylsulfonyl)butanamide C20H25NO6S 详情 详情
(X) 42375 2-bromo-1-propene；2-bromopropene;Isopropenyl bromide;a-Methylvinyl bromide 557-93-7 C3H5Br 详情 详情
(XI) 63112 (2S)-4-methyl-1-(tetrahydro-2H-pyran-2-yloxy)-4-penten-2-ol C11H20O3 详情 详情
(XII) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XIII) 63113 allyl (1S)-3-methyl-1-[(tetrahydro-2H-pyran-2-yloxy)methyl]-3-butenyl ether; 2-{[(2S)-2-(allyloxy)-4-methyl-4-pentenyl]oxy}tetrahydro-2H-pyran C14H24O3 详情 详情
(XIV) 63114 2-{[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]methoxy}tetrahydro-2H-pyran; [(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]methyl tetrahydro-2H-pyran-2-yl ether C12H20O3 详情 详情
(XV) 61173 [(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]methanol C7H12O2 详情 详情
(XVI) 61148 (2S)-4-methyl-3,6-dihydro-2H-pyran-2-carbaldehyde C7H10O2 详情 详情
(XVII) 63115 (2S)-2-(2,2-dibromovinyl)-4-methyl-3,6-dihydro-2H-pyran C8H10Br2O 详情 详情
(XVIII) 63116 (4S)-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-6-(phenylsulfonyl)-1-hexyn-3-ol C26H30O6S 详情 详情
(XIX) 63117 (4S)-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-6-(phenylsulfonyl)-1-hexyn-3-one C26H28O6S 详情 详情
(XX) 63118 (3S,4S)-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-6-(phenylsulfonyl)-1-hexyn-3-ol C26H30O6S 详情 详情
(XXI) 63119 (E,3S,4S)-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-6-(phenylsulfonyl)-1-hexene-3,4-diol C18H24O5S 详情 详情
(XXII) 63120 2-((4S,5S)-2-(4-methoxyphenyl)-5-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-1,3-dioxolan-4-yl)ethyl phenyl sulfone; (2S)-2-((E)-2-{(4S,5S)-2-(4-methoxyphenyl)-5-[2-(phenylsulfonyl)ethyl]-1,3-dioxolan-4-yl}ethenyl)-4-methyl-3,6-dihydro-2H-pyran C26H30O6S 详情 详情
(XXIII) 63121 (3S,4S,5E)-4-[(4-methoxybenzyl)oxy]-6-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-1-(phenylsulfonyl)-5-hexen-3-ol C26H32O6S 详情 详情

合成路线65

该中间体在本合成路线中的序号：(XXIX)

Synthesis of the target Laulimalide. The condensation of the tin derivative (XXVI) with the chiral isopropenyl boron derivative (XXVII) gives the secondary alcohol (XXVIII), which is alkylated with allyl bromide (XXIX) and KHMDS to yield the allyl ether (XXX). The ring closing metathesis reaction in (XXX) by means of Schrock catalyst affords the dihydropyranyl stannane (XXXI), which is treated with N-iodosuccinimide to provide the iodovinyl compound (XXXII). The reaction of (XXXII) with BuLi and MgBr2 gives the vinylmagnesium derivative (XXXIII), which is condensed with the unsaturated aldehyde intermediate (XXV) to yield the olefinic alcohol (XXXIV). The reaction of (XXXIV) with Tbdms-Cl and imidazole affords the silyl ether (XXXV), which is selectively deprotected with formic acid, and oxidated with DMP to provide the chiral unsaturated aldehyde (XXXVI).

参考文献 中间体
合成目标
【1】 Nelson, S.G.; Cheung, W.S.; Kassick, A.J.; Hilfiker, M.A.; A de novo enantioselective total synthesis of (-)-laulimalide. J Am Chem Soc 2002, 124, 46, 13654.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXV) 63887 (2S,4E)-2-[(4-methoxybenzyl)oxy]-6-(trityloxy)-4-hexenal C33H32O4 详情 详情
(XXVI) 63888 (E)-3-(tributylstannyl)-2-propenal C15H30OSn 详情 详情
(XXVII) 63889 　 C5H11B 详情 详情
(XXVIII) 63890 (1E)-5-methyl-1-(tributylstannyl)-1,5-hexadien-3-ol C19H38OSn 详情 详情
(XXIX) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XXX) 63891 [(1E)-3-(allyloxy)-5-methyl-1,5-hexadienyl](tributyl)stannane; allyl 3-methyl-1-[(E)-2-(tributylstannyl)ethenyl]-3-butenyl ether C22H42OSn 详情 详情
(XXXI) 63894 tributyl{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}stannane C20H38OSn 详情 详情
(XXXII) 63893 (2S)-2-[(E)-2-iodoethenyl]-4-methyl-3,6-dihydro-2H-pyran C8H11IO 详情 详情
(XXXIII) 63892 bromo{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}magnesium C8H11BrMgO 详情 详情
(XXXIV) 63895 (1E,3S,4S,6E)-4-[(4-methoxybenzyl)oxy]-1-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-8-(trityloxy)-1,6-octadien-3-ol C41H44O5 详情 详情
(XXXV) 63896 tert-butyl(dimethyl)silyl (1S,2S,4E)-2-[(4-methoxybenzyl)oxy]-1-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-6-(trityloxy)-4-hexenyl ether; tert-butyl{[(1S,2S,4E)-2-[(4-methoxybenzyl)oxy]-1-{(E)-2-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]ethenyl}-6-(trityloxy)-4-hexenyl]oxy}dimethylsilane C47H58O5Si 详情 详情
(XXXVI) 63897 (2E,5S,6S,7E)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-2,7-octadienal C28H42O5Si 详情 详情

合成路线66

该中间体在本合成路线中的序号：(A)

The condensation of 6-acetyl-7-hydroxy-1,2,3,4-tetrahydronaphthalene (I) with allyl bromide (A) by means of K2CO3 in DMF gives 6-acetyl-7-allyloxy-1,2,3,4-tetrahydronaphthalene (II), which is isomerized to 5-allyl-7-acetyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene (III) by heating at 200 C. Hydrogenation of (III) with H2 over Pd/C in ethanol affords 5-propyl-7-acetyl-6-hydroxy-1,2,3,4-tetrahydronaphthalene (IV), which is then cyclized with diethyl oxalate (B) by means of sodium ethoxide in refluxing etha-nol to yield ethyl 10-propyl-4-oxo-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carboxylate (V) [an alternative way to prepare (V) is the cyclization of (III) with diethyl oxalate (B) by means of sodium ethoxide to give ethyl 10-allyl-4-oxo-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carboxylate (VI), which is then reduced to (V) with H2 over Pd/C in ethanol]. The nitration of (V) with nitric acid in sulfuric acid gives ethyl 10-propyl-4-oxo-5-nitro-6,7,8,9-tetrahydro-4H-naphtho[2,3-b]pyran-2-carboxylate (VII), which is reduced with H2 over Pd/C in ethanol-acetic acid to afford the corresponding amino derivative (VIII). Finally, this compound is diazotated with NaNO2 and H2SO4 and then treated with 50% H2SO4 at 120 C.

参考文献 中间体
合成目标
【1】 Brown, R.C.; et al.; DE 2553688 .
【2】 BE 0836121 .
【3】 Castañer, J.; Blancafort, P.; Hillier, K.; Serradell, M.N.; Proxicromil. Drugs Fut 1979, 4, 12, 889.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(B) 17571 Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate 95-92-1 C6H10O4 详情 详情
(I) 39625 1-(3-hydroxy-5,6,7,8-tetrahydro-2-naphthalenyl)-1-ethanone C12H14O2 详情 详情
(II) 39626 1-[3-(allyloxy)-5,6,7,8-tetrahydro-2-naphthalenyl]-1-ethanone C15H18O2 详情 详情
(III) 39627 1-(4-allyl-3-hydroxy-5,6,7,8-tetrahydro-2-naphthalenyl)-1-ethanone C15H18O2 详情 详情
(IV) 39628 1-(3-hydroxy-4-propyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-ethanone C15H20O2 详情 详情
(V) 39629 ethyl 4-oxo-10-propyl-6,7,8,9-tetrahydro-4H-benzo[g]chromene-2-carboxylate C19H22O4 详情 详情
(VI) 39630 ethyl 10-allyl-4-oxo-6,7,8,9-tetrahydro-4H-benzo[g]chromene-2-carboxylate C19H20O4 详情 详情
(VII) 39631 ethyl 5-nitro-4-oxo-10-propyl-6,7,8,9-tetrahydro-4H-benzo[g]chromene-2-carboxylate C19H21NO6 详情 详情
(VIII) 39632 ethyl 5-amino-4-oxo-10-propyl-6,7,8,9-tetrahydro-4H-benzo[g]chromene-2-carboxylate C19H23NO4 详情 详情

合成路线67

该中间体在本合成路线中的序号：

This compound has been obtained by three related ways: 1.- The Grignard condensation of ethyl cyclohexanecarboxylate (I) with benzylmagnesium bromide (II) in THF gives 1-cyclohexyl-2-phenylethanone (III), which is condensed with bromoacetaldehyde diethyl acetal (IV) by means of potassium tert-butoxide in DMSO to yield 4-cyclohexyl-4-oxo-3-phenylbutyraldehyde diethylacetal (V). The methylation of (V) by means of methyl iodide and potassium tert-butoxide in the same solvent affords 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde diethylacetal (VI), which is treated with HCl in acetone to give the corresponding aldehyde (VII). The reductocondensation of (VII) with 1-(2-methoxyphenyl)piperazine (VIII) by means of sodium triacetoxyborohydride in dichloromethane/acetic acid yields 1-cyclohexyl-4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-methyl-2-phenyl-1-butanone (X) as a racemic mixture, which is resolved by chiral chromatography over a Chiralpak AD column. 2.- The Grignard condensation of 2-phenylpropionaldehyde (XI) with cyclohexylmagnesium chloride (XII) in ethyl ether/THF gives 1-cyclohexyl-2-phenyl-1-propanol (XIII), which is oxidized with DMSO and P2O5 in dichloromethane yielding the corresponding ketone (XIV). The condensation of (XIV) with allyl bromide by means of potassium tert-butoxide in THF affords 1-cyclohexyl-2-methyl-2-phenyl-4-penten-1-one (XV), which is ozonolyzed with O3 in methanol catalyzed by a small amount of Sudan III affording the previously reported aldehyde (VII). 3.- The condensation of aldehyde (VII) with 1-(2-methoxyphenyl)piperazine (VIII) can also be performed in isopropyl acetate giving 1-cyclohexyl-4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-methyl-2-phenyl-3-buten-1-one (IX), which is hydrogenated with H2 over Pd/C in isopropanol to afford the previously reported racemic mixture (X).

参考文献 中间体
合成目标
【1】 Xu, Y.C.; et al.; Synthesis and pharmacology of LY426965: A potent, selective orally active, and long-lasting 5-HT1A receptor antagonist. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 107.
【2】 Kohlman, D.T.; O'Toole, J.C.; Godfrey, A.G.; Xu, Y.-C.; Zhang, T.Y. (Eli Lilly and Company); Arylpiperazines having activity at the serotonin 1A receptor. EP 0924205; WO 9931077 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(I) 31858 ethyl cyclohexanecarboxylate 3289-28-9 C9H16O2 详情 详情
(II) 28308 benzyl(bromo)magnesium; benzylmagnesium bromide 1589-82-8 C7H7BrMg 详情 详情
(III) 31859 1-cyclohexyl-2-phenyl-1-ethanone C14H18O 详情 详情
(IV) 12113 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal 2032-35-1 C6H13BrO2 详情 详情
(V) 31860 1-cyclohexyl-4,4-diethoxy-2-phenyl-1-butanone C20H30O3 详情 详情
(VI) 31861 1-cyclohexyl-4,4-diethoxy-2-methyl-2-phenyl-1-butanone C21H32O3 详情 详情
(VII) 31862 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutanal C17H22O2 详情 详情
(VIII) 11882 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine 35386-24-4 C11H16N2O 详情 详情
(IX) 31863 (E)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-2-methyl-2-phenyl-3-buten-1-one C28H36N2O2 详情 详情
(X) 31864 1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-2-methyl-2-phenyl-1-butanone C28H38N2O2 详情 详情
(XI) 31865 hydratropaldehyde 93-53-8 C9H10O 详情 详情
(XII) 31866 chloro(cyclohexyl)magnesium C6H11ClMg 详情 详情
(XIII) 31867 1-cyclohexyl-2-phenyl-1-propanol C15H22O 详情 详情
(XIV) 31868 1-cyclohexyl-2-phenyl-1-propanone C15H20O 详情 详情
(XV) 31869 1-cyclohexyl-2-methyl-2-phenyl-4-penten-1-one C18H24O 详情 详情

合成路线68

该中间体在本合成路线中的序号：(VII)

Commercially available Corey aldehyde benzoate (I) was oxidized to carboxylic acid (II) by Jones reagent at 0 C. Subsequent chlorination of (II) with SOCl2 afforded acid chloride (III). The crude acid chloride (III) was condensed with 3-hydroxy-4-methylthiazole-2-thione (IV) to yield the thiohydroxamate ester (V). Decarboxylation of (V) by means of tris(phenylthio)antimony in a flask open to air furnished alcohol (VI). Alkylation of alcohol (VI) with allyl bromide (VII) afforded allyl ether (VIII), which by epoxidation using m-chloroperbenzoic acid provided the epoxide (IX). Regiospecific epoxide opening with the Grignard reagent (X) gave alcohol (XI) as a diastereomeric mixture. The hydroxyl groups of (XI) were then protected as the bis-tetrahydropyranyl ether (XII) using dihydropyran and p-toluenesulfonic acid. Lactone reduction with DIBAL in toluene at -78 C gave the lactol (XIII).

