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【结 构 式】

【分子编号】10498

【品名】Benzaldehyde;Benzoic aldehyde;Phenylmethanal

【CA登记号】100-52-7

【 分 子 式 】C7H6O

【 分 子 量 】106.12404

【元素组成】C 79.23% H 5.7% O 15.08%
与该中间体有关的原料药合成路线共 84 条
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合成路线1

该中间体在本合成路线中的序号：(XXVI)

Condensation of benzaldehyde (XXVI) with ethyl glycinate hydrochloride (XXVII) by means of Na2SO4 and Et3N in tert-butyl methyl ether gives 2-(benzylideneamino)acetic acid ethyl ester (XXVIII), which cyclizes with 1,4-dibromo-2(E)-butene (XXIX) in the presence of t-BuOLi in dry toluene to yield, after imine hydrolysis, the cyclopropylamine derivative (XXX). Protection of amine (XXX) with Boc2O furnishes the racemic N-Boc amino ester (XXXI), which is subjected to kinetic resolution by means of enzymes such as Acalase®, Savinase® or Esperase® in DMSO to afford unreacted (1R,2S)-isomer (XXXII). Saponification of ethyl ester (XXXII) using LiOH in THF/MeOH gives the cyclopropanecarboxylic acid derivative (XXXIII), which, after activation with CDI in refluxing THF, is coupled with cyclopropanesulfonamide (XXXIV) (prepared by treatment of cyclopropanesulfonyl chloride [XXXV] with NH3 in THF) in the presence of DBU to yield the N-acylsulfonamide (XXXVI). Alternatively, the sulfonamide intermediate (XXXIV) can be prepared by condensation of 3-chloropropanesulfonyl chloride (XXXVIII) with tert-butylamine in THF to give N-tert-butyl-(3-chloro)propylsulfonamide (XXXIX), which then cyclizes to the cyclopropyl derivative (XL) by treatment with n-BuLi in THF at –78 °C. Removal of the N-tert-butyl group in intermediate (XL) using CF3CO2H then furnishes cyclopropanesulfonamide (XXXIV). After N-Boc group cleavage in (XXXVI) by means of CF3CO2H in DCM, acidification with HCl in Et2O affords intermediate (IV) . Intermediate (VIII) can be obtained by vinyl group reduction in (IV) with H2 and Pd/C in EtOAc. Intermediate (VIII) can also be obtained by reduction of vinylcyclopropylamine derivative (XXXVI) with H2 over Ru/C in MeOH to yield N-Boc-ethylcyclopropylamine (XXXVII), which is finally N-deprotected by means of HCl in CH2Cl2 .

参考文献 中间体
合成目标
【1】 Sun, L.-Q., Sit, S.-Y., Scola, P.M. et al. (Bristol-Myers Squibb Co.). Hepatitis C virus inhibitors. EP 1505963, JP 2005533028, US 2004106559, US 6995174, WO 2003099274.
【2】 Holloway, M.K., Liverton, N.J., McCauley, J.A., Rudd, M.T., Vacca, J.P., Ludmerer, S.W., Olsen, D.B. (Merck & Co., Inc.). Macrocyclic peptides as HCV NS3 protease inhibitors. EP 1913016, JP 2009503080, WO 200701641.
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) 69058 (1S,2R)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride 　 C9H14N2O3S.HCl 详情 详情
(VIII) 69059 (1S,2S)-1-amino-N-(cyclopropylsulfonyl)-2-ethylcyclopropanecarboxamide hydrochloride 　 C9H16N2O3S.HCl 详情 详情
(XXVI) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(XXVII) 67884 methyl glycinate hydrochloride 5680-79-5 C3H7NO2.HCl 详情 详情
(XXVIII) 68235 (E)-ethyl 2-(benzylideneamino)acetate;2-(benzylideneamino)acetic acid ethyl ester；ethyl N-benzylideneglycinate；Benzylideneglycine ethyl ester；N-Benzylideneglycineethyl ester；ethyl(benzylideneamino)acetate 40682-54-0 C11H13NO2 详情 详情
(XXIX) 18349 (E)-1,4-dibromo-2-butene；trans-1,4-dibromo-2-butene 821-06-7 C4H6Br2 详情 详情
(XXX) 68236 ethyl 1-amino-2-vinylcyclopropanecarboxylate 787548-29-2 C8H13NO2 详情 详情
(XXXI) 68238 ethyl 1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylate 681807-59-0 C13H21NO4 详情 详情
(XXXII) 69076 (1R,2R)-ethyl 1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylate 　 C13H21NO4 详情 详情
(XXXIII) 69077 (1R,2R)-1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylic acid 　 C11H17NO4 详情 详情
(XXXIV) 68242 cyclopropanesulfonamide；Cyclopropanesulfonyl amide 154350-29-5 C3H7NO2S 详情 详情
(XXXV) 67915 cyclopropanesulfonyl chloride;Cyclopropylsulfonylchloride;Cyclopropylsulphonyl chloride 139631-62-2 C3H5ClO2S 详情 详情
(XXXVI) 69078 tert-butyl ((1R,2R)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate 　 C14H22N2O5S 详情 详情
(XXXVII) 69079 tert-butyl ((1R,2R)-1-((cyclopropylsulfonyl)carbamoyl)-2-ethylcyclopropyl)carbamate 　 C14H24N2O5S 详情 详情
(XXXVIII) 39225 g-Chloropropanesulfonyl chloride;3-Chloropropansulfonyl chloride;1-Chloro-3-propanesulfonylchloride;3-Chloropropanesulfonyl chloride;3-chloro-1-propanesulfonyl chloride;3-chloropropane-1-sulfonyl chloride 1633-82-5 C3H6Cl2O2S 详情 详情
(XXXIX) 68244 N-tert-butyl-(3-chloro)propylsulfonamide;N-tert-butyl-3-chloropropane-1-sulfonamide;3-Chloro-N-(1,1-dimethylethyl)-1-propanesulfonamide;1-Propanesulfonamide,3-chloro-N-(1,1-dimethylethyl)- 63132-85-4 C7H16ClNO2S 详情 详情
(XL) 68245 N-(tert-butyl)cyclopropanesulfonamide;N-tert-butylcyclopropanesulfonamide;N-(tert-butyl)cyclopropanesulfonamide 　 C7H15NO2S 详情 详情

合成路线2

该中间体在本合成路线中的序号：(B)

3) By reaction of 4-methoxybenzylamine (I) with methyl isothiocyanate (B) in ether to yield N-(4-methoxybenzyl)-N'-methylthiourea (III), which is then methylated with MeI in refluxing methanol affording N-(4-methoxybenzyl)-N',S-dimethylisothiourea (IV). Finally, this compound is treated first with methylamine in refluxing methanol and then with H2SO4.

参考文献 中间体
合成目标
【1】 Castaner, J.; Loren, J.G.; Cefoxitin. Drugs Fut 1978, 3, 6, 434.
【2】 Christensen, B.G.; Ratcliffe, R.W.; Total synthesis of beta-lactam antibiotics. I. alpha-Thioformamido-diethylphosphonioacetates. Tetrahedron Lett 1973, 46, 4645-48.
【3】 Christensen, B.G.; Ratcliffe, R.W.; Total synthesis of beta-lactam antibiotics. II. (rac)-Cephalotin. Tetrahedron Lett 1973, 46, 4649-52.
【4】 Christensen, B.G.; Ratcliffe, R.W. (Merck & Co., Inc.); 7-Azido-cephalosporin compounds and their preparation. DE 2365406; FR 2182953; GB 1424373; JP 49014488 .
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(A) 12714 diethyl phosphonate; diethyl phosphite 762-04-9 C4H11O3P 详情 详情
(I) 39815 1,3,5-tribenzyl-1,3,5-triazinane 2547-66-2 C24H27N3 详情 详情
(II) 39816 diethyl (benzylamino)methylphosphonate C12H20NO3P 详情 详情
(III) 39817 diethyl aminomethylphosphonate C5H14NO3P 详情 详情
(IV) 39818 diethyl [[(E)-benzylidene]amino]methylphosphonate 50917-73-2 C12H18NO3P 详情 详情
(V) 39819 1-[[(chlorocarbonyl)oxy]methyl]-4-methoxybenzene C9H9ClO3 详情 详情
(VI) 39820 4-methoxybenzyl 2-(diethoxyphosphoryl)-2-[[(E)-benzylidene]amino]acetate C21H26NO6P 详情 详情
(VII) 39821 4-methoxybenzyl 2-amino-2-(diethoxyphosphoryl)acetate C14H22NO6P 详情 详情
(VIII) 39822 O-ethyl thioformate C3H6OS 详情 详情
(IX) 39823 4-methoxybenzyl 2-(diethoxyphosphoryl)-2-(thioformylamino)acetate C15H22NO6PS 详情 详情
(X) 39824 3-chloro-2-oxopropyl acetate 40235-68-5 C5H7ClO3 详情 详情
(XI) 39825 4-methoxybenzyl 5-[(acetoxy)methyl]-6H-1,3-thiazine-4-carboxylate C16H17NO5S 详情 详情
(XII) 39826 2-azidoacetyl chloride C2H2ClN3O 详情 详情
(XIII) 39827 4-methoxybenzyl (6R,7R)-3-[(acetoxy)methyl]-7-azido-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C18H18N4O6S 详情 详情
(XIV) 39828 4-methoxybenzyl (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C18H20N2O6S 详情 详情
(XV) 39829 4-methoxybenzyl (6R,7R)-3-[(acetoxy)methyl]-7-[[(E)-(4-nitrophenyl)methylidene]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C25H23N3O8S 详情 详情
(C) 18184 4-Nitrobenzaldehyde 555-16-8 C7H5NO3 详情 详情

合成路线3

该中间体在本合成路线中的序号：(B)

The phenylhydrazone of benzaldehyde (I) is obtained in the usual way, phenylhydrazine (A) with benzaldehyde (B), which by reaction with benzoyl chloride (II) gives (C) and further treatment with HCl in an organic solvent results in the substituted hydrazine hydrochloride (III). Finally, this compound is condensed with levulinic acid (IV) at high temperature.

参考文献 中间体
合成目标
【1】 Francia, E.; Marin, A. (Uriach & Cia S.A.); Procedimiento de obtencion del acido 1-benzoil-2-metilindol-3-acetico. ES 471436 .
【2】 Francia, E.; Garcia Rafanell, J.; Delmetacin. Drugs Fut 1983, 8, 9, 764.
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(A) 11818 Phenyl hydrazine; 1-Phenylhydrazine 100-63-0 C6H8N2 详情 详情
(I) 36167 benzaldehyde N-phenylhydrazone 588-64-7 C13H12N2 详情 详情
(II) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(III) 36169 N-phenylbenzohydrazide C13H12N2O 详情 详情
(IV) 36170 4-oxopentanoic acid 123-76-2 C5H8O3 详情 详情
(C) 36168 N-phenyl-N'-[(E)-benzylidene]benzohydrazide C20H16N2O 详情 详情

合成路线4

该中间体在本合成路线中的序号：(II)

The condensation of 6-(2-amino-2-phenylacetamido)penicillanic acid sodium salt (I) with benzaldehyde (II) in DMF gives the corresponding imine (III), which is then condensed with iodomethyl penicillanate 1,1-dioxide (IV) in DMF to yield the bisester (V). Finally, this compound is deprotected by means of Girard P reagent and TsOH in methanol to afford the target bis-penicillanate.

参考文献 中间体
合成目标
【1】 del Pozo, C.; et al.; Synthesis of 1,1-dioxopenicillanoyloxymethyl 6-[D-alpha-(benzylideneaminophenylacetamido)]penicillanate and analogs. New intermediates in the preparation of sultamicillin. Tetrahedron 2001, 57, 29, 6209.
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) 48606 sodium (2S,5R,6R)-6-[((2R)-2-[[(benzyloxy)carbonyl]amino]-2-phenylethanoyl)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C24H24N3NaO6S 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 48607 sodium (2S,5R,6R)-3,3-dimethyl-7-oxo-6-[((2R)-2-phenyl-2-[[(E)-benzylidene]amino]ethanoyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C23H22N3NaO4S 详情 详情
(IV) 48608 iodomethyl (2S,5R)-3,3-dimethyl-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C9H12INO5S 详情 详情
(V) 48609 [([(2S,5R,6R)-3,3-dimethyl-7-oxo-6-[((2R)-2-phenyl-2-[[(E)-benzylidene]amino]ethanoyl)amino]-4-thia-1-azabicyclo[3.2.0]hept-2-yl]carbonyl)oxy]methyl (2S,5R)-3,3-dimethyl-4,4,7-trioxo-4lambda(6)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate C32H34N4O9S2 详情 详情

合成路线5

该中间体在本合成路线中的序号：(II)

4-Methyl-5-nitroimidazole (I) is condensed with benzaldehyde (II) in the presence of piperidine to produce the 4-styryl imidazole (III). Alkylation of imidazole (III) with benzyl chloride leads to a 3:1 mixture of regioisomeric N-benzyl imidazoles (IV) and (V). Ozonolysis of this mixture, followed by oxidative work-up of the ozonide with performic acid, allows isolation of the desired imidazolecarboxylic acid (VI) by employing a differential precipitation technique. Activation of acid (VI) with CDI, and further treatment of the resultant imidazolide with potassium methanenitronate gives rise to nitro ketone (VII). Both nitro groups of (VII) are then reduced by SnCl2 in concentrated HCl to furnish diamine (VIII). Then, removal of the N-benzyl group of (VIII) by catalytic hydrogenation over Pd/C yields imidazole (IX). Ring closure of (IX) in the presence of triethyl orthoformate produces the imidazodiazepinone (X)

参考文献 中间体
合成目标
【1】 Chan, E.; et al.; Total synthesis of (8R)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (pentostatin), the potent inhibitor of adenosine deaminase. J Org Chem 1982, 47, 18, 3457.
【2】 Baker, D.C.; Putt, S.R.; A total synthesis of pentostatin, the potent inhibitor of adenosine deaminase. J Am Chem Soc 1979, 101, 20, 6127.
【3】 Baker, D.C.; Putt, S.R. (Pfizer Inc.); 2-Amino-1-(5-amino-1H-imidazol-4-yl)ethanone and method of preparation. DE 2835144; ES 472478; ES 479618; GB 2005661; GB 2013680; US 4117229 .
【4】 Baker, D.C.; Putt, S.R. (Pfizer Inc.); Imidazole cpds., methods for their production and conversion of said cpds. into (R)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazol[4,5-d][1,3]diazepin-8-ol. US 4195176 .
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) 62513 4-methyl-5-nitro-1H-imidazole C4H5N3O2 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 62514 5-nitro-4-[(E)-2-phenylethenyl]-1H-imidazole C11H9N3O2 详情 详情
(IV) 62515 1-benzyl-4-nitro-5-[(E)-2-phenylethenyl]-1H-imidazole C18H15N3O2 详情 详情
(V) 62516 1-benzyl-5-nitro-4-[(E)-2-phenylethenyl]-1H-imidazole C18H15N3O2 详情 详情
(VI) 62517 1-benzyl-4-nitro-1H-imidazole-5-carboxylic acid C11H9N3O4 详情 详情
(VII) 62518 1-(1-benzyl-4-nitro-1H-imidazol-5-yl)-2-nitro-1-ethanone C12H10N4O5 详情 详情
(VIII) 62519 2-amino-1-(4-amino-1-benzyl-1H-imidazol-5-yl)-1-ethanone C12H14N4O 详情 详情
(IX) 62520 2-amino-1-(5-amino-1H-imidazol-4-yl)-1-ethanone C5H8N4O 详情 详情
(X) 40806 6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one C6H6N4O 详情 详情

合成路线6

该中间体在本合成路线中的序号：(VII)

A new partial synthesis of taxol has been described: The esterification of (1S,2R)-2-phenylcyclohexanol (I) with benzyloxyacetyl chloride (II) gives the corresponding chiral ester (III), which is deprotected by hydrogenolysis to the hydroxy ester (IV). Silylation of (IV) with triisopropylsilyl chloride affords the silylated ester (V), which is cyclized with trimethylsilylbenzaldimine (VI) [obtained from benzaldehyde (VII) and hexamethyldisilazane (HMSA)] by means of butyllithium in THF giving (3R,4S)-3-(triisopropylsilyloxy)-4-phenylazetidin-2-one (VIII). The deprotection of (VIII) with tetrabutylammonium fluoride affords (3R,4S)-3-hydroxy-4-phenylazetidin-2-one (IX), which is treated with ethyl vinyl ether to give the 1-ethoxyethyl ether (X). The benzoylation of (X) with benzoyl chloride (XI) by means of dimethylaminopyridine and triethylamine yields (3R,4S)-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (XII), which is condensed with 7-O-(triethylsilyl)baccatin III (XIII) by means of NaH in THF, affording 2'-O-(1-ethoxyethyl)-7-O-(triethylsilyl)taxol (XIV). Finally, this compound is deprotected with HCl in ethanol.

