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【结 构 式】

【分子编号】14689

【品名】Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate

【CA登记号】2605-67-6

【 分 子 式 】C21H19O2P

【 分 子 量 】334.354422

【元素组成】C 75.44% H 5.73% O 9.57% P 9.26%
与该中间体有关的原料药合成路线共 30 条
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合成路线1

该中间体在本合成路线中的序号：(III)

The ozonolysis of cylcoheptene (I) with O3 in dichloromethane, followed by a treatment with methanol and p-toluenesulfonic acid gives 7,7-dimethoxyheptanal (II), which is condensed with methoxycarbonyl-methylenetriphenylphosphorane (III) in methanol yielding methyl 9,9-dimethoxy-2-nonenoate (IV). The condensation of (IV) with 2(S)-(tetrahydropyranyloxy)propanal (V) by means of LDA in THF/HMPA affords the beta-hydroxyester (VI), which is cyclized by means of p-toluenesulfonic acid and mesyl chloride affording the furanone (VII). The hydrolysis of the acetal group of (VII) with Amberlyst 15 gives the aldehyde (VIII), which is condensed with the phosphorane (IX) yielding the unsaturated thioester (X). The cyclization of (XV) by means of Et2AlCl in toluene affords the tricyclic thioester (XI), which is reduced with RaNi in ethanol/ethyl ether affording the carbinol (XII). The reaction of (XII) with tosyl chloride and thiophenol provides the pheylsulfanyl derivative (XIII), which is reduced at the lactone group with iBu2AlH in ethyl ether giving the lactol (XIV). The methylation of the lactol (XIV) with BF3/Et2O and methanol yields the cyclic ketal (XV), which is finally oxidized with meta-chloroperbenzoic acid (MCPBA) in dichloromethane to afford the desired tricyclic sulfone intermediate (XVI).

参考文献 中间体
合成目标
【1】 Hart, D.J.and Wu, W.-L.; Total syntheses of (+)-Himbacine and (-)-Himbeline. J Am Chem Soc 1995, 117, 9369.
【2】 Wu, W.-L.; Hart, D.J.; Li, J.; Applications of Organosulfur Chemistry to Organic Synthesis: Total Synthesis of (+)-Himbeline and (-)-Himbacine. J Org Chem 1997, 62, 5023.
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) 33179 1-cycloheptene 628-92-2 C7H12 详情 详情
(II) 33180 7,7-dimethoxyheptanal C9H18O3 详情 详情
(III) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(IV) 33181 methyl (E)-9,9-dimethoxy-2-nonenoate C12H22O4 详情 详情
(V) 33182 (2R)-2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)propanal C9H16O3 详情 详情
(VI) 33183 methyl (E)-2-[(2R)-1-hydroxy-2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-9,9-dimethoxy-3-nonenoate C21H38O7 详情 详情
(VII) 33184 (5S)-3-[(E)-7,7-dimethoxy-1-heptenyl]-5-methyl-2(5H)-furanone C14H22O4 详情 详情
(VIII) 33185 (E)-7-[(5S)-5-methyl-2-oxo-2,5-dihydro-3-furanyl]-6-heptenal C12H16O3 详情 详情
(IX) 33186 S-ethyl 2-(triphenylphosphoranylidene)ethanethioate C22H21OPS 详情 详情
(X) 33187 S-ethyl (2E,8E)-9-[(5S)-5-methyl-2-oxo-2,5-dihydro-3-furanyl]-2,8-nonadienethioate C16H22O3S 详情 详情
(XI) 33188 S-ethyl (3S,3aR,4R,4aS,8aS)-3-methyl-1-oxo-1,3,3a,4,4a,5,6,7,8,8a-decahydronaphtho[2,3-c]furan-4-carbothioate C16H22O3S 详情 详情
(XII) 33189 (3S,3aR,4R,4aS,8aR,9aS)-4-(hydroxymethyl)-3-methyldecahydronaphtho[2,3-c]furan-1(3H)-one C14H22O3 详情 详情
(XIII) 33190 (3S,3aS,4R,4aS,8aR,9aS)-3-methyl-4-[(phenylsulfanyl)methyl]decahydronaphtho[2,3-c]furan-1(3H)-one C20H26O2S 详情 详情
(XIV) 33191 (1S,3S,3aS,4R,4aS,8aR,9aS)-3-methyl-4-[(phenylsulfanyl)methyl]dodecahydronaphtho[2,3-c]furan-1-ol C20H28O2S 详情 详情
(XV) 33192 (1S,3S,3aS,4R,4aS,8aR,9aS)-3-methyl-4-[(phenylsulfanyl)methyl]dodecahydronaphtho[2,3-c]furan-1-yl methyl ether; (1S,3S,3aS,4R,4aS,8aR,9aS)-1-methoxy-3-methyl-4-[(phenylsulfanyl)methyl]dodecahydronaphtho[2,3-c]furan C21H30O2S 详情 详情
(XVI) 33193 [(1S,3S,3aS,4R,4aS,8aR,9aS)-1-methoxy-3-methyldodecahydronaphtho[2,3-c]furan-4-yl]methyl phenyl sulfone; (1S,3S,3aS,4R,4aS,8aR,9aS)-1-methoxy-3-methyl-4-[(phenylsulfonyl)methyl]dodecahydronaphtho[2,3-c]furan C21H30O4S 详情 详情

合成路线2

该中间体在本合成路线中的序号：(III)

The intermediate (XVI) has been obtained as follows: The ozonolysis of (2S,3S,4S)-2,4-dimethyl-1-(tert-butyldimethylsilyloxy)-5-hexen-3-ol (I) with O3 in DMSO gives the aldehyde (II), which is condensed with phosphorane (III) to yield the chiral heptenoic acid methyl ester (IV). The reaction of (IV) with benzaldehyde (V) by means of KHMDS affords the cyclic ketal (VI), which is desilylated with HF to provide the carbinol (VII). The oxidation of (VII) in methanol gives the dimethylacetal (VIII), which is treated with CSA in methanol to yield the tetrahydropyranylacetic acid methyl ester (IX). The silylation of the OH group of (IX) with Tbdms-OTf affords the silyl ether (X), which is hydrolyzed with LiOH to the corresponding free acetic acid (XI). The condensation of (XI) with N,O-dimethylhydroxylamine (XII) by means of DCC and HOBT provides the methoxyamide (XIII), which is treated with phenylsulfanyltrimethylsilane (XIV), ZnI2 and tetrabutylammonium iodide to give the phenylsulfanyl derivative (XV). Finally, the methoxyamide group of (XV) is reduced with LiAlH4 to afford the target acetaldehyde derivative (XVI).

参考文献 中间体
合成目标
【1】 Hung, D.T.; et al.; Syntheses of discodermolides useful for investigating microtubule binding and stabilization. J Am Chem Soc 1996, 118, 45, 11054.
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) 42688 (2S,3S,4S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-hexen-3-ol C14H30O2Si 详情 详情
(II) 42689 (2R,3R,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-2,4-dimethylpentanal C13H28O3Si 详情 详情
(III) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(IV) 42690 methyl (E,4S,5S,6S)-7-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4,6-dimethyl-2-heptenoate C16H32O4Si 详情 详情
(V) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VI) 42691 methyl 2-[(4S,5R,6R)-6-((1S)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methylethyl)-5-methyl-2-phenyl-1,3-dioxan-4-yl]acetate C23H38O5Si 详情 详情
(VII) 42692 methyl 2-[(4S,5R,6R)-6-[(1S)-2-hydroxy-1-methylethyl]-5-methyl-2-phenyl-1,3-dioxan-4-yl]acetate C17H24O5 详情 详情
(VIII) 42693 methyl 2-[(4S,5R,6S)-6-[(1R)-2,2-dimethoxy-1-methylethyl]-5-methyl-2-phenyl-1,3-dioxan-4-yl]acetate C19H28O6 详情 详情
(IX) 42694 methyl 2-[(2S,3R,4S,5R)-4-hydroxy-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-yl]acetate C11H20O5 详情 详情
(X) 42695 methyl 2-((2S,3S,4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-yl)acetate C17H34O5Si 详情 详情
(XI) 42696 2-((2S,3S,4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-yl)acetic acid C16H32O5Si 详情 详情
(XII) 13361 (Methoxyamino)methane; N,O-Dimethylhydroxylamine 1117-97-1 C2H7NO 详情 详情
(XIII) 42697 2-((2S,3S,4S,5R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxy-3,5-dimethyltetrahydro-2H-pyran-2-yl)-N-methoxy-N-methylacetamide C18H37NO5Si 详情 详情
(XIV) 42698 trimethyl(phenylsulfanyl)silane; phenyl trimethylsilyl sulfide 4551-15-9 C9H14SSi 详情 详情
(XV) 42699 2-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]-N-methoxy-N-methylacetamide C23H39NO4SSi 详情 详情
(XVI) 42700 2-[(2S,3S,4S,5R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-2-yl]acetaldehyde C21H34O3SSi 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XXIX)

The condensation of propane-1,3-diol (XXV) with benzaldehyde by means of p-toluenesulfonic acid gives the corresponding cyclic acetal (XXVI), which is reduced with diisobutylaluminum hydride in toluene yielding 3-benzoyloxy-1-propanol (XXVII). The oxidation of (XXVII) with oxalyl chloride as before affords the corresponding aldehyde (XXVIII), which is submitted to a Wittig condensation with 2-(triphenylphosphoranylidene)acetic acid methyl ester (XXIX) giving (E)-5-benzyloxy-2-pentenoic acid methyl ester (XXX). The hydrolysis of (XXX) with NaOH in THF-water yields the corresponding acid (XXXI), which is condensed with pivaloyl chloride (XXXII) to afford the mixed anhydride (XXXIII). The condensation of (XXXIII) with 4(S)-benzyloxazolidin-2-one (XXXIV) by means of BuLi in THF gives 4(S)-benzyl-3-[5-benzyloxy-2(E)-pentenoyl]oxazolidin-2-one (XXXV), which is submitted to a Diels-Alder cycloaddition with cyclopentadiene (XXXVI) to yield 4-benzyl-3-[(3R,4R,5S,6S)-5-(2-benzyloxyethyl)bicyclo[2.2.1]hept-2-en-4-ylcarbonyl]oxazolidin-2-one (XXXVII). Hydrogenation of (XXXVII) with H2 over Pt in ethylacetate, followed by hydrolysis with H2O2 and LiOH affords (1R,2R,3S,4S)-3-(2-benzyloxyethyl)bicyclo[2.2.1]heptane-2-carboxylic acid (XXXVIII). The formation of the corresponding azide with ethyl chloroformate and sodium azide followed by degradation in refluxing toluene gives the amine (XXXIX), which is acylated with benzenesulfonyl chloride as before yielding the sulfonamide (XL). The deprotection of (XL) by hydrogenolysis with H2 over Pd/C in ethanol affords the substituted ethanol (XLI). Oxidation of (XLI) with oxalyl chloride as before gives the aldehyde (XLII), which is finally submitted to a Wittig condensation with 4-carboxybutyl triphenylphosphonium bromide and t-BuOK to yield acid (XIV) enantiomerically pure, already obtained.