参考文献 中间体
合成目标
【1】 Feng, Z.; et al.; Design and synthesis of 13-oxa prostaglandin analogs as antiglaucoma agents. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 236.
【2】 Feng, Z.; Hellberg, M.R. (Alcon Laboratories, Inc.); 13-Oxa prostaglandins for the treatment of glaucoma and ocular hypertension. US 6232344; WO 9932441 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 35585 (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate 39746-01-5 C15H14O5 详情 详情
(II) 50695 (3aR,4R,5R,6aS)-5-(benzoyloxy)-2-oxohexahydro-2H-cyclopenta[b]furan-4-carboxylic acid C15H14O6 详情 详情
(III) 50696 (3aR,4R,5R,6aS)-4-(chlorocarbonyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C15H13ClO5 详情 详情
(IV) 50697 3-Hydroxy-4-methyl-2(3H)thiazolethione; N-Hydroxy-4-methyl-2-thiazolethione; 2-Mercapto-4-methylthiazole 3-oxide 49762-08-5 C4H5NOS2 详情 详情
(V) 50698 (3aR,4R,5R,6aS)-4-([[4-methyl-2-thioxo-1,3-thiazol-3(2H)-yl]oxy]carbonyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C19H17NO6S2 详情 详情
(VI) 50699 (3aR,4R,5R,6aS)-4-hydroxy-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C14H14O5 详情 详情
(VII) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VIII) 50700 (3aR,4R,5R,6aS)-4-(allyloxy)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C17H18O5 详情 详情
(IX) 50701 (3aR,4R,5R,6aS)-4-(2-oxiranylmethoxy)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate C17H18O6 详情 详情
(X) 50702 bromo[3-(trifluoromethyl)benzyl]magnesium C8H6BrF3Mg 详情 详情
(XI) 50703 (3aR,4R,5R,6aS)-5-hydroxy-4-[2-hydroxy-4-[3-(trifluoromethyl)phenyl]butoxy]hexahydro-2H-cyclopenta[b]furan-2-one C18H21F3O5 详情 详情
(XII) 50704 (3aR,4R,5R,6aS)-5-(tetrahydro-2H-pyran-2-yloxy)-4-[2-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenyl]butoxy]hexahydro-2H-cyclopenta[b]furan-2-one C28H37F3O7 详情 详情
(XIII) 50705 (3aR,4R,5R,6aS)-5-(tetrahydro-2H-pyran-2-yloxy)-4-[2-(tetrahydro-2H-pyran-2-yloxy)-4-[3-(trifluoromethyl)phenyl]butoxy]hexahydro-2H-cyclopenta[b]furan-2-ol C28H39F3O7 详情 详情

合成路线69

该中间体在本合成路线中的序号：(II)

The title compound was prepared by two related ways from 3-iodo-8-methoxy-4-(2-methylphenyl)aminoquinoline (I). Alkylationof (I) with allyl bromide (II) and NaH afforded the N-allyl amine (III). Subsequent intramolecular palladium-catalyzed Heck reaction in (III) produced the title pyrroloquinoline. In an alternative procedure, the intermolecular palladium-catalyzed heteroannulation of (I) with 1-trimethylsilylpropyne (IV) gave the silyl pyrroloquinoline (V), which was finally desilylated by means of trifluoroacetic acid.

参考文献 中间体
合成目标
【1】 Yum, E.K.; et al.; Synthesis and pharmacological profile of 1-aryl-3-substituted pyrrolo[3,2-c]quinolones. Bioorg Med Chem Lett 1999, 9, 19, 2819.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 34558 3-iodo-8-methoxy-N-(2-methylphenyl)-4-quinolinamine; N-(3-iodo-8-methoxy-4-quinolinyl)-N-(2-methylphenyl)amine C17H15IN2O 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 34559 N-allyl-3-iodo-8-methoxy-N-(2-methylphenyl)-4-quinolinamine; N-allyl-N-(3-iodo-8-methoxy-4-quinolinyl)-N-(2-methylphenyl)amine C20H19IN2O 详情 详情
(IV) 34560 trimethyl(1-propynyl)silane 6224-91-5 C6H12Si 详情 详情

合成路线70

该中间体在本合成路线中的序号：(VI)

Condensation of 4-methylpentanoyl chloride (I) with (S)-4-benzyl-2-oxazolidinone using n-BuLi afforded the N-acyloxazolidinone (III). Asymmetric alkylation of (III) with tert-butyl bromoacetate and LDA gave (IV), and subsequent removal of the chiral auxiliary by hydrolysis with lithium peroxide yielded (R)-2-isobutylsuccinic acid mono tert-butyl ester (V). This was further alkylated with allyl bromide (VI) and LDA to provide the (R,R)-2,3-disubstituted succinate (VII). Epimerization of (VII) to the required (2R,3S)-isomer (VIII) was accomplished by treatment with LDA and Et2AlCl. Benzyl ester (IX) was then prepared by reaction of (VIII) with benzyl bromide and DBU. Hydroboration of the olefinic double bond of (IX) by means of 9-borabicyclononane, followed by oxidative treatment with H2O2 gave rise to the primary alcohol (X). This was converted to carbonate (XI) upon reaction with p-nitrophenyl chloroformate and N-methylmorpholine (NMM). Coupling of (XI) with lysine derivative (XII) then yielded carbamate (XIII).

参考文献 中间体
合成目标
【1】 Xue, C.-B.; Cherney, R.J.; DeCicco, C.P.; Degrado, W.F.; He, X.; Hodge, C.N.; Jacobson, I.C.; Magolda, R.L.; Arner, E.C.; Duan, J.; Nelson, D.J. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0863885; JP 2000502050; WO 9718207 .
【2】 Nelson, D.; Magolda, R.L.; Jacobson, I.C.; He, X.; Arner, E.; Cherney, R.J.; Duan, J.; Xue, C.-B.; Decicco, C.P.; Degrado, W.F. (DuPont Pharmaceuticals Co.); Novel macrocyclic cpds. as metalloprotease inhibitors. EP 0981521; WO 9851665 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(I) 25390 4-methylpentanoyl chloride 38136-29-7 C6H11ClO 详情 详情
(II) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(III) 25391 (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one C16H21NO3 详情 详情
(IV) 25392 tert-butyl (3R)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-5-methylhexanoate C22H31NO5 详情 详情
(V) 25393 (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid C12H22O4 详情 详情
(VI) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VII) 35082 (2R,3R)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid C15H26O4 详情 详情
(VIII) 35083 (2R,3S)-3-(tert-butoxycarbonyl)-2-isobutyl-5-hexenoic acid C15H26O4 详情 详情
(IX) 35084 4-benzyl 1-(tert-butyl) (2S,3R)-2-allyl-3-isobutylbutanedioate C22H32O4 详情 详情
(X) 35085 4-benzyl 1-(tert-butyl) (2S,3R)-2-(3-hydroxypropyl)-3-isobutylbutanedioate C22H34O5 详情 详情
(XI) 35086 1-benzyl 4-(tert-butyl) (2R,3S)-2-isobutyl-3-(3-[[(4-nitrophenoxy)carbonyl]oxy]propyl)butanedioate C29H37NO9 详情 详情
(XII) 35087 methyl (2S)-6-amino-2-[[(benzyloxy)carbonyl]amino]hexanoate C15H22N2O4 详情 详情
(XIII) 35088 17-benzyl 16-(tert-butyl) 5-methyl (5S,16S,17R)-19-methyl-3,11-dioxo-1-phenyl-2,12-dioxa-4,10-diazaicosane-5,16,17-tricarboxylate C38H54N2O10 详情 详情

合成路线71

该中间体在本合成路线中的序号：(I)

The preparation of the intermediate aminoboronate (VII) is shown in Scheme 27968701a. Addition of catecholborane (II) to allyl bromide (I) provided boronic ester (III). Subsequent exchange with (+)-alpha-pinanediol (IV) afforded the chiral borane (V). Insertion of dichloromethyllithium in (V) produced the alpha-chloroboronic ester (VI). The required amino compound was then obtained by displacement of the halogen with lithium hexamethyldisilazide, followed by acid-catalyzed desilylation.

参考文献 中间体
合成目标
【1】 Verbeuren, T.; Rupin, A.; De Nanteuil, G.; Gloanec, P.; New dicarbonyl cycloalkyl based thrombin inhibitors with improved activity and selectivity compared to (D)-Phe-Pro-boroArg derivatives . 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 201.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(II) 32533 1,3,2-benzodioxaborole 274-07-7 C6H5BO2 详情 详情
(III) 35558 2-(3-bromopropyl)-1,3,2-benzodioxaborole C9H10BBrO2 详情 详情
(IV) 32535 (1R,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol C10H18O2 详情 详情
(V) 35559 (1R,2S,6R,8R)-4-(3-bromopropyl)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]decane C13H22BBrO2 详情 详情
(VI) 35560 (1R,2S,6R,8R)-4-[(1S)-4-bromo-1-chlorobutyl]-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]decane C14H23BBrClO2 详情 详情
(VII) 35561 (1R)-4-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]-1-butanamine; (1R)-4-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]butylamine C14H25BBrNO2 详情 详情

合成路线72

该中间体在本合成路线中的序号：(XIII)

The dihydroxylation of 2-[3-(tert-butyldimethylsilyloxy)-1-propenyl]furan (I) with OsO4 and NMO gives the racemic diol (II), which is oxidized with MCPBA to yield the dhydropyranone (III). The cyclization of (III) by means of Ts-OH affords the racemic bicyclic enone (IV), which is reduced with NaBH4 to the racemic alcohol (V). The reaction of (V) with Ac2O and pyridine provides the racemic acetate (VI), which is treated with Lipase PS and vinyl acetate, furnishing a mixture of unreacted chiral acetate (-)-(VI) and the chiral alcohol (+)-(VII), which are easily separated. The reduction of (-)-(VII) with H2 over PtO2 gives the bicyclic alcohol (VIII), which is treated with Ms-Cl and TEA to yield the mesylate (IX). The reaction of (IX) with sodium azide in THF affords the azido derivative (X), which is reduced with LiAlH4 in THF to provide the bicyclic amine (XI). The protection of (XI) with benzyl chloroformate gives the carbamate (XII), which is alkylated with allyl bromide (XIII) and NaH in DMF to yield the N-allyl carbamate (XIV). The desilylation of (XIV) with TBAF, followed by a treatment with Ms-Cl and TEA, affords the mesylate (XV). The reaction of (XV) with LiI, and then reaction of the intermediate iodide with Zn/HOAc, provides the hemiacetal (XVI), which is further reduced with NaBH4 in ethanol to give the dihydroxydiene (XVII). The ring-closing metathesis reaction of (XVII) by means of Grubbs' catalyst yields the tetrahydropyridine (XVIII), which is reduced with H2 over PtO2 to afford the chiral dihydroxy piperidine (XIX). The reaction of (XIX) with diphenyl disulfide and tributyl phosphine provides the thioether (XX), which is treated with benzyl bromide and NaH to give the piperidin benzyl ether (XXI).

参考文献 中间体
合成目标
【1】 Taniguchi, T.; et al.; Lipase-mediated preparation of sugar building blocks. Synthesis 1999, 8, 1325.
【2】 Taniguchi, T.; Ofasawara, K.; A diastereocontrolled synthesis of (+)-febrifugine: A potent antimalarial piperidine alkaloid. Org Lett 2000, 2, 20, 3193.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(rac)-(VI) 51249 (rac)-7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-6,8-dioxabicyclo[3.2.1]oct-3-en-2-yl acetate C15H26O5Si 详情 详情
(-)-(VI) 51263 (-)-7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-6,8-dioxabicyclo[3.2.1]oct-3-en-2-yl acetate C15H26O5Si 详情 详情
(+)(VII) 65206 (+)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6,8-dioxabicyclo[3.2.1]oct-3-en-2-ol C13H24O4Si 详情 详情
(I) 51244 tert-butyl(dimethyl)silyl (E)-3-(2-furyl)-2-propenyl ether; tert-butyl[[(E)-3-(2-furyl)-2-propenyl]oxy]dimethylsilane C13H22O2Si 详情 详情
(II) 51245 (1S,2R)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-(2-furyl)-1,2-propanediol C13H24O4Si 详情 详情
(III) 51246 (2S)-2-((1R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxyethyl)-6-hydroxy-2H-pyran-3(6H)-one C13H24O5Si 详情 详情
(IV) 51247 7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-6,8-dioxabicyclo[3.2.1]oct-3-en-2-one C13H22O4Si 详情 详情
(V) 51248 (rac)-7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-6,8-dioxabicyclo[3.2.1]oct-3-en-2-ol C13H24O4Si 详情 详情
(VIII) 51250 7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-6,8-dioxabicyclo[3.2.1]octan-2-ol C13H26O4Si 详情 详情
(IX) 51251 7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-6,8-dioxabicyclo[3.2.1]oct-2-yl methanesulfonate C14H28O6SSi 详情 详情
(X) 51252 [[(2S)-2-azido-6,8-dioxabicyclo[3.2.1]oct-7-yl]methoxy](tert-butyl)dimethylsilane; [(2S)-2-azido-6,8-dioxabicyclo[3.2.1]oct-7-yl]methyl tert-butyl(dimethyl)silyl ether C13H25N3O3Si 详情 详情
(XI) 51253 (2S)-7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-6,8-dioxabicyclo[3.2.1]oct-2-ylamine; (2S)-7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-6,8-dioxabicyclo[3.2.1]octan-2-amine C13H27NO3Si 详情 详情
(XII) 51254 benzyl (2S)-7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-6,8-dioxabicyclo[3.2.1]oct-2-ylcarbamate C21H33NO5Si 详情 详情
(XIII) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XIV) 51255 benzyl allyl[(2S)-7-([[tert-butyl(dimethyl)silyl]oxy]methyl)-6,8-dioxabicyclo[3.2.1]oct-2-yl]carbamate C24H37NO5Si 详情 详情
(XV) 51256 ((2S)-2-[allyl[(benzyloxy)carbonyl]amino]-6,8-dioxabicyclo[3.2.1]oct-7-yl)methyl methanesulfonate C19H25NO7S 详情 详情
(XVI) 51257 benzyl allyl[(2S,3R)-6-hydroxy-2-vinyltetrahydro-2H-pyran-3-yl]carbamate C18H23NO4 详情 详情
(XVII) 51258 benzyl allyl[(1R,2S)-2-hydroxy-1-(3-hydroxypropyl)-3-butenyl]carbamate C18H25NO4 详情 详情
(XVIII) 51259 benzyl (2R,3S)-3-hydroxy-2-(3-hydroxypropyl)-3,6-dihydro-1(2H)-pyridinecarboxylate C16H21NO4 详情 详情
(XIX) 51260 benzyl (2R,3S)-3-hydroxy-2-(3-hydroxypropyl)-1-piperidinecarboxylate C16H23NO4 详情 详情
(XX) 51261 benzyl (2R,3S)-3-hydroxy-2-[3-(phenylsulfanyl)propyl]-1-piperidinecarboxylate C22H27NO3S 详情 详情
(XXI) 51262 benzyl (2R,3S)-3-(benzyloxy)-2-[3-(phenylsulfanyl)propyl]-1-piperidinecarboxylate C29H33NO3S 详情 详情