参考文献 中间体
合成目标
【1】 Habus, I.; Zhao, M.; Brigaud, T.; Zucco, M.; Ojima, I.; Sun, C.M.; Park, Y.H.; New and efficient approaches to the semisynthesis of taxol and its C-13 side chain analogs by means of beta-lactam synthon method. Tetrahedron 1992, 48, 34, 6985.
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) 10492 (1S,2R)-(+)-trans-2-Phenyl-1-cyclohexanol; (1S,2R)-2-Phenylcyclohexanol 2362-61-0 C12H16O 详情 详情
(II) 10493 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride 19810-31-2 C9H9ClO2 详情 详情
(III) 10494 (1S,2R)-2-phenylcyclohexyl 2-(benzyloxy)acetate C21H24O3 详情 详情
(IV) 10495 (1S,2R)-2-phenylcyclohexyl 2-hydroxyacetate C14H18O3 详情 详情
(V) 10496 (1S,2R)-2-phenylcyclohexyl 2-(triisopropylsilyl)acetate C23H38O2Si 详情 详情
(VI) 10507 Trimethyl-N-[(E)-benzylidene]silanamine; N-[(E)-Benzylidene]-N-(trimethylsilyl)amine 17599-61-0 C10H15NSi 详情 详情
(VII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VIII) 10499 (3R,4S)-4-Phenyl-3-[(triisopropylsilyl)oxy]-2-azetanone C18H29NO2Si 详情 详情
(IX) 10459 (3R,4S)-3-Hydroxy-4-phenyl-2-azetanone C9H9NO2 详情 详情
(X) 10462 (3R,4S)-3-(1-Ethoxyethoxy)-4-phenyl-2-azetanone C13H17NO3 详情 详情
(XI) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XII) 10464 (3R,4S)-1-Benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetanone C20H21NO4 详情 详情
(XIII) 10473 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C37H52O11Si 详情 详情
(XIV) 10505 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-(1-ethoxyethoxy)-3-phenylpropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C57H73NO15Si 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

3) The condensation of (4S,5R)-3-(bromoacetyl)-4-methyl-5-phenyloxazolidin-2-one (I) with benzaldehyde (II) by means of dibutylboron triflate gives intermediate (III), which by treatment with lithium ethoxide yields (R,R)-3-phenyloxirane-2-carboxylic acid ethyl ester (IV). The reaction of (IV) with sodium azide in ethanol affords the hydroxy ester (V), which is hydrogenated with H2 over Pd/C in ethyl acetate, giving the amino ester (VI). The protection of (VI) with tert-butoxycarbonyl anhydride affords the protected amino ester (VII), which is treated with 2-methoxypropene and pyridinium p-toluenesulfonate to give the oxazolidine (VIII). The hydrolysis of (VIII) with LiOH in ethanol/water yields (4S,5R)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyloxazolidine-5-carboxylic acid (IX), which is condensed with the protected baccatin III (X) by means of dicyclohexylcarbodiimide (DCC) and DMAP to afford the oxazolidine ester (XI). The treatment of (XI) with formic acid gives the amino ester (XII), which is benzoylated with benzoyl chloride and NaHCO3 to the protected paclitaxel (XIII). Finally, this compound is deprotected by treatment with Zn/acetic acid. (Commercon, A. et al. Tetrahedron Lett 1992, 33(36): 5185).

参考文献 中间体
合成目标
【1】 Guy, R.K.; Nicolaou, K.C.; Dai, W.M.; Chemistry and biology of taxol. Angew Chem. Int Ed Engl 1994, 33, 1, 15.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
63033 2-(ethyloxy)-1-propene; ethyl 1-methylethenyl ether C5H10O 详情 详情
(I) 10544 (4S,5R)-3-(2-Bromoacetyl)-4-methyl-5-phenyl-1,3-oxazolan-2-one C12H12BrNO3 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 10545 (4S,5R)-3-[(2S,3R)-2-Bromo-3-hydroxy-3-phenylpropanoyl]-4-methyl-5-phenyl-1,3-oxazolan-2-one C19H18BrNO4 详情 详情
(IV) 10546 ethyl (2R,3R)-3-phenyl-2-oxiranecarboxylate 121-39-1 C11H12O3 详情 详情
(V) 10547 ethyl (2R,3S)-3-azido-2-hydroxy-3-phenylpropanoate C11H13N3O3 详情 详情
(VI) 10548 ethyl (2R,3S)-3-amino-2-hydroxy-3-phenylpropanoate C11H15NO3 详情 详情
(VII) 10549 ethyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate C16H23NO5 详情 详情
(VIII) 10550 3-(tert-butyl) 5-ethyl (4S,5R)-2,2-dimethyl-4-phenyl-1,3-oxazolidine-3,5-dicarboxylate C19H27NO5 详情 详情
(IX) 10551 (4S,5R)-3-(tert-Butoxycarbonyl)-2,2-dimethyl-4-phenyl-1,3-oxazolane-5-carboxylic acid C17H23NO5 详情 详情
(X) 10448 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C34H39Cl3O13 详情 详情
(XI) 10553 5-((1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-2-(benzoyloxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl) 3-(tert-butyl) (4S,5R)-2,2-dimethyl-4-phenyl-1,3-oxazolidine-3,5-dicarboxylate C51H60Cl3NO17 详情 详情
(XII) 10554 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C43H48Cl3NO15 详情 详情
(XIII) 10555 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C43H48Cl3NO15 详情 详情

合成路线8

该中间体在本合成路线中的序号：(III)

A new synthesis of [14C]-labeled paclitaxel has been published: The protection of L-threonine methyl ester (I) with tert-butoxydiphenylchlorosilane (BPS-Cl) gives the compound (II), which is condensed with [14C]-labeled benzaldehyde (III), yielding the imine (IV). The cyclization of (IV) with acetoxyacetyl chloride (V) by means of triethylamine affords the azetidinone (VI), which is deprotected with tetrabutylammonium fluoride to the hydroxy ester (VII). The dehydration of (VII) with p-toluenesulfonyl chloride and triethylamine affords the unsaturated ester (VIII), which by ozonolysis is converted to the oxalimide (IX). Elimination of the oxalyl group with hydrazine gives the labeled azetidinone (X), which is deacetylated to the hydroxyazetidinone (XI) and protected with triethylchlorosilane (TES-Cl) to (XII). The benzoylation of (XII) with benzoyl chloride (XIII) and dimethylaminopyridine (DMAP) yields the corresponding benzoylated compound (XIV), which is then condensed with triethylsilyl-baccatin III (XV) by means of butyllithium to afford silylated labeled paclitaxel (XVI). Finally, this compound is deprotected with HCl. The intermediate silylated baccatin III (XV) is obtained from paclitaxel (XVII) by hydrogenolysis with NaBH4 to baccatin III (XVIII) and silylation with triethylsilyl chloride to (XV).

参考文献 中间体
合成目标
【1】 Walker, D.G.; Swigor, J.E.; Standridge, R.T.; Synthesis of paclitaxel-C3'-C-14. J Label Compd Radiopharm 1995, 36, 5, 479.
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) 10674 (2S,3R)-3-Hydroxy-1-methoxy-1-oxo-2-butanaminium chloride C5H12ClNO3 详情 详情
(II) 10675 methyl (2S,3R)-2-amino-3-methoxybutanoate C21H29NO4Si 详情 详情
(III) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 44663 benzaldehyde C7H6O 详情 详情
(IV) 10677 methyl (2S,3R)-3-methoxy-2-[[(E)-benzylidene]amino]butanoate C28H33NO4Si 详情 详情
(IV) 44664 methyl (2S,3R)-3-methoxy-2-[[(E)-benzylidene]amino]butanoate C13H17NO3 详情 详情
(V) 10456 Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate 13831-31-7 C4H5ClO3 详情 详情
(VI) 10679 methyl (2S,3R)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-methoxybutanoate C32H37NO7Si 详情 详情
(VI) 44665 methyl (2S,3R)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-methoxybutanoate C17H21NO6 详情 详情
(VII) 10680 methyl (2S,3R)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-hydroxybutanoate C16H19NO6 详情 详情
(VII) 44666 methyl (2S,3R)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-hydroxybutanoate C16H19NO6 详情 详情
(VIII) 10681 methyl (Z)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-butenoate C16H17NO5 详情 详情
(VIII) 44667 methyl (Z)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-butenoate C16H17NO5 详情 详情
(IX) 10682 methyl 2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-oxoacetate C14H13NO6 详情 详情
(IX) 44668 methyl 2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-oxoacetate C14H13NO6 详情 详情
(X) 10683 methyl 2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-oxoacetate C14H13NO6 详情 详情
(X) 44669 (3R,4S)-2-oxo-4-phenylazetidinyl acetate C11H11NO3 详情 详情
(XI) 10459 (3R,4S)-3-Hydroxy-4-phenyl-2-azetanone C9H9NO2 详情 详情
(XI) 44670 (3R,4S)-3-hydroxy-4-phenyl-2-azetidinone C9H9NO2 详情 详情
(XII) 10685 (3R,4S)-4-Phenyl-3-[(triethylsilyl)oxy]-2-azetidinone C15H23NO2Si 详情 详情
(XII) 44673 (3R,4S)-3-hydroxy-4-phenyl-2-azetidinone C9H9NO2 详情 详情
(XIII) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XIV) 10687 (3R,4S)-1-Benzoyl-3-hydroxy-4-phenyl-2-azetidinone C16H13NO3 详情 详情
(XIV) 44671 (3R,4S)-1-benzoyl-3-hydroxy-4-phenyl-2-azetidinone C16H13NO3 详情 详情
(XV) 10473 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C37H52O11Si 详情 详情
(XVI) 10689 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate n/a AB 详情 详情
(XVI) 44672 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C47H51NO14 详情 详情
(XVII) 10595 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate 33069-62-4 C47H51NO14 详情 详情
(XVIII) 10447 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,9,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C31H38O11 详情 详情

合成路线9

该中间体在本合成路线中的序号：(A)

It can be obtained in two different ways, both starting from ethyl alpha-(4-aminophenyl)propionate (I): 1) The condensation of the amino compound (I) with benzaldehyde (A), followed by reduction of the Schiff base with H2 over Pt in ethanol gives ethyl alpha-(benzylaminophenyl)propionate (II), which by reaction with phosgene in toluene affords ethyl alpha-[N-chlorocarbonyl-(4-benzylaminophenyl)]propionate (III); the cyclization of this compound with AlCl3 in CH2Cl2 yields ethyl alpha-[4-(1-oxo-2-iso-indolinyl)phenyl]propionate (IV), which is finally saponified with K2CO3 in ethanol - water. 2) The cyclization of the amino compound (I) with 2-cyanobenzyl bromide (B) in refluxing ethanol affords ethyl alpha-[4-(1-imino-2-iso-indolinyl)phenyl]propionate (V). which is finally hydrolyzed and saponified with K2CO3 as before. The starting aminoester (I) is obtained as follows: The nitration of alpha-phenylpropionitrile (VI) gives alpha-(4-nitrophenyl)propionitrile (VII), which is hydrolyzed with H2SO4 to alpha-(4-nitrophenyl)propionic acid (VIII). Esterification of this acid with ethanol and H2SO4 yields ethyl alpha-(4-nitrophenyl)propionate (IX), which is finally reduced with H2 over Pd/C in ethanol giving the aminoester (I), b.p.(0.5mm) 125 C.