参考文献 中间体
合成目标
【1】 Wong and F.F. Sun (Eds.), Raven Press, Ltd., New York 1989, 19, 659-62.
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) 14674 (Z)-7-[(1R,2S,3S,4S)-3-[(phenylsulfonyl)amino]bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid C20H27NO4S 详情 详情
(XXV) 14685 1,3-propanediol; Trimethylene Glycol 504-63-2 C3H8O2 详情 详情
(XXVI) 14686 2-phenyl-1,3-dioxane C10H12O2 详情 详情
(XXVII) 14687 3-(benzyloxy)-1-propanol; 3-(Benzyloxy)propanol 4799-68-2 C10H14O2 详情 详情
(XXVIII) 14688 3-(benzyloxy)propanal C10H12O2 详情 详情
(XXIX) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(XXX) 14690 Methyl (E)-5-(benzyloxy)-2-pentenoate C13H16O3 详情 详情
(XXXI) 14691 (E)-5-(Benzyloxy)-2-pentenoic acid C12H14O3 详情 详情
(XXXII) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(XXXIII) 14693 (E)-4-(Benzyloxy)-2-pentenoic 1,1-Dimethylpropionic anhydride C17H22O4 详情 详情
(XXXIV) 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
(XXXV) 14695 (4S)-4-benzyl-3-[(E)-5-(benzyloxy)-2-pentenoyl]-1,3-oxazolan-2-one C22H23NO4 详情 详情
(XXXVI) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(XXXVII) 14697 (4S)-4-benzyl-3-([(1R,2S,3S,4S)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]hept-5-en-2-yl]carbonyl)-1,3-oxazolan-2-one C27H29NO4 详情 详情
(XXXVIII) 14698 (1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]heptane-2-carboxylic acid C17H22O3 详情 详情
(XXXIX) 14699 (1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]heptan-2-amine; (1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]hept-2-ylamine C16H23NO 详情 详情
(XL) 14700 N-[(1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]hept-2-yl]benzenesulfonamide C22H27NO3S 详情 详情
(XLI) 14701 N-[(1S,2S,3S,4R)-3-(2-hydroxyethyl)bicyclo[2.2.1]hept-2-yl]benzenesulfonamide C15H21NO3S 详情 详情
(XLII) 14673 N-[(1S,2S,3S,4R)-3-(2-oxoethyl)bicyclo[2.2.1]hept-2-yl]benzenesulfonamide C15H19NO3S 详情 详情

合成路线4

该中间体在本合成路线中的序号：

Scheme shows the synthesis of Galardin(TM) from the two starting materials, 4-methyl-2-oxopentanoic acid sodium salt (I) and tert-butyloxycarbonyl-L-tryptophan (V). The pentanoic acid is protected as a benzyl ester and then condensed with the ylide methyl (triphenylphosphoranylidene)acetate to give methyl 3-benzyloxycarbonyl-5-methyl-2-hexenoate (III). Deprotection and reduction of (III) gives the key intermediate 2(R,S)-2-methoxycarbonylmethyl-4-methylpentanoic acid (IV) in high overall yield. The protected L-tryptophan starting material (V) is coupled with methylamine to give (VI), which is deprotected to give the second key intermediate, L-tryptophan methylamide hydrochloride (VII). Coupling of (IV) and (VII) gives the mixture of diastereomers 2(R,S)-2-methoxycarbonylmethyl-4-methylpentanoyl-L-tryptophan methylamide. Low-pressure column chromatography on silica gel gives 2(R)-2-methoxycarbonylmethyl-4-methylpentanoyl-L-tryptophan methylamide (VIII) in high yield. Direct hydroxaminolysis of the methyl ester (VIII) in methanol in the presence of potassium hydroxide gives crude Galardin(TM). Recrystallization gives the drug substance.

参考文献 中间体
合成目标
【1】 Bodden, M.K.; Engler, J.A.; Moore, W.G.I.; Windsor, L.J.; Birkedal-Hansen, H.; Birkedal-Hansen, B.; DeCarlo, A.; Matrix metalloproteinases: A review. Crit Rev Oral Biol Med 1993, 4, 2, 197-250.
【2】 Galardy, R.E.; Galardin (TM). Drugs Fut 1993, 18, 12, 1109.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(I) 16110 sodium 4-methyl-2-oxopentanoate C6H9NaO3 详情 详情
(II) 16111 benzyl 4-methyl-2-oxopentanoate C13H16O3 详情 详情
(III) 16112 1-benzyl 4-methyl (E)-2-isobutyl-2-butenedioate C16H20O4 详情 详情
(IV) 16113 2-(2-methoxy-2-oxoethyl)-4-methylpentanoic acid C9H16O4 详情 详情
(V) 16114 N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid 13139-14-5 C16H20N2O4 详情 详情
(VI) 16115 tert-butyl N-[(1S)-1-(1H-indol-3-ylmethyl)-2-(methylamino)-2-oxoethyl]carbamate C17H23N3O3 详情 详情
(VII) 16116 (2S)-2-amino-3-(1H-indol-3-yl)-N-methylpropanamide C12H15N3O 详情 详情
(VIII) 16117 methyl (3R)-3-([[(1S)-1-(1H-indol-3-ylmethyl)-2-(methylamino)-2-oxoethyl]amino]carbonyl)-5-methylhexanoate C21H29N3O4 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IV)

An enantioselective total synthesis of (+)-calanolide A has been reported: The silylation of 2'-hydroxy-4',6'-dimethoxybutyrophenone (I) with TIPS-Cl by means of benzylltriethylammonium chloride and NaOH in benzene gives the silyl ether (II), which is demethylated with BCl3 in dichloromethane yielding 2'-hydroxy-4'-methoxy-6'-(triisopropylsilyloxy)butyrophenone (III). The Wittig condensation of (III) with the phosphorane (IV) in N,N-diethylaniline with simultaneous cyclization, affords the benzopyranone (V), which is submitted to a Friedel-Crafts condensation with the acyl chloride (VI) by means of SnCl4 in dichloromethane to provide the 8-acylbenzopyranone (VII). The desilylation of (VII) by means of TBAF in THF/dichloromethane gives the 5-hydroxy compound (VIII) which is submitted to a propargylation with alcohol (IX) and DBU and then to a Claisen rearrangement with N,N-diethylaniline affording the pyrano-benzopyran (X). Demethylation of (X) with MgI2 in refluxing benzene gives the phenol (XI), which is submitted to a (-)-quinine-catalyzed asymmetric intramolecular oxo-Michael addition in chlorobenzene yielding an 80:20 mixture of the chiral cis- and trans-benzotripyrans (XII) (94% ee) and (XIII), respectively. Since the desired compound is the minor component (XIII), the preceding mixture is treated with MgI2 in refluxing benzene to afford an equilibrated 50:50 mixture that is separated by chromatography, and the undesired cis-isomer can be recycled by repeating the MgI2 treatment. The enantiomerically rich trans-isomer (XIII) is finally reduced with LiAlH(Ot-Bu)3 in THF.

参考文献 中间体
合成目标
【1】 Tanaka, T.; et al.; Enantioselective total synthesis of anti HIV-1 active (+)-calanolide A through a quinine-catalyzed asymmetric intramolecular oxo-Michael addition. Tetrahedron Lett 2000, 41, 52, 10229.
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) 45726 1-(2-hydroxy-4,6-dimethoxyphenyl)-1-butanone C12H16O4 详情 详情
(II) 45727 1-[2,4-dimethoxy-6-[(triisopropylsilyl)oxy]phenyl]-1-butanone C21H36O4Si 详情 详情
(III) 45728 1-[2-hydroxy-4-methoxy-6-[(triisopropylsilyl)oxy]phenyl]-1-butanone C20H34O4Si 详情 详情
(IV) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(V) 45729 7-methoxy-4-propyl-5-[(triisopropylsilyl)oxy]-2H-chromen-2-one C22H34O4Si 详情 详情
(VI) 45730 Tigloyl chloride; (E)-2-methyl-2-butenoyl chloride 35660-94-7 C5H7ClO 详情 详情
(VII) 45731 7-methoxy-8-[(E)-2-methyl-2-butenoyl]-4-propyl-5-[(triisopropylsilyl)oxy]-2H-chromen-2-one C27H40O5Si 详情 详情
(VIII) 45732 5-hydroxy-7-methoxy-8-[(E)-2-methyl-2-butenoyl]-4-propyl-2H-chromen-2-one C18H20O5 详情 详情
(IX) 22416 3-chloro-3-methyl-1-butyne 1111-97-3 C5H7Cl 详情 详情
(X) 45733 5-methoxy-2,2-dimethyl-6-[(E)-2-methyl-2-butenoyl]-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one C23H26O5 详情 详情
(XI) 45734 5-hydroxy-2,2-dimethyl-6-[(E)-2-methyl-2-butenoyl]-10-propyl-2H,8H-pyrano[2,3-f]chromen-8-one C22H24O5 详情 详情
(XII) 22411 (10R,11S)-6,6,10,11-tetramethyl-4-propyl-10,11-dihydro-2H,6H,12H-dipyrano[2,3-f:2,3-h]chromene-2,12-dione C22H24O5 详情 详情
(XIII) 22410 (10R,11R)-6,6,10,11-tetramethyl-4-propyl-10,11-dihydro-2H,6H,12H-dipyrano[2,3-f:2,3-h]chromene-2,12-dione C22H24O5 详情 详情

合成路线6

该中间体在本合成路线中的序号：(XIII)

Intermediate (VII) can be obtained by following two different pathways: 1. Hydrogenation of 4-pyridine acetic acid (IX) over PtO2 in AcOH affords piperidinyl derivative (X), which is then protected with Boc2O and NaOH in THF to yield (XI). Reduction of the CO2H group of (XI) with BH3.THF in THF gives alcohol (XII), which is then subjected to Swern oxidation with oxalyl chloride and DMSO in CH2Cl2, followed by reaction with Wittig reagent (XIII) and N-methyl morpholine (NMM), to provide crotonate (XIV). Hydrogenation of (XIV) over Pd/C in MeOH furnishes methyl butyrate (XV), which is finally hydrolyzed with NaOH in MeOH. 2. Alternatively, intermediate (VII) can be obtained by reaction of diethyl malonate (XVI) with 4-vinylpyridine and NaH in EtOH to afford derivative (XVIII), which is hydrolyzed and decarboxylated with HCl/H2O and then hydrogenated over PtO2 to provide piperidine derivative (XIX). Finally, (XIX) is protected by reaction with Boc2O and NaOH in THF.

参考文献 中间体
合成目标
【1】 Molino, B.F.; Klein, S.I.; Czekaj, M.; et al.; Design of a new class of orally active fibrinogen receptor antagonists. J Med Chem 1998, 41, 14, 2492.
【2】 Klein, S.I.; Molino, B.F. (Aventis Pharma SA); Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides. EP 0812205; JP 1997507213; US 5866685; WO 9510295 .
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) 45852 4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butyric acid C14H25NO4 详情 详情
(IX) 17883 2-(4-pyridinyl)acetic acid 28356-58-3 C7H7NO2 详情 详情
(X) 45854 2-(4-piperidinyl)acetic acid; 4-piperidinylacetic acid 51052-78-9 C7H13NO2 详情 详情
(XI) 19346 1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid 157688-46-5 C12H21NO4 详情 详情
(XII) 43453 tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate C12H23NO3 详情 详情
(XIII) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(XIV) 45855 tert-butyl 4-[(E)-4-methoxy-4-oxo-2-butenyl]-1-piperidinecarboxylate C15H25NO4 详情 详情
(XV) 45856 tert-butyl 4-(4-methoxy-4-oxobutyl)-1-piperidinecarboxylate C15H27NO4 详情 详情
(XVI) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XVII) 45857 4-vinylpyridine C7H7N 详情 详情
(XVIII) 45858 diethyl 2-[2-(4-pyridinyl)ethyl]malonate C14H19NO4 详情 详情
(XIX) 45859 4-(4-piperidinyl)butyric acid C9H17NO2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(IX)

The intermediate 4-(4-chlorophenylsulfonyl)aminocyclohexanone (V) was prepared by two synthetic ways. Reductive condensation of 4,4-diethoxycyclohexanone (I) with benzylamine in the presence of sodium triacetoxyborohydride and AcOH provided the benzylcyclohexylamine (II). Further hydrogenolysis of the N-benzyl group of (II) in the presence of Pd/C and oxalic acid yielded cyclohexylamine (III) as the oxalate salt. Sulfonamide (V) was then obtained by condensation with 4-chlorophenylsulfonyl chloride (IV), followed by hydrolysis of the diethyl acetal with aqueous HCl. lternatively, treatment of trans-4-aminocyclohexanol hydrochloride (VI) with sulfonyl chloride (IV) in the presence of Et3N provided the sulfonamide (VII), which was subsequently oxidized with chromic anhydride and H2SO4 to the target ketone (V). Condensation of this intermediate (V) with ethyl formate in the presence of NaH produced the hydroxymethylene cyclohexanone (VIII), which was submitted to a Wittig reaction with phosphorane (IX) to give the cyclohexylidenpropanoic ester (X). Cyclization of this compound using anhydrous p-toluenesulfonic acid in refluxing toluene furnished pyranone (XI), which by subsequent bromination in acetic acid yielded the 3-bromopyranone (XII). The key tetrahydronaphthalene system (XIV) was then obtained by Diels-Alder reaction with methyl propiolate (XIII) with concomitant decarboxylation at 200 C. Finally, the ester function of (XIV) was reduced to alcohol (XV) with LiAlH4.