合成路线73

该中间体在本合成路线中的序号：(III)

Intermediate (VII) is first synthesized by following one of two different routes: 1. Esterification of vanillic acid (I) by treatment with refluxing H2SO4/MeOH affords ester (II), which is then O-alkylated with NaH and allyl bromide (III) in THF to provide allyloxy derivative (IV). Nitration of (IV) by treatment either with SnCl4/HNO3 in dichloromethane or simply with HNO3 yields nitro derivative (V), which is finally hydrolyzed with aqueous NaOH in THF. 2. Alternatively, acid (I) is directly alkylated with NaH and allyl bromide (III) in THF, affording allyloxy derivative (VI), which is then nitrated by means of HNO3 and SnCl4 in dichloromethane to provide (VII). Once intermediate (VII) is obtained, the synthesis of the target product can be accomplished as follows: Coupling of carboxylic acid (VII) with diethyl thioacetal derivative (VIII) by means of DCC in dichloromethane gives nitro thioacetal (IX), whose nitro group is then reduced with SnCl2 in refluxing MeOH to provide amino thioacetal (X). Protection of the amino group of (X) with Fmoc-Cl and Na2CO3 in dioxane yields derivative (XI), which is then subjected to ring closure by treatment with HgCl2 and CaCO3 in acetonitrile to afford the tricyclic compound (XII). Epoxidation of the allyloxy group of (XII) with m-chloroperbenzoic acid (m-CPBA) in dichloromethane furnishes epoxide (XIII), whose Fmoc group is finally removed by treatment with tetrabutylammonium fluoride (TBAF) in DMF.

参考文献 中间体
合成目标
【2】 Wilson, S.C.; et al.; Design and synthesis of a novel epoxide-containing pyrrolo[2,1-c][1,4]benzodiazepine (PBD) via a new cyclization procedure. Tetrahedron Lett 1995, 36, 35, 6333.
【1】 Adams, L.J.; Thurston, D.E.; Jenkins, T.C.; Wilson, S.C.; Hartley, J.A.; Howard, P.W.; Kelland, L.R.; Forrow, S.M.; Design and synthesis and evaluation of a novel sequence-selective epoxide-containing DNA cross-linking agent based on the pyrrolo[2,1-c][1,4]benzodiazepine system. J Med Chem 1999, 42, 20, 4028.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17786 4-hydroxy-3-methoxybenzoic acid; Vanillic acid 121-34-6 C8H8O4 详情 详情
(II) 29176 methyl 4-hydroxy-3-methoxybenzoate 3943-74-6 C9H10O4 详情 详情
(III) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(IV) 47620 methyl 4-(allyloxy)-3-methoxybenzoate C12H14O4 详情 详情
(V) 47621 methyl 4-(allyloxy)-5-methoxy-2-nitrobenzoate C12H13NO6 详情 详情
(VI) 47622 4-(allyloxy)-3-methoxybenzoic acid C11H12O4 详情 详情
(VII) 47623 4-(allyloxy)-5-methoxy-2-nitrobenzoic acid C11H11NO6 详情 详情
(VIII) 47624 (2S)-2-[bis(propylsulfanyl)methyl]pyrrolidine; propyl (propylsulfanyl)[(2S)pyrrolidinyl]methyl sulfide C11H23NS2 详情 详情
(IX) 47625 [4-(allyloxy)-5-methoxy-2-nitrophenyl][(2S)-2-[bis(propylsulfanyl)methyl]pyrrolidinyl]methanone C22H32N2O5S2 详情 详情
(X) 47626 [4-(allyloxy)-2-amino-5-methoxyphenyl][(2S)-2-[bis(propylsulfanyl)methyl]pyrrolidinyl]methanone C22H34N2O3S2 详情 详情
(XI) 47627 9H-fluoren-9-ylmethyl 5-(allyloxy)-2-([(2S)-2-[bis(propylsulfanyl)methyl]pyrrolidinyl]carbonyl)-4-methoxyphenylcarbamate C37H44N2O5S2 详情 详情
(XII) 47628 9H-fluoren-9-ylmethyl (11aS)-8-(allyloxy)-11-hydroxy-7-methoxy-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate C31H30N2O6 详情 详情
(XIII) 47629 9H-fluoren-9-ylmethyl (11aS)-11-hydroxy-7-methoxy-8-(2-oxiranylmethoxy)-5-oxo-2,3,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-10(5H)-carboxylate C31H30N2O7 详情 详情

合成路线74

该中间体在本合成路线中的序号：(XII)

The reductocondensation of 3-methyl-4-oxopiperidine-1-carboxylic acid methyl ester (I) with aniline (II) by means of TsOH and NaBH4 in refluxing toluene gives 3-methyl-4-(phenylamino)piperidine-1-carboxylic acid methyl ester (III), which is acylated with propionyl anhydride yielding the corresponding propionamide as a mixture of cis and trans isomers, from which the racemic cis isomer (rac)-(IV) is isolated by crystallization. The optical resolution of (rac)-(IV) with d-tartaric acid followed by treatment with NaOH affords (3S.4R)-3-methyl-4-(phenylamino)piperidine (3S,4R)-(V), which is methylated with methyl iodide and K2CO3 to provide (3S,4R)-1,3-dimethyl-4-(phenylamino)piperidine (VI) (1). The condensation of (VI) with the 4-fluorobenzoate (VII) by means of BuLi in THF furnishes the corresponding tertiary amine (VIII), which is transesterified with NaOMe and hydrolyzed with ethanol/water to give the free benzoic acid (IX). The condensation of (IX) with diethylamine by means of BOP and TEA yields the corresponding diethylamide (X), which is demethylated by acylation with phenyl chloroformate and cleavage with KOH to afford the free piperidine NH compound (XI). Finally this piperidine derivative is allylated with allyl bromide (XII) and K2CO3 in ethanol.

参考文献 中间体
合成目标
【1】 Niemegeers, C.J.E.; Van Bever, W.F.M.; Janssen, P.A.J.; Synthetic analgesics. Synthesis and pharmacology of the diastereoisomers of N-[3-methyl-1-(2-phenylethyl)-4-piperidyl]-N-phenylpropanamide and N-[3-methyl-1-(1-methyl-2-phenylethyl)-4-piperidyl]-N-phenylpropanamide. J Med Chem 1974, 17, 10, 1047-1051.
【2】 Carroll, F.I.; Thomas, J.B.; Dersch, C.M.; Rothman, R.B.; Mascarella, S.W.; Burges, J.P.; Xu, H.; Herault, X.M.; Horel, R.B.; (±)-4-[(N-Allyl-cis-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide displays selective binding for the delta opioid receptor. Bioorg Med Chem Lett 1999, 9, 20, 3053.
【3】 Carroll, F.I.; Horel, R.B.; Rothman, R.B.; Mascarella, S.W.; Dersch, C.M.; Atkinson, R.N.; Xu, H.; Herault, X.M.; Thomas, J.B.; Optically pure (-)-4-[(N-allyl-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide displays selective binding and full agonist activity for the delta opioid receptor. Bioorg Med Chem Lett 1999, 9, 23, 3347.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 41454 methyl 3-methyl-4-oxo-1-piperidinecarboxylate C8H13NO3 详情 详情
(II) 12294 Aniline; Phenylamine 62-53-3 C6H7N 详情 详情
(III) 41455 methyl 4-anilino-3-methyl-1-piperidinecarboxylate C14H20N2O2 详情 详情
(IV) 41456 methyl (3S,4R)-3-methyl-4-(propionylanilino)-1-piperidinecarboxylate C17H24N2O3 详情 详情
(V) 41457 N-[(3S,4R)-3-methylpiperidinyl]-N-phenylamine; (3S,4R)-3-methyl-N-phenyl-4-piperidinamine C12H18N2 详情 详情
(VI) 41459 N-[(3S,4R)-1,3-dimethylpiperidinyl]-N-phenylamine; (3S,4R)-1,3-dimethyl-N-phenyl-4-piperidinamine C13H20N2 详情 详情
(VII) 41458 2,6-di(tert-butyl)-4-methoxyphenyl 4-fluorobenzoate C22H27FO3 详情 详情
(VIII) 41460 2,6-di(tert-butyl)-4-methoxyphenyl 4-[[(3S,4R)-1,3-dimethylpiperidinyl]anilino]benzoate C35H46N2O3 详情 详情
(IX) 41461 4-[[(3S,4R)-1,3-dimethylpiperidinyl]anilino]benzoic acid C20H24N2O2 详情 详情
(X) 41462 4-[[(3S,4R)-1,3-dimethylpiperidinyl]anilino]-N,N-diethylbenzamide C24H33N3O 详情 详情
(XI) 41463 N,N-diethyl-4-[[(3S,4R)-3-methylpiperidinyl]anilino]benzamide C23H31N3O 详情 详情
(XII) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情

合成路线75

该中间体在本合成路线中的序号：

(S)-2-Hydroxyisovaleric acid (IX) was obtained from L-valine (VIII) by diazotization in the presence of sulfuric acid. After protection as the allyl ester (X), coupling with isostatine derivative (VII) using DCC and DMAP afforded (XI). Then, removal of the allyl group of (XI) by means of Pd(PPh3)4 gave acid (XIII), which was activated as the pentafluorophenyl ester (XIII).

参考文献 中间体
合成目标
【1】 Liang, B.; et al.; The first total synthesis of (-)-tamadarin A. Org Lett 1999, 1, 8, 1319.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VII) 37827 (3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoic acid C25H43NO5Si 详情 详情
(VIII) 37828 L-2-Amino-3-methylbutyric acid; L-2-Aminoisovaleric acid; 2-Aminoisovaleric acid; L-2-Amino-3-methylbutyric acid; L-alpha-Aminoisovaleric acid; L-valine; (S)-(+)-Valine; (S)-alpha-Aminoisovaleric acid 72-18-4 C5H11NO2 详情 详情
(IX) 37829 (2S)-2-hydroxy-3-methylbutyric acid C5H10O3 详情 详情
(X) 37830 allyl (2S)-2-hydroxy-3-methylbutanoate C8H14O3 详情 详情
(XI) 37831 (1S)-1-[(allyloxy)carbonyl]-2-methylpropyl (3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoate C33H55NO7Si 详情 详情
(XII) 37832 (2S)-2-([(3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoyl]oxy)-3-methylbutyric acid C30H51NO7Si 详情 详情
(XIII) 37833 (1S)-2-methyl-1-[(2,3,4,5,6-pentafluorophenoxy)carbonyl]propyl (3S,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]heptanoate C36H50F5NO7Si 详情 详情

合成路线76

该中间体在本合成路线中的序号：(XI)

The synthesis of the carboxylic acid intermediate (VIII) has been performed as follows: The reaction of D-valine (I) with benzyl chloroformate and NaHCO3 gives the protected valine (II), which is esterified with pentafluorophenol and EDAC to yield the activated ester (III). The condensation of (III) with the lithium enolate of methyl acetate (IV) affords the beta ketoester (V), which is stereoselectively reduced with KBH4 and crystallized to afford the desired enantiomeric beta hydroxyester (VI). The silylation of (VI) with Tips-OTf and lutidine provides the silyl ether (VII), which is hydrolyzed with NaOH to give the desired carboxylic acid intermediate (VIII). The synthesis of the activated ester intermediate (XV) has been performed as follows: The reaction of L-valine (IX) with NaNO2 and H2SO4 gives the hydroxyacid (X), which is esterified with allyl bromide (XI) and K2CO3 to yield the allyl ester (XII). The condensation of (XII) with the intermediate (VIII) by means of EDAC and DMAP affords the adduct (XIII), which is treated with Pd(PPh3)4 to provide the carboxylic acid (XIV). Finally, this compound is esterified with C6F5-OTf to give the activated ester intermediate (XV).