参考文献 中间体
合成目标
【1】 Castaner, J.; Arrigoni, Martelli, E.; Indoprofen. Drugs Fut 1976, 1, 5, 242.
【2】 Nanini, G.; et al.; New analgesic-anti-inflammatory drugs. 1-oxo-2-substituted isoindoline derivatives. Arzneim-Forsch 1973, 23, Suppl. 3, 1090.
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(B) 33303 2-(bromomethyl)benzonitrile 22115-41-9 C8H6BrN 详情 详情
(I) 33984 ethyl 2-(4-aminophenyl)propanoate C11H15NO2 详情 详情
(II) 60734 ethyl 2-[4-(benzylamino)phenyl]propanoate C18H21NO2 详情 详情
(III) 60737 ethyl 2-{4-[benzyl(chlorocarbonyl)amino]phenyl}propanoate C19H20ClNO3 详情 详情
(IV) 60738 ethyl 2-[4-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]propanoate C19H19NO3 详情 详情
(V) 60739 ethyl 2-[4-(1-imino-1,3-dihydro-2H-isoindol-2-yl)phenyl]propanoate C19H20N2O2 详情 详情
(VI) 60735 hydratroponitrile C9H9N 详情 详情
(VII) 60736 2-(4-nitrophenyl)propanenitrile C9H8N2O2 详情 详情
(VIII) 52520 2-(4-nitrophenyl)propanoic acid C9H9NO4 详情 详情
(IX) 33983 ethyl 2-(4-nitrophenyl)propanoate C11H13NO4 详情 详情

合成路线10

该中间体在本合成路线中的序号：(III)

The reduction of L-pyroglutamic acid (I) with NaBH4 gives 5(S)-(hydroxymethyl)pyrrolidin-2-one (II), which is cyclized with benzaldehyde (III) by means of p-toluenesulfonic acid yielding the perhydropyrrolooxazolone (IV). The alkylation of (IV) with 2-cyclohexenyl bromide (V) and LDA in THF affords the corresponding cyclohexenyl derivative (VI), which is reduced with LiAlH4 in THF to give 1-benzyl-3(S)-(2-cyclohexenyl)-5(S)-(hydroxymethyl)pyrrolidine (VII). Elimination of the benzyl protecting group of (VII) with H2 over Pd/C yields the pyrrolidine (VIII), which is reprotected with benzyl chloroformate and K2CO3 to afford the carbamate (IX). The oxidation of the carbinol group of (IX) with Jones reagent or oxygen and platinum black gives the protected proline (X), which is finally deprotected with H2 over Pd/C providing the desired intermediate trans-4-cyclohexyl-L-proline (XI).

参考文献 中间体
合成目标
【1】 Thottathil, J.K.; et al.; Conversion of L-pyroglutamic acid to 4-alkyl substituted L-prolines. The synthesis of trans-4-cyclohexyl L-proline. J Org Chem 1986, 51, 16, 3140.
【2】 Thottathil, J.K. (Bristol-Myers Squibb Co.); Process and intermediates for preparing trans-4-substd.-S-prolines. EP 0183390; US 4588819 .
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) 32046 (3aR,4S,5R,6aS)-4-[(E,3R)-4-phenoxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-butenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one C29H40O7 详情 详情
(II) 38560 (5S)-5-(hydroxymethyl)-2-pyrrolidinone 17342-08-4 C5H9NO2 详情 详情
(III) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(IV) 38561 (3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one 103201-79-2 C12H13NO2 详情 详情
(V) 30800 3-bromo-1-cyclohexene 1521-51-3 C6H9Br 详情 详情
(VI) 38562 (3R,6S,7aS)-6-[(1S)-2-cyclohexen-1-yl]-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one C18H21NO2 详情 详情
(VII) 38563 [(2S,4S)-1-benzyl-4-[(1S)-2-cyclohexen-1-yl]pyrrolidinyl]methanol C18H25NO 详情 详情
(VIII) 38564 [(2S,4S)-4-cyclohexylpyrrolidinyl]methanol; trans-4-cyhexyl-L-Proline 90657-55-9 C11H21NO 详情 详情
(IX) 38565 benzyl (2S,4S)-4-cyclohexyl-2-(hydroxymethyl)-1-pyrrolidinecarboxylate C19H27NO3 详情 详情
(X) 38566 (2S,4S)-1-[(benzyloxy)carbonyl]-4-cyclohexyl-2-pyrrolidinecarboxylic acid C19H25NO4 详情 详情
(XI) 38567 (2S,4S)-4-cyclohexyl-2-pyrrolidinecarboxylic acid C11H19NO2 详情 详情

合成路线11

该中间体在本合成路线中的序号：(III)

The reduction of L-pyroglutamic acid (I) with NaBH4 gives the chiral pyrrolidinone (II), which is cyclized with benzaldehyde (III) by means of Ts-OH in refluxing toluene to yield the N,O-acetal (IV). The reaction of (IV) with isobutyl chloroformate (V) and phenylselanyl chloride by means of LiHMDS in THF affords the selenoester (VI), which is treated directly with H2O2 in dichloromethane to provide the unsaturated bicyclic lactam (VII). The diastereoselective reaction of (VII) with lithium di(4-fuorophenyl)cuprate (VIII) gives the all-trans trisubstituted pyrrolidone (IX). The reduction of the carbonyl group (IX) with BH3 in THF that also causes the cleavage of the C-O bond of the oxazolidinone yields the pyrrolidine methanol derivative (X), which is submitted to ring expansion by treatment with MsCl, DCE and TEA to afford the expected trisubstituted 3-chloropiperidine (XI). The dechlorination of (XI) by means of Bu3SnH and AIBN in refluxing toluene provides the trans-1-benzyl-4-(4-fluorophenyl)piperidine-3-carboxylic acid isobutyl ester (XII), which is reduced with LiAlH4 in THF to furnish the carbinol (XIII). The reaction of (XIII) with Ms-Cl and TEA in dichloromethane gives the corresponding mesylate (XIV), which is condensed with 1,3-benzodioxol-5-ol (XV) by means of sodium isopropoxide in refluxing isopropanol to yield the aryl ether (XVI). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol to afford the target trans-piperidine derivative.

参考文献 中间体
合成目标
【1】 Liu, L.T.; Hong, P.-C.; Huang, H.-L.; Chen, S.-F.; Wang, C.-L. J.; Wen, Y.-S.; ASsymetric syntheses of trans-3,4-disubstituted 2-piperidinones and piperidines. Tetrahedron Asymmetry 2001, 12, Suppl. 3, 419-26.
【2】 Cossy, J.; et al.; Ring expansion: Formal total synthesis of (-)-paroxetine. Tetrahedron Lett 2001, 42, 33, 5705.
【3】 Thottathil, J.K.; et al.; Conversion of L-pyroglutamic acid to 4-alkyl substituted L-prolines. The synthesis of trans-4-cyclohexyl L-proline. J Org Chem 1986, 51, 16, 3140.
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) 12085 (2R)-5-Oxotetrahydro-1H-pyrrole-2-carboxylic acid; 5-Oxo-D-proline; D-Pyroglutamic acid; (R)-(+)-2-Pyrrolidone-5-carboxylic acid 4042-36-8 C5H7NO3 详情 详情
(II) 56485 (5S)-5-(hydroxymethyl)-2-pyrrolidinone C5H9NO2 详情 详情
(III) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(IV) 38561 (3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one 103201-79-2 C12H13NO2 详情 详情
(V) 13423 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate 543-27-1 C5H9ClO2 详情 详情
(VI) 56478 isobutyl (3R,7aS)-5-oxo-3-phenyl-6-(phenylselanyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate C23H25NO4Se 详情 详情
(VII) 56479 isobutyl (3R,7aS)-5-oxo-3-phenyl-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate C17H19NO4 详情 详情
(VIII) 56475 　 C27H25CuF4Li 详情 详情
(IX) 56480 isobutyl (3R,6S,7R,7aS)-7-(4-fluorophenyl)-5-oxo-3-phenyltetrahydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate C23H24FNO4 详情 详情
(X) 56481 isobutyl (3S,4R,5S)-1-benzyl-4-(4-fluorophenyl)-5-(hydroxymethyl)-3-pyrrolidinecarboxylate C23H28FNO3 详情 详情
(XI) 56482 isobutyl (3S,4R,5R)-1-benzyl-5-chloro-4-(4-fluorophenyl)-3-piperidinecarboxylate C23H27ClFNO2 详情 详情
(XII) 56483 isobutyl (3S,4R)-1-benzyl-4-(4-fluorophenyl)-3-piperidinecarboxylate C23H28FNO2 详情 详情
(XIII) 44020 [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methanol C19H22FNO 详情 详情
(XIV) 56484 [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl methanesulfonate C20H24FNO3S 详情 详情
(XV) 10985 1,3-Benzodioxol-5-ol; Sesamol 533-31-3 C7H6O3 详情 详情
(XVI) 44022 (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-1-benzyl-4-(4-fluorophenyl)piperidine; 1,3-benzodioxol-5-yl [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl ether C26H26FNO3 详情 详情

合成路线12

该中间体在本合成路线中的序号：(VI)

The reaction of (II) with benzaldehyde (VI) in refluxing toluene gives ethyl p-benzylideneamino-alpha-methylphenylacetate (VII), which is reduced with H2 over PtO2 in ethanol to the N-benzyl derivative (VIII). The acylation of (VIII) with phosgene by means of pyridine in toluene yields the N-chlorocarbonyl compound (IX), which is then cyclized to the isoindolinone (IV) with AlCl3 in refluxing 1,2-dichloroethane. Finally, this compound is hydrolyzed with K2CO3 in refluxing ethanol - water.

参考文献 中间体
合成目标
【1】 Giraldi, P.N.; et al.; Verfahren zur Herstellung von Isoindolinderivaten. AT 325604B; CA 994785; CH 581106; JP 48057965; NL 7215830 .
【2】 Nannini, G.; et al.; New analgesic-antiinflammatory drugs. 1-oxo-2-substituted isoindoline derivatives. Arzneim-Forsch Drug Res 1973, 23, 8, 1090.
【3】 de Angelis, L.; Castaner, J.; Indobufen. Drugs Fut 1979, 4, 2, 109.
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) 33295 ethyl 2-(4-aminophenyl)butanoate C12H17NO2 详情 详情
(IV) 33297 ethyl 2-[4-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]butanoate C20H21NO3 详情 详情
(VI) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VII) 33299 ethyl 2-(4-[[(E)-benzylidene]amino]phenyl)butanoate C19H21NO2 详情 详情
(VIII) 33300 ethyl 2-[4-(benzylamino)phenyl]butanoate C19H23NO2 详情 详情
(IX) 33301 ethyl 2-[4-[benzyl(chlorocarbonyl)amino]phenyl]butanoate C20H22ClNO3 详情 详情

合成路线13

该中间体在本合成路线中的序号：(VI)

The reaction of benzaldehyde (VI) with p-amino-alpha-ethylphenylacetonitrile (XIV) in refluxing toluene gives p-benzylideneamino-alpha-ethylphenylacetonitrile (XV), which is reduced with H2 over PtO2 in ethanol yielding p-benzylamino-alpha-ethylphenylacetonitrile (XVI). The acylation of (XVI) with phosgene by means of pyridine in toluene affords the N-chlorocarbo-nyl compound (XVII), which is cyclized with AlCl3 in refluxing 1,2-dichloroethane to yield 1-oxo-2-[p-(alpha-ethyl-cyanomethyl)phenyl]isoindoline (XVIII). Finally, this compound is hydrolyzed with H2SO4 in refluxing water.

参考文献 中间体
合成目标
【1】 Giraldi, P.N.; et al.; Verfahren zur Herstellung von Isoindolinderivaten. AT 325604B; CA 994785; CH 581106; JP 48057965; NL 7215830 .
【2】 de Angelis, L.; Castaner, J.; Indobufen. Drugs Fut 1979, 4, 2, 109.
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(XIV) 33305 2-(4-aminophenyl)butanenitrile C10H12N2 详情 详情
(XV) 33306 2-(4-[[(E)-benzylidene]amino]phenyl)butanenitrile C17H16N2 详情 详情
(XVI) 33307 2-[4-(benzylamino)phenyl]butanenitrile C17H18N2 详情 详情
(XVII) 33308 1-[benzyl(chlorocarbonyl)amino]-4-(1-cyanopropyl)benzene C18H17ClN2O 详情 详情
(XVIII) 33309 2-[4-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]butanenitrile C18H16N2O 详情 详情

合成路线14

该中间体在本合成路线中的序号：(II)

By reaction of D-glucose (I) with benzaldheyde (II) by means of ZnCl2.

参考文献 中间体
合成目标
【1】 Dorcheus, S.H.; Williams, D.G.; Study of the reactions in the zinc chloride-benzal. J Org Chem 1963, 28, 775.
【2】 Prous, J.; Castaner, J.; KBG. Drugs Fut 1988, 13, 9, 829.
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) 23276 5-(hydroxymethyl)-1,2,3,4-cyclohexanetetrol C6H12O6 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情

合成路线15

该中间体在本合成路线中的序号：

This compound has been obtained by two related ways: 1) The saponification of 2-(5-chloro-2-oxobenzothiazolin-3-yl)acetic acid methyl ester (I) with NaOH in methanol/water gives the corresponding free acid (II), which is condensed with piperazine (III) by means of TiCl4 in THF yielding the acyl piperazine (IV). The nitrosation of (IV) with isoamyl nitrite in dichloromethane affords the N-nitrosopiperazine (V), which is finally reduced with Zn and acetic acid to the target amino derivative. 2) The nitrosation of piperazine (III) with NaNO2 and acetic acid gives 1-nitrosopiperazine (VI), which is reduced with Zn and acetic acid to 1-aminopiperazine (VII). The reaction of (VII) with benzaldehyde affords 1-(benzylideneamino)piperazine (VIII), which is condensed with of 2-(5-chloro-2-oxobenzothiazolin-3-yl)acetic acid (II) by means of SOCl2 and triethylamine in dichloromethane yielding the acyl piperazine (IX). Finally, this compound is debenzylated with hydroxylamine and HCl in acetonitrile/water.

参考文献 中间体
合成目标
【1】 Matsuo, M.; Nakaguchi, O.; Okumura, H.; Tsuji, K.; Ueda, I. (Fujisawa Pharmaceutical Co., Ltd.); N-Containing fused heterocyclic cpds., processes for the preparation thereof and pharmaceutical compsn. comprising the same. EP 0232740; JP 1987181253; US 4797399 .
【2】 Zanka, A.; et al.; Process development of a platelet aggregation inhibitor. Org Process Res Dev 1998, 2, 6, 418.
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
(I) 35662 methyl 2-[5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl]acetate C10H8ClNO3S 详情 详情
(II) 35663 2-[5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl]acetic acid C9H6ClNO3S 详情 详情
(III) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(IV) 35664 5-chloro-3-[2-oxo-2-(1-piperazinyl)ethyl]-1,3-benzothiazol-2(3H)-one C13H14ClN3O2S 详情 详情
(V) 35665 5-chloro-3-[2-(4-nitroso-1-piperazinyl)-2-oxoethyl]-1,3-benzothiazol-2(3H)-one C13H13ClN4O3S 详情 详情
(VI) 17260 1-nitrosopiperazine C4H9N3O 详情 详情
(VII) 35666 1-piperazinylamine; 1-piperazinamine C4H11N3 详情 详情
(VIII) 35667 N-[(E)-benzylidene]-N-(1-piperazinyl)amine; N-[(E)-benzylidene]-1-piperazinamine C11H15N3 详情 详情
(IX) 35668 5-chloro-3-[2-oxo-2-(4-[[(E)-benzylidene]amino]-1-piperazinyl)ethyl]-1,3-benzothiazol-2(3H)-one C20H19ClN4O2S 详情 详情

合成路线16

该中间体在本合成路线中的序号：

Reaction of 1,7-diaminoheptane with acrylonitrile gives the dinitrile (II). Reduction of the nitrile functionality yields the tetraamine (III). Reductive alkylation gives the dibenzyltetraamine MDL 27,695.