参考文献 中间体
合成目标
【1】 Cimetière, B.; Dubuffet, T.; Landras, C.; Descombes, J.J.; Simonet, S.; Verbeuren, T.J.; Lavielle, G.; New tetrahydronaphthalene derivatives as combined thromboxane receptor antagonists and thromboxane synthase inhibitors. Bioorg Med Chem Lett 1998, 8, 11, 1381.
【2】 Lavielle, G.; Dubuffet, T.; Muller, O.; Laubie, M.; Verbeuren, T.; Simonet, S.; Descombes, J.-J. (ADIR et Cie.); 1,2,3,4-Tetrahydronaphthalene, chroman and thiochroman derivs. as antithrombotic agents. CA 2118102; EP 0648741; FR 2711139; JP 1995188155 .
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) 19576 4,4-diethoxycyclohexanone C10H18O3 详情 详情
(II) 19577 N-benzyl-4,4-diethoxycyclohexanamine; N-benzyl-N-(4,4-diethoxycyclohexyl)amine C17H27NO2 详情 详情
(III) 19578 4,4-diethoxycyclohexanamine; 4,4-diethoxycyclohexylamine C10H21NO2 详情 详情
(V) 19580 4-chloro-N-(4-oxocyclohexyl)benzenesulfonamide C12H14ClNO3S 详情 详情
(VI) 19581 trans-4-Aminocyclohexanol；trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; 27489-62-9 C6H13NO 详情 详情
(VII) 19582 4-chloro-N-(4-hydroxycyclohexyl)benzenesulfonamide C12H16ClNO3S 详情 详情
(VIII) 19583 4-chloro-N-[3-[(Z)-hydroxymethylidene]-4-oxocyclohexyl]benzenesulfonamide C13H14ClNO4S 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) 19585 methyl 3-(5-[[(4-chlorophenyl)sulfonyl]amino]-2-oxocyclohexylidene)propanoate C16H18ClNO5S 详情 详情
(XI) 19586 4-chloro-N-(2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)benzenesulfonamide C15H14ClNO4S 详情 详情
(XII) 19587 N-(3-bromo-2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)-4-chlorobenzenesulfonamide C15H13BrClNO4S 详情 详情
(XIII) 19588 methyl propiolate 922-67-8 C4H4O2 详情 详情
(XIV) 19589 methyl 3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenecarboxylate C18H17BrClNO4S 详情 详情
(XV) 19590 N-[7-bromo-5-(hydroxymethyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-4-chlorobenzenesulfonamide C17H17BrClNO3S 详情 详情

合成路线8

该中间体在本合成路线中的序号：(IX)

The alcohol (XV) was oxidized with 4-benzylpyridinium dichromate to the aldehyde (XVI). 3-(Tributylstannylmethyl)pyridine (XVIII), prepared from lithiated 3-picoline (XVII) and Bu3SnCl in the presence of HMPA, was coupled to bromotetrahydronaphthalene (XVI) under palladium catalysis to provide the pyridylmethyl derivative (XIX). Wittig reaction of (XIX) with phosphorane (IX) gave acrylate (XX), which was reduced with NaBH4 and CoCl2 to the tetrahydronaphthylpropionic ester (XXI). Finally, the ester group of (XXI) was hydrolyzed with NaOH in MeOH-H2O to give the title acid.

参考文献 中间体
合成目标
【1】 Cimetière, B.; Dubuffet, T.; Landras, C.; Descombes, J.J.; Simonet, S.; Verbeuren, T.J.; Lavielle, G.; New tetrahydronaphthalene derivatives as combined thromboxane receptor antagonists and thromboxane synthase inhibitors. Bioorg Med Chem Lett 1998, 8, 11, 1381.
【2】 Lavielle, G.; Dubuffet, T.; Muller, O.; Laubie, M.; Verbeuren, T.; Simonet, S.; Descombes, J.-J. (ADIR et Cie.); 1,2,3,4-Tetrahydronaphthalene, chroman and thiochroman derivs. as antithrombotic agents. CA 2118102; EP 0648741; FR 2711139; JP 1995188155 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(XVI) 19591 N-(7-bromo-5-formyl-1,2,3,4-tetrahydro-2-naphthalenyl)-4-chlorobenzenesulfonamide C17H15BrClNO3S 详情 详情
(XVII) 19592 (3-pyridinylmethyl)lithium C6H6LiN 详情 详情
(XVIII) 19572 3-[(tributylstannyl)methyl]pyridine C18H33NSn 详情 详情
(XIX) 19594 4-chloro-N-[5-formyl-7-(3-pyridinylmethyl)-1,2,3,4-tetrahydro-2-naphthalenyl]benzenesulfonamide C23H21ClN2O3S 详情 详情
(XX) 19595 methyl (E)-3-[6-[[(4-chlorophenyl)sulfonyl]amino]-3-(3-pyridinylmethyl)-5,6,7,8-tetrahydro-1-naphthalenyl]-2-propenoate C26H25ClN2O4S 详情 详情
(XXI) 19596 methyl 3-[6-[[(4-chlorophenyl)sulfonyl]amino]-3-(3-pyridinylmethyl)-5,6,7,8-tetrahydro-1-naphthalenyl]propanoate C26H27ClN2O4S 详情 详情

合成路线9

该中间体在本合成路线中的序号：(VIII)

The reaction of 4(R)-hydroxy-L-proline (I) with allyl chloroformate (II) and NaOH gives the protected proline (III), which is esterified with MeOH and sulfuric acid to yield the methyl prolinate (IV). The reaction of (IV) with Ms-Cl and TEA affords the mesylate (V), which is reduced with NaBH4 to provide the prolinol derivative (VI). The Swern oxidation of alcohol (VI) gives the carbaldehyde (VII), which is condensed with the phosphorane (VIII) by means of NaOMe, yielding the acrylate (IX). The reduction of (IX) with DIBAL affords the substituted allyl alcohol (X), which is condensed with phthalimide (XI) by means of PPh3 and DIAD to provide the adduct (XII). The cleavage of the phthalimido group of (XII) with hydrazine gives the amino derivative (XIII), which is treated with Ms-Cl and TEA to yield the sulfonamide (XIV). The reaction of (XIV) with potassium thioacetate affords the acetylsulfanyl pyrrolidine (XV), which is hydrolyzed with HCl to provide the thiol (XVI). The condensation of the thiol (XVI) with the carbapenem derivative (XVII) by means of DIEA gives the protected adduct (XVIII), which is finally treated with Pd(II) and Bu3SnH in order to eliminate the allyl protecting groups. The intermediate carbapenem derivative (XVII) has been obtained from azetidinone (XIX) by known methods as indicated in the scheme.

参考文献 中间体
合成目标
【1】 Kwon, J.W.; Kim, W.B.; Kim, S.H.; Lee, M.G.; DA-1131. Drugs Fut 2001, 26, 11, 1040.
【2】 Shin, H.C.; Kim, J.Y.; Kim, G.W.; Lee, C.W.; Lim, J.I.; Chang, M.S.; Kim, N.S.; Kim, D.S.; Im, W.B.; Rhee, J.K. (Dong-A Pharmaceutical Co., Ltd.); Carbapenem derivs. and processes for preparing the same. WO 9514692 .
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) 14489 (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline 51-35-4 C5H9NO3 详情 详情
(II) 38115 3-[(chlorocarbonyl)oxy]-1-propene 2937-50-0 C4H5ClO2 详情 详情
(III) 47730 (2S,4R)-1-[(allyloxy)carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid C9H13NO5 详情 详情
(IV) 42200 1-allyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate C10H15NO5 详情 详情
(V) 42201 1-allyl 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]-1,2-pyrrolidinedicarboxylate C11H17NO7S 详情 详情
(VI) 42202 allyl (2S,4R)-2-(hydroxymethyl)-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C10H17NO6S 详情 详情
(VII) 49446 allyl (2S,4R)-2-formyl-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C10H15NO6S 详情 详情
(VIII) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(IX) 49447 allyl (2S,4R)-2-[(E)-3-methoxy-3-oxo-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C13H19NO7S 详情 详情
(X) 49448 allyl (2S,4R)-2-[(E)-3-hydroxy-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C12H19NO6S 详情 详情
(XI) 12376 Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione 85-41-6 C8H5NO2 详情 详情
(XII) 49449 allyl (2S,4R)-2-[(E)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C20H22N2O7S 详情 详情
(XIII) 49450 allyl (2S,4R)-2-[(E)-3-amino-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C12H20N2O5S 详情 详情
(XIV) 50598 allyl (2S,4R)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C13H22N2O7S2 详情 详情
(XV) 49451 allyl (2S,4S)-4-(acetylsulfanyl)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate C14H22N2O5S2 详情 详情
(XVI) 49452 allyl (2S,4S)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-sulfanyl-1-pyrrolidinecarboxylate C12H20N2O4S2 详情 详情
(XVII) 32617 allyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C25H26NO8P 详情 详情
(XVIII) 49454 allyl (4R,5S,6S)-3-[((3S,5S)-1-[(allyloxy)carbonyl]-5-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C25H35N3O8S2 详情 详情
(XIX) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(XX) 50599 　 C17H27N3O6Si 详情 详情
(XXI) 16074 Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate 2524-64-3 C12H10ClO3P 详情 详情

合成路线10

该中间体在本合成路线中的序号：(VII)

In a different synthetic strategy, the known Garner's aldehyde (I) is subjected to a Wittig reaction with phosphorane (II) to give the unsaturated ester (III), which is subsequently hydrogenated, producing (IV) as an inseparable mixture of diastereoisomers. Oxazolidine hydrolysis in (IV), followed by cyclization under acidic conditions leads to lactone (V). This is then converted to the thiolactone (VI) upon treatment with Lawesson's reagent in hot toluene. Condensation of thiolactone (VI) with the Wittig reagent (VII), followed by double bond isomerization in the presence of DBU furnishes the dihydropyran derivative (VIII). Stereoselective hydrogenation of the double bond of (VIII) with PtO2 gives rise to the desired all-cis isomer (IX). The methyl vester group of (IX) is then reduced to aldehyde (X) by means of DIBAL in cold toluene.