参考文献 中间体
合成目标
【1】 Liang, B.; et al.; Total syntheses and biological investigations of tamandarins A and B and tamandarin A analogs. J Am Chem Soc 2001, 123, 19, 4469.
【2】 Joullie, M.M.; et al.; Total synthesis of (-)-tamandarin B. Tetrahedron Lett 2000, 41, 49, 9373.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 21056 (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid 640-68-6 C5H11NO2 详情 详情
(II) 49332 (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid C13H17NO4 详情 详情
(III) 49323 2,3,4,5,6-pentafluorophenyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate C19H16F5NO4 详情 详情
(IV) 49324 　 C3H5LiO2 详情 详情
(V) 49325 methyl (4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-oxohexanoate C16H21NO5 详情 详情
(VI) 49326 methyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-methylhexanoate C16H23NO5 详情 详情
(VII) 49327 methyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoate C25H43NO5Si 详情 详情
(VIII) 49328 (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoic acid C24H41NO5Si 详情 详情
(IX) 37828 L-2-Amino-3-methylbutyric acid; L-2-Aminoisovaleric acid; 2-Aminoisovaleric acid; L-2-Amino-3-methylbutyric acid; L-alpha-Aminoisovaleric acid; L-valine; (S)-(+)-Valine; (S)-alpha-Aminoisovaleric acid 72-18-4 C5H11NO2 详情 详情
(X) 37829 (2S)-2-hydroxy-3-methylbutyric acid C5H10O3 详情 详情
(XI) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XII) 37830 allyl (2S)-2-hydroxy-3-methylbutanoate C8H14O3 详情 详情
(XIII) 49329 (1S)-1-[(allyloxy)carbonyl]-2-methylpropyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoate C32H53NO7Si 详情 详情
(XIV) 49330 (2S)-2-([(3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoyl]oxy)-3-methylbutyric acid C29H49NO7Si 详情 详情
(XV) 49331 (1S)-2-methyl-1-[(2,3,4,5,6-pentafluorophenoxy)carbonyl]propyl (3S,4R)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-[(triisopropylsilyl)oxy]hexanoate C35H48F5NO7Si 详情 详情

合成路线77

该中间体在本合成路线中的序号：(V)

Condensation of 4-fluorophenylacetyl chloride (I) with ethylene in the presence of AlCl3 provided the beta-tetralone (II). After conversion of (III) into enamine (IV) upon reaction with pyrrolidine (III) in MeOH, alkylation with allyl bromide (V) afforded iminium salt (VI). Acid hydrolysis of (VI) generated the allyl tetralone (VII), which was subjected to reductive amination with ammonium acetate and sodium cyanoborohydride to produce the cis-1-allyl-2-aminotetralin (VIII) as the major isomer. Coupling of (VIII) with carboxylic acid (IX) using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) gave amide (X), which was finally reduced to the target aminotetralin derivative with LiAlH4.

参考文献 中间体
合成目标
【1】 Lovenberg, T.W.; McNally, J.J.; Youngman, M.A.; et al.; alpha-Substituted N-(sulfonamido)alkyl-beta-aminotetralins: Potent and selective neuropeptide Y Y5 receptor antagonists. J Med Chem 2000, 43, 3, 346.
【2】 Reitz, A.B.; Lovenberg, T.W.; Dax, S.L.; Youngman, M.A.; McNally, J.J. (Ortho-McNeil Pharmaceutical, Inc.); N-Substd. aminotetralins as ligands for the neuropeptide Y Y5 receptor useful in the treatment of obesity and other disorders. WO 9955667 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 37014 2-(4-fluorophenyl)acetyl chloride 459-04-1 C8H6ClFO 详情 详情
(II) 37015 6-fluoro-3,4-dihydro-2(1H)-naphthalenone C10H9FO 详情 详情
(III) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(IV) 37016 1-(6-fluoro-3,4-dihydro-2-naphthalenyl)pyrrolidine C14H16FN 详情 详情
(V) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VI) 37017 1-[1-allyl-6-fluoro-3,4-dihydro-2(1H)-naphthalenylidene]pyrrolidinium bromide C17H21BrFN 详情 详情
(VII) 37018 1-allyl-6-fluoro-3,4-dihydro-2(1H)-naphthalenone C13H13FO 详情 详情
(VIII) 37019 (1S,2R)-1-allyl-6-fluoro-1,2,3,4-tetrahydro-2-naphthalenamine; (1S,2R)-1-allyl-6-fluoro-1,2,3,4-tetrahydro-2-naphthalenylamine C13H16FN 详情 详情
(IX) 37020 4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxylic acid C14H19NO4S 详情 详情
(X) 37021 N-[(1S,2R)-1-allyl-6-fluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-4-[[(phenylsulfonyl)amino]methyl]cyclohexanecarboxamide C27H33FN2O3S 详情 详情

合成路线78

该中间体在本合成路线中的序号：(II)

Alkylation of 3-chlorophenylacetic acid (I) with allyl bromide (II) using lithium hexamethyldisilazide provided racemic (III), which was resolved by recrystallization of the corresponding diastereoisomeric salts with (S)-alpha-methylbenzylamine. The desired (S)-carboxylic acid (IV) was converted to acid chloride and then treated with methylamine yielding amide (V). Reduction of (V) with LiAlH4 gave amine (VI), which was acylated with benzenesulfonyl chloride to afford sulfonamide (VII). A two-step oxidation of the allyl group of (VII) with osmium tetroxide and N-methylmorpholine N-oxide, followed by sodium periodate cleavage of the resulting diol produced aldehyde (VIII). Reductive condensation of (VIII) with spiro piperidine (IX) using NaBH(OAc)3 furnished adduct (X). Final oxidation of the sulfide group of (X) with one equivalent of Oxone(r) afforded the title sulfoxide.

参考文献 中间体
合成目标
【1】 Meurer, L.C.; Oates, B.; Finke, P.E.; et al.; Discovery of potent human CCR5 antagonists for the treatment of HIV-1 infection. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 118.
【2】 Mills, S.G.; MacCoss, M.; Springer, M.S. (Merck & Co., Inc.); Spiro-substd. azacycles as modulators of chemokine receptor activity. US 5962462; WO 9825605 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 39705 2-(3-chlorophenyl)acetic acid; 3-chlorophenylacetic acid 1878-65-5 C8H7ClO2 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 39706 2-(3-chlorophenyl)-4-pentenoic acid C11H11ClO2 详情 详情
(IV) 39707 (2S)-2-(3-chlorophenyl)-4-pentenoic acid C11H11ClO2 详情 详情
(V) 39708 (2S)-2-(3-chlorophenyl)-N-methyl-4-pentenamide C12H14ClNO 详情 详情
(VI) 39709 N-[(2S)-2-(3-chlorophenyl)-4-pentenyl]-N-methylamine; (2S)-2-(3-chlorophenyl)-N-methyl-4-penten-1-amine C12H16ClN 详情 详情
(VII) 39710 N-[(2S)-2-(3-chlorophenyl)-4-pentenyl]-N-methylbenzenesulfonamide C18H20ClNO2S 详情 详情
(VIII) 39711 N-[(2S)-2-(3-chlorophenyl)-4-oxobutyl]-N-methylbenzenesulfonamide C17H18ClNO3S 详情 详情
(IX) 39712 　 C12H15NS 详情 详情
(X) 39713 　 C29H33ClN2O2S2 详情 详情

合成路线79

该中间体在本合成路线中的序号：(V)

Treatment of 4-phenoxyphenol (I) with N,N-dimethylthiocarbamoyl chloride afforded the O-aryl thiocarbamate (II), which was thermally rearranged to the S-aryl thiocarbamate (III). Basic hydrolysis of (III) provided 4-phenoxythiophenol (IV). Subsequent alkylation of (IV) with allyl bromide (V) led to the allyl thioether (VI). Further oxidation of (VI) with m-chloroperbenzoic acid (MCPBA) gave rise to the epoxisulfone (VII). This was finally converted to the target thiirane derivative upon treatment with ammonium thiocyanate.

参考文献 中间体
合成目标
【1】 Kotra, L.P.; Brown, S.; Bernardo, M.M.; Tanaka, Y.; Li, Z.-H.; Fridman, R.; Mobashery, S.; Potent and selective mechanism-based inhibition of gelatinases. J Am Chem Soc 2000, 122, 28, 6799.
【2】 Mobashery, S.; Fridman, R. (Wayne State University); Inhibitors of matrix metalloproteinases. WO 0192244 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 27080 4-Phenoxyphenol 831-82-3 C12H10O2 详情 详情
(II) 27081 O-(4-phenoxyphenyl) dimethylcarbamothioate C15H15NO2S 详情 详情
(III) 46031 S-(4-phenoxyphenyl) dimethylcarbamothioate C15H15NO2S 详情 详情
(IV) 26254 4-phenoxybenzenethiol; 4-phenoxyphenylhydrosulfide C12H10OS 详情 详情
(V) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VI) 46032 1-(allylsulfanyl)-4-phenoxybenzene; 4-(allylsulfanyl)phenyl phenyl ether C15H14OS 详情 详情
(VII) 46033 2-[[(4-phenoxyphenyl)sulfonyl]methyl]oxirane; 2-oxiranylmethyl 4-phenoxyphenyl sulfone C15H14O4S 详情 详情

合成路线80

该中间体在本合成路线中的序号：(VIII)

Alkylation of phenylacetic acid (VII) with allyl bromide (VIII) using lithium bis(trimethylsilyl)amide furnished 2-phenyl-4-pentenoic acid (IX). Reduction of the carboxylate group of (IX) by means of LiAlH4 and AlCl3 gave rise to alcohol (X), which was subsequently converted to triflate (XI). The triflate group of (XI) was then displaced with benzimidazole (XII) to produce adduct (XIII). Dihydroxylation of the double bond of (XIII) with N-methylmorpholine-N-oxide in the presence of OsO4, followed by oxidative cleavage with NaIO4, yielded aldehyde (XIV). Finally, aldehyde (XIV) was reductively condensed with piperidine (VI) in the presence of sodium triacetoxyborohydride.

参考文献 中间体
合成目标
【1】 Kim, D.; Wang, L.; Caldwell, C.G.; et al.; Design, synthesis, and SAR of heterocycle-containing human CCR5 antagonists for the treatment of HIV-1 infection. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 84.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 43905 4-nitrobenzyl allyl(4-piperidinyl)carbamate C16H21N3O4 详情 详情
(VII) 16148 Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid 103-82-2 C8H8O2 详情 详情
(VIII) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(IX) 44294 2-phenyl-4-pentenoic acid C11H12O2 详情 详情
(X) 44295 2-phenyl-4-penten-1-ol C11H14O 详情 详情
(XI) 44296 2-phenyl-4-pentenyl trifluoromethanesulfonate C12H13F3O3S 详情 详情
(XII) 44297 1H-benzimidazole 51-17-2 C7H6N2 详情 详情
(XIII) 44298 1-(2-phenyl-4-pentenyl)-1H-benzimidazole C18H18N2 详情 详情
(XIV) 44299 4-(1H-benzimidazol-1-yl)-3-phenylbutanal C17H16N2O 详情 详情

合成路线81

该中间体在本合成路线中的序号：(II)

Isovanillin (I) was protected as the allyl ether (III) by treatment with allyl bromide (II) and K2CO3. Aldehyde reduction of (III) with NaBH4 gave alcohol (IV), which was converted to chloride (V) using SOCl2. Condensation of chloride (V) with the sodium salt of 3,4,5-trimethoxyphenol (VI) produced the corresponding ether (VII). Finally, deprotection of the allyl group of (VII) was achieved by treatment with Wilkinson’s catalyst and DABCO.

参考文献 中间体
合成目标
【1】 McGown, A.T.; Hadfield, J.A.; Rennison, D.; Woo, M.; Lawrence, N.J.; Antimitotic and cell growth inhibitory properties of combrestastatin A-4-like ethers. Bioorg Med Chem Lett 2001, 11, 1, 51.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 18455 3-hydroxy-4-methoxybenzaldehyde; Isovanillin 621-59-0 C8H8O3 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 48348 3-Allyloxy-4-methoxybenzaldehyde C11H12O3 详情 详情
(IV) 48349 [3-(allyloxy)-4-methoxyphenyl]methanol C11H14O3 详情 详情
(V) 48350 allyl 5-(chloromethyl)-2-methoxyphenyl ether; 2-(allyloxy)-4-(chloromethyl)-1-methoxybenzene C11H13ClO2 详情 详情
(VI) 37163 3,4,5-trimethoxyphenol C9H12O4 详情 详情
(VII) 48351 allyl 2-methoxy-5-[(3,4,5-trimethoxyphenoxy)methyl]phenyl ether; 5-[[3-(allyloxy)-4-methoxybenzyl]oxy]-1,2,3-trimethoxybenzene C20H24O6 详情 详情

合成路线82

该中间体在本合成路线中的序号：

Swern oxidation of derivative (I) by means of oxalyl chloride and DMSO in CH2Cl2 followed by Wittig reaction with MePPh3Br and BuLi in THF yields alkene (II), which is then converted into alcohol (III) by hydroboration with 9-BBN in EtOH and oxidation with NaOH and H2O2 in THF followed by isomer separation. Benzylation of (III) by means of NaH and BnBr (IV) in DMF, followed by hydrolysis with acetyl chloride (V) in CH2Cl2/MeOH, affords derivative (VI), which is further benzylated with BnBr (IV) and NaH in DMF and then hydrolyzed with HCl in MeOH to provide diol (VII). Derivative (VII) is O-stannylated by means of Bu2SnO in refluxing toluene and selectively allylated with allyl bromide and CsF to furnish compound (VIII), which is then benzylated with BnBr (IV) and NaH in DMF to give completely protected derivative (IX). Removal of the allyl group of (IX) is then performed by catalytic treatment with RhCl(PPh3)3 and DABCO in refluxing EtOH, and subsequent hydrolysis with HCl in refluxing acetone yields inositol derivative (X). Conversion of (X) into protected phosphatidylinositol (XII) is then performed by a standard phosphitylation protocol with BnOP(N-i-Pr2)2 and diisopropylamine-tetrazole, followed by treatment with the imidazolyl derivative (XI) in the presence of tetrazole and final adjustment of the oxidation state of the P atom by means of tert-BuOOH. Finally, hydrogenolysis of the benzyl groups of compound (XII) with Pd(OH)2/C in tert-butanol gives the desired phosphate.