参考文献 中间体
合成目标
【1】 Dumont, J.A.; Stemerick, D.M.; Sjoerdsma, A.; McCann, P.P.; Edwards, M.L.; Bitonti, A.J.; Antimalarial polyamine analogs. J Med Chem 1991, 34, 2, 569-74.
【2】 Baumann, R.J.; Bitonti, A.J.; Edwards, M.L.; MDL 27,695. Drugs Fut 1991, 16, 10, 908.
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
(I) 12941 7-Aminoheptylamine; 1,7-Diaminoheptane; 1,7-Heptanediamine 646-19-5 C7H18N2 详情 详情
(II) 12942 3-([7-[(2-Cyanoethyl)amino]heptyl]amino)propanenitrile C13H24N4 详情 详情
(III) 12943 N-(3-Aminopropyl)-N-[7-[(3-aminopropyl)amino]heptyl]amine; N(1),N(7)-Bis(3-aminopropyl)-1,7-heptanediamine C13H32N4 详情 详情

合成路线17

该中间体在本合成路线中的序号：(II)

Alkylation of the sodium salt of 1-naphthol with benzyl bromide provides DuP-654. Alternatively, condensation of 1-tetralone (I) with benzaldehyde (II) in the presence of potassium hydroxide yields 2-benzylidene-1-tetralone (III), which may be isomerized to DuP-654 using rhodium chloride or a soluble iridium complex. A mixture of (I) and (II) may also be directly converted to DuP-654 by treating with potassium tert-butoxide in refluxing tert-butanol.

参考文献 中间体
合成目标
【1】 Batt, D.G. (E.I. Du Pont de Nemours & Co.); 2-Substituted-1-naphthols as 5-lipoxygenase inhibitors. AU 8657186; EP 0201071; ES 8801780; US 4833164 .
【2】 Harris, R.R.; Batt, D.G.; Galbraith, W.; Gans, K.R.; Jaffee, B.D.; Kerr, J.S.; Ackerman, N.R.; Mackin, W.M.; DuP-654. Drugs Fut 1989, 14, 11, 1040.
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) 20720 3,4-dihydro-1(2H)-naphthalenone 529-34-0 C10H10O 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 21491 2-[(E)-benzylidene]-3,4-dihydro-1(2H)-naphthalenone 6261-32-1 C17H14O 详情 详情

合成路线18

该中间体在本合成路线中的序号：(I)

In the original synthesis of the title compound, Knoevenagel condensation of benzaldehyde (I) with malonic acid (II) in the presence of ammonium acetate produced the beta-aminoacid (III). Reductive alkylation of the amino group of (III) with formaldehyde produced the dimethyl amine (IV). Then, Fischer esterification of (IV) with ethanolic HCl furnished the intermediate amino ester (V). Amino ester (V) was alternatively obtained by Michael addition of dimethylamine to ethyl cinnamate (VI). Reduction of the ester function of (V) provided amino alcohol (VII). The sodium alkoxide of (VII) was then coupled with 1-fluoronaphthalene (VIII) to produce the racemic amino ether, which was finally resolved into enantiomers by means of tartaric acid.

参考文献 中间体
合成目标
【1】 Robertson, D.W.; Thompson, D.C.; Wong, D.T. (Eli Lilly and Company); 1-Phenyl-3-naphthalenyloxypropanamines. AU 8814335; EP 0288188; JP 1988258837; US 5135947 .
【2】 Wheeler, W.J.; O'Bannon, D.D.; A chiral synthesis of dapoxetine hydrochloride, a serotonin reuptake inhibitor, and its 14C isotopomer. J Label Compd Radiopharm 1992, 31, 4, 305.
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(II) 12963 Malonic acid 141-82-2 C3H4O4 详情 详情
(III) 59224 3-(3-Aminophenyl)propionic acid; beta-Aminohydrocinnamic acid; DL-3-Amino-3-phenylpropionic acid; 3-Amino-3-phenylpropionic acid 614-19-7 C9H11NO2 详情 详情
(IV) 59221 N,N-dimethyl-3-phenyl-beta-alanine C11H15NO2 详情 详情
(V) 59222 ethyl 3-(dimethylamino)-3-phenylpropanoate C13H19NO2 详情 详情
(VI) 54905 Cinnamic acid ethylester; Ethyl cinnamate C11H12O2 详情 详情
(VII) 59223 3-(dimethylamino)-3-phenyl-1-propanol C11H17NO 详情 详情
(VIII) 40503 1-fluoronaphthalene 321-38-0 C10H7F 详情 详情

合成路线19

该中间体在本合成路线中的序号：(I)

Reaction of benzaldehyde (I) with dimethyl malonate (II) in refluxing toluene in the presence of piperidine and HOAc provides dimethyl benzylidene malonate (III), which is then hydrogenated over Pd/C to afford dimethyl benzyl malonate (IV). Reduction of (IV) with LiAlH4 in refluxing THF furnishes 2-benzyl-1,3-propanediol (V), which is then subjected to reaction with vinyl acetate (VI) by means of Novozym 435 enzyme to yield diacetate (VII). Enantioselective removal of one acetyl group from (VII) by treatment with Pseudomonas fluorescens Lipase in acetone/phosphate buffer (pH = 7) at 30 C gives 3-acetoxy-2(S)-benzyl-propanol (S)-(VIII), which is then oxidized by means of Jones reagent in acetone/isopropanol to provide carboxylic acid (R)-(IX). The hydrolysis of (IX) with LiOH in THF/H2O gives 2(R)-benzyl-3-hydroxypropanoic acid (R)-(X). Alternatively, intermediate (X) can also be synthesized as follows: Condensation of benzaldehyde (I) with methyl acrylate (XV) by means of diaza-1,4-bicyclo[2.2.2.]octane affords methyl beta-hydroxy-alpha-methylene-benzenepropanoate (XVI), which is then subjected to hydrolysis with KOH in MeOH/H2O to yield carboxylic acid (XVII). Treatment of (XVII) with p-toluenesulfonic acid in refluxing HOAc gives (E)-2-(acetoxymethyl)-3-phenylpropionic acid (XVIII), which is finally converted into (X) by enantioselective hydrogenation in the presence of S-Binap and ruthenium catalyst [CodRu(all)2]. Derivative (R)-(X) is then converted into 3-(acetylsulfanyl)-2(S)-benzylpropionic acid (XI) by means of a Mitsunobu reaction with thioacetic acid, diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPh3). Compound (XI) is then subjected to optical purification by formation and isolation of the corresponding salt with (-)-ephedrine and subsequent hydrolysis with HCl to furnish enantiomerically pure (S)-(XII). Finally, carboxylic acid (S)-(XII) is converted into ecadotril by its coupling with benzyl glycinate (XIV), either by means of Et3N, DCC and HOBt in CHCl3, or by first reaction with thionyl chloride to give acid chloride (S)-(XIII) and subsequent coupling with glycinate (XIV) by means of Et3N in CH2Cl2.

参考文献 中间体
合成目标
【1】 Monteil, T.; et al.; New asymmetric synthesis of dexecadotril and ecadotril starting from a single precursor. Synth Commun 2001, 31, 2, 211.
【2】 Duhamel, P.; Duhamel, L.; Danvy, D.; Plaquevent, J.-C.; Giros, B.; Gros, C.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Enantiomeric derivs. of amino acids, process for their preparation and their pharmaceutical applications. EP 0318377; FR 2623498; JP 1990000161; JP 1996059606; US 5296509; US 5331008 .
【3】 Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Novel pharmaceutical compsns. for the treatment of functional colophaties and their process of obtention. EP 0501870; JP 1993105627 .
【4】 Schwartz, J.-C.; Danvy, D.; Lecomte, J.-M.; Duhamel, P.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Method for the asymmetrical synthesis of S-acylated derivs. of 2-mercaptomethyl 3-phenyl propanoic acid, and use thereof for synthesising N-(mercaptoacyl)amino acid derivs.. WO 9729086 .
【5】 Lecomte, J.-M.; Duhamel, P.; Danvy, D.; Schwartz, J.-C.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Process for the synthesis of alpha-substd. acrylic acids and their application. EP 0729936 .
【6】 Henry, J.C.; Genet, J.P.; Dellis, P.; Vidal, V.; Binay, P. (Fournier Industrie et Santé); Preparation of S- and R-isomers of 2-mercaptomethyl-3-aryl propanoic acid by asymmetric reduction of an aryl propenoic acid. FR 2772027 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(S)-(VIII) 49464 (2S)-2-benzyl-3-hydroxypropyl acetate C12H16O3 详情 详情
(R)-(IX) 49465 (2R)-3-(acetoxy)-2-benzylpropionic acid C12H14O4 详情 详情
(R)-(X) 49466 (2R)-2-benzyl-3-hydroxypropionic acid C10H12O3 详情 详情
(XI),(S)-(XII) 49467 (2S)-3-(acetylsulfanyl)-2-benzylpropionic acid C12H14O3S 详情 详情
(I) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(II) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(III) 49460 Dimethyl benzylidenemalonate C12H12O4 详情 详情
(IV) 49461 dimethyl 2-benzylmalonate C12H14O4 详情 详情
(V) 49462 2-Benzylpropane-1,3-diol C10H14O2 详情 详情
(VI) 24543 vinyl acetate 108-05-4 C4H6O2 详情 详情
(VII) 49463 3-(acetoxy)-2-benzylpropyl acetate C14H18O4 详情 详情
(XIII) 49468 S-[(2R)-2-benzyl-3-chloro-3-oxopropyl] ethanethioate C12H13ClO2S 详情 详情
(XIV) 49469 1-amino-3-phenylacetone C9H11NO 详情 详情
(XV) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(XVI) 49470 methyl 2-[hydroxy(phenyl)methyl]acrylate C11H12O3 详情 详情
(XVII) 49471 2-[hydroxy(phenyl)methyl]acrylic acid C10H10O3 详情 详情
(XVIII) 49472 (E)-2-[(acetoxy)methyl]-3-phenyl-2-propenoic acid C12H12O4 详情 详情

合成路线20

该中间体在本合成路线中的序号：(II)

The condensation of 2'-bromo-4'-methylacetophenone (I) with benzaldehyde (II) by means of NaOMe in methanol gives the propenone (III), which is cyclized by means of PdCl2, PPh3 and K2CO3 in DMF, yielding 5-methyl-3-phenyl-1-indenone (IV). The enantioselective reduction of (IV) by means of borane/Me2S complex and (R)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole [(R)-MeCBS] as chiral catalyst in THF affords 5-methyl-3(S)-phenylindan-1-ol (V), which is oxidized with 1,4-diazabicyclo[2,2,2]octane (DABCO) in refluxing THF/TEA to provide the corresponding indanone (VI). The oxidation of (VI) with MCPBA in dichloromethane gives 6-methyl-4(S)-phenyl-3,4-dihydro-2H-1-benzopyran-2-one (VII), which is reduced with DIBAL in toluene to yield 6-methyl-4(S)-phenyl-3,4-dihydro-2H-1-benzopyran-2-ol (VIII). Finally, this compound is reductocondensed with diisopropylamine (IX) by means of H2 over Pd/C in methanol to afford the target compound.

参考文献 中间体
合成目标
【1】 Andersson, P.G.; Hedberg, C. (Pharmacia & Upjohn AB); Process of preparing tolterodine and analogues there of as well as intermediates prepared in the process. WO 0149649 .
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) 55510 1-(2-bromo-4-methylphenyl)-1-ethanone C9H9BrO 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 55511 (E)-1-(2-bromo-4-methylphenyl)-3-phenyl-2-propen-1-one C16H13BrO 详情 详情
(IV) 55512 5-methyl-3-phenyl-1H-inden-1-one C16H12O 详情 详情
(V) 55513 (3R)-5-methyl-3-phenyl-2,3-dihydro-1H-inden-1-ol C16H16O 详情 详情
(VI) 55514 (3R)-5-methyl-3-phenyl-2,3-dihydro-1H-inden-1-one C16H14O 详情 详情
(VII) 55515 (4R)-6-methyl-4-phenyl-3,4-dihydro-2H-chromen-2-one C16H14O2 详情 详情
(VIII) 55516 (4R)-6-methyl-4-phenyl-3,4-dihydro-2H-chromen-2-ol C16H16O2 详情 详情
(IX) 13565 N-Isopropyl-2-propanamine; Bis(isopropyl)amine; N,N-Diisopropylamine 108-18-9 C6H15N 详情 详情

合成路线21

该中间体在本合成路线中的序号：(II)

Ketalization of chartreusin (I) with benzaldehyde (II) using p-toluenesulfonic acid in the presence of molecular sieves, yielded the corresponding 3',4'-O-benzylidene derivative as a mixture of endo- and exo-isomers, which were separated by column chromatography. The required exo-isomer (III) was then esterified with 3-ethoxypropionic acid (IV) by means of DCC, producing the title ester.

参考文献 中间体
合成目标
【1】 Kon, K.; et al.; Synthesis and cytostatic activity of the antitumor antibiotic chartreusin derivatives. J Antibiot 1990, 43, 4, 372.
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) 59134 10-[((2S,3R,4S,5R,6R)-3-{[(2R,3R,4S,5R,6R)-3,5-dihydroxy-4-methoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-4,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy]-6-hydroxy-1-methylbenzo[h]chromeno[5,4,3-cde]chromene-5,12-dione C32H32O14 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 59135 10-[((2S,3aR,4R,6S,7R,7aS)-7-{[(2R,3R,4S,5R,6R)-3,5-dihydroxy-4-methoxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-4-methyl-2-phenyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl)oxy]-6-hydroxy-1-methylbenzo[h]chromeno[5,4,3-cde]chromene-5,12-dione C39H36O14 详情 详情
(IV) 59136 3-Ethoxypropionic acid; o-Ethoxypropionic acid 4324-38-3 C5H10O3 详情 详情

合成路线22

该中间体在本合成路线中的序号：(VII)

Alternatively, the condensation of dimethyl malonate (VI) with benzaldehyde (VII) by means of piperidine in refluxing toluene gives dimethyl benzylidenemalonate (VIII), which is reduced with H2 over Pd/C in toluene to yield the corresponding benzyl derivative (IX). The hydrolysis of (IX) with NaOH in water affords the benzylmalonic acid (X). Alternatively, intermediate (X) can also be obtained starting from diethyl malonate (XI), which is condensed with with benzaldehyde (VII) by means of piperidine in refluxing toluene to give diethyl benzylidenemalonate (XII). Reduction of (XII) with H2 over Pd/C in toluene yields the corresponding benzyl derivative (XIII), which is then hydrolized with NaOH in water. The monodecarboxylation of (X) and its condensation with paraformaldehyde and diethylamine in refluxing ethyl acetate provides 2-benzylacrylic acid (XIV), which is condensed with thioacetic acid (V) by heating at 70 C to afford 2-(acetylsulfanylmethyl)-3-phenylpropionic acid (XV). Finally, this compound is condensed with N-tosylglycine benzyl ester (XVI) by means of HOBt, DCC and TEA in THF.