参考文献 中间体
合成目标
【1】 Horigome, M.; Motoyoshi, H.; Watanabe, H.; Kitahara, T.; A synthesis of FR901464. Tetrahedron Lett 2001, 42, 46, 8207.
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) 62140 tert-butyl (4S,5R)-4-formyl-2,2,5-trimethyl-1,3-oxazolidine-3-carboxylate C12H21NO4 详情 详情
(II) 37071 ethyl 2-(triphenylphosphoranylidene)propanoate 5717-37-3 C23H23O2P 详情 详情
(III) 62141 tert-butyl (4R,5R)-4-[(E)-3-ethoxy-2-methyl-3-oxo-1-propenyl]-2,2,5-trimethyl-1,3-oxazolidine-3-carboxylate C17H29NO5 详情 详情
(IV) 62142 tert-butyl (4R,5R)-4-(3-ethoxy-2-methyl-3-oxopropyl)-2,2,5-trimethyl-1,3-oxazolidine-3-carboxylate C17H31NO5 详情 详情
(V) 62143 tert-butyl (2R,3R)-2,5-dimethyl-6-oxotetrahydro-2H-pyran-3-ylcarbamate C12H21NO4 详情 详情
(VI) 62144 tert-butyl (2R,3R,5R)-2,5-dimethyl-6-thioxotetrahydro-2H-pyran-3-ylcarbamate C12H21NO3S 详情 详情
(VII) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(VIII) 62145 methyl 2-{(2R,3R)-3-[(tert-butoxycarbonyl)amino]-2,5-dimethyl-3,4-dihydro-2H-pyran-6-yl}acetate C15H25NO5 详情 详情
(IX) 62146 methyl 2-{(2S,3S,5R,6R)-5-[(tert-butoxycarbonyl)amino]-3,6-dimethyltetrahydro-2H-pyran-2-yl}acetate C15H27NO5 详情 详情
(X) 62147 tert-butyl (2R,3R,5S,6S)-2,5-dimethyl-6-(2-oxoethyl)tetrahydro-2H-pyran-3-ylcarbamate C14H25NO4 详情 详情

合成路线11

该中间体在本合成路线中的序号：

Wittig reaction of N-(benzyloxycarbonyl)-L-phenylalaninal (I) with methyl (triphenylphosphoranylidene)acetate produced unsaturated ester (II). Double bond reduction in (II) with concomitant cyclization and N-deprotection upon treatment with Mg in MeOH furnished (R)-5-benzyl-2-pyrrolidinone (III), which was further protected as the N-Boc derivative (IV) (1). Alkylation of (IV) with benzyl bromide in the presence of LDA in THF at -78 C provided the trans-3,5-dimethylpyrrolidinone (V) as the predominant diastereoisomer. After Boc group cleavage using trifluoroacetic acid, pyrrolidinone (VI) was coupled with epoxide (VII) yielding adduct (VIII). The acetonide protecting group of (VIII) was finally hydrolyzed with HCl to give the title compound.

参考文献 中间体
合成目标
【1】 Kazmierski, W.; Andrews, W. III; Baker, C.; et al.; Heterocyclic isosteres of the P1/P2 domain of amprenavir: Discovery of novel, picomolar HIV-1 protease inhibitors. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 126.
【2】 Tung, R.D.; Salituro, F.G.; Deininger, D.D.; Bhisetti, G.R.; Baker, C.T.; Spaltenstein, A.; Kazmierski, W.M.; Andrews, C.W. III (Vertex Pharmaceuticals Inc.); Aspartyl protease inhibitors. JP 2000501111; US 5945413; WO 9727180 .
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
14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(I) 16586 benzyl N-[(1S)-1-benzyl-2-oxoethyl]carbamate C17H17NO3 详情 详情
(II) 38970 methyl (E,4S)-4-[[(benzyloxy)carbonyl]amino]-5-phenyl-2-pentenoate C20H21NO4 详情 详情
(III) 38971 (5R)-5-benzyl-2-pyrrolidinone C11H13NO 详情 详情
(IV) 38972 tert-butyl (2R)-2-benzyl-5-oxo-1-pyrrolidinecarboxylate C16H21NO3 详情 详情
(V) 38973 tert-butyl (3S,5R)-3,5-dibenzyl-2-oxo-1-pyrrolidinecarboxylate C23H27NO3 详情 详情
(VI) 38974 (3S,5R)-3,5-dibenzyl-2-pyrrolidinone C18H19NO 详情 详情
(VII) 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
(VIII) 38975 (3S,5R)-1-[(2S,4R)-5-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-4-benzyl-2-hydroxy-5-oxopentyl]-3,5-dibenzyl-2-pyrrolidinone C42H46N2O4 详情 详情

合成路线12

该中间体在本合成路线中的序号：(XVII)

Methyl 6-methylnicotinate (XII) was condensed with 4-pyridinecarboxaldehyde (XIII) in AcOH-Ac2O at 120 C to produce (XIV). Then, ester group was reduced with LiAlH4 to alcohol (XV), and this was subsequently oxidized with DMSO and SO3-pyridine complex to give aldehyde (XVI). Wittig reaction with phosphorane (XVII) afforded ester (XVIII), which was saponified to yield acid (XIX). Finally, coupling of acid (XIX) with amine (XI) in the presence of EDC and HOBt provided the title amide.

参考文献 中间体
合成目标
【1】 Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Inamura, N.; Asano, M.; Aramori, I.; Hatori, C.; Sawai, H.; Oku, T.; Tanaka, H.; A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 3. Discovering bioisosteres of the imidazo[1,2-a]pyridine moiety. J Med Chem 1998, 41, 21, 4062.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 18600 2-amino-N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-N-methylacetamide C20H19Cl2N3O2 详情 详情
(XII) 14160 methyl 6-methylnicotinate 5470-70-2 C8H9NO2 详情 详情
(XIII) 17203 4-Pyridinecarboxaldehyde; isonicotinaldehyde 872-85-5 C6H5NO 详情 详情
(XIV) 18603 methyl 6-[(E)-2-(4-pyridinyl)ethenyl]nicotinate C14H12N2O2 详情 详情
(XV) 18604 [6-[(E)-2-(4-pyridinyl)ethenyl]-3-pyridinyl]methanol C13H12N2O 详情 详情
(XVI) 18605 6-[(E)-2-(4-pyridinyl)ethenyl]nicotinaldehyde C13H10N2O 详情 详情
(XVII) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(XVIII) 18607 methyl (E)-3-[6-[(E)-2-(4-pyridinyl)ethenyl]-3-pyridinyl]-2-propenoate C16H14N2O2 详情 详情
(XIX) 18608 (E)-3-[6-[(E)-2-(4-pyridinyl)ethenyl]-3-pyridinyl]-2-propenoic acid C15H12N2O2 详情 详情

合成路线13

该中间体在本合成路线中的序号：(IX)

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14

该中间体在本合成路线中的序号：(IX)

The intermediate 4-(4-chlorophenylsulfonyl)aminocyclohexanone (V) was prepared by two synthetic ways: 1) Reductive condensation of 4,4-diethoxycyclohexanone (I) with benzylamine in the presence of sodium triacetoxyborohydride and AcOH provided the benzylcyclohexylamine (II). Further hydrogenolysis of the N-benzyl group of (III) in the presence of Pd/C and oxalic acid yielded cyclohexylamine (III) as the oxalate salt. Sulfonamide (V) was then obtained by condensation with 4-chlorophenylsulfonyl chloride (IV), followed by hydrolysis of the diethyl acetal with aqueous HCl. 2) Alternatively, treatment of trans-4-aminocyclohexanol hydrochloride (VI) with sulfonyl chloride (IV) in the presence of Et3N provided the sulfonamide (VII), which was subsequently oxidized with chromic anhydride and H2SO4 to the target ketone (V). 3) Condensation of this intermediate with ethyl formate in the presence of NaH produced the hydroxymethylene cyclohexanone (VIII), which was submitted to a Wittig reaction with phosphorane (IX) to give the cyclohexylidenpropanoic ester (X). Cyclization of this compound using anhydrous p-toluenesulfonic acid in refluxing toluene furnished pyranone (XI), which by subsequent bromination in acetic acid yielded the 3-bromopyranone (XII) (1). The key tetrahydronaphthalene system (XIV) was then obtained by Diels-Alder reaction with refluxing methyl hexynoate (XIII) with concomitant decarboxylation. The ester function of (XIV) was reduced to alcohol (XV) with LiAlH4.

参考文献 中间体
合成目标
【1】 Cimetière, B.; Dubuffet, T.; Landras, C.; Descombes, J.J.; Simonet, S.; Verbeuren, T.J.; Lavielle, G.; New tetrahydronaphthalene derivatives as combined thromboxane receptor antagonists and thromboxane synthase inhibitors. Bioorg Med Chem Lett 1998, 8, 11, 1381.
【2】 Lavielle, G.; Dubuffet, T.; Muller, O.; Laubie, M.; Verbeuren, T.; Simonet, S.; Descombes, J.-J. (ADIR et Cie.); 1,2,3,4-Tetrahydronaphthalene, chroman and thiochroman derivs. as antithrombotic agents. CA 2118102; EP 0648741; FR 2711139; JP 1995188155 .
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) 19576 4,4-diethoxycyclohexanone C10H18O3 详情 详情
(II) 19577 N-benzyl-4,4-diethoxycyclohexanamine; N-benzyl-N-(4,4-diethoxycyclohexyl)amine C17H27NO2 详情 详情
(III) 19578 4,4-diethoxycyclohexanamine; 4,4-diethoxycyclohexylamine C10H21NO2 详情 详情
(IV) 15787 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride 98-60-2 C6H4Cl2O2S 详情 详情
(V) 19580 4-chloro-N-(4-oxocyclohexyl)benzenesulfonamide C12H14ClNO3S 详情 详情
(VI) 19581 trans-4-Aminocyclohexanol；trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; 27489-62-9 C6H13NO 详情 详情
(VII) 19582 4-chloro-N-(4-hydroxycyclohexyl)benzenesulfonamide C12H16ClNO3S 详情 详情
(VIII) 19583 4-chloro-N-[3-[(Z)-hydroxymethylidene]-4-oxocyclohexyl]benzenesulfonamide C13H14ClNO4S 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) 19585 methyl 3-(5-[[(4-chlorophenyl)sulfonyl]amino]-2-oxocyclohexylidene)propanoate C16H18ClNO5S 详情 详情
(XI) 19586 4-chloro-N-(2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)benzenesulfonamide C15H14ClNO4S 详情 详情
(XII) 19587 N-(3-bromo-2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)-4-chlorobenzenesulfonamide C15H13BrClNO4S 详情 详情
(XIII) 19609 methyl 2-hexynoate 18937-79-6 C7H10O2 详情 详情
(XIV) 19610 methyl 3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-2-propyl-5,6,7,8-tetrahydro-1-naphthalenecarboxylate C21H23BrClNO4S 详情 详情
(XV) 19611 N-[7-bromo-5-(hydroxymethyl)-6-propyl-1,2,3,4-tetrahydro-2-naphthalenyl]-4-chlorobenzenesulfonamide C20H23BrClNO3S 详情 详情

合成路线15

该中间体在本合成路线中的序号：(IX)

Then group of (XV) was oxidized with 4-benzylpyridinium dichromate to the aldehyde (XVI). 3-(Tributylstannylmethyl)pyridine (XVIII), prepared from lithiated 3-picoline (XVII) and Bu3SnCl in the presence of HMPA, was coupled to bromotetrahydronaphthalene (XVI) under palladium catalysis to provide the pyridylmethyl derivative (XIX). Wittig reaction of (XIX) with phosphorane (IX) gave acrylate (XX), which was reduced with SmI2 or with NaBH4 and CoCl2 to the tetrahydronaphthylpropionic ester (XXI). Finally, the ester group of (XXI) was hydrolyzed with NaOH in MeOH-H2O to give the title acid.