参考文献 中间体
合成目标
【1】 Hu, Y.; et al.; 3-(Hydroxymethyl)-bearing phosphatidylinositol ether lipid analogues and carbonate surrogates block PI3-K, Akt, and cancer cell growth. J Med Chem 2000, 43, 16, 3045.
【2】 Meuillet, E.J.; Kozikowski, A.P.; Hu, Y.; Berggren, M.; Powis, G.; 3-Deoxy-3-substituted-D-myo-inositol imidazolyl ether lipid phosphates and carbonate as inhibitors of the phosphatidylinositol 3-kinase pathway and cancer cell growth. Bioorg Med Chem Lett 2001, 11, 2, 173.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(I) 48135 (3aR,4aR,7aR,8aS)-8-(benzyloxy)-2,2,6,6-tetramethylhexahydro[1,3]dioxolo[4,5-f][1,3]benzodioxol-4-ol C19H26O6 详情 详情
(II) 48136 (3aR,4aS,7aR,8aR)-4-(benzyloxy)-2,2,6,6-tetramethyl-8-methylenehexahydro[1,3]dioxolo[4,5-f][1,3]benzodioxole; (3aR,4aS,7aR,8aR)-2,2,6,6-tetramethyl-8-methylenehexahydro[1,3]dioxolo[4,5-f][1,3]benzodioxol-4-yl benzyl ether C20H26O5 详情 详情
(III) 48137 [(3aR,4aR,7aR,8aS)-8-(benzyloxy)-2,2,6,6-tetramethylhexahydro[1,3]dioxolo[4,5-f][1,3]benzodioxol-4-yl]methanol C20H28O6 详情 详情
(IV) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(V) 19273 acetyl chloride 75-36-5 C2H3ClO 详情 详情
(VI) 48138 (3aS,4R,5S,6R,7S,7aR)-4-(benzyloxy)-7-[(benzyloxy)methyl]-2,2-dimethylhexahydro-1,3-benzodioxole-5,6-diol C24H30O6 详情 详情
(VII) 48139 (1R,2R,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]-1,2-cyclohexanediol C35H38O6 详情 详情
(VIII) 48140 (1R,2R,3S,4S,5R,6R)-2-(allyloxy)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]cyclohexanol C38H42O6 详情 详情
(IX) 48141 1-[([(1S,2R,3R,4R,5R,6S)-2-(allyloxy)-3,5,6-tris(benzyloxy)-4-[(benzyloxy)methyl]cyclohexyl]oxy)methyl]benzene; allyl (1R,2S,3S,4R,5R,6R)-2,3,4,6-tetrakis(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl ether C45H48O6 详情 详情
(X) 48142 (1R,2S,3S,4R,5R,6R)-2,3,4,6-tetrakis(benzyloxy)-5-[(benzyloxy)methyl]cyclohexanol C42H44O6 详情 详情
(XI) 48143 (2R)-2-(1H-imidazol-1-yl)-3-(octadecyloxy)-1-propanol C24H46N2O2 详情 详情
(XII) 48144 benzyl (2S)-2-(1H-imidazol-1-yl)-3-(octadecyloxy)propyl (1R,2R,3S,4R,5S,6R)-2,3,4,6-tetrakis(benzyloxy)-5-[(benzyloxy)methyl]cyclohexyl phosphate C73H95N2O10P 详情 详情

合成路线83

该中间体在本合成路线中的序号：(IV)

Reaction of betulin (I) and 2,2-dimethylsuccinic acid (II) in refluxing pyridine, followed by HPLC separation of the two products obtained, affords derivative (III). Protection of the carboxylic group of (III) is then performed by formation of the corresponding allyl ester derivative (V) by reaction with allyl bromide (IV) and K2CO3 in acetone. Separately, 2,2-dimethylsuccinic acid (II) is treated with allyl alcohol (VI) in refluxing pyridine to give an isomeric mixture of compounds from which allyl succinate derivative (VII) is chromatographically isolated. Formation of the corresponding acid chloride (VIII) is finally performed by treatment of (VII) with (COCl)2 in refluxing benzene. Condensation between alcohol (V) and acid chloride (VIII) by means of DMAP in CH2Cl2 provides compound (IX), which is finally converted into the target product by removal of the allyl protecting groups by means of Pd(Ph3P)4 and morpholine.

参考文献 中间体
合成目标
【1】 Chiyo, J.; Ikeshiro, Y.; Cosentino, L.M.; Kashiwada, Y.; Fowke, K.; Lee, K.H.; Okabe, H.; Nagao, T.; 3,28-Di-O-(dimethylsuccinyl)-betulin isomers as anti-HIV agents. Bioorg Med Chem Lett 2001, 11, 2, 183.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 50064 (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(hydroxymethyl)-1-isopropenyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-ol C30H50O2 详情 详情
(II) 46622 2,2-dimethylsuccinic acid C6H10O4 详情 详情
(III) 50065 4-[[(1R,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-1-isopropenyl-5a,5b,8,8,11a-pentamethylicosahydro-3aH-cyclopenta[a]chrysen-3-yl]methoxy]-3,3-dimethyl-4-oxobutyric acid C36H58O5 详情 详情
(IV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(V) 50066 1-[[(1R,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-1-isopropenyl-5a,5b,8,8,11a-pentamethylicosahydro-3aH-cyclopenta[a]chrysen-3-yl]methyl] 4-allyl 2,2-dimethylsuccinate C39H62O5 详情 详情
(VI) 12234 2-Propen-1-ol; Allyl alcohol 107-18-6 C3H6O 详情 详情
(VII) 50067 4-(allyloxy)-3,3-dimethyl-4-oxobutyric acid C9H14O4 详情 详情
(VIII) 50068 allyl 4-chloro-2,2-dimethyl-4-oxobutanoate C9H13ClO3 详情 详情
(IX) 50069 4-[(1R,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-([[4-(allyloxy)-2,2-dimethyl-4-oxobutanoyl]oxy]methyl)-1-isopropenyl-5a,5b,8,8,11a-pentamethylicosahydro-3aH-cyclopenta[a]chrysen-9-yl] 1-allyl 2,2-dimethylsuccinate C48H74O8 详情 详情

合成路线84

该中间体在本合成路线中的序号：(VII)

In an alternative procedure, diol (II) was selectively protected as the 14-allyl ether (VIII) by O-alkylation with allyl bromide (VII) in the presence of K2CO3. Displacement of the 16-hydroxyl of (VIII) with diethylaminosulfur trifluoride provided fluoride (IX). The O-allyl protecting group of (IX) was finally removed employing p-toluenesulfonic acid and palladium tetrakis(triphenylphosphine).

参考文献 中间体
合成目标
【1】 Barriere, J.-C.; Achard, D.; Grisoni, S.; Bacque, E.; Ribeill, Y.; Bouquerel, J.; Desmazeau, P.; Leconte, J.-P.; Ronan, B. (Aventis Pharma SA); Streptogramin derivs., preparation and compsns. containing them. EP 1187847; FR 2795733; WO 0102427 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 59396 (7R,10R,11R,21S,23S)-21,23-dihydroxy-10-isopropyl-11,19-dimethyl-9,26-dioxa-3,15,28-triazatricyclo[23.2.1.0~3,7~]octacosa-1(27),12,17,19,25(28)-pentaene-2,8,14-trione C28H39N3O7 详情 详情
(VII) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VIII) 59397 (7R,10R,11R,21S,23S)-21-{[tert-butyl(diphenyl)silyl]oxy}-23-hydroxy-10-isopropyl-11,19-dimethyl-9,26-dioxa-3,15,28-triazatricyclo[23.2.1.0~3,7~]octacosa-1(27),12,17,19,25(28)-pentaene-2,8,14-trione C44H57N3O7Si 详情 详情
(IX) 59398 (7R,10R,11R,21S,23R)-21-{[tert-butyl(diphenyl)silyl]oxy}-23-fluoro-10-isopropyl-11,19-dimethyl-9,26-dioxa-3,15,28-triazatricyclo[23.2.1.0~3,7~]octacosa-1(27),12,17,19,25(28)-pentaene-2,8,14-trione C44H56FN3O6Si 详情 详情

合成路线85

该中间体在本合成路线中的序号：(X)

Synthesis of undecenoic ester intermediate (XXI): The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, Ts-OH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and Me-Li in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and RaNi in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and Ts-OH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).

参考文献 中间体
合成目标
【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12641 Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol 126-30-7 C5H12O2 详情 详情
(II) 44529 3-(benzyloxy)-2,2-dimethyl-1-propanol C12H18O2 详情 详情
(III) 44504 3-(benzyloxy)-2,2-dimethylpropanal C12H16O2 详情 详情
(IV) 33891 Methyl ethyl ketone; 2-Butanone 78-93-3 C4H8O 详情 详情
(V) 44505 (E)-7-(benzyloxy)-6,6-dimethyl-4-hepten-3-one C16H22O2 详情 详情
(VI) 44506 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone C16H22O3 详情 详情
(VII) 44507 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone O-methyloxime C17H25NO3 详情 详情
(VIII) 44508 (4R,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone O-methyloxime C18H29NO3 详情 详情
(IX) 44509 (4S,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone C17H26O3 详情 详情
(X) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XI) 44510 (4S,6S,7R)-9-(benzyloxy)-7-hydroxy-4,6,8,8-tetramethyl-1-nonen-5-one C20H30O3 详情 详情
(XII) 44511 (3R,4R,5S,6S)-1-(benzyloxy)-2,2,4,6-tetramethyl-8-nonene-3,5-diol C20H32O3 详情 详情
(XIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XIV) 44512 benzyl 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propyl ether; (4R,5S,6S)-4-[2-(benzyloxy)-1,1-dimethylethyl]-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxane C23H36O3 详情 详情
(XV) 44513 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]-1-propanol C16H30O3 详情 详情
(XVI) 44514 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propanal C16H28O3 详情 详情

合成路线86

该中间体在本合成路线中的序号：(XV)

The oxidation of the lactol (XIII) with Br2 and BaCO3 gives the lactone (XIV), which is stereoselectively alkylated with allyl bromide (XV) by means of LDA in HMPA to yield lactone (XVI). The opening of the lactone ring of (XVI) with MeONa affords the dihydroxyester (XVII), which is protected by reaction with anisaldehyde dimethylacetal (XVIII) and CSA to provide the benzylidene derivative (XIX). The reduction of the ester group of (XIX) with LiAlH4 gives the corresponding carbinol (XX), which is acylated with Ms-Cl and TEA to yield the mesylate (XXI). The reduction of the mesyloxy group of (XXI) with LiAlH4 affords the dimethyl compound (XXII), which is submitted to a regioselective cleavage of the Pmp protecting group by means of DIBAL in toluene to provide the primary alcohol (XXIII). The oxidation of (XXIII) with DMP gives the corresponding aldehyde (XXIV), which is condensed with tert-butyl isobutyrylacetate (XXV) by means of NaH and BuLi to yield the unsaturated ketoester (XXVI). Stereoselective reduction of the beta-oxo group of (XXVI) by means of Me4NBH(OAc)3 affords the desired diol (XXVII), which is regioselectively silylated at the beta-hydroxy group by means of Tbdms-OTf to provide the monosilyl ether (XXVIII). The oxidation of the remaining hydroxy group of (XXVIII) by means of DMP gives the unsaturated ketoester (XXIX).

参考文献 中间体
合成目标
【1】 Wong, C.-H.; Liu, J.; Aldolase-catalyzed asymmetric synthesis of novel pyranose synthons as a new entry to heterocycles and epothilones. Angew Chem. Int Ed 2002, 41, 8, 1404.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 54267 (4S,5S)-5-methyltetrahydro-2H-pyran-2,4-diol C6H12O3 详情 详情
(XIV) 54268 (4S,5S)-4-hydroxy-5-methyltetrahydro-2H-pyran-2-one C6H10O3 详情 详情
(XV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XVI) 54269 (3S,4R,5S)-3-allyl-4-hydroxy-5-methyltetrahydro-2H-pyran-2-one C9H14O3 详情 详情
(XVII) 54270 methyl (2S)-2-[(1R,2S)-1,3-dihydroxy-2-methylpropyl]-4-pentenoate C10H18O4 详情 详情
(XVIII) 26485 1-(dimethoxymethyl)-4-methoxybenzene 2186-92-7 C10H14O3 详情 详情
(XIX) 54271 methyl (2S)-2-[(4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-pentenoate n/a C18H24O5 详情 详情
(XX) 54272 (2R)-2-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-penten-1-ol n/a C17H24O4 详情 详情
(XXI) 54273 (2R)-2-[(4R,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-4-pentenyl methanesulfonate n/a C18H26O6S 详情 详情
(XXII) 54274 (4S,5S)-2-(4-methoxyphenyl)-5-methyl-4-[(1S)-1-methyl-3-butenyl]-1,3-dioxane; methyl 4-{(4S,5S)-5-methyl-4-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-2-yl}phenyl ether n/a C17H24O3 详情 详情
(XXIII) 54275 (2S,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-6-hepten-1-ol n/a C17H26O3 详情 详情
(XXIV) 54276 (2R,3S,4S)-3-[(4-methoxybenzyl)oxy]-2,4-dimethyl-6-heptenal n/a C17H24O3 详情 详情
(XXV) 54277 tert-butyl 4-methyl-3-oxopentanoate 94250-54-1 C10H18O3 详情 详情
(XXVI) 54278 tert-butyl (5S,6S,7S,8S)-5-hydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-3-oxo-10-undecenoate n/a C27H42O6 详情 详情
(XXVII) 54279 tert-butyl (3S,5S,6S,7S,8S)-3,5-dihydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-10-undecenoate n/a C27H44O6 详情 详情
(XXVIII) 54280 tert-butyl (3S,5S,6S,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-10-undecenoate n/a C33H58O6Si 详情 详情
(XXIX) 54281 tert-butyl (3S,6R,7S,8S)-3-{[tert-butyl(dimethyl)silyl]oxy}-7-[(4-methoxybenzyl)oxy]-4,4,6,8-tetramethyl-5-oxo-10-undecenoate n/a C33H56O6Si 详情 详情

合成路线87

该中间体在本合成路线中的序号：(XXII)

Bromochromanone (XVI) was prepared by bromination of 4-chromanone (XV). Subsequent reduction of (XVI) with NaBH4 provided bromohydrin (XVII). Ritter reaction of (XVII) with acetonitrile and sulfuric acid, followed by acidic hydrolysis, led to racemic cis-3-bromo-4-chromanol, which was then resolved by means of (S)-(+)-mandelic acid. The desired (S,S)-isomer (XVIII) was coupled with hydrocinnamic acid (XIX) giving amide (XX). After protection of hydroxy amide (XX) as the acetonide (XXI), the lithium enolate of amide (XXI) was alkylated with allyl bromide (XXII) to furnish the (S)-2-benzyl-4-pentenamide (XXIII) as the main diastereoisomer. Halogenation of (XXIII) with N-iodosuccinimide in H2O-EtOAc afforded iodohydrin (XXIV), which was cyclized to epoxide (XXV) in the presence of NaOMe.