参考文献 中间体
合成目标
【1】 Roques, B.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Amino acid derivs. and their therapeutic application. EP 0038758 .
【2】 Lecomte, J.-M.; Duhamel, P.; Danvy, D.; Schwartz, J.-C.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Process for the synthesis of alpha-substd. acrylic acids and their application. EP 0729936 .
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) 12893 Ethanethioic S-acid C2H4OS 详情 详情
(VI) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(VII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VIII) 49460 Dimethyl benzylidenemalonate C12H12O4 详情 详情
(IX) 49461 dimethyl 2-benzylmalonate C12H14O4 详情 详情
(X) 37280 2-benzylmalonic acid 616-75-1 C10H10O4 详情 详情
(XI) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XII) 37482 diethyl 2-benzylidenemalonate 5292-53-5 C14H16O4 详情 详情
(XIII) 20208 diethyl 2-benzylmalonate 607-81-8 C14H18O4 详情 详情
(XIV) 37279 2-benzylacrylic acid C10H10O2 详情 详情
(XV) 55230 3-(acetylsulfanyl)-2-benzylpropanoic acid C12H14O3S 详情 详情
(XVI) 55228 N-p-Tosylglycine benzyl ester C16H17NO4S 详情 详情

合成路线23

该中间体在本合成路线中的序号：(V)

The oxidation of mannitol diacetonide (I) with Pb(OAc)4 in benzene gives the glyceraldehyde acetonide (II), which is reductocondensed with benzylamine (III) by means of H2 over Pd/C in methanol to yield, after acidification with HCl, (S)-3-(benzylamino)propane-1,2-diol (IV). The cyclization of (IV) with benzaldehyde (V) in refluxing toluene affords the chiral oxazolidine (VI), which is treated with tosyl chloride and pyridine to provide the corresponding tosylate (VII). The condensation of (VII) with 4-[2-(cyclopropylmethoxy)ethyl]phenol (VIII) by means of NaH in DMF gives the phenolic ether (IX), which is treated with conc. HCl to open the oxazolidine ring and yield the chiral propanolamine (X). The alkylation of the secondary amino group of (X) with isopropyl iodide (XI) in refluxing ethanol affords the tertiary amine (XII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to provide the target betaxolol.

参考文献 中间体
合成目标
【1】 Kitteringham, J.; Mitchell, M.B. (GlaxoSmithKline plc); Stereoselective process and chiral intermediates for aryloxydropanolamines. WO 8606368 .
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) 55678 (4S)-4-{(1S,2S)-2-[(4S)-1,3-dioxolan-4-yl]-1-methylpropyl}-2,2-dimethyl-1,3-dioxolane C12H22O4 详情 详情
(II) 36759 (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde 15186-48-8 C6H10O3 详情 详情
(III) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(IV) 55679 (2S)-3-(benzylamino)-1,2-propanediol C10H15NO2 详情 详情
(V) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VI) 55680 [(5S)-3-benzyl-2-phenyl-1,3-oxazolidin-5-yl]methanol C17H19NO2 详情 详情
(VII) 55681 [(5S)-3-benzyl-2-phenyl-1,3-oxazolidin-5-yl]methyl 4-methylbenzenesulfonate C24H25NO4S 详情 详情
(VIII) 33330 4-[2-(Cyclopropylmethoxy)ethyl]phenol; p-(Cyclopropylmethoxyethyl)phenol C12H16O2 详情 详情
(IX) 55682 (5S)-3-benzyl-5-({4-[2-(cyclopropylmethoxy)ethyl]phenoxy}methyl)-2-phenyl-1,3-oxazolidine; 4-{[(5S)-3-benzyl-2-phenyl-1,3-oxazolidin-5-yl]methoxy}phenethyl cyclopropylmethyl ether C29H33NO3 详情 详情
(X) 55683 (2S)-1-(benzylamino)-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol C22H29NO3 详情 详情
(XI) 19369 2-iodopropane 75-30-9 C3H7I 详情 详情
(XII) 55684 (2S)-1-[benzyl(isopropyl)amino]-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol C25H35NO3 详情 详情

合成路线24

该中间体在本合成路线中的序号：(VI)

The 3-(isopropylamino)propane-1,2(S)-diol (IV) intermediate has been obtained by two different methods: 1. The oxidation of 1,2,5,6-O-diisopropylidene-D-mannitol (I) with Pb(OAc)4 in THF gives (R)-2,3-O-isopropylideglyceraldehyde (II), which is reductocondensed with isopropylamine by means of H2 over Pd/C in methanol to yield (S)-3-(isopropylamino)-1,2-O-isopropylidenepropane-1,2-diol (III). The cleavage of the isopropylidene protecting group of (III) in hot 6N HCl affords the desired 3-(isopropylamino)propane-1,2-diol (IV) intermediate. 2. The reductocondensation of (R)-glyceraldehyde (V) with isopropylamine by means of H2 over Pd/C in methanol gives the desired 3-(isopropylamino)propane-1,2-diol (IV) intermediate. The cyclization of (IV) with benzaldehyde (VI) by heating at 150 C gives the oxazolidine (VII), which is treated with Ts-Cl and K2CO3 in pyridine to yield the tosylate (VIII). Finally, this compound is condensed with 4-[2-(cyclopropylmethoxy)ethyl]phenol (IX) by means of NaH in DMF and hydrolyzed with conc. aq. HCl to provide the target isopropanol derivative.

参考文献 中间体
合成目标
【1】 Baldwin, J.J.; et al.; J Med Chem 1979, 22, 11, 1284.
【2】 Weinstock, L.M.; et al.; J Org Chem 1976, 41, 19, 3121.
【3】 Manoury, P.; Binet, J. (Sanofi-Synthelabo); S isomer of betaxolol, its preparation and its application in therapy. GB 2130585 .
【4】 Manoury, P.M.; et al.; Synthesis of a series of compounds related to betaxolol, a new beta1-adrenoceptor antagonist with a pharmacological and pharmacokinetic profile optimized for the treatment of chronic cardiovascular diseases. J Med Chem 1987, 30, 6, 1003-11.
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) 45944 (1S,2S)-1,2-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,2-ethanediol 1707-77-3 C12H22O6 详情 详情
(II) 36759 (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde 15186-48-8 C6H10O3 详情 详情
(III) 55685 N-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-N-isopropylamine; N-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2-propanamine C9H19NO2 详情 详情
(IV) 55687 (2S)-3-(isopropylamino)-1,2-propanediol C6H15NO2 详情 详情
(V) 55686 (R)-(+)-2,3-Dihydroxypropanal; D-(+)-Glyceraldehyde; D-Glyceraldehyde 453-17-8 C3H6O3 详情 详情
(VI) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VII) 55688 [(5S)-3-isopropyl-2-phenyl-1,3-oxazolidin-5-yl]methanol C13H19NO2 详情 详情
(VIII) 55689 [(5S)-3-isopropyl-2-phenyl-1,3-oxazolidin-5-yl]methyl 4-methylbenzenesulfonate C20H25NO4S 详情 详情
(IX) 33330 4-[2-(Cyclopropylmethoxy)ethyl]phenol; p-(Cyclopropylmethoxyethyl)phenol C12H16O2 详情 详情

合成路线25

该中间体在本合成路线中的序号：(V)

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26

该中间体在本合成路线中的序号：(XLV)

8) The synthesis of the 4-(4-fluorophenyl)-2-isobutyryl-4-oxo-N-phenylbutyramide (XXXII) is carried out as follows: The condensation of 4-methyl-3-oxo-N-phenylpentanamide (XLIV) with benzaldehyde (XLV) gives 2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide (XLVI), which is then condensed with 4-fluorobenzaldehyde (XLVII) by means of triethylamine in hot ethanol. 9) The cyclization of (XXXII) with intermediate (XLII) (preceding synthesis) in refluxing toluene yields the protected dehydroxyheptanoate (XLIII), which is deprotected with HCl in methanol and finally hydrolyzed with NaOH and treated with calcium acetate in water.

参考文献 中间体
合成目标
【1】 Graul, A.; Castaner, J.; Atorvastatin Calcium. Drugs Fut 1997, 22, 9, 956.
【2】 McKenzie, A.T. (Pfizer Inc.); Form III crystalline (R-(R*,R*))-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methyl-ethyl) -3-phenyl-4- ((phenylamino)carbonyl)-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin). JP 1999509229; WO 9703958 .
【3】 Lin, M.; Schweiss, D. (Pfizer Inc.); Novel process for the production of amorphous [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1). JP 1999510486; WO 9703960 .
【4】 Briggs, C.A.; Jennings, R.A.; Wade, R.A.; Harasawa, K.; Ichikawa, S.; Minohara, K.; Nakagawa, S. (Pfizer Inc.); Crystalline [R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl) -3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin). JP 1999509230; WO 9703959 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXXII) 15426 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide 125971-96-2 C26H24FNO3 详情 详情
(XLII) 15444 (4R,6R)-tert-Butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate; (4R-Cis)-1,1-Dimethylethyl-6-aminoethyl-2,2-dimethyl-1,3-dioxoane-4-acetate 125995-13-3 C14H27NO4 详情 详情
(XLIII) 15452 tert-butyl 2-((4R,6R)-6-[2-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate C40H47FN2O5 详情 详情
(XLIV) 15448 4-Methyl-3-oxo-N-phenylpentanamide; 4-Methyl-3-oxopentanoic acid anilide 124401-38-3 C12H15NO2 详情 详情
(XLV) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(XLVI) 15450 (Z)-2-isobutyryl-N,3-diphenyl-2-propenamide 125971-57-5 C19H19NO2 详情 详情
(XLVII) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情

合成路线27

该中间体在本合成路线中的序号：(V)

The synthesis of ring labeled [14C]-atorvastatin has been described: The Grignard reaction of phenylmagnesium chloride (I) with [14C]-labeled CO2 (II) in THF/ethyl ether gives the benzoic acid (III), which is reduced with LiAlH4 in ethyl ether to the benzyl alcohol (IV). The oxidation of (IV) with pyridinium dichromate affords the benzaldehyde (V), which is condensed with the isobutyrylacetamide (VI) by means of beta-alanine in acetic acid yielding a mixture of the cis- and trans-benzylidene derivatives (VII). The condensation of (VII) with 4-fluorobenzaldehyde (VIII) by means of triethylamine and a thiazolium bromide catalyst affords the 1,4-dione (IX), which is cyclized with the chiral amino ester (X) in hot heptane/toluene/THF providing the protected pyrroloheptanoic ester (XI). The deprotection of (XI) in acidic medium, followed by the hydrolysis of the ester group with NaOH affords the sodium salt (XII), which is finally treated with calcium acetate in THF/water.

参考文献 中间体
合成目标
【1】 Woo, P.W.K.; et al.; Atorvastatin, an HMG-CoA reductase inhibitor and efficient lipid-regulating agent. Part I. Synthesis of ring-labeled [C-14] atorvastatin. J Label Compd Radiopharm 1999, 42, 2, 121.
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) 27910 chloro(phenyl)magnesium 100-59-4 C6H5ClMg 详情 详情
(III) 10202 Benzoic acid 65-85-0 C7H6O2 详情 详情
(III) 45234 benzoic acid C7H6O2 详情 详情
(IV) 18710 Benzyl alcohol; Phenylmethanol 100-51-6 C7H8O 详情 详情
(IV) 45235 phenylmethanol C7H8O 详情 详情
(V) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(V) 44663 benzaldehyde C7H6O 详情 详情
(VI) 15448 4-Methyl-3-oxo-N-phenylpentanamide; 4-Methyl-3-oxopentanoic acid anilide 124401-38-3 C12H15NO2 详情 详情
(VII) 15450 (Z)-2-isobutyryl-N,3-diphenyl-2-propenamide 125971-57-5 C19H19NO2 详情 详情
(VII) 45236 (Z)-2-isobutyryl-N,3-diphenyl-2-propenamide C19H19NO2 详情 详情
(VIII) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(IX) 15426 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide 125971-96-2 C26H24FNO3 详情 详情
(IX) 45237 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide C26H24FNO3 详情 详情
(X) 15444 (4R,6R)-tert-Butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate; (4R-Cis)-1,1-Dimethylethyl-6-aminoethyl-2,2-dimethyl-1,3-dioxoane-4-acetate 125995-13-3 C14H27NO4 详情 详情
(XI) 15452 tert-butyl 2-((4R,6R)-6-[2-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate C40H47FN2O5 详情 详情
(XI) 45238 tert-butyl 2-((4R,6R)-6-[2-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate C40H47FN2O5 详情 详情
(XII) 27911 sodium (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate C33H34FN2NaO5 详情 详情
(XII) 45239 sodium (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate C33H34FN2NaO5 详情 详情

合成路线28

该中间体在本合成路线中的序号：(I)

The synthesis of atorvastatin has been described: The condensation of benzaldehyde (I) with the isobutyrylacetamide (II) by means of beta-alanine in acetic acid yields a mixture of cis- and trans-benzylidene derivatives (III). The condensation of (III) with 4-fluorobenzaldehyde (IV) by means of triethylamine and a thiazolium bromide catalyst affords the 1,4-dione (V), which is cyclized with the chiral amino ester (VI) in hot heptane/toluene/THF to provide the protected pyrroloheptanoic ester (VII). The deprotection of (VII) in acidic medium, followed by the hydrolysis of the ester group with NaOH affords the sodium salt (VIII), which is finally treated with calcium acetate in THF/water.

参考文献 中间体
合成目标
【1】 Woo, P.W.K.; et al.; Atorvastatin, an HMG-CoA reductase inhibitor and effective lipid regulating agent. Part III. Synthesis of [H-2(5)]-, [C-13(8)], and [C-13(7)],N-15]atorvastatin and their application in metabolic and pharmacokinetic studies. J Label Compd Radiopharm 1999, 42, 2, 135.
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(II) 15448 4-Methyl-3-oxo-N-phenylpentanamide; 4-Methyl-3-oxopentanoic acid anilide 124401-38-3 C12H15NO2 详情 详情
(III) 15450 (Z)-2-isobutyryl-N,3-diphenyl-2-propenamide 125971-57-5 C19H19NO2 详情 详情
(IV) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(V) 15426 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide 125971-96-2 C26H24FNO3 详情 详情
(VI) 15444 (4R,6R)-tert-Butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate; (4R-Cis)-1,1-Dimethylethyl-6-aminoethyl-2,2-dimethyl-1,3-dioxoane-4-acetate 125995-13-3 C14H27NO4 详情 详情
(VII) 15452 tert-butyl 2-((4R,6R)-6-[2-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate C40H47FN2O5 详情 详情
(VIII) 27911 sodium (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate C33H34FN2NaO5 详情 详情

合成路线29

该中间体在本合成路线中的序号：(I)

The synthesis of atorvastatin has been described: The condensation of benzaldehyde (I) with the isobutyrylacetamide (II) by means of beta-alanine in acetic acid yields a mixture of cis- and trans-benzylidene derivatives (III). The condensation of (III) with 4-fluorobenzaldehyde (IV) by means of triethylamine and a thiazolium bromide catalyst affords the 1,4-dione (V), which is cyclized with the chiral amino ester (VI) in hot heptane/toluene/THF to provide the protected pyrroloheptanoic ester (VII). The deprotection of (VII) in acidic medium, followed by the hydrolysis of the ester group with NaOH affords the sodium salt (VIII), which is finally treated with calcium acetate in THF/water.