参考文献 中间体
合成目标
【1】 Cimetière, B.; Dubuffet, T.; Landras, C.; Descombes, J.J.; Simonet, S.; Verbeuren, T.J.; Lavielle, G.; New tetrahydronaphthalene derivatives as combined thromboxane receptor antagonists and thromboxane synthase inhibitors. Bioorg Med Chem Lett 1998, 8, 11, 1381.
【2】 Lavielle, G.; Dubuffet, T.; Muller, O.; Laubie, M.; Verbeuren, T.; Simonet, S.; Descombes, J.-J. (ADIR et Cie.); 1,2,3,4-Tetrahydronaphthalene, chroman and thiochroman derivs. as antithrombotic agents. CA 2118102; EP 0648741; FR 2711139; JP 1995188155 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(XV) 19611 N-[7-bromo-5-(hydroxymethyl)-6-propyl-1,2,3,4-tetrahydro-2-naphthalenyl]-4-chlorobenzenesulfonamide C20H23BrClNO3S 详情 详情
(XVI) 19612 N-(7-bromo-5-formyl-6-propyl-1,2,3,4-tetrahydro-2-naphthalenyl)-4-chlorobenzenesulfonamide C20H21BrClNO3S 详情 详情
(XVII) 19592 (3-pyridinylmethyl)lithium C6H6LiN 详情 详情
(XVIII) 19572 3-[(tributylstannyl)methyl]pyridine C18H33NSn 详情 详情
(XIX) 19615 4-chloro-N-[5-formyl-6-propyl-7-(3-pyridinylmethyl)-1,2,3,4-tetrahydro-2-naphthalenyl]benzenesulfonamide C26H27ClN2O3S 详情 详情
(XX) 19616 methyl (E)-3-[6-[[(4-chlorophenyl)sulfonyl]amino]-2-propyl-3-(3-pyridinylmethyl)-5,6,7,8-tetrahydro-1-naphthalenyl]-2-propenoate C29H31ClN2O4S 详情 详情
(XXI) 19617 methyl 3-[6-[[(4-chlorophenyl)sulfonyl]amino]-2-propyl-3-(3-pyridinylmethyl)-5,6,7,8-tetrahydro-1-naphthalenyl]propanoate C29H33ClN2O4S 详情 详情

合成路线16

该中间体在本合成路线中的序号：(II)

The target FR-165649 has been obtained by condensation of cinnamic acid (V) with amine (XIII) using EDC and HOBt as coupling agents. The two intermediates (V) and (XIII) have been obtained as follows: 1) Wittig reaction of 4-formylbenzoic acid (I) and methyl (triphenylphosphoranylidene)acetate (II) in THF gave methyl 4-carboxycinnamate (III), which was converted into amide (IV) by reaction with methylamine hydrochloride in the presence of EDC and HOBt. Further hydrolysis of the ester group with NaOH provided 4-(methylcarbamoyl)cinnamic acid (V). 2) The alkylation of 8-hydroxy-2-methylquinoline (VI) with benzylic chloride (VII) in the presence of NaH and a catalytic amount of tetrabutylammonium iodide in DMF afforded ether (VIII). Subsequent reduction of the nitro group with iron powder and HCl in refluxing aqueous methanol gave amine (IX), which was coupled with phthalimidoacetyl chloride (X) in the presence of DMAP in a mixture of N-methylpyrrolidone and pyridine to yield amide (XI). Then, alkylation at the amide N with CH3I and NaH provided (XII), and further hydrazinolysis of the phthalimido group yielded the primary amine (XIII). Finally, the target amide was obtained by condensation of cinnamic acid (V) with amine (XIII) using EDC and HOBt as the coupling reagents.

参考文献 中间体
合成目标
【1】 Oku, T.; Kayakiri, H.; Satoh, S.; Abe, Y.; Sawada, Y.; Inoue, T.; Tanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Pyridopyrimidones, quinolines and fused N-heterocycles as bradykinin antagonists. EP 0807105; JP 1998507764; WO 9613485 .
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) 18922 4-formylbenzoic acid 619-66-9 C8H6O3 详情 详情
(II) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(III) 18924 4-[(E)-3-methoxy-3-oxo-1-propenyl]benzoic acid C11H10O4 详情 详情
(IV) 18925 methyl (E)-3-[4-[(methylamino)carbonyl]phenyl]-2-propenoate C12H13NO3 详情 详情
(V) 18926 (E)-3-[4-[(methylamino)carbonyl]phenyl]-2-propenoic acid C11H11NO3 详情 详情
(VI) 18598 2-methyl-8-quinolinol 826-81-3 C10H9NO 详情 详情
(VII) 18928 1,3-dichloro-2-(chloromethyl)-4-nitrobenzene C7H4Cl3NO2 详情 详情
(VIII) 18929 2,6-dichloro-3-nitrobenzyl 2-methyl-8-quinolinyl ether; 8-[(2,6-dichloro-3-nitrobenzyl)oxy]-2-methylquinoline C17H12Cl2N2O3 详情 详情
(IX) 18930 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenylamine; 2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]aniline C17H14Cl2N2O 详情 详情
(X) 10278 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride 6780-38-7 C10H6ClNO3 详情 详情
(XI) 18932 N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetamide C27H19Cl2N3O4 详情 详情
(XII) 18599 N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-methylacetamide C28H21Cl2N3O4 详情 详情
(XIII) 18600 2-amino-N-(2,4-dichloro-3-[[(2-methyl-8-quinolinyl)oxy]methyl]phenyl)-N-methylacetamide C20H19Cl2N3O2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(XI)

On the other hand, Wittig condensation of isobutyraldehyde (X) with methyl (triphenylphosphoranylidene)acetate (XI) afforded (E)-4-methylpent-2-enoic acid methyl ester (XII). Sharpless catalytic asymmetric dihydroxylation of (XII) gave diol (XIII). Condensation of diol (XIII) with trimethyl orthobenzoate in the presence of BF3.Et2O, followed by treatment of the crude cyclic orthoester with acetyl bromide produced bromo ester (XIV). The required alpha-amino group was then introduced by nucleophilic displacement of the bromide of (XIV) with NaN3 in DMSO, followed by catalytic hydrogenation of the resulting azide (XV). The intermediate amino ester (XVI) was then rearranged to hydroxy amide (XVII) upon refluxing in EtOAc. Cyclization of (XVII) to the required trans oxazoline (XVIII) was then achieved by treatment with p-toluenesulfonic acid in boiling toluene.

参考文献 中间体
合成目标
【1】 Soucy, F.; et al.; A novel and efficient synthesis of a highly active analogue clasto-lactacystin beta-lactone. J Am Chem Soc 1999, 121, 43, 9967.
【2】 Plamondon, L.; Soucy, F.; Behnke, M.; Roush, W.; Synthesis of clasto-lactacystin beta-lactone and analogs thereof. WO 9909006 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 13226 2-Methylpropanal; Isobutyraldehyde 78-84-2 C4H8O 详情 详情
(XI) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(XII) 37799 methyl (E)-4-methyl-2-pentenoate C7H12O2 详情 详情
(XIII) 37800 methyl (2S,3R)-2,3-dihydroxy-4-methylpentanoate C7H14O4 详情 详情
(XIV) 37801 (1S,2S)-2-bromo-1-isopropyl-3-methoxy-3-oxopropyl benzoate C14H17BrO4 详情 详情
(XV) 37802 (1S,2R)-2-azido-1-isopropyl-3-methoxy-3-oxopropyl benzoate C14H17N3O4 详情 详情
(XVI) 37803 (1S,2R)-2-amino-1-isopropyl-3-methoxy-3-oxopropyl benzoate C14H19NO4 详情 详情
(XVII) 37804 methyl (2R,3S)-2-(benzoylamino)-3-hydroxy-4-methylpentanoate C14H19NO4 详情 详情
(XVIII) 37805 methyl (4R,5S)-5-isopropyl-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate C14H17NO3 详情 详情

合成路线18

该中间体在本合成路线中的序号：(VIII)

Diels-Alder condensation of benzopyran (I) with methyl (trimethylsilyl)propynoate (II) gave rise to tetrahydronaphthalene (III). After reduction of the ester group of (III) with LiAlH4, the resulting alcohol (IV) was further oxidized to aldehyde (V) by means of 4-benzylpyridinium dichromate. Treatment of (V) with iodine monochloride produced iodonaphthalene (VI). Subsequent reaction of (VI) with vinyl tributyltin and palladium tetrakis(triphenylphosphine) yielded the vinyl naphthalene (VII). Wittig reaction of (VIII with (carbomethoxymethylidene)triphenylphosphorane (VIII) gave the arylpropenoate ester (IX), which was reduced to the saturated ester (X) employing samarium iodide.

参考文献 中间体
合成目标
【1】 Lavielle, G.; Cimetiere, B.; Verbeuren, T.; Simonet, S.; Descombes, J.-J. (ADIR et Cie.); Nouveaux dérivés de benzènsessulfonylamine, leur procédé depréparation et les compositions pharmaceutiques qui les contiennent. EP 0864561 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
24920 tributyl(vinyl)stannane；Tributylvinylstannane;Vinyltributylstannane 7486-35-3 C14H30Sn 详情 详情
(I) 19586 4-chloro-N-(2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)benzenesulfonamide C15H14ClNO4S 详情 详情
(II) 32594 methyl 3-(trimethylsilyl)-2-propynoate C7H12O2Si 详情 详情
(III) 32595 methyl 6-[[(4-chlorophenyl)sulfonyl]amino]-2-(trimethylsilyl)-5,6,7,8-tetrahydro-1-naphthalenecarboxylate C21H26ClNO4SSi 详情 详情
(IV) 32596 4-chloro-N-[5-(hydroxymethyl)-6-(trimethylsilyl)-1,2,3,4-tetrahydro-2-naphthalenyl]benzenesulfonamide C20H26ClNO3SSi 详情 详情
(V) 32597 4-chloro-N-[5-formyl-6-(trimethylsilyl)-1,2,3,4-tetrahydro-2-naphthalenyl]benzenesulfonamide C20H24ClNO3SSi 详情 详情
(VI) 19571 4-chloro-N-(5-formyl-6-iodo-1,2,3,4-tetrahydro-2-naphthalenyl)benzenesulfonamide C17H15ClINO3S 详情 详情
(VII) 32598 4-chloro-N-(5-formyl-6-vinyl-1,2,3,4-tetrahydro-2-naphthalenyl)benzenesulfonamide C19H18ClNO3S 详情 详情
(VIII) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(IX) 32599 methyl (E)-3-(6-[[(4-chlorophenyl)sulfonyl]amino]-2-vinyl-5,6,7,8-tetrahydro-1-naphthalenyl)-2-propenoate C22H22ClNO4S 详情 详情
(X) 32600 methyl 3-(6-[[(4-chlorophenyl)sulfonyl]amino]-2-vinyl-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate C22H24ClNO4S 详情 详情

合成路线19

该中间体在本合成路线中的序号：(II)

Taxane intermediates (XIII) and (XIV) were prepared by two related ways. Wittig condensation of cyclopropanecarboxaldehyde (I) with methoxycarbonylmethylenetriphenyl phosphorane (II) gave methyl trans-cyclopropylacrylate (III). This was oxidized with potassium ferricyanide in the presence of OsO4 and the chiral catalyst 1,4-bis(9-O-dihydroquinidyl)phthalazine to furnish (2S,3R)-diol (IV). After conversion of (IV) to tosylate (V), its cyclization by means of K2CO3 produced epoxide (VI). Subsequent epoxide opening with NaN3 gave azide (VII), which was hydrogenated in the presence of Pd/C and di tert-butyl dicarbonate to furnish carbamate (VIII). Treatment of (VIII) with isopropenyl methyl ether (IX) and pyridinium tosylate, followed by ester hydrolysis, produced oxazolidine (X). This was coupled to protected taxane (XI) by means of DCC and DMAP to provide ester (XII). Oxazolidine hydrolysis in (XII) with formic acid, followed by reprotection of the amine with Boc2O, furnished intermediate (XIII). Optionally, the trichloroethoxycarbonyl groups of (XIII) were removed upon treatment with Zn and AcOH to produce intermediate (XIV).