参考文献 中间体
合成目标
【1】 gamma-Hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides as HIV protease inhibitors. EP 1242426; WO 0138332 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 14461 2,3-Dihydro-4H-chromen-4-one; 4-Chromanone 491-37-2 C9H8O2 详情 详情
(XVI) 56263 3-bromo-2,3-dihydro-4H-chromen-4-one C9H7BrO2 详情 详情
(XVII) 56264 3-bromo-4-chromanol C9H9BrO2 详情 详情
(XVIII) 56265 (3S,4S)-4-amino-3,4-dihydro-2H-chromen-3-ol C9H11NO2 详情 详情
(XIX) 49181 Hydrocinnamic acid; 3-Phenylpropionic acid; Benzylacetic acid 501-52-0 C9H10O2 详情 详情
(XX) 56266 N-[(3S,4S)-3-hydroxy-3,4-dihydro-2H-chromen-4-yl]-3-phenylpropanamide C18H19NO3 详情 详情
(XXI) 56267 1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-3-phenyl-1-propanone C21H23NO3 详情 详情
(XXII) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XXIII) 56268 (2S)-1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-2-benzyl-4-penten-1-one C24H27NO3 详情 详情
(XXIV) 56269 (2R,4S)-1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-2-benzyl-4-hydroxy-5-iodo-1-pentanone C24H28INO4 详情 详情
(XXV) 56270 (2R)-1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone C24H27NO4 详情 详情

合成路线88

该中间体在本合成路线中的序号：(III)

The esterification of 3,4-dichlorophenylacetic acid (I) with methanol and ClH gives the methyl ester (II), which is alkylated with allyl bromide and LDA in THF to yield 2-(3,4-dichlorophenyl)-4-pentenoic acid methyl ester (IV). The hydrolysis of (IV) with LiOH in MeOH/water affords the corresponding free acid (V), which is epoxidated with MCPBA in refluxing chloroform to provide epoxide (VI), which, without isolation, is treated in acid medium, giving the tetrahydrofuranone (VII). The silylation of the OH group of (VII) with Tbdms-Cl and imidazole in DMF yields the protected silyl ether (VIII), which is treated with LDA in THF to afford the lithium enolate (IX). The reaction of (IX) with phenylselenyl chloride in THF provides the phenylselenyl derivative (X), which is oxidized with MCPBA to the corresponding selenoxide. This nonisolated compound undergoes spontaneous syn elimination to give, after hydrolysis of the silyl ether with AcOH, 3-(3,4-dichlorophenyl)-5-(hydroxymethyl)furan-2(5H)-one (XI). Finally, this compound is esterified with pivaloyl chloride and pyridine in dichloromethane to afford the target ester.

参考文献 中间体
合成目标
【1】 Pour, M.; et al.; 3-Phenyl-5-acyloxymethyl-2H,5H-furan-2-ones: Synthesis and biological activity of a novel group of potential antifungal drugs. J Med Chem 2001, 44, 17, 2701.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 30414 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid 5807-30-7 C8H6Cl2O2 详情 详情
(II) 47947 methyl 2-(3,4-dichlorophenyl)acetate C9H8Cl2O2 详情 详情
(III) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(IV) 50420 methyl 2-(3,4-dichlorophenyl)-4-pentenoate C12H12Cl2O2 详情 详情
(V) 50421 2-(3,4-dichlorophenyl)-4-pentenoic acid C11H10Cl2O2 详情 详情
(VI) 50422 2-(3,4-dichlorophenyl)-3-(2-oxiranyl)propionic acid C11H10Cl2O3 详情 详情
(VII) 50423 3-(3,4-dichlorophenyl)-5-(hydroxymethyl)dihydro-2(3H)-furanone C11H10Cl2O3 详情 详情
(VIII) 50424 5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-(3,4-dichlorophenyl)dihydro-2(3H)-furanone C17H24Cl2O3Si 详情 详情
(IX) 50425 　 C17H23Cl2LiO3Si 详情 详情
(X) 50426 5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-(3,4-dichlorophenyl)-3-(phenylselanyl)dihydro-2(3H)-furanone C23H28Cl2O3SeSi 详情 详情
(XI) 50427 3-(3,4-dichlorophenyl)-5-(hydroxymethyl)-2(5H)-furanone C11H8Cl2O3 详情 详情
(XII) 44281 pivalic acid 75-98-9 C5H10O2 详情 详情

合成路线89

该中间体在本合成路线中的序号：(XVI)

The intermediate phosphonate (XXI) has been obtained as follows: The reaction of tert-butyl mercaptan (XV) with allyl bromide (XVI) by means of NaOH in ethanol gives the sulfide (XVII), which is oxidized with Oxone in methanol/water to yield the sulfone (XVIII). The bromination of (XVIII) with Br2 in CCl4 followed by dehydrobromination with TEA affords the bromosulfone (XIX), which is finally condensed with tributyl phosphite (XX) by heating at 130 C to provide the target intermediate phosphonate (XXI). The silylation of the known diol (XXII) (obtained by degradation of vitamin D2) with Tes-OTf and lutidine gives the bis silyl ether (XXIII), which is submitted to a Swern oxidation ((COCl)2), yielding the carbaldehyde (XXIV). The Wadsworth-Emmons condensation of aldehyde (XXIV) with the intermediate phosphonate (XXI) by means of tBu-OLi affords the diinsaturated sulfone (XXV), which is desilylated with HF in THF to provide the alcohol (XXVI). The oxidation of (XXVI) with TPAP and NMO furnishes the ketone (XXVII), which is submitted to a Wittig-Horner condensation with the intermediate phosphine oxide (XIV) by means of PhLi, giving the silylated precursor (XXVIII). Finally, this compound is desilylated with HF in ethanol to afford the target vitamin D3 analogue.

参考文献 中间体
合成目标
【1】 Posner, G.H.; et al.; A non-calcemic sulfone version of the vitamin D3 analogue seocalcitol (EB 1089): Chemical synthesis, biological evaluation and potency enhancement of the anticancer drug adriamycin. Bioorg Med Chem 2001, 9, 9, 2365.
【2】 Fall, Y.; A new approach to the synthesis of the 25-hydroxy-22-oxa-vitamin D3 side chain. Tetrahedron Lett 1997, 38, 27, 4909.
【3】 Lee, J.K.; Crawford, K.R.; Wang, Q.; Posner, G.H.; Han, G. (Johns Hopkins University); Non-calcemic, antiproliferative, transcriptionally active sulfur-containing analogs of 1alpha,25-dihydroxyvitamin D3. US 6380408; WO 0059513 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIV) 42574 [2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl](oxo)diphenylphosphorane; 2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethyl(diphenyl)phosphine oxide C33H51O3PSi2 详情 详情
(XV) 52551 tert-Butyl mercaptan; 2-Methyl-2-propanethiol 75-66-1 C4H10S 详情 详情
(XVI) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XVII) 52552 1,1-dimethylethyl 2-propenyl sulfide; 3-[(1,1-dimethylethyl)sulfanyl]-1-propene C7H14S 详情 详情
(XVIII) 52553 (1,1-dimethylethyl)(dioxo)2-propenyl-lambda~6~-sulfane; 1,1-dimethylethyl 2-propenyl sulfone C7H14O2S 详情 详情
(XIX) 52554 (3-bromo-1-propenyl)(1,1-dimethylethyl)dioxo-lambda~6~-sulfane; 3-bromo-1-propenyl 1,1-dimethylethyl sulfone C7H13BrO2S 详情 详情
(XX) 52555 Tri-n-butylphosphite; Tributyl phosphite; Phosphorous acid Tri-N-butyl ester 102-85-2 C12H27O3P 详情 详情
(XXI) 52556 dibutyl 3-[(1,1-dimethylethyl)sulfonyl]-2-propenylphosphonate C15H31O5PS 详情 详情
(XXII) 52151 (1R,3aR,4S,7aR)-1-[(1S)-2-hydroxy-1-methylethyl]-7a-methyloctahydro-1H-inden-4-ol C13H24O2 详情 详情
(XXIII) 52557 7a-methyl-1-{1-methyl-2-[(triethylsilyl)oxy]ethyl}octahydro-1H-inden-4-yl triethylsilyl ether; [(7a-methyl-1-{1-methyl-2-[(triethylsilyl)oxy]ethyl}octahydro-1H-inden-4-yl)oxy](triethyl)silane C25H52O2Si2 详情 详情
(XXIV) 52558 2-{7a-methyl-4-[(triethylsilyl)oxy]octahydro-1H-inden-1-yl}propanal C19H36O2Si 详情 详情
(XXV) 52559 [(1-{5-[(1,1-dimethylethyl)sulfonyl]-1-methyl-2,4-pentadienyl}-7a-methyloctahydro-1H-inden-4-yl)oxy](triethyl)silane; 5-{7a-methyl-4-[(triethylsilyl)oxy]octahydro-1H-inden-1-yl}-1,3-hexadienyl 1,1-dimethylethyl sulfone C26H48O3SSi 详情 详情
(XXVI) 52560 1-{5-[(1,1-dimethylethyl)sulfonyl]-1-methyl-2,4-pentadienyl}-7a-methyloctahydro-1H-inden-4-ol C20H34O3S 详情 详情
(XXVII) 52561 1-{5-[(1,1-dimethylethyl)sulfonyl]-1-methyl-2,4-pentadienyl}-7a-methyloctahydro-4H-inden-4-one C20H32O3S 详情 详情
(XXVIII) 52562 (1,1-dimethylethyl)({3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-[2-(1-{5-[(1,1-dimethylethyl)sulfonyl]-1-methyl-2,4-pentadienyl}-7a-methyloctahydro-4H-inden-4-ylidene)ethylidene]-4-methylidenecyclohexyl}oxy)dimethylsilane; 5-{4-[2-(3,5-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methylidenecyclohexylidene)ethylidene]-7a-methyloctahydro-4H-inden-1-yl}-1,3-hexadienyl 1,1-dimethylethyl sulfone C41H72O4SSi2 详情 详情

合成路线90

该中间体在本合成路线中的序号：(IX)

Esterification of 3-(4-hydroxyphenyl)propionic acid (I), followed by alkylation of the phenolic hydroxyl, provided methyl 3-(4-benzyloxyphenyl)propionate (II), which was hydrolyzed to the corresponding carboxylic acid (III) by means of LiOH. Coupling of carboxylic acid (III) with the chiral auxiliary (S)-4-benzyl-2-oxazolidinone (IV) gave the oxazolide (V), which was subjected to diastereoselective alkylation with tert-butyl bromoacetate (VI), yielding (VII). Subsequent removal of the chiral auxiliary group of (VII) using lithium hydroperoxide afforded the (R)-acid (VIII). Alkylation of the dianion of acid (VIII) with allyl bromide (IX) and further epimerization in the presence of LDA and Et2AlCl furnished the anti-dialkylated succinate (X). The carboxyl group of (X) was then alkylated using benzyl bromide and DBU to produce the corresponding benzyl ester (XI). Olefin (XI) hydroboration followed by oxidative work-up gave rise to the primary alcohol (XII). This was acylated with 4-nitrophenyl chloroformate (XIII) to provide the activated carbonate (XIV).