参考文献 中间体
合成目标
【1】 Woo, P.W.K.; et al.; Atorvastatin, an HMG-CoA reductase inhibitor and effective lipid regulating agent. Part III. Synthesis of [H-2(5)]-, [C-13(8)], and [C-13(7)],N-15]atorvastatin and their application in metabolic and pharmacokinetic studies. J Label Compd Radiopharm 1999, 42, 2, 135.
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(II) 15448 4-Methyl-3-oxo-N-phenylpentanamide; 4-Methyl-3-oxopentanoic acid anilide 124401-38-3 C12H15NO2 详情 详情
(III) 15450 (Z)-2-isobutyryl-N,3-diphenyl-2-propenamide 125971-57-5 C19H19NO2 详情 详情
(IV) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(V) 15426 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide 125971-96-2 C26H24FNO3 详情 详情
(VI) 15444 (4R,6R)-tert-Butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate; (4R-Cis)-1,1-Dimethylethyl-6-aminoethyl-2,2-dimethyl-1,3-dioxoane-4-acetate 125995-13-3 C14H27NO4 详情 详情
(VII) 15452 tert-butyl 2-((4R,6R)-6-[2-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate C40H47FN2O5 详情 详情
(VIII) 27911 sodium (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate C33H34FN2NaO5 详情 详情

合成路线30

该中间体在本合成路线中的序号：(I)

The synthesis of atorvastatin has been described: The condensation of benzaldehyde (I) with the isobutyrylacetamide (II) by means of beta-alanine in acetic acid yields a mixture of cis- and trans-benzylidene derivatives (III). The condensation of (III) with 4-fluorobenzaldehyde (IV) by means of triethylamine and a thiazolium bromide catalyst affords the 1,4-dione (V), which is cyclized with the chiral amino ester (VI) in hot heptane/toluene/THF to provide the protected pyrroloheptanoic ester (VII). The deprotection of (VII) in acidic medium, followed by the hydrolysis of the ester group with NaOH affords the sodium salt (VIII), which is finally treated with calcium acetate in THF/water.

参考文献 中间体
合成目标
【1】 Woo, P.W.K.; et al.; Atorvastatin, an HMG-CoA reductase inhibitor and effective lipid regulating agent. Part III. Synthesis of [H-2(5)]-, [C-13(8)], and [C-13(7)],N-15]atorvastatin and their application in metabolic and pharmacokinetic studies. J Label Compd Radiopharm 1999, 42, 2, 135.
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(II) 15448 4-Methyl-3-oxo-N-phenylpentanamide; 4-Methyl-3-oxopentanoic acid anilide 124401-38-3 C12H15NO2 详情 详情
(III) 15450 (Z)-2-isobutyryl-N,3-diphenyl-2-propenamide 125971-57-5 C19H19NO2 详情 详情
(IV) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(V) 15426 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-N-phenylpentanamide 125971-96-2 C26H24FNO3 详情 详情
(VI) 15444 (4R,6R)-tert-Butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate; (4R-Cis)-1,1-Dimethylethyl-6-aminoethyl-2,2-dimethyl-1,3-dioxoane-4-acetate 125995-13-3 C14H27NO4 详情 详情
(VII) 15452 tert-butyl 2-((4R,6R)-6-[2-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl)acetate C40H47FN2O5 详情 详情
(VIII) 27911 sodium (3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoate C33H34FN2NaO5 详情 详情

合成路线31

该中间体在本合成路线中的序号：(II)

Starting from N-pentylamine (I), the intermediate N-methyl-N-pentylamine (IV) is condensed with methyl methacrylate to give N-methyl-N-pentyl-beta-alanine methyl ester (V). After hydrolysis of the methyl ester (V), the bisphosphonate is produced in the common way using phosphorous oxychloride/phosphorous acid.

参考文献 中间体
合成目标
【1】 Muhlbauer, R.C.; Bauss, F.; BM-21.0955, Monosodium Salt, Monohydrate. Drugs Fut 1994, 19, 1, 13.
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) 15764 amylamine; 1-pentanamine; pentylamine 110-58-7 C5H13N 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 15766 N-pentyl-N-[(E)-benzylidene]amine; N-[(E)-benzylidene]-1-pentanamine C12H17N 详情 详情
(IV) 15767 N-Methylamylamine; N-methyl-N-pentylamine; N-methyl-1-pentanamine 25419-06-1 C6H15N 详情 详情
(V) 15768 methyl 3-[methyl(pentyl)amino]propanoate C10H21NO2 详情 详情
(VI) 15769 3-[methyl(pentyl)amino]propionic acid C9H19NO2 详情 详情

合成路线32

该中间体在本合成路线中的序号：(II)

The condensation of dimethyl succinate (I) with benzaldehyde (II) by means of NaOMe in refluxing methanol followed by hydrolysis with NaOH in methanol/water gives 2-benzylidenesuccinic acid (III). Compound (III) is treated with refluxing Ac2O, yielding the corresponding anhydride (IV), which by reaction with cis-perhydroisoindole (V) in toluene affords the monoamide (VI). This amide is reduced with H2 over a chiral Rhodium catalyst and treated with (R)-1-phenylethylamine (VII) to provide the chiral salt (VIII) as a single diastereomer isolated by crystallization. Finally, this salt is treated first with aqueous NH4OH and then with aqueous CaCl2.

参考文献 中间体
合成目标
【1】 Castaner, R.M.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; Mitiglinide Calcium Hydrate. Drugs Fut 2000, 25, 10, 1034.
【2】 Lecouve, J.-P.; Souvie, J.-C.; Fugier, C. (ADIR et Cie.); Method for preparing a substd. perhydroisoindole. FR 2765578; US 6133454; WO 9901430 .
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) 41056 dimethyl succinate 106-65-0 C6H10O4 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 41057 2-[(Z)-benzylidene]succinic acid C11H10O4 详情 详情
(IV) 41058 3-[(Z)-benzylidene]-2,5(4H)-furandione C11H8O3 详情 详情
(V) 41059 (3aR,7aS)octahydro-1H-isoindole C8H15N 详情 详情
(VI) 41060 (Z)-2-[2-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-oxoethyl]-3-phenyl-2-propenoic acid C19H23NO3 详情 详情
(VII) 10039 (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine 3886-69-9 C8H11N 详情 详情
(VIII) 41061 (1R)-1-phenyl-1-ethanaminium (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate C27H36N2O3 详情 详情

合成路线33

该中间体在本合成路线中的序号：(II)

The condensation of diethyl succinate (IX) with benzaldehyde (II) gives 2-benzylidenesuccinic acid (III), which is treated with refluxing Ac2O to yield the corresponding anhydride (IV). Reaction of (IV) with cis-perhydroisoindole (V) in toluene affords the monoamide (VI), which is reduced with H2 over Pd/C in ethanol to provide the racemic benzylsuccinamic acid (X). Esterification of (X) with (S)-N-benzylmandelamide (XI) by means of DCC and DMAP in dichloromethane gives a mixture of diastereomeric esters, which were separated by column chromatography on silica gel to provide the desired diastereomer (XII). The hydrolysis of (XII) with NaOH in methanol yields the chiral acid (XIII), which is finally treated first with NaOH and then with CaCl2 in water. The preceding optical resolution of racemic acid (X) can also be performed with (R)-1-phenylethylamine (VII) or (R)-1-(1-naphthyl)ethylamine (XIV) by fractional crystallization of the corresponding diastereomeric salts and treatment with 2N HCl.

参考文献 中间体
合成目标
【1】 Castaner, R.M.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; Mitiglinide Calcium Hydrate. Drugs Fut 2000, 25, 10, 1034.
【2】 Yamaguchi, T.; et al.; Preparation of optically active succinic acid derivatives. I. Optical resolution of 2-benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl)propionic acid. Chem Pharm Bull 1997, 45, 9, 1518.
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 41057 2-[(Z)-benzylidene]succinic acid C11H10O4 详情 详情
(IV) 41058 3-[(Z)-benzylidene]-2,5(4H)-furandione C11H8O3 详情 详情
(V) 41059 (3aR,7aS)octahydro-1H-isoindole C8H15N 详情 详情
(VI) 41060 (Z)-2-[2-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-oxoethyl]-3-phenyl-2-propenoic acid C19H23NO3 详情 详情
(VII) 10039 (1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine 3886-69-9 C8H11N 详情 详情
(IX) 12313 diethyl succinate 123-25-1 C8H14O4 详情 详情
(X) 41062 4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutyric acid C19H25NO3 详情 详情
(XI) 41063 (2S)-N-benzyl-2-hydroxy-2-phenylethanamide C15H15NO2 详情 详情
(XII) 41065 (1S)-2-(benzylamino)-2-oxo-1-phenylethyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate C34H38N2O4 详情 详情
(XIII) 41064 (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutyric acid C19H25NO3 详情 详情
(XIV) 17443 (1R)-1-(1-naphthyl)ethylamine; (1R)-1-(1-naphthyl)-1-ethanamine 3886-70-2 C12H13N 详情 详情

合成路线34

该中间体在本合成路线中的序号：(V)

The reaction of 1(R)-phenylethane-1,2-diol (I) with N-hydroxyphthalimide (II) by means of DEAD and PPh3 gives the N-alcoxyphthalimide (III) with(S)-configuration. The hydrazinolysis of (III) with hydrazine hydrate affords the O-alkylhydroxylamine (IV), which is condensed with benzaldehyde (V) to provide the alkylated benzaldoxime (VI). The alkylation of the oxime (VI) with vinyl lithium (VII) in toluene gives the N, O dialkylated hydroxylamine (VIII), which is treated with Zn and AcOH to yield 1(R)-phenylallylamine (IX). The protection of the amine (IX) with Boc2O and NaOH affords the carbamate (X), which is oxidized at the vinyl double bond by means of OsO4 and NaIO4 to provide the acetaldehyde (XI). The reaction of aldehyde (XI) with allylmagnesium bromide (XII) in ethyl ether gives the aminoalcohol (XIII), which is protected with Tbdms-Cl and imidazole to yield the silyl ether (XIV).

参考文献 中间体
合成目标
【1】 Yamazaki, N.; et al.; Nucleophilic addition of methyllithium to chiral oxime ethers: Asymmetric preparation of 1-(aryl)ethylamines and application to a synthesis of calcimimetics (+)-NPS R-568 and its thio analogue. Tetrahedron Lett 2001, 42, 30, 5029.
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) 56141 (R)-(-)-1-Phenyl-1,2-ethanediol; (R)-(-)-alpha,beta-Dihydroxyethylbenzene; (R)-(-)-Phenyl-1,2-ethanediol; (R)-(-)-Styrene glycol; (-)-Styrene glycol 16355-00-3 C8H10O2 详情 详情
(II) 13505 N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione 524-38-9 C8H5NO3 详情 详情
(III) 56142 2-{[(1S)-2-hydroxy-1-phenylethyl]oxy}-1H-isoindole-1,3(2H)-dione C16H13NO4 详情 详情
(IV) 56143 (2S)-2-(aminooxy)-2-phenyl-1-ethanol C8H11NO2 详情 详情
(V) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VI) 62256 benzaldehyde O-[(1S)-2-hydroxy-1-phenylethyl]oxime C15H15NO2 详情 详情
(VII) 42368 vinyllithium 917-57-7 C2H3Li 详情 详情
(VIII) 62257 (2S)-2-phenyl-2-({[(1R)-1-phenyl-2-propenyl]amino}oxy)-1-ethanol C17H19NO2 详情 详情
(IX) 62258 (1R)-1-phenyl-2-propenylamine; (1R)-1-phenyl-2-propen-1-amine C9H11N 详情 详情
(X) 62259 tert-butyl (1R)-1-phenyl-2-propenylcarbamate C14H19NO2 详情 详情
(XI) 45428 tert-butyl (1S)-2-oxo-1-phenylethylcarbamate C13H17NO3 详情 详情
(XII) 61128 　 C4H8 详情 详情
(XIII) 62260 tert-butyl (1S)-2-hydroxy-1-phenyl-4-pentenylcarbamate C16H23NO3 详情 详情
(XIV) 62261 tert-butyl (1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenyl-4-pentenylcarbamate C22H37NO3Si 详情 详情

合成路线35

该中间体在本合成路线中的序号：(IV)

The reaction of the silylated 5-isopropylpyrimidine (I) with chloromethyl ethyl ether (II) by means of KI in dichloromethane gives 1-(ethoxymethyl)-5-isopropyl-2-thiouracil (III), which is condensed with benzaldehyde (IV) by means of lithium diisopropylamide (LDA) in THF, and desulfurized by reaction with H2O2 and NaOH in water to afford 1-(ethoxymethyl)-5-isopropyl-6-(alpha-hydroxybenzyl)uracil (V). The reaction of (V) with acetic anhydride and pyridine gives the acetate (VI), which is finally submitted to hydrogenolysis with H2 over Pd/C in acetic acid/water/dioxane.

参考文献 中间体
合成目标
【1】 Walker, R.T.; Baba, M.; De Clerq, E.; Takashima, H.; Inouye, N.; Ubasawa, M.; Miyasaka, T.; Sekiya, K.; Shigeta, S.; Tanaka, H.; Synthesis and antiviral activity of 6-benzyl analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as potent and selective anti-HIV-1 agents. J Med Chem 1995, 38, 15, 2860.
【2】 Ubasawa, M.; Tanaka, H.; Walker, R.T.; Yuasa, S.; Miyasaka, T.; De Clerq, E.; Baba, M.; HEPT derivatives: 6-benzyl-1-ethoxymethyl-5-isopropyluracil (MKC-442). Nucleosides Nucleotides 1995, 14, 3-5, 575.
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) 27025 5-isopropyl-4-[(trimethylsilyl)methyl]-2-[(trimethylsilyl)sulfanyl]pyrimidine C14H28N2SSi2 详情 详情
(II) 13149 1-(Chloromethoxy)ethane; Chloromethyl ethyl ether 3188-13-4 C3H7ClO 详情 详情
(III) 27026 1-(ethoxymethyl)-5-isopropyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone C10H16N2O2S 详情 详情
(IV) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(V) 27027 1-(ethoxymethyl)-6-[hydroxy(phenyl)methyl]-5-isopropyl-2,4(1H,3H)-pyrimidinedione C17H22N2O4 详情 详情
(VI) 27028 [3-(ethoxymethyl)-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinyl](phenyl)methyl acetate C19H24N2O5 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 5-isopropyluracil (VII) with chloromethyl ethyl ether (II) by means of bis(trimethylsilyl)acetamide (BSA) and tetrabutylammonium iodide (TBI) in dichloromethane gives 1-(ethoxy-methyl)-5-isopropyluracil (VIII)(3), which is then condensed with benzaldehyde (IV) by means of LDA in THF to afford 1-(ethoxymethyl)-5-isopropyl-6-(alpha-hydroxybenzyl)uracil (V), already obtained.