参考文献 中间体
合成目标
【1】 Tsujihari, K.; Hashiyama, T.; Ohashi, M.; Nakanishi, N. (Tanabe Seiyaku Co., Ltd.); Baccatin derivs. and processes for preparing the same. CA 2162759; EP 0712854; JP 1997151181; US 5589502 .
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) 26463 cyclopropanecarbaldehyde 1489-69-6 C4H6O 详情 详情
(II) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(III) 26464 methyl (E)-3-cyclopropyl-2-propenoate C7H10O2 详情 详情
(IV) 26465 methyl (2S,3R)-3-cyclopropyl-2,3-dihydroxypropanoate C7H12O4 详情 详情
(V) 26466 methyl (2S,3R)-3-cyclopropyl-3-hydroxy-2-[[(4-methylphenyl)sulfonyl]oxy]propanoate C14H18O6S 详情 详情
(VI) 26467 methyl (2R,3R)-3-cyclopropyl-2-oxiranecarboxylate C7H10O3 详情 详情
(VII) 26468 methyl (2R,3S)-3-azido-3-cyclopropyl-2-hydroxypropanoate C7H11N3O3 详情 详情
(VIII) 26469 methyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-cyclopropyl-2-hydroxypropanoate C12H21NO5 详情 详情
(IX) 26470 3-methoxy-1-butene C5H10O 详情 详情
(X) 26471 (4S,5R)-3-(tert-butoxycarbonyl)-4-cyclopropyl-2,2-dimethyl-1,3-oxazolidine-5-carboxylic acid C14H23NO5 详情 详情
(XI) 23892 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C35H38Cl6O14 详情 详情
(XII) 26472 methyl (9S,12S)-4-methoxy-12-[[(2S,5S,8S,11R)-5-(4-methoxybenzyl)-2,6,8,11,15,15-hexamethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl](methyl)amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C49H59Cl6NO18 详情 详情
(XIII) 26473 methyl (9S,12S)-4-methoxy-12-[[(2S,5S,8S,11R)-5-(4-methoxybenzyl)-2,6,8,11,15,15-hexamethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl](methyl)amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C46H55Cl6NO18 详情 详情
(XIV) 26474 methyl (9S,12S)-4-methoxy-12-[[(2S,5S,8S,11R)-5-(4-methoxybenzyl)-2,6,8,11,15,15-hexamethyl-4,7,10,13-tetraoxo-14-oxa-3,6,9,12-tetraazahexadec-1-anoyl](methyl)amino]-11-oxo-2-oxa-10-azatricyclo[12.2.2.1(3,7)]nonadeca-1(16),3(19),4,6,14,17-hexaene-9-carboxylate C40H53NO14 详情 详情

合成路线20

该中间体在本合成路线中的序号：(XVII)

The Stille coupling of the benzodioxanone (XII) with allyltributyltin (XIII) by means of trifurylphosphine (TFP) and Pd2(dba)3 gives the 6-allylsalicylic acid (XIV), which is esterified with the intermediate (XI) by means of DEAD and PPH3 in ethyl ether to yield the ester (XV). Hydrolysis of the lactol group of (XV) with Ac-OH affords the carbaldehyde (XVI), which is condensed with the phosphorane (XVII) to provide the unsaturated ester (XVIII). The silylation of the free OH groups of (XVIII) with Tbdms-OTf and lutidine gives the protected compound (XIX), which is submitted to a rig closing metathesis reaction catalyzed by a Ru catalyst in dichloromethane to yield the macrolactone (XX). The selective hydrolysis of the methyl ester group of (XX) by treatment with (Bu3Sn)2O in refluxing toluene affords the unsaturated carboxylic acid (XXI), which is treated with DPPA in refluxing benzene to provide the corresponding isocyanate (XXII). The reaction of the isocyanate group of (XXII) with (1Z,3Z)-hexadienyl cuprate, prepared in situ by reaction of Et-Li, CuBr/Me2S and acetylene, gives the silylated heptadienamide (XXIII), along with some pentanamide and nonatrienamide derivatives that are separated by chromatography. Finally, compound (XXIII) is desilylated by means of HF and pyridine in THF to provide the target salicylhalamide A.

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
(XI) 56942 (4S,6R)-2-methoxy-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-4-ol C11H20O3 详情 详情
(XII) 56943 2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-5-yl trifluoromethanesulfonate C11H9F3O6S 详情 详情
(XIII) 40599 Allyltributyltin; Tributyl-2-propenylstannane 24850-33-7 C15H32Sn 详情 详情
(XIV) 56944 2-allyl-6-hydroxybenzoic acid C10H10O3 详情 详情
(XV) 56945 (4R,6R)-2-methoxy-6-[(1S)-1-methyl-3-butenyl]tetrahydro-2H-pyran-4-yl 2-allyl-6-hydroxybenzoate C21H28O5 详情 详情
(XVI) 56946 (1R,3R,4S)-3-hydroxy-4-methyl-1-(2-oxoethyl)-6-heptenyl 2-allyl-6-hydroxybenzoate C20H26O5 详情 详情
(XVII) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(XVIII) 56947 (1S,3R,4S)-3-hydroxy-1-[(E)-4-methoxy-4-oxo-2-butenyl]-4-methyl-6-heptenyl 2-allyl-6-hydroxybenzoate C23H30O6 详情 详情
(XIX) 56948 (1S,3R,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-[(E)-4-methoxy-4-oxo-2-butenyl]-4-methyl-6-heptenyl 2-allyl-6-{[tert-butyl(dimethyl)silyl]oxy}benzoate C35H58O6Si2 详情 详情
(XX) 56949 methyl (E)-4-((3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenoate C33H54O6Si2 详情 详情
(XXI) 56950 (E)-4-((3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-2-butenoic acid C32H52O6Si2 详情 详情
(XXII) 56951 (3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-3-[(E)-3-isocyanato-2-propenyl]-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one C32H51NO5Si2 详情 详情
(XXIII) 56952 (2Z,4Z)-N-[(E)-3-((3S,5R,6S)-5,14-bis{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-1-oxo-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)-1-propenyl]-2,4-heptadienamide C38H61NO5Si2 详情 详情

合成路线21

该中间体在本合成路线中的序号：(XVI)

A new Wittig condensation of aldehyde (XV) with phosphorane (XVI) in refluxing benzene gives the diunsaturated ester (XVII), which is reduced with DIBAL to the corresponding alcohol, and oxidated with DMP yielding the aldehyde (XVIII). The condensation of (XVIII) with the chiral propionyloxazolidinethione (XIX) by means of Sn(OTf)2 and 1-ethylpiperidine in dichloromethane affords the adduct (XX), which is treated with NaBH4 in THF to eliminate the chiral auxiliary and afford diol (XXI). The metalation of (XXI) with Bu3SnH and a Pd catalyst gives the vinylstannane (XXII), which is desilylated with TBAF in THF yielding the trihydroxycompound (XXIII). The condensation of stannane (XXIII) with iodobutenoic ester (XXIV) by means of a Pd catalyst affords the diunsaturated ester (XXV), which is selectively disilylated with TBDMSCl and imidazole in hot DMF to provide the disilyl ether (XXVI).

参考文献 中间体
合成目标
【1】 Guzzupe, A.N.; et al.; Total synthesis of the epidermal growth factor inhibitor (-)-reveromycin B. J Org Chem 2001, 66, 7, 2382.
【2】 Cuzzupe, A.N.; et al.; Total synthesis of (-)-reveromycin B. Org Lett 2000, 2, 2, 191.
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) 41549 (E)-4-[(2R,5S,7R,8S)-2-butyl-2-((1S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-8-methyl-1,6-dioxaspiro[4.5]dec-7-yl]-2-methyl-2-butenal n/a C27H46O4Si 详情 详情
(XVI) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(XVII) 41550 methyl (2E,4E)-6-[(2R,5S,7R,8S)-2-butyl-2-((1S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-8-methyl-1,6-dioxaspiro[4.5]dec-7-yl]-4-methyl-2,4-hexadienoate n/a C30H50O5Si 详情 详情
(XVIII) 41551 (2E,4E)-6-[(2R,5S,7R,8S)-2-butyl-2-((1S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-8-methyl-1,6-dioxaspiro[4.5]dec-7-yl]-4-methyl-2,4-hexadienal C29H48O4Si 详情 详情
(XIX) 41552 1-[(4S)-4-isopropyl-2-thioxo-1,3-oxazolidin-3-yl]-1-propanone C9H15NO2S 详情 详情
(XX) 41553 (2R,3S,4E,6E)-8-[(2R,5S,7R,8S)-2-butyl-2-((1S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-8-methyl-1,6-dioxaspiro[4.5]dec-7-yl]-3-hydroxy-1-[(4S)-4-isopropyl-2-thioxo-1,3-oxazolidin-3-yl]-2,6-dimethyl-4,6-octadien-1-one C38H63NO6SSi 详情 详情
(XXI) 41554 (2S,3S,4E,6E)-8-[(2R,5S,7R,8S)-2-butyl-2-((1S)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-8-methyl-1,6-dioxaspiro[4.5]dec-7-yl]-2,6-dimethyl-4,6-octadiene-1,3-diol C32H56O5Si 详情 详情
(XXII) 41555 (2S,3S,4E,6E)-8-[(2R,5S,7R,8S)-2-butyl-2-[(1S,2E)-1-[[tert-butyl(dimethyl)silyl]oxy]-3-(tributylstannyl)-2-propenyl]-8-methyl-1,6-dioxaspiro[4.5]dec-7-yl]-2,6-dimethyl-4,6-octadiene-1,3-diol n/a C44H84O5SiSn 详情 详情
(XXIII) 41556 (2S,3S,4E,6E)-8-[(2R,5S,7R,8S)-2-butyl-2-[(1S,2E)-1-hydroxy-3-(tributylstannyl)-2-propenyl]-8-methyl-1,6-dioxaspiro[4.5]dec-7-yl]-2,6-dimethyl-4,6-octadiene-1,3-diol n/a C38H70O5Sn 详情 详情
(XXIV) 41557 2-(trimethylsilyl)ethyl (E)-3-iodo-2-butenoate n/a C9H17IO2Si 详情 详情
(XXV) 41558 2-(trimethylsilyl)ethyl (2E,4E,6S)-6-[(2R,5S,7R,8S)-2-butyl-7-[(2E,4E,6S,7S)-6,8-dihydroxy-3,7-dimethyl-2,4-octadienyl]-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-6-hydroxy-3-methyl-2,4-hexadienoate n/a C35H60O7Si 详情 详情
(XXVI) 41559 2-(trimethylsilyl)ethyl (2E,4E,6S)-6-[(2R,5S,7R,8S)-7-((2E,4E,6S,7S)-6,8-bis[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-2,4-octadienyl)-2-butyl-8-methyl-1,6-dioxaspiro[4.5]dec-2-yl]-6-hydroxy-3-methyl-2,4-hexadienoate n/a C47H88O7Si3 详情 详情

合成路线22

该中间体在本合成路线中的序号：(XVI)

The condensation of 3-(tert-butyldimethylsilyloxy)propanal (XXXIII) with the chiral borane (XXXIV) by means of H2O2 and NaHCO3 gives the chiral alcohol (XXXV), which is oxidized with OsO4 and NaIO4 to yield the aldehyde (XXXVI). The Wittig condensation of (XXXVI) with phosphorane (XVI) affords the heptenoic ester (XXXVII), which is reduced with H2 over Pd/C to provide the saturated hydroxy ester (XXXVIII). The cyclization of (XXXVIII) by means of PPTS in refluxing dichloromethane gives the lactone (XXXIX), which by reaction with Cp2TiMe2 yields the methylene derivative (I).