参考文献 中间体
合成目标
【1】 Xue, C.-B.; et al.; Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1', a series of selective TNF-alpha converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-alpha release. J Med Chem 2001, 44, 21, 3351.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 25691 3-(4-hydroxyphenyl)propionic acid 501-97-3 C9H10O3 详情 详情
(II) 53167 methyl 3-[4-(benzyloxy)phenyl]propanoate n/a C17H18O3 详情 详情
(III) 53168 3-[4-(benzyloxy)phenyl]propanoic acid 50463-48-4 C16H16O3 详情 详情
(IV) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(V) 53169 (4S)-4-benzyl-3-{3-[4-(benzyloxy)phenyl]propanoyl}-1,3-oxazolidin-2-one n/a C26H25NO4 详情 详情
(VI) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(VII) 53170 tert-butyl (3R)-4-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-[4-(benzyloxy)benzyl]-4-oxobutanoate n/a C32H35NO6 详情 详情
(VIII) 53171 (2R)-2-[4-(benzyloxy)benzyl]-4-(tert-butoxy)-4-oxobutanoic acid n/a C22H26O5 详情 详情
(IX) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(X) 53172 (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(tert-butoxycarbonyl)-5-hexenoic acid n/a C25H30O5 详情 详情
(XI) 53173 4-benzyl 1-(tert-butyl) (2S,3R)-2-allyl-3-[4-(benzyloxy)benzyl]butanedioate n/a C32H36O5 详情 详情
(XII) 53174 1-benzyl 4-(tert-butyl) (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(3-hydroxypropyl)butanedioate n/a C32H38O6 详情 详情
(XIII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XIV) 53175 1-benzyl 4-(tert-butyl) (2R,3S)-2-[4-(benzyloxy)benzyl]-3-(3-{[(4-nitrophenoxy)carbonyl]oxy}propyl)butanedioate n/a C39H41NO10 详情 详情

合成路线91

该中间体在本合成路线中的序号：(V)

The reaction of 15-methylerythromycin A (I) with hydroxylamine, cyclohexanone di-isopropylacetal (II) and PPTS gives the substituted oxime (III), which is regioselectively silylated with Tms-Cl and imidazole to yield the disilylated compound (IV). The alkylation of (IV) with allyl bromide (V) and tBu-OK affords the 6-O-allyl derivative (VI),which is treated with HOAc and HCOOH to cleave the oxime group and furnish the 6-O-allyl-15-methylerythromycin A (VII). The cleavage of the 3-O-carbohydrate moiety of (VII) by means of aq. HCl, followed by benzoylation with Bz2O, gives the benzoyl intermediate (VIII), which is oxidized with NCS and Me2S and dehydrated with Ms-Cl, pyridine and DBU to yield the ketolide (IX). The fluorination of (IX) by means of (PhSO2)2N-F and tBu-OK affords the 2-fluoro derivative (X).

参考文献 中间体
合成目标
【1】 Macielag, M.; et al.; Structure-antibacterial activty relationships of ketolides derived from 15-methylerythromycin A. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1174.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 54474 (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-7,12,13-trihydroxy-6-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione C38H69NO13 详情 详情
(II) 45909 1-isopropoxycyclohexyl isopropyl ether; 1,1-diisopropoxycyclohexane 1132-95-2 C12H24O2 详情 详情
(III) 54475 (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7,12,13-trihydroxy-6-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] C47H86N2O14 详情 详情
(IV) 54476 (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7,12,13-trihydroxy-6-({(2S,3S,6R)-4-isopropyl-6-methyl-3-[(trimethylsilyl)oxy]morpholinyl}oxy)-4-({(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}oxy)-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] C53H102N2O14Si2 详情 详情
(V) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VI) 54477 (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7-(allyloxy)-12,13-dihydroxy-6-({(2S,3S,6R)-4-isopropyl-6-methyl-3-[(trimethylsilyl)oxy]morpholinyl}oxy)-4-({(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}oxy)-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] C56H106N2O14Si2 详情 详情
(VII) 54478 (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-12,13-dihydroxy-6-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione C41H73NO13 详情 详情
(VIII) 54479 (2S,3S,6R)-2-{[(3R,4S,5S,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-4,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-14-propyloxacyclotetradecanyl]oxy}-4-isopropyl-6-methylmorpholinyl benzoate C40H63NO11 详情 详情
(IX) 54480 (2S,3S,6R)-2-{[(3R,5R,6R,7S,9R,13S,14R)-7-(allyloxy)-13-hydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxo-14-propyloxa-11-cyclotetradecen-6-yl]oxy}-4-isopropyl-6-methylmorpholinyl benzoate C40H59NO10 详情 详情
(X) 54481 (2S,3S,6R)-2-{[(3S,5S,6R,7S,9R,13S,14R)-7-(allyloxy)-3-fluoro-4,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-14-propyloxa-11-cyclotetradecen-6-yl]oxy}-4-isopropyl-6-methylmorpholinyl benzoate C40H60FNO10 详情 详情

合成路线92

该中间体在本合成路线中的序号：(V)

The reaction of 15-methylerythromycin A (I) with hydroxylamine, cyclohexanone di-isopropylacetal (II) and PPTS gives the substituted oxime (III), which is regioselectively silylated with Tms-Cl and imidazole to yield the disilylated compound (IV). The alkylation of (IV) with allyl bromide (V) and tBu-OK affords the 6-O-allyl derivative (VI),which is treated with HOAc and HCOOH to cleave the oxime group and furnish the 6-O-allyl-15-methylerythromycin A (VII). The cleavage of the 3-O-carbohydrate moiety of (VII) by means of aq. HCl, followed by benzoylation with Bz2O, gives the benzoyl intermediate (VIII), which is oxidized with NCS and Me2S and dehydrated with Ms-Cl, pyridine and DBU to yield the ketolide (IX). The fluorination of (IX) by means of (PhSO2)2N-F and tBu-OK affords the 2-fluoro derivative (X).

参考文献 中间体
合成目标
【1】 Macielag, M.; et al.; Structure-antibacterial activty relationships of ketolides derived from 15-methylerythromycin A. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1174.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 54474 (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-7,12,13-trihydroxy-6-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione C38H69NO13 详情 详情
(II) 45909 1-isopropoxycyclohexyl isopropyl ether; 1,1-diisopropoxycyclohexane 1132-95-2 C12H24O2 详情 详情
(III) 54475 (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7,12,13-trihydroxy-6-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] C47H86N2O14 详情 详情
(IV) 54476 (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7,12,13-trihydroxy-6-({(2S,3S,6R)-4-isopropyl-6-methyl-3-[(trimethylsilyl)oxy]morpholinyl}oxy)-4-({(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}oxy)-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] C53H102N2O14Si2 详情 详情
(V) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VI) 54477 (3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7-(allyloxy)-12,13-dihydroxy-6-({(2S,3S,6R)-4-isopropyl-6-methyl-3-[(trimethylsilyl)oxy]morpholinyl}oxy)-4-({(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}oxy)-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime] C56H106N2O14Si2 详情 详情
(VII) 54478 (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-12,13-dihydroxy-6-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione C41H73NO13 详情 详情
(VIII) 54479 (2S,3S,6R)-2-{[(3R,4S,5S,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-4,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-14-propyloxacyclotetradecanyl]oxy}-4-isopropyl-6-methylmorpholinyl benzoate C40H63NO11 详情 详情
(IX) 54480 (2S,3S,6R)-2-{[(3R,5R,6R,7S,9R,13S,14R)-7-(allyloxy)-13-hydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxo-14-propyloxa-11-cyclotetradecen-6-yl]oxy}-4-isopropyl-6-methylmorpholinyl benzoate C40H59NO10 详情 详情
(X) 54481 (2S,3S,6R)-2-{[(3S,5S,6R,7S,9R,13S,14R)-7-(allyloxy)-3-fluoro-4,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-14-propyloxa-11-cyclotetradecen-6-yl]oxy}-4-isopropyl-6-methylmorpholinyl benzoate C40H60FNO10 详情 详情

合成路线93

该中间体在本合成路线中的序号：(III)

Direct amination of veratrole (I) with lithium dimethylamide produces 2-methoxy-N,N-dimethylaniline (II). The title ammonium salt is then prepared by quaternization of the tertiary amine (II) with allyl bromide (III).

参考文献 中间体
合成目标
【1】 Tarver, G.J.; Kaur, J.; Zhang, M.-Q.; Pow, E.; Muir, A.W.; Grove, S.J.A.; Oxyaniliniums as acetylcholinesterase inhibitors for the reversal of neuromuscular block. Bioorg Med Chem Lett 2002, 12, 2, 193.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 17398 2-methoxyphenyl methyl ether; Veratrole; 1,2-dimethoxybenzene 91-16-7 C8H10O2 详情 详情
(II) 59068 N-(2-methoxyphenyl)-N,N-dimethylamine; 2-methoxy-N,N-dimethylaniline C9H13NO 详情 详情
(III) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情

合成路线94

该中间体在本合成路线中的序号：(V)

Condensation of 2,4-diaminotoluene (I) with methyl 4-methoxyacetoacetate (II) produces quinolinone (III). Conversion of the 7-aminoquinolinone (III) into the 7-hydroxy analogue (IV) is achieved by diazotization, followed by hydrolysis in hot sulfuric acid. Alkylation of phenol (IV) with allyl bromide (V) gives allyl ether (VI). Subsequent methylation of (VI) by means of dimethyl sulfate leads to a mixture of the desired N-methyl quinoline (VII) along with minor amounts of the O-methyl isomer (VIII), which are separated by column chromatography. Claisen rearrangement of the allyl ether (VII) in refluxing N,N-dimethylaniline affords the 7-hydroxy-8-allyl quinolone (IX), which is further acetylated to (X) by means of acetic anhydride and sodium acetate. Bromination of the allyl group of (X) in HOAc yields the dibromo compound (XI).

参考文献 中间体
合成目标
【1】 Chilin, A.; et al.; Synthesis and biological evaluation of a new furo(2,3-h)quinolin-2(1H)-one. J Med Chem 2002, 45, 5, 1146.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 57682 4-methyl-1,3-benzenediamine; 3-amino-4-methylphenylamine C7H10N2 详情 详情
(II) 57683 ethyl 4-methoxy-3-oxobutanoate C7H12O4 详情 详情
(III) 57684 7-amino-4-(methoxymethyl)-6-methyl-2(1H)-quinolinone C12H14N2O2 详情 详情
(IV) 57685 7-hydroxy-4-(methoxymethyl)-6-methyl-2(1H)-quinolinone C12H13NO3 详情 详情
(V) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VI) 57686 7-(allyloxy)-4-(methoxymethyl)-6-methyl-2(1H)-quinolinone C15H17NO3 详情 详情
(VII) 57687 7-(allyloxy)-4-(methoxymethyl)-1,6-dimethyl-2(1H)-quinolinone C16H19NO3 详情 详情
(VIII) 57688 7-(allyloxy)-2-methoxy-4-(methoxymethyl)-6-methylquinoline; allyl 2-methoxy-4-(methoxymethyl)-6-methyl-7-quinolinyl ether C16H19NO3 详情 详情
(IX) 57689 8-allyl-7-hydroxy-4-(methoxymethyl)-1,6-dimethyl-2(1H)-quinolinone C16H19NO3 详情 详情
(X) 57690 8-allyl-4-(methoxymethyl)-1,6-dimethyl-2-oxo-1,2-dihydro-7-quinolinyl acetate C18H21NO4 详情 详情
(XI) 57691 8-(2,3-dibromopropyl)-4-(methoxymethyl)-1,6-dimethyl-2-oxo-1,2-dihydro-7-quinolinyl acetate C18H21Br2NO4 详情 详情

合成路线95

该中间体在本合成路线中的序号：(XV)

Alkylation of the enolate derived from N-Boc ethyl isonipecotate (XIV) with allyl bromide (XV) gives the alpha-allyl ester (XVI). Double bond ozonolysis in (XIV) with reductive work-up in the presence of NaBH4 leads to lactone (XVII). Reductive ring-opening of lactone (XVII) by means of DIBAL affords diol (XVIII). This is then cyclized under Mitsunobu conditions to the spirocyclic amine (XIX). Acidic Boc group cleavage in (XIX) provides 2-oxa-8-azaspiro[4.5]decane (XX). Finally, reductive amination of cyclohexanone (XIII) with the bicyclic amine (XX) gives rise to a cis/trans mixture of diamino cyclohexanes, from which the desired trans isomer is isolated by chromatography.

参考文献 中间体
合成目标
【1】 Cooper, L.C.; et al.; 4,4-Disubstituted cyclohexylamine NK1 receptor antagonists II. Bioorg Med Chem Lett 2002, 12, 13, 1759.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 57089 2-[3,5-bis(trifluoromethyl)phenyl]-N-(4-oxo-1-phenylcyclohexyl)propanamide C23H21F6NO2 详情 详情
(XIV) 49847 1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine 142851-03-4 C13H23NO4 详情 详情
(XV) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XVI) 57090 1-(tert-butyl) 4-ethyl 4-allyl-1,4-piperidinedicarboxylate C16H27NO4 详情 详情
(XVII) 57091 tert-butyl 1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate C13H21NO4 详情 详情
(XVIII) 57092 tert-butyl 4-(2-hydroxyethyl)-4-(hydroxymethyl)-1-piperidinecarboxylate C13H25NO4 详情 详情
(XIX) 57093 tert-butyl 2-oxa-8-azaspiro[4.5]decane-8-carboxylate C13H23NO3 详情 详情
(XX) 57094 2-oxa-8-azaspiro[4.5]decane C8H15NO 详情 详情

合成路线96

该中间体在本合成路线中的序号：(III)

5,5-Dimethylthiazolidine-4-carboxylic acid (I) is protected as the N-Boc derivative (II), and subsequently treated with allyl bromide (III) and triethylamine to form the allyl ester (IV). Acidic Boc group cleavage in (IV) provides amino ester (V), which is further coupled to the lactone acid (VI) to furnish amide (VII). The allyl ester group of (VII) is then removed by treatment with morpholine and Pd(PPh3)4, yielding acid (VIII). This is then coupled to (3,5-dimethylisothiazol-4-yl)methyl amine (IX) employing EDC/HOAt to afford the corresponding amide (X). Lactone ring opening in (X) by hydrolysis with LiOH gives rise to the hydroxy acid (XI), which is further protected as the silyl ether (XII) employing t-butyldimethylsilyl triflate.