参考文献 中间体
合成目标
【1】 Ubasawa, M.; Yuasa, S. (Mitsubishi Chemical Corp.); Antiviral combinations of 2',3'-dideoxyribonucleosides with 6-benzyl-1-ethoxymethyl-5-substd. uracil derivs.. EP 0631783; JP 1995097324 .
【2】 Ubasawa, M.; et al. (Mitsubishi Chemical Corp.); Production of 6-aralkyl substituted pyrimidine derivative. JP 1996003143 .
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) 27029 trimethylsilyl 4-[(trimethylsilyl)methyl]-2-pyrimidinyl sulfide C11H22N2SSi2 详情 详情
(II) 13149 1-(Chloromethoxy)ethane; Chloromethyl ethyl ether 3188-13-4 C3H7ClO 详情 详情
(IV) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(V) 27027 1-(ethoxymethyl)-6-[hydroxy(phenyl)methyl]-5-isopropyl-2,4(1H,3H)-pyrimidinedione C17H22N2O4 详情 详情
(VI) 27028 [3-(ethoxymethyl)-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinyl](phenyl)methyl acetate C19H24N2O5 详情 详情
(VII) 27030 5-isopropyl-2,4(1H,3H)-pyrimidinedione C7H10N2O2 详情 详情
(VIII) 27031 1-(ethoxymethyl)-5-isopropyl-2,4(1H,3H)-pyrimidinedione C10H16N2O3 详情 详情

合成路线37

该中间体在本合成路线中的序号：(I)

The cyclization of benzaldehyde (I) with methyl 4-nitrobutyrate (II) and ammonium acetate in refluxing acetic acid gives 5-nitro-6-phenylpiperidone (III), which is treated with ozone and t-BuOK in dichloromethane/methanol to yield 2-phenylpiperidine-3,6-dione (IV). The reduction of (IV) by means of LiAlH4 in THF affords 2-phenylpiperidin-3-ol (V) as a mixture of cis- and trans-isomers. The reaction of (V) with TsOH, followed by crystallization in methanol/ethyl acetate provides the corresponding tosylate (VI) as the (rac)(cis)-isomer. The neutralization of the tosylate (VI) with Na2CO3 in ethyl acetate/water gives 2-phenylpiperidin-3-ol (VII) as a racemic cis mixture, which is submitted to optical resolution with (+)-dibenzoyltartaric acid to yield (+)(cis)-(VIII). The reaction of (VIII) with Boc2O affords the N-protected compound (IX), which is alkylated with 3,5-bis(trifluoromethyl)benzyl bromide (X) and NaH to provide the benzyl ether (XI). Finally, this compound is N-deprotected by means of TFA to obtain the target piperidine.

参考文献 中间体
合成目标
【1】 Baker, R.; Harrison, T.; Swain, C.J.; Williams, B.J. (Merck Sharp & Dohme Ltd.); Azacyclic cpds., processes for their preparation and pharmaceutical compsns. containing them. EP 0528495; EP 0600952; JP 1994510034; WO 9304040 .
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(II) 64492 methyl 4-nitrobutanoate C5H9NO4 详情 详情
(III) 64493 5-nitro-6-phenyl-2-piperidinone C11H12N2O3 详情 详情
(IV) 64494 6-phenyl-2,5-piperidinedione C11H11NO2 详情 详情
(V) 64495 (cis),(trans)2-phenyl-3-piperidinol C11H15NO 详情 详情
(VI) 64496 (rac)(cis)3-hydroxy-2-phenylpiperidinium 4-methylbenzenesulfonate C18H23NO4S 详情 详情
(VII) 64497 (rac)(cis)[(2S,3S)-2-phenyl-3-piperidinol] C11H15NO 详情 详情
(VIII) 64498 (2S,3S)-2-phenyl-3-piperidinol C11H15NO 详情 详情
(IX) 64499 tert-butyl (2S,3S)-3-hydroxy-2-phenyl-1-piperidinecarboxylate C16H23NO3 详情 详情
(X) 27677 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene 32247-96-4 C9H5BrF6 详情 详情
(XI) 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38

该中间体在本合成路线中的序号：(I)

Addition of lithium bis(trimethylsilyl)amide to a cooled solution of benzaldehyde (I), followed by treatment with the lithiated anion of 2-picoline (II), gave rise to the silylated amino intermediate (III), which, upon acidic quenching, yielded the racemic alpha-phenyl-2-pyridineethanamine (IV). Resolution of amine (IV) with S-(+)-mandelic acid in EtOAc provided the target (S)-amine mandelate salt (V). Liberation of the free amine with NaOH and subsequent treatment with HCl in EtOAc furnished the corresponding dihydrochloride

参考文献 中间体
合成目标
【1】 Murray, R.J.; Mathisen, D.; Balestra, M. (Celltech Group plc); (S)-Alpha-phenyl-2-pyridineethanamine (S)-malate and its use as a medicament. EP 0691957; EP 0691958; JP 1996508292; JP 1996508475; WO 9422831; WO 9422832 .
【2】 Griffith, R.C.; Murray, R.J.; Balestra, M. (Celltech Group plc); Enantiomeric 1-phenyl-2-(2-pyridinyl)ethylamine for the treatment of neurodegenerative disorders. EP 0633879; JP 2000319259; WO 9320052 .
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(II) 17590 2-methylpyridine; 2-picoline 109-06-8 C6H7N 详情 详情
(III) 60500 N-[1-phenyl-2-(2-pyridinyl)ethyl]-N,N-bis(trimethylsilyl)amine; trimethyl-N-[1-phenyl-2-(2-pyridinyl)ethyl]-N-(trimethylsilyl)silanamine C19H30N2Si2 详情 详情
(IV) 60501 1-phenyl-2-(2-pyridinyl)-1-ethanamine; 1-phenyl-2-(2-pyridinyl)ethylamine C13H14N2 详情 详情
(V) 60502 　 C21H22N2O3 详情 详情

合成路线39

该中间体在本合成路线中的序号：(VI)

D-Alaninol (I) was protected as the tert-butyl carbamate (II) and then converted to mesylate (III). Displacement of the mesylate group of (III) with NaCN furnished nitrile (IV), which was hydrogenated over Raney Nickel to give diamine (V). Condensation of (V) with benzaldehyde (VI) in the presence of molecular sieves produced imine (VII) and subsequent reduction by means of NaBH4 gave rise to the benzyl amine (VIII). This amine was alkylated with 4-chlorobutyronitrile (IX) to afford nitrile (X), which was further converted to the triamino compound (XI) by hydrogenation over Raney Nickel. Reaction of (XI) with methyl 2-[(phenoxycarbonyl)oxy]acetate (XII) provided carbamate (XIII). The ester group of (XIII) was then hydrolyzed with NaOH to give carboxylic acid (XIV).

参考文献 中间体
合成目标
【1】 Lebreton, L.; et al.; Structure - Immunosuppressive activity relationships of new analogues of 15-deoxyspergualin. 2. Structural modifications of the spermidine moiety. J Med Chem 1999, 42, 23, 4749.
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) 21414 (2R)-2-Amino-1-propanol; D-Alaninol; D-(-)-Alaninol 35320-23-1 C3H9NO 详情 详情
(II) 31758 tert-butyl (1R)-2-hydroxy-1-methylethylcarbamate C8H17NO3 详情 详情
(III) 31803 (2R)-2-[(tert-butoxycarbonyl)amino]propyl methanesulfonate C9H19NO5S 详情 详情
(IV) 31804 tert-butyl (1R)-2-cyano-1-methylethylcarbamate C9H16N2O2 详情 详情
(V) 31805 tert-butyl (1R)-3-amino-1-methylpropylcarbamate C9H20N2O2 详情 详情
(VI) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VII) 31806 tert-butyl (1R)-1-methyl-3-[[(E)-benzylidene]amino]propylcarbamate C16H24N2O2 详情 详情
(VIII) 31807 tert-butyl (1R)-3-(benzylamino)-1-methylpropylcarbamate C16H26N2O2 详情 详情
(IX) 11179 4-Chlorobutanenitrile; 4-Chlorobutyronitrile 628-20-6 C4H6ClN 详情 详情
(X) 31808 tert-butyl (1R)-3-[benzyl(3-cyanopropyl)amino]-1-methylpropylcarbamate C20H31N3O2 详情 详情
(XI) 31809 tert-butyl (1R)-3-[(4-aminobutyl)(benzyl)amino]-1-methylpropylcarbamate C20H35N3O2 详情 详情
(XII) 22341 methyl 2-[(phenoxycarbonyl)oxy]acetate C10H10O5 详情 详情
(XIII) 31810 methyl (6R)-9-benzyl-2,2,6-trimethyl-4,15-dioxo-3,16-dioxa-5,9,14-triazaoctadecan-18-oate C24H39N3O6 详情 详情
(XIV) 31811 (6R)-9-benzyl-2,2,6-trimethyl-4,15-dioxo-3,16-dioxa-5,9,14-triazaoctadecan-18-oic acid C23H37N3O6 详情 详情

合成路线40

该中间体在本合成路线中的序号：

Protection of the 4- and 6-hydroxyl groups of (XI) was achieved by conversion into the benzylidene acetal (XII) upon treatment with benzaldehyde and formic acid. The remaining 2- and 3-hydroxyl groups of (XII) were benzoylated with benzoyl chloride to afford the corresponding benzoate ester (XIII). After reduction of the azide group of (XIII) to amine (XIV) with H2S and pyridine, condensation with hexadecanoyl chloride produced the corresponding amide (XV). Deprotection of the acetal group of (XV) with TFA in CH2Cl2 gave diol (XVI), which was finally treated with SO3-Me3N complex, and then with NaHCO3 to form the title disulfate sodium salt.

参考文献 中间体
合成目标
【1】 Banville, J.; Martel, A.; Aruffo, A.A. (Bristol-Myers Squibb Co.); Sulfated beta-glycolipid derivs. as cell adhesion inhibitors. EP 0671406; JP 1995285985; US 5565433 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
16480 Palmitoyl Chloride; hexadecanoyl chloride 112-67-4 C16H31ClO 详情 详情
(XI) 26515 (1R,2Z)-1-((1S)-1-azido-2-[[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]ethyl)-2-hexadecenyl benzoate C31H49N3O8 详情 详情
(XII) 26516 (1R,2Z)-1-((1S)-2-[[(2S,4aR,6S,7R,8R,8aR)-7,8-dihydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-1-azidoethyl)-2-hexadecenyl benzoate C38H53N3O8 详情 详情
(XIII) 26517 (1R,2Z)-1-((1S)-2-[[(2S,4aR,6S,7R,8S,8aS)-7,8-bis(benzoyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-1-azidoethyl)-2-hexadecenyl benzoate C52H61N3O10 详情 详情
(XIV) 26518 (1R,2Z)-1-((1S)-2-[[(2S,4aR,6S,7R,8S,8aS)-7,8-bis(benzoyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-1-aminoethyl)-2-hexadecenyl benzoate C52H63NO10 详情 详情
(XV) 26519 (1R,2Z)-1-[(1S)-2-[[(2S,4aR,6S,7R,8S,8aS)-7,8-bis(benzoyloxy)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-1-(palmitoylamino)ethyl]-2-hexadecenyl benzoate C68H93NO11 详情 详情
(XVI) 26520 (1R,2Z)-1-[(1S)-2-[[(2S,3R,4S,5S,6R)-3,4-bis(benzoyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy]-1-(palmitoylamino)ethyl]-2-hexadecenyl benzoate C61H89NO11 详情 详情

合成路线41

该中间体在本合成路线中的序号：(VI)

The 2-phenylpyridine-3-amine (V), an intermediate in the synthesis of 235944, has been obtained with better yields by three related ways: 1. The acylation of 2-chloropyridine-3-amine (I) with Ac2O and TEA in dichloromethane gives the corresponding acetamide (II), which is condensed with phenylboronic acid (III) by means of Pd(PPh3)4 and Na2CO3 in ethanol/toluene, yielding N-(2-phenylpyridin-3-yl)acetamide (IV). Finally, this compound is hydrolyzed with HCl in methanol to afford the target 2-phenylpyridine-3-amine (V) intermediate. 2. The condensation of 2-chloropyridine-3-amine (I) with benzaldehyde (VI) in refluxing toluene gives the corresponding imine (VII), which is condensed with phenylboronic acid (III) as before to yield the 2-phenylpyridine derivative (VIII). Finally, the imino group of (VIII) is hydrolyzed with aqueous HCl to afford the target intermediate (V). 3. The one-pot condensation of 2-chloropyridine-3-amine (I), boronic acid (III) and benzaldehyde (VI) by means of Pd(PPh3)2Cl2 and Na2CO3 in hot toluene gives the already reported 2-phenylpyridine derivative (VIII), which is hydrolyzed as before to afford the target intermediate (V).