参考文献 中间体
合成目标
【1】 Guzzupe, A.N.; et al.; Total synthesis of the epidermal growth factor inhibitor (-)-reveromycin B. J Org Chem 2001, 66, 7, 2382.
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) 41537 tert-butyl(dimethyl)[2-[(2R,3S)-3-methyl-6-methylenetetrahydro-2H-pyran-2-yl]ethoxy]silane; tert-butyl(dimethyl)silyl 2-[(2R,3S)-3-methyl-6-methylenetetrahydro-2H-pyran-2-yl]ethyl ether C15H30O2Si 详情 详情
(XVI) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(XXXIII) 45546 3-[[tert-butyl(dimethyl)silyl]oxy]propanal 570-24-1 C9H20O2Si 详情 详情
(XXXIV) 50353 (E)-2-butenyl[bis[(1R,2R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]]borane C24H41B 详情 详情
(XXXV) 50354 (3R,4S)-1-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-hexen-3-ol C13H28O2Si 详情 详情
(XXXVI) 50355 (2R,3R)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxy-2-methylpentanal C12H26O3Si 详情 详情
(XXXVII) 50356 methyl (E,4S,5R)-7-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4-methyl-2-heptenoate C15H30O4Si 详情 详情
(XXXVIII) 50357 methyl (4S,5R)-7-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4-methylheptanoate C15H32O4Si 详情 详情
(XXXIX) 50358 (5S,6R)-6-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methyltetrahydro-2H-pyran-2-one C14H28O3Si 详情 详情

合成路线23

该中间体在本合成路线中的序号：(II)

The condensation of benzylated D-arabinofuranose (I) with phosphonate (II) in benzene gives the unsaturated ester (III), which is reduced with DIBAL in dichloromethane, yielding the alcohol (IV). The selective monosilylation of (IV) with Tbdms-Cl, TEA and DMAP in DMF affords the silyl ether (V), which is treated with chloromethylsulfonyl chloride and pyridine to provide the sulfonate (VI). The reaction of (VI) with CsOAc and a crown ether in toluene gives the acetate (VII) with inversion of the configuration at the acetoxy group. Hydrolysis of the acetate group with NaOMe in THF yields the alcohol (VIII), which is chloromesylated as before, affording the sulfonate (IX). The treatment of (IX) with HCl in THF eliminates the silyl group, providing the unsaturated alcohol (X), which is epoxidized with tBu-OOH, Ti(OAc)4 and D-(-)-diethyl tartrate to give the chiral epoxide (XI). The reaction of (XI) with sodium azide in DMF yields the azido compound (XII) with the correct steric configuration. The reductive cyclization of (XII) with PPh3, H2 and Pd/C in methanol affords the pyrrolidine (XIII), which is N-protected with Boc2O and TEA in dichloromethane, providing the carbamate (XIV). Oxidative cleavage of the vicinal diol of (XIV) with Pb(OAc)4 in toluene gives the carbaldehyde (XV).

参考文献 中间体
合成目标
【1】 Takebayashi, M.; Kajimoto, T.; Kanie, O.; Hiranuma, S.; Kanie, Y.; Wong, C.-H.; A versatile synthetic strategy for the preparation and discovery of new iminocyclitols as inhibitors of glucosidases. J Org Chem 1999, 64, 14, 5280.
【2】 Wong, C.-H.; Liu, J. (Scripps Research Institute); Iminocyclitol inhibitors of hexoaminidase and glycosidase. WO 0068194 .
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) 47654 (3S,4S,5R)-3,4-bis(benzyloxy)-5-[(benzyloxy)methyl]tetrahydro-2-furanol C26H28O5 详情 详情
(II) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(III) 47655 methyl (E,4R,5R,6R)-4,5,7-tris(benzyloxy)-6-hydroxy-2-heptenoate C29H32O6 详情 详情
(IV) 47656 (E,4R,5R,6R)-4,5,7-tris(benzyloxy)-2-heptene-1,6-diol C28H32O5 详情 详情
(V) 47657 (2R,3R,4R,5E)-1,3,4-tris(benzyloxy)-7-[[tert-butyl(dimethyl)silyl]oxy]-5-hepten-2-ol C34H46O5Si 详情 详情
(VI) 47658 (1R,2S,3R,4E)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6-[[tert-butyl(dimethyl)silyl]oxy]-4-hexenyl chloromethanesulfonate C35H47ClO7SSi 详情 详情
(VII) 47659 (1S,2S,3R,4E)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6-[[tert-butyl(dimethyl)silyl]oxy]-4-hexenyl acetate C36H48O6Si 详情 详情
(VIII) 47660 (2S,3R,4R,5E)-1,3,4-tris(benzyloxy)-7-[[tert-butyl(dimethyl)silyl]oxy]-5-hepten-2-ol C34H46O5Si 详情 详情
(IX) 47661 (1S,2S,3R,4E)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6-[[tert-butyl(dimethyl)silyl]oxy]-4-hexenyl chloromethanesulfonate C35H47ClO7SSi 详情 详情
(X) 47662 (1S,2S,3R,4E)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6-hydroxy-4-hexenyl chloromethanesulfonate C29H33ClO7S 详情 详情
(XI) 47663 (1S,2S,3S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-3-[(2S,3R)-3-(hydroxymethyl)oxiranyl]propyl chloromethanesulfonate C29H33ClO8S 详情 详情
(XII) 47664 [(2R,3S)-3-[(1S,2R,3R)-3-azido-1,2,4-tris(benzyloxy)butyl]oxiranyl]methanol C28H31N3O5 详情 详情
(XIII) 47665 (1S)-1-[(2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-[(benzyloxy)methyl]pyrrolidinyl]-1,2-ethanediol C28H33NO5 详情 详情
(XIV) 47666 tert-butyl (2R,3R,4R,5R)-3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5-[(1S)-1,2-dihydroxyethyl]-1-pyrrolidinecarboxylate C33H41NO7 详情 详情
(XV) 47667 tert-butyl (2R,3R,4R,5S)-3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5-formyl-1-pyrrolidinecarboxylate C32H37NO6 详情 详情

合成路线24

该中间体在本合成路线中的序号：(A)

The Wittig reaction of 2,6-dinitrobenzaldehyde (I) with (ethoxycarbonylmethylene)triphenylphosphorane (A) produced methyl 2,6-dinitrocinnamate (II). Hydrogenation of the nitro groups and the olefinic double bond of (II) with concomitant cyclization furnished the tetrahydroquinolinone (III). Reductive alkylation of (III) with 6,6-dimethylheptadiynal (IV) and sodium cyanoborohydride produced the secondary amine (V). Finally, the N-methyl group was introduced by a second reductive alkylation with formaldehyde.

参考文献 中间体
合成目标
【1】 Masabuchi, K.; Umeda, I.; Taniguchi, M.; et al.; Synthesis and structure-activity relationships of novel fungal chitin synthase inhibitors. Bioorg Med Chem Lett 2000, 10, 13, 1459.
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) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(I) 39891 2,6-dinitrobenzaldehyde 606-31-5 C7H4N2O5 详情 详情
(II) 44995 methyl (E)-3-(2,6-dinitrophenyl)-2-propenoate C10H8N2O6 详情 详情
(III) 44996 5-amino-3,4-dihydro-2(1H)-quinolinone C9H10N2O 详情 详情
(IV) 44997 6,6-dimethyl-2,4-heptadiynal C9H10O 详情 详情
(V) 44998 5-[(6,6-dimethyl-2,4-heptadiynyl)amino]-3,4-dihydro-2(1H)-quinolinone C18H20N2O 详情 详情

合成路线25

该中间体在本合成路线中的序号：(LXVII)

The reaction of the chiral dibenzoyloxy-dihydropyran (LXV) with H2SO4 and HgSO4 gives the unsaturated aldehyde (LXVI), which is condensed with the phosphorane (LXVII) to yield the hepatdienoic ester (LXVIII). The hydrogenation of (LXVIII) with H2 over Pd/C affords the heptanoic ester (LXIX), which is treated with Ts-Cl and pyridine to provide the tosyloxy derivative (LXX). The cyclization of (LXX) by means of K2CO3 gives the chiral epoxide (LXXI), which is condensed with vinylmagnesium bromide (LXXII) to yield 6(S)-hydroxy-8-nonenoic acid methyl ester (LXXIII). The oxidation of the terminal double bond of (LXXIII) with ozone affords the carbaldehyde (LXXIV), which is reduced with NaBH4 to provide 6(S),8-dihydroxyoctanoic acid methyl ester (XLVIII). The reaction of (XLVIII) with Ms-Cl and pyridine gives the dimesylate (XLIX), which is treated with Na2S2 to yield the lipoic acid methyl ester (L), which is hydrolyzed to the target acid with KOH in H2O.

参考文献 中间体
合成目标
【1】 Adger, B.; et al.; The synthesis of (R)-(+)-lipoic acid using a monooxygenase-catalysed biotransformation as the key step. Bioorg Med Chem 1997, 5, 2, 253.
【2】 Adger, B.; et al.; Application of enzymatic Baeyer-Villiger oxidations of 2-substituted cycloalkanones to the total synthesis of (R)-(+)-lipoic acid. J Chem Soc Chem Commun 1995, 15, 1563.
【3】 McCague, R.; Roberts, S.M.; Adger, B.M. (Celltech Group plc); Process for the production of lipoic acid. WO 9638437 .
【4】 Villani, F.; Nardi, A.; Salvi, A.; Falabella, G.; Synthesis of R(+)alpha-lipoic acid. WO 0230919 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XLVIII) 57977 methyl (6S)-6,8-dihydroxyoctanoate C9H18O4 详情 详情
(XLIX) 57975 methyl (6S)-6,8-bis[(methylsulfonyl)oxy]octanoate C11H22O8S2 详情 详情
(L) 57976 methyl 5-[(3R)-1,2-dithiolan-3-yl]pentanoate C9H16O2S2 详情 详情
(LXV) 57990 (3R,4S)-4-(benzoyloxy)-3,4-dihydro-2H-pyran-3-yl benzoate C19H16O5 详情 详情
(LXVI) 57991 (1S,2E)-1-(hydroxymethyl)-4-oxo-2-butenyl benzoate C12H12O4 详情 详情
(LXVII) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(LXVIII) 57992 (1S,2E,4E)-1-(hydroxymethyl)-6-methoxy-6-oxo-2,4-hexadienyl benzoate C15H16O5 详情 详情
(LXIX) 57993 (1S)-1-(hydroxymethyl)-6-methoxy-6-oxohexyl benzoate C15H20O5 详情 详情
(LXX) 57994 (1S)-6-methoxy-1-({[(4-methylphenyl)sulfonyl]oxy}methyl)-6-oxohexyl benzoate C22H26O7S 详情 详情
(LXXI) 57995 methyl 5-[(2S)oxiranyl]pentanoate C8H14O3 详情 详情
(LXXII) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(LXXIII) 57996 methyl (6S)-6-hydroxy-8-nonenoate C10H18O3 详情 详情
(LXXIV) 57997 methyl (6S)-6-hydroxy-8-oxooctanoate C9H16O4 详情 详情

合成路线26

该中间体在本合成路线中的序号：(II)

Wittig reaction between aldehyde (I) and methyl(triphenylphosphoranylidene triphenyl)-acetate (II) in refluxing toluene provides E-olefin (III), which is then subjected to reaction with lithium derivative (IV) in THF to afford adduct (V). Benzyl groups of (V) are removed by hydrogenation over Pd(OH)2 in HOAc:MeOH:EtOAc to furnish amine (VI), which is then coupled to Z-Orn(Boc)-OH using 1-ethyl-3-dimethylaminopropylcarbodiimide (WSCD.HCl) and HOBt in CH2Cl2 to give beta-amino acid derivative (VIII). Saponification of the methyl ester group in (VIII) by means of LiOH, followed by condensation with HOBt by means of WSCD.HCl, yields activated ester (IX).