参考文献 中间体
合成目标
【1】 Bohn, J.; Lu, Z.; Raghavan, S.; Charest, M.; Stahlhut, M.; Rutkowski, C.A.; Himmelberger, A.L.; Olsen, D.B.; Scheleif, W.A.; Carella, A.; Gabryelski, L.; Jin, L.; Lin, J.H.; Tata, J.R.; Chapman, K.; Synthesis of highly potent HIV protease inhibitors with activity against protease resistant virus. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 205.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 34776 (4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid 72778-00-8 C6H11NO2S 详情 详情
(II) 34777 (4R)-3-(tert-butoxycarbonyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid C11H19NO4S 详情 详情
(III) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(IV) 65046 4-allyl 3-(tert-butyl) (4R)-5,5-dimethyl-1,3-thiazolidine-3,4-dicarboxylate C14H23NO4S 详情 详情
(V) 65047 allyl (4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate C9H15NO2S 详情 详情
(VI) 65048 (2S,4R)-4-benzyl-5-oxotetrahydro-2-furancarboxylic acid C12H12O4 详情 详情
(VII) 65049 allyl (4R)-3-{[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]carbonyl}-5,5-dimethyl-1,3-thiazolidine-4-carboxylate C21H25NO5S 详情 详情
(VIII) 65050 (4R)-3-{[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]carbonyl}-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid C18H21NO5S 详情 详情
(IX) 65059 (3,5-dimethyl-4-isothiazolyl)methanamine; (3,5-dimethyl-4-isothiazolyl)methylamine C6H10N2S 详情 详情
(X) 65060 (4R)-3-{[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]carbonyl}-N-[(3,5-dimethyl-4-isothiazolyl)methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide C24H29N3O4S2 详情 详情
(XI) 65061 (2R,4S)-2-benzyl-5-[(4R)-4-({[(3,5-dimethyl-4-isothiazolyl)methyl]amino}carbonyl)-5,5-dimethyl-1,3-thiazolidin-3-yl]-4-hydroxy-5-oxopentanoic acid C24H31N3O5S2 详情 详情
(XII) 65062 (2R,4S)-2-benzyl-4-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4R)-4-({[(3,5-dimethyl-4-isothiazolyl)methyl]amino}carbonyl)-5,5-dimethyl-1,3-thiazolidin-3-yl]-5-oxopentanoic acid C30H45N3O5S2Si 详情 详情

合成路线97

该中间体在本合成路线中的序号：(II)

Benzazepinone (I) is alkylated by allyl bromide (II) in the presence of NaH to furnish (III). Ozonolysis of the N-allyl group of (III) in cold CH2Cl2 then produces aldehyde (IV). This is then reductively aminated with 5-fluoro-1-(piperidin-4-yl)-2,3-dihydro-1H-benzimidazol-2-one (V) employing NaBH(OAc)3 in 1,2-dichloroethane to yield the title compound.

参考文献 中间体
合成目标
【1】 Forbes, I.T.; Cooper, D.G.; Dodds, E.K.; Douglas, S.E.; Gribble, A.D.; Ife, R.J.; Lightfoot, A.P.; Meeson, M.; Campbell, L.P.; Coleman, T.; Riley, G.J.; Thomas, D.R.; Identification of a novel series of selective 5-HT7 receptor antagonists. Bioorg Med Chem Lett 2003, 13, 6, 1055.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 63710 2,3,4,5-tetrahydro-1H-2-benzazepin-1-one C10H11NO 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 63711 2-(2-propenyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one C13H15NO 详情 详情
(IV) 63712 2-(1-oxo-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)acetaldehyde C12H13NO2 详情 详情
(V) 63713 5-fluoro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one C12H14FN3O 详情 详情

合成路线98

该中间体在本合成路线中的序号：(VI)

Alkylation of 14-hydroxycodeinone (I) with cinnamyl bromide (II) in the presence of NaH in DMF gives 14-cinnamyloxycodeinone (III). Catalytic hydrogenation of (III) over Pd/C catalyst affords the corresponding 7,8-dihydro-14-phenylpropoxy derivative (IV). N-Demethylation of (IV) is accomplished by treatment with 1-chloroethyl chloroformate, followed by cleavage of the intermediate chloroethyl carbamate in refluxing MeOH. The resulting N-nor derivative (V) is then alkylated with allyl bromide (VI) using K2CO3 in DMF to provide the N-allyl amine (VII). O-Demethylation of (VII) with boiling 48% HBr yields phenol (VIII). Finally, catalytic hydrogenation of the N-allyl group of (VIII) in the presence of Pd/C affords the title N-propyl derivative.

参考文献 中间体
合成目标
【1】 Greiner, E.; Spetea, M.; Krassnig, R.; Schullner, F.; Aceto, M.; Harris, L.S.; Traynor, J.R.; Woods, J.H.; Coop, A.; Schmidhammer, H.; Synthesis and biological evaluation of 14-alkoxymorphinans. 18.(1) N-substituted 14-phenylpropyloxymorphinan-6-ones with unanticipated agonist properties: Extending the scope of common structure-activity relationships. J Med Chem 2003, 46, 9, 1758.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 64962 17-hydroxy-4-methyl-10-(methyloxy)-12-oxa-4-azapentacyclo[9.6.1.0~1,13~.0~5,17~.0~7,18~]octadeca-7(18),8,10,15-tetraen-14-one C18H19NO4 详情 详情
(II) 21131 1-[(E)-3-bromo-1-propenyl]benzene 4392-24-9 C9H9Br 详情 详情
(III) 64963 　 C27H27NO4 详情 详情
(IV) 64964 　 C27H31NO4 详情 详情
(V) 64965 　 C26H29NO4 详情 详情
(VI) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VII) 64966 　 C29H33NO4 详情 详情
(VIII) 64967 　 C28H31NO4 详情 详情

合成路线99

该中间体在本合成路线中的序号：(II)

Synthesis of the perhydroindole intermediate (XIII): The alkylation of the N-protected glutamate (I) with allyl bromide (II) by means of LiHMDS in THF gives the protected chiral allyl glutamate (III) (1), which is cyclized by means of TFA in dichloromethane to yield the pyroglutamate (IV). The reduction of (IV) with LiHBEt3 in THF affords the hydroxy compound (V), which is treated with Ac2O and DMAP in dichloromethane to provide the expected hemiaminal derivative (VI). The reaction of (VI) with allyl tributylstannane (VII) by means of BF3/Et2O in toluene gives the diallyl pyrrolidine (VIII), which is submitted to a ring closure by olefin metathesis using a Grubbs Ru catalyst in dichloromethane to yield the hexahydroindole derivative (IX). The reaction of (IX) with mCPBA in dichloromethane affords the epoxide (X), which is hydrolyzed with TFA to yield the dihydroxy compound (XI). The reaction of (XI) with Mom-Cl and DIEA in dichloromethane provides the bis mom ether (XII), which is treated with H2 over Pd/C in methanol to yield the desired perhydroindole intermediate (XIII) (2).

参考文献 中间体
合成目标
【1】 Hanessian, S.; Margarita, R.; 1,3-Asymmetric induction in dianionic allylation reactions of amino acid derivatives-synthesis of functionally useful enantiopure glutamates, pipecolates and pyroglutamates. Tetrahedron Lett 1998, 39, 33, 5887.
【2】 Hanessian, S.; Margarita, R.; Hall, A.; Johnstone, S.; Tremblay, M.; Parlanti, L.; Total synthesis and structural confirmation of the marine natural product Dysinosin A: A novel inhibitor of thrombin and Factor VIIa. J Am Chem Soc 2002, 124, 45, 13342.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 64903 dimethyl 2-({[(phenylmethyl)oxy]carbonyl}amino)pentanedioate C15H19NO6 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 64904 dimethyl 2-({[(phenylmethyl)oxy]carbonyl}amino)-4-(2-propenyl)pentanedioate C18H23NO6 详情 详情
(IV) 64905 2-methyl 1-(phenylmethyl) 5-oxo-4-(2-propenyl)-1,2-pyrrolidinedicarboxylate C17H19NO5 详情 详情
(V) 64906 2-methyl 1-(phenylmethyl) 5-hydroxy-4-(2-propenyl)-1,2-pyrrolidinedicarboxylate C17H21NO5 详情 详情
(VI) 64907 2-methyl 1-(phenylmethyl) 5-(acetyloxy)-4-(2-propenyl)-1,2-pyrrolidinedicarboxylate C19H23NO6 详情 详情
(VII) 40599 Allyltributyltin; Tributyl-2-propenylstannane 24850-33-7 C15H32Sn 详情 详情
(VIII) 64908 2-methyl 1-(phenylmethyl) 4,5-di(2-propenyl)-1,2-pyrrolidinedicarboxylate C20H25NO4 详情 详情
(IX) 64909 2-methyl 1-(phenylmethyl) 2,3,3a,4,7,7a-hexahydro-1H-indole-1,2-dicarboxylate C18H21NO4 详情 详情
(X) 64910 4-methyl 3-(phenylmethyl) octahydro-3H-oxireno[2,3-f]indole-3,4-dicarboxylate C18H21NO5 详情 详情
(XI) 64911 2-methyl 1-(phenylmethyl) 5,6-dihydroxyoctahydro-1H-indole-1,2-dicarboxylate C18H23NO6 详情 详情
(XII) 64912 2-methyl 1-(phenylmethyl) 5,6-bis{[(methyloxy)methyl]oxy}octahydro-1H-indole-1,2-dicarboxylate C22H31NO8 详情 详情
(XIII) 64913 methyl 5,6-bis{[(methyloxy)methyl]oxy}octahydro-1H-indole-2-carboxylate C14H25NO6 详情 详情

合成路线100

该中间体在本合成路线中的序号：(V)

O-Alkylation of 5-nitrosalicylaldehyde (I) with 1,2-dichloroethane (IIa) or 1-bromo-2-chloroethane (IIb) (3) by means of K2CO3 in DMF at 100-5 °c or 60 °c affords 2-(2-chloroethoxy)-5-nitrobenzaldehyde (III), which by reduction with nabH4 in THF or MeoH yields the corresponding alcohol (IV). O-Alkylation of alcohol (IV) with allyl bromide (V) and KoH and Bu4NHSo4 or Bu4Ni at 40 °c gives 2-(allyloxymethyl)-1-(2-chloroethoxy)-4-nitrobenzene (VI), which is then reduced with Fe in the presence of nH4cl in EtoH to yield the corresponding aniline (VII). condensation of amine (VII) with 4-[3-(allyloxymethyl)phenyl]-2-chloropyrimidine (VIII) by means of Hcl in buoH at 80 °c affords the 2-anilinopyrimidine derivative (IX), which then undergoes ring-closing metathesis in the presence of Grubbs’ second-generation catalyst and HCl in CH2Cl2 at 40-45 °c to yield macrocycle (X). Finally, compound (X) is submitted to microwave-assisted condensation with pyrrolidine (XI) in dimethylacetamide at 80 °c .
intermediate (VIII) can be prepared by Suzuki coupling of 2,4-dichloropyrimidine (XII) with 3-(hydroxymethyl)phenylboronic acid (XIII) in the presence of Pd(OAc)2, PPh3 and na2co3 in THF at 70 °c or Pd(PPh3)4 and Na2CO3 in DME at 80-5 °c to give [3-(2-chloropyrimidin-4-yl)phenyl]methanol (XIV), which is finally O-alkylated with allyl bromide (V) and KOH and Bu4NHSO4 or Cs2CO3 in DMF at 40 °c .

参考文献 中间体
合成目标
【1】 William, A.D., Lee, A.c., blanchard, S. et al. Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma. J Med chem 2011, 54(13): 4638-58.
【2】 Lee, A., William, A., Poulsen, A. et al. Design, synthesis and SAR studies leading to SB1518, a novel macrocyclic JAK2/FLT3 inhibitor in phase 2 clinical trials for myelofibrosis and lymphoma. 102nd Annu Meet Am Assoc cancer Res (AAcR) (April 2-6, orlando) 2011, Abst 3564.
【3】 blanchard, S., Lee, c.H.A., nagaraj, H.K.M., Poulsen, A., Sun, E.t., tan, Y.L.E., William, A.D. (S*bio Pte. Ltd.). EP 1951729, JP 2009515954, US 8153632, Wo 2007058627.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IIa) 16170 1,2-dichloroethane 107-06-2 C2H4Cl2 详情 详情
(IIb) 24271 1-bromo-2-chloroethane 107-04-0 C2H4BrCl 详情 详情
(IX) 68053 N-(3-((allyloxy)methyl)-4-(2-chloroethoxy)phenyl)-4-(3-((allyloxy)methyl)phenyl)pyrimidin-2-amine 　 C26H28ClN3O3 详情 详情
(I) 42307 2-hydroxy-5-nitrobenzaldehyde；5-nitrosalicylaldehyde 97-51-8 C7H5NO4 详情 详情
(III) 68048 2-(2-chloroethoxy)-5-nitrobenzaldehyde 　 C9H8ClNO4 详情 详情
(IV) 68049 (2-(2-chloroethoxy)-5-nitrophenyl)methanol 　 C9H10ClNO4 详情 详情
(V) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(VI) 68050 2-((allyloxy)methyl)-1-(2-chloroethoxy)-4-nitrobenzene 　 C12H14ClNO4 详情 详情
(VII) 68051 3-((allyloxy)methyl)-4-(2-chloroethoxy)aniline 　 C12H16ClNO2 详情 详情
(VIII) 68052 4-[3-(allyloxymethyl)phenyl]-2-chloropyrimidine 　 C14H13ClN2O 详情 详情
(X) 68054 　 　 C24H24ClN3O3 详情 详情
(XI) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(XII) 54377 2,4-Dichloropyrimidine 3934-20-1 C4H2Cl2N2 详情 详情
(XIII) 68055 3-(hydroxymethyl)phenylboronic acid；(3-Hydroxymethyl)phenylboronic acid;(m-Hydroxymethyl)phenylboronic acid;3-Hydroxymethylbenzeneboronic acid 87199-15-3 C7H9BO3 详情 详情
(XIV) 68056 [3-(2-chloropyrimidin-4-yl)phenyl]methanol 　 C11H9ClN2O 详情 详情
Extended Information