参考文献 中间体
合成目标
【1】 Hashimoto, S.; Hashimoto, M.; Tanaka, A.; Fujie, A.; Shigematsu, N.; Barrett, D.; An expedient synthesis of the amide analog of the potent antifungal lipopeptidolactone FR901469. Tetrahedron Lett 2001, 42, 4, 703.
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) 50186 Myristaldehyde; Myristyl aldehyde; Tetradecanal; Myristic aldehyde trimer; Tetradecyl aldehyde 124-25-4 C14H28O 详情 详情
(II) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(III) 50187 methyl (E)-2-hexadecenoate C17H32O2 详情 详情
(IV) 30864 N-Benzyl-N-(1(R)-phenylethyl)amide lithium salt C15H16LiN 详情 详情
(V) 50188 methyl (3R)-3-[benzyl[(1R)-1-phenylethyl]amino]hexadecanoate C32H49NO2 详情 详情
(VI) 50189 methyl (3R)-3-aminohexadecanoate C17H35NO2 详情 详情
(VII) 50190 (2S)-2-[[(benzyloxy)carbonyl]amino]-5-[(tert-butoxycarbonyl)amino]pentanoic acid C18H26N2O6 详情 详情
(VIII) 50191 methyl (3R)-3-([(2S)-2-[[(benzyloxy)carbonyl]amino]-5-[(tert-butoxycarbonyl)amino]pentanoyl]amino)hexadecanoate C35H59N3O7 详情 详情
(IX) 50192 tert-butyl (4S)-5-([(1R)-1-[2-(1H-1,2,3-benzotriazol-1-yloxy)-2-oxoethyl]tetradecyl]amino)-4-[[(benzyloxy)carbonyl]amino]-5-oxopentylcarbamate C40H60N6O7 详情 详情

合成路线27

该中间体在本合成路线中的序号：(V)

Treatment of gamma-butyrolactone (I) with N,O-dimethylhydroxylamine in the presence of dimethylaluminium chloride afforded the corresponding Weinreb amide (II), which was converted to the keto-alcohol (III) by addition of pentylmagnesium bromide. Swern oxidation of alcohol (III), followed by Wittig reaction of the resultant aldehyde (IV) with (methoxycarbonylmethylene)triphenylphosphorane (V), provided the unsaturated keto ester (VI). Subsequent scandium triflate-mediated peroxyhemiacetalyzation of ketone (VI) gave rise to (VII). Then, intramolecular Michael addition of the hydroperoxy ester (VII) in the presence of diethylamine generated the target cyclic peroxide.

参考文献 中间体
合成目标
【1】 Murakami, N.; Horii, T.; Itagaki, S.; Kobayashi, M.; Kawanishi, M.; New readily accessible peroxides with high anti-malarial potency. Bioorg Med Chem Lett 2002, 12, 1, 69.
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) 20576 dihydro-2(3H)-furanone 96-48-0 C4H6O2 详情 详情
(II) 59681 4-hydroxy-N-methoxy-N-methylbutanamide C6H13NO3 详情 详情
(III) 59682 1-hydroxy-4-nonanone C9H18O2 详情 详情
(IV) 59683 4-oxononanal C9H16O2 详情 详情
(V) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(VI) 59684 methyl (E)-6-oxo-2-undecenoate C12H20O3 详情 详情
(VII) 59685 methyl (E)-6-hydroperoxy-6-methoxy-2-undecenoate C13H24O5 详情 详情

合成路线28

该中间体在本合成路线中的序号：(VI)

Dimethylaluminium chloride-catalyzed ring opening of butyrolactone (I) with N,O-dimethylhydroxylamine furnishes the N-methoxy amide (II). Subsequent condensation of the Weinreb amide (II) with pentylmagnesium bromide (III) gives rise to the hydroxy ketone (IV). Further oxidation of the primary alcohol function of (IV) under Swern conditions leads to keto aldehyde (V). Then, Wittig condensation of aldehyde (V) with (methoxycarbonylmethylene) triphenylphosphorane (VI) affords the unsaturated ester (VII). Treatment of (VII) with urea-hydrogen peroxide in the presence of scandium triflate generates the hydroperoxide compound (VIII), which undergoes further intramolecular ring closure in the presence of triethylamine, leading to the 1,2-dioxane (IX). Enzymatic hydrolysis of ester (IX) employing pig liver esterase gives acid (X). After activation of (X) as the corresponding pentafluorophenyl ester (XI), condensation with propylamine in pyridine provides the title N-propyl amide

参考文献 中间体
合成目标
【1】 Murakami, N.; Kawanishi, M.; Mostaqul, H.M.; Tsuruta, K.; Itagaki, S.; Horii, T.; Kobayashi, M.; Exploitation for new antimalarials using spongean peroxides as scaffolds. 22nd Symp Med Chem (Nov 27 2002, Shizuoka) 2002, Abst 1P-12.
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) 20576 dihydro-2(3H)-furanone 96-48-0 C4H6O2 详情 详情
(II) 59681 4-hydroxy-N-methoxy-N-methylbutanamide C6H13NO3 详情 详情
(III) 31871 bromo(pentyl)magnesium 693-25-4 C5H11BrMg 详情 详情
(IV) 59682 1-hydroxy-4-nonanone C9H18O2 详情 详情
(V) 59683 4-oxononanal C9H16O2 详情 详情
(VI) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(VII) 59684 methyl (E)-6-oxo-2-undecenoate C12H20O3 详情 详情
(VIII) 59685 methyl (E)-6-hydroperoxy-6-methoxy-2-undecenoate C13H24O5 详情 详情
(IX) 60083 methyl 2-(6-methoxy-6-pentyl-1,2-dioxan-3-yl)acetate C13H24O5 详情 详情
(X) 60084 2-(6-methoxy-6-pentyl-1,2-dioxan-3-yl)acetic acid C12H22O5 详情 详情
(XI) 60085 2,3,4,5,6-pentafluorophenyl 2-(6-methoxy-6-pentyl-1,2-dioxan-3-yl)acetate C18H21F5O5 详情 详情

合成路线29

该中间体在本合成路线中的序号：(IV)

In an alternative method, 4-(t-butyldimethylsilyloxy)-3-(1-adamantyl)bromobenzene (I) undergoes Suzuki coupling with 4-formylbenzeneboronic acid (II) to provide the biphenyl aldehyde (III). Subsequent Wittig condensation of (III) with methyl triphenylphosphoranylideneacetate (IV) yields the unsaturated ester (V). This is finally hydrolyzed with LiOH to furnish the title compound.

参考文献 中间体
合成目标
【1】 Penco, S.; Merlini, L.; Giannini, G.; Vesci, L.; Pisano, C.; Dallavalle, S. (Sigma-Tau Industrie Farmaceutiche Riunite SpA); Retinoid derivs. with antiangiogenic, antitumoral and proapoptotic activities. WO 0311808 .
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) 63332 4-bromo-2-tricyclo[3.3.1.1~3,7~]dec-1-ylphenyl (1,1-dimethylethyl)(dimethyl)silyl ether; [(4-bromo-2-tricyclo[3.3.1.1~3,7~]dec-1-ylphenyl)oxy](1,1-dimethylethyl)dimethylsilane C22H33BrOSi 详情 详情
(II) 61564 4-Formylphenylboronic acid; 4-Formylbenzeneboronic acid; 4-Boronobenzaldehyde; Benzaldehyde-4-boronic acid; 4-Formylphenylboronic acid 87199-17-5 C7H7BO3 详情 详情
(III) 63333 4'-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3'-tricyclo[3.3.1.1~3,7~]dec-1-yl[1,1'-biphenyl]-4-carbaldehyde C29H38O2Si 详情 详情
(IV) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(V) 63334 methyl 3-(4'-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3'-tricyclo[3.3.1.1~3,7~]dec-1-yl[1,1'-biphenyl]-4-yl)-2-propenoate C32H42O3Si 详情 详情

合成路线30

该中间体在本合成路线中的序号：(LXII)

Conjugate addition of acrolein (LVIII) to nitromethane in the presence of KOH in MeOH followed by treatment with Na2S2O5 in H2O gives the nitrodisulfonate (LIX), which is hydrolyzed with glyoxylic acid by means of NaHCO3 to yield 4-nitroheptanedial (LX). Compound (LX) is cyclized in the presence of pyrrolidine and PhCOOH in CH2Cl2, providing 5-nitro-1-cyclohexenecarbaldehyde (LXI). Wittig reaction of aldehyde (LXI) with (methoxycarbonylmethylene)triphenylphosphorane (LXII) leads to conjugated ester (LXIII), which is finally saponified with NaOH .
Acid (XXXVII) can be alternatively prepared by Knoevenagel condensation of aldehyde (LXI) with malonic acid (LXIV) .
Hydrolysis of ethylene ketal (XVI) with aqueous p-toluenesulfonic acid gives ketone (LXV), which, without isolation, is converted to oxime (LXVI) by addition of hydroxylamine hydrochloride. Subsequent oxidation of oxime (LXVI) using sodium molybdate and H2O2 leads to compound (XXXVII) .

参考文献 中间体
合成目标
【1】 Wu, G., Sudhakar, A.R., Wang, T. et al. (Schering Corp.). Exo- and diastereo- selective synthesis of himbacine analogs. CA 2594871, EP 1848705, EP 2196454, EP 2196468, EP 2206697, JP 2008526972, US 2006247450, WO 2006076415.
【2】 Thiruvengadam, T.K., Wang, T., Chiu, J.S., Liao, J. (Schering Corp.). Synthesis of 3-(5-nitrocyclohex-1-enyl)acrylic acid and esters thereof. EP 2035364, JP 2009542675, US 2008009651, WO 2008005344.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVI) 68716 (E)-3-(1,4-dioxaspiro[4.5]dec-7-en-7-yl)acrylic acid 　 C11H14O4 详情 详情
(XXXVII) 68733 (E)-3-(5-nitrocyclohex-1-en-1-yl)acrylic acid;3-(5-nitro-1-cyclohexenyl)-2-propenoic acid 　 C9H11NO4 详情 详情
(LVIII) 17668 acrylaldehyde; Acrolein 107-02-8 C3H4O 详情 详情
(LIX) 68754 sodium 1,7-dihydroxy-4-nitroheptane-1,7-disulfonate 　 C7H13NNa2O10S2 详情 详情
(LX) 68755 4-nitroheptanedial 　 C7H11NO4 详情 详情
(LXI) 68756 5-nitro-1-cyclohexenecarbaldehyde 　 C7H9NO3 详情 详情
(LXII) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(LXIII) 68757 (E)-methyl 3-(5-nitrocyclohex-1-en-1-yl)acrylate 　 C10H13NO4 详情 详情
(LXIV) 12963 Malonic acid 141-82-2 C3H4O4 详情 详情
(LXV) 68758 (E)-3-(5-oxocyclohex-1-en-1-yl)acrylic acid 　 C9H10O3 详情 详情
(LXVI) 68759 (E)-3-((E)-5-(hydroxyimino)cyclohex-1-en-1-yl)acrylic acid 　 C9H11NO3 详情 详情
Extended Information