参考文献 中间体
合成目标
【1】 Caron, S.; et al.; An efficient and cost-effective synthesis of 2-phenyl-3-aminopyridine. Org Process Res Dev 2001, 5, 3, 254.
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) 11160 2-Chloro-3-pyridinamine; 2-Chloro-3-pyridinylamine; 3-Amino-2-chloropyridine; 2-Chloro-3-aminopyridine 6298-19-7 C5H5ClN2 详情 详情
(II) 51952 N-(2-Chloropyridin-3-yl)acetamide C7H7ClN2O 详情 详情
(III) 16593 Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide 98-80-6 C6H7BO2 详情 详情
(IV) 51953 N-(2-phenyl-3-pyridinyl)acetamide C13H12N2O 详情 详情
(V) 51954 2-phenyl-3-pyridinylamine; 2-phenyl-3-pyridinamine C11H10N2 详情 详情
(VI) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VII) 51955 N-(2-chloro-3-pyridinyl)-N-[(E)-benzylidene]amine; 2-chloro-N-[(E)-benzylidene]-3-pyridinamine C12H9ClN2 详情 详情
(VIII) 51956 2-phenyl-N-[(E)-benzylidene]-3-pyridinamine; N-[(E)-benzylidene]-N-(2-phenyl-3-pyridinyl)amine C18H14N2 详情 详情

合成路线42

该中间体在本合成路线中的序号：(IV)

A new enantioselective synthesis of (S)-fluoxetine has been reported: Reduction of 3-furaldehyde (I) under Wolff-Kishner conditions provided the desired 3-methylene-2,3-dihydrofuran (II) along with minor amounts of 3-methylfuran (III), which were used in the next step without previous separation. The asymmetric carbonyl-ene reaction of (II) with benzaldehyde (IV) using (S)-1,1'-binaphthol and titanium isopropoxide furnished the target (S)-2-(3-furyl)-1-phenylethanol (V). Condensation of the sodium alkoxide of (V) with 4-fluorobenzotrifluoride (VI) gave rise to ether (VII). Carboxylic acid (VIII) was then obtained by oxidative cleavage of the furan derivative (VII) with RuCl3/NaIO4. Coupling of acid (VIII) with methylamine gave amide (IX). Finally, amide reduction employing borane in THF yielded the title compound.

参考文献 中间体
合成目标
【1】 Miles, W.H.; et al.; Enantioselective synthesis of (S)- and (R)-fluoxetine hydrochloride. Tetrahedron 2001, 57, 50, 9925.
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) 47247 3-Furaldehyde 498-60-2 C5H4O2 详情 详情
(II) 55641 3-methylene-2,3-dihydrofuran C5H6O 详情 详情
(III) 55642 3-Methylfuran 930-27-8 C5H6O 详情 详情
(IV) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(V) 55651 (1S)-2-(3-furyl)-1-phenyl-1-ethanol C12H12O2 详情 详情
(VI) 52131 4-Fluorobenzotrifluoride; alpha,alpha-4-Tetrafluorotoluene 402-44-8 C7H4F4 详情 详情
(VII) 55652 (1S)-2-(3-furyl)-1-phenylethyl 4-(trifluoromethyl)phenyl ether; 3-{(2S)-2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl}furan C19H15F3O2 详情 详情
(VIII) 55653 (3S)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propanoic acid C16H13F3O3 详情 详情
(IX) 55654 (3S)-N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propanamide C17H16F3NO2 详情 详情

合成路线43

该中间体在本合成路线中的序号：(VIII)

Alkylation of methyl [1-(4-chlorobenzyl)but-3-enyl]carbamate (I) with chloromethyl ethyl ether in the presence of NaH afforded carbamate (II). Cyclization of (II) using chlorosulfonic acid in acetonitrile gave the trans-acetylamino piperidine (III). After removal of the carbamate group of (III) with HBr in HOAc, the racemic piperidine (IV) was resolved by acylation with (S)-O-acetylmandelic acid chloride (V), followed by recrystallization of the desired diastereoisomer (VI). Hydrolysis of (VI) with aqueous HCl furnished the chiral amino piperidine (VII), which was selectively protected with benzaldehyde (VIII) at the primary amino group as the corresponding benzaldimine (IX). Condensation of piperidine (IX) with 3,5-bis(trifluoromethyl)benzoyl chloride (X) followed by acid hydrolysis of the benzaldimine function produced the amino amide (XI). This was finally coupled with quinoline-4-carbonyl chloride (XII), yielding the title compound.

参考文献 中间体
合成目标
【1】 Ofner, S.; Veenstra, S.J.; Schilling, W. (Novartis AG); Aroyl-piperidine derivs.. CA 2160444; EP 0707006; JP 1996176145; US 5965562 .
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) 46477 methyl 1-(4-chlorobenzyl)-3-butenylcarbamate C13H16ClNO2 详情 详情
(II) 46478 methyl 1-(4-chlorobenzyl)-3-butenyl(ethoxymethyl)carbamate C16H22ClNO3 详情 详情
(III) 46479 methyl (2R,4S)-4-(acetamido)-2-(4-chlorobenzyl)-1-piperidinecarboxylate C16H21ClN2O3 详情 详情
(IV) 46480 N-[(2R,4S)-2-(4-chlorobenzyl)piperidinyl]acetamide C14H19ClN2O 详情 详情
(V) 46481 (1S)-2-chloro-2-oxo-1-phenylethyl acetate C10H9ClO3 详情 详情
(VI) 46482 (1S)-2-[(2R,4S)-4-(acetamido)-2-(4-chlorobenzyl)piperidinyl]-2-oxo-1-phenylethyl acetate C24H27ClN2O4 详情 详情
(VII) 46483 (2R,4S)-2-(4-chlorobenzyl)piperidinylamine; (2R,4S)-2-(4-chlorobenzyl)-4-piperidinamine C12H17ClN2 详情 详情
(VIII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(IX) 46484 N-[(2R,4S)-2-(4-chlorobenzyl)piperidinyl]-N-[(E)-benzylidene]amine; (2R,4S)-2-(4-chlorobenzyl)-N-[(E)-benzylidene]-4-piperidinamine C19H21ClN2 详情 详情
(X) 18290 3,5-Bis(trifluoromethyl)benzoyl chloride 785-56-8 C9H3ClF6O 详情 详情
(XI) 46485 [(2R,4S)-4-amino-2-(4-chlorobenzyl)piperidinyl][3,5-bis(trifluoromethyl)phenyl]methanone C21H19ClF6N2O 详情 详情
(XII) 46486 4-quinolinecarbonyl chloride C10H6ClNO 详情 详情

合成路线44

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45

该中间体在本合成路线中的序号：(II)

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46

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47

该中间体在本合成路线中的序号：(II)

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48

该中间体在本合成路线中的序号：(I)

The target compound can be obtained by heating benzaldehyde (I) with ethyl acetoacetate (II) in HOAc in the presence of ZnCl2 and Ac2O.

参考文献 中间体
合成目标
【1】 Jacobson, K.A.; Li, A.H.; Ji, X.-D.; Melman, N.; Kim, H.S.; Pyran template approach to the design of novel A3 adenosine receptor antagonists. Drug Dev Res 1999, 48, 4, 171.
【2】 Urbahns, K.; Heine, H.-G.; Junge, B.; Mauler, F.; Glaser, T.; Wittka, R.; De Vry, J.-M.-V. (Bayer AG); Substd. 4H-pyrans with a modulating effect on potassium channels. CA 2183048; DE 19529858; EP 0758648; JP 1997059271; US 5760073 .
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(II) 11819 ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate 141-97-9 C6H10O3 详情 详情

合成路线49

该中间体在本合成路线中的序号：(XVIII)

Synthesis of morpholine intermediate (I): Treatment of 4-fluorophenyl acetic acid (X) with trimethylacetyl chloride (XI) and Et3N in Et2O followed by reaction with 4-(S)-benzyl-2-oxazolidinone (XII) in THF and n-BuLi in hexane affords oxazolidinone derivative (XIII). Conversion of (XIII) into azido derivative (XV) is achieved by first treatment of (XIII) in THF with a potassium bis(trimethylsilyl)amide solution in toluene followed by treatment with 2,4,6-triisopropylphenylsulfonyl azide (XIV) in THF. Hydrolysis of azido-oxazolidinone derivative (XV) by means of LiOH in THF/H2O yields azido acetic acid derivative (XVI), which is then hydrogenated over Pd/C in H2O/HOAc to afford (S)-(4-fluorophenyl)glycine (XVII). Treatment of (S)-(4-fluorophenyl)glycine (XVII) with benzaldehyde (XVIII), NaOH and NaBH4 in MeOH yields N-benzyl (S)-(4-fluorophenyl)glycine (XIX), which is then cyclized with 1,2-dibromoethane (XX) in the presence of DIEA in DMF to furnish morpholine intermediate (I).

参考文献 中间体
合成目标
【1】 Castaner, J.; Silvestre, J.S.; Bayes, M.; Sorbera, L.A.; Aprepitant and L-758298. Drugs Fut 2002, 27, 3, 211.
【2】 Dorn, C.P.; Hale, J.J.; Maccoss, M.; Mills, S.G. (Merck & Co., Inc.); Prodrugs of morpholine tachykinin receptor antagonists. EP 0748320; JP 1997509935; US 5691336; WO 9523798 .
【3】 Dorn, C.P.; Hale, J.J.; Maccoss, M.; Mills, S.G.; Ladduwahetty, T.; Shah, S.K. (Merck & Co., Inc.); Morpholine and thiomorpholine tachykinin receptor antagonists. EP 0577394; JP 1994172178; US 5719147; WO 9400440; WO 9516679 .
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) 18288 (3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinone C17H16FNO2 详情 详情
(X) 18999 4-Fluorophenylacetic acid; 2-(4-Fluorophenyl)acetic acid 405-50-5 C8H7FO2 详情 详情
(XI) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(XII) 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
(XIII) 44186 (4S)-4-benzyl-3-[2-(4-fluorophenyl)acetyl]-1,3-oxazolidin-2-one C18H16FNO3 详情 详情
(XIV) 44187 2,4,6-triisopropylbenzenesulfonyl azide C15H23N3O2S 详情 详情
(XV) 44188 (4S)-3-[(2S)-2-azido-2-(4-fluorophenyl)ethanoyl]-4-benzyl-1,3-oxazolidin-2-one C18H15FN4O3 详情 详情
(XVI) 44189 (2S)-2-azido-2-(4-fluorophenyl)ethanoic acid C8H6FN3O2 详情 详情
(XVII) 43098 (2R)-2-amino-2-(4-fluorophenyl)ethanoic acid 7292-73-1 C8H8FNO2 详情 详情
(XVIII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(XIX) 44190 (2S)-2-(benzylamino)-2-(4-fluorophenyl)ethanoic acid C15H14FNO2 详情 详情
(XX) 10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情

合成路线50

该中间体在本合成路线中的序号：(IV)

NXY-059 is synthesized by condensation of N-tert-butylhydroxylamine (I) or its acetate or hydrochloride salts and disodium benzaldehyde-2,4-disulfonate (II) directly in refluxing MeOH or mixtures of MeOH/water or i-PrOH/MeOH/water or by means of MeONa in refluxing MeOH/water or i-PrOH/MeOH/water. N-tert-butylhydroxylamine (I) can be prepared as follows: a) Reduction of 2-methyl-2-nitropropane (III) with either Zn in HOAc/EtOH or aluminum foil and HgCl2 in EtOH/ether/H2O. b) Condensation of benzaldehyde (IV) with tert-butyl-amine (V) in refluxing toluene provides N-benzylidene-N-tert-butylamine (VI), which is oxidized with meta-chloroperbenzoic acid and Na2CO3 in water/toluene/ EtOH to furnish the phenyloxaziridine derivative (VII). Finally, the oxaziridine ring of (VII) is opened by treatment with H2SO4/HOAc in EtOH/H2O. c) Heating of the phenyloxaziridine derivative (VII) at 130 C gives N-tert-butylphenylnitrone (VIII), which is finally treated with H2SO4/HOAc in toluene. Disodium benzaldehyde-2,4-disulfonate (II) can be obtained as follows: a) Heating of 2,4-dichlorobenzaldehyde (IX) with sodium sulfite at 170 °C in water in water, followed by oxidation with sodium hypochlorite. b) Reaction of 2,4-dichlorobenzal chloride (X) with sodium sulfite and Na2CO3 or NaHCO3 at 170 C in water, followed by oxidation with sodium hypochlorite.

参考文献 中间体
合成目标
【1】 Leeson, P.A.; del Fresno, M.; Castañer, J.; Sorbera, L.A.; NXY-059. Drugs Fut 2002, 27, 3, 240.
【2】 Carney, J.M. (Oklahoma Medical Research Foundation; University of Kentucky); 2,4-Disulfo phenyl butyl nitrone, its salts and their use as pharmaceuticals. US 5780510 .
【3】 Carney, J.M. (Oklahoma Medical Research Foundation; University of Kentucky); 2,4-Disulfonyl phenyl butyl nitrone, its salts, and their use as pharmaceuticals. WO 9517876 .
【4】 Metz, H.J. (Aventis Pharma AG); Process for the preparation of alkali metal and alkaline earth salts of benzaldehyde-2,4-disulfonic acid. DE 3434038; US 4715995 .
【5】 Metz, H.J. (Aventis Pharma AG); Process for the preparation of alkali metal and alkaline earth salts of benzaldehyde-2,4-di-sulfonic acid. DE 3434079; US 4710322 .
【6】 Blixt, J. (AstraZeneca AB); Novel salts of N-tert-butylhydroxylamine. WO 0002848 .
【7】 Kruk, H.; McGinley, J.; Pouhov, S.; Blixt, J.; Vajda, J. (AstraZeneca AB; Centaur Pharmaceuticals, Inc.); Novel process for the preparation of alpha-(2,4-disulfophenyl)-N-tert-butylnitrone and pharmaceutically acceptable salts thereof. WO 0151460 .
【8】 Wilcox, A.; Blixt, J.; Kruk, H.; Larsson, U.; McGinley, J.; Pouhov, S.; Vajda, J. (AstraZeneca AB; Centaur Pharmaceuticals, Inc.); Novel process for the preparation of alpha-(2,4-disulfophenyl)-N-tert-butylnitrone and pharmaceutically acceptable salts thereof. WO 0151461 .
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) 35455 N-(tert-butyl)hydroxylamine; 2-(hydroxyamino)-2-methylpropane C4H11NO 详情 详情
(II) 37311 Benzaldehyde-2,4-disulfonic acid disodium; disodium 4-formyl-1,3-benzenedisulfonate 33513-44-9 C7H4Na2O7S2 详情 详情
(III) 37310 2-methyl-2-nitropropane 594-70-7 C4H9NO2 详情 详情
(IV) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(V) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(VI) 52176 N-(tert-butyl)-N-[(Z)-benzylidene]amine; 2-methyl-N-[(Z)-benzylidene]-2-propanamine C11H15N 详情 详情
(VII) 52177 2-(tert-butyl)-3-phenyl-1,2-oxaziridine C11H15NO 详情 详情
(VIII) 52178 tert-butyl[(Z)-benzylidene]ammoniumolate C11H15NO 详情 详情
(IX) 22196 2,4-dichlorobenzaldehyde 874-42-0 C7H4Cl2O 详情 详情
(X) 52179 2,4-dichloro-1-(dichloromethyl)benzene C7H4Cl4 详情 详情

合成路线51

该中间体在本合成路线中的序号：(II)

4-(Aminomethyl)piperidine (I) was protected as the benzylideneimine (III) by condensation with benzaldehyde (II). Further acylation of (III) at the secondary amino group by treatment with di-tert--butyl dicarbonate gave, after acid hydrolysis of the imine, the N-Boc-piperidine (IV). The benzoic acid derivative (V) was activated as the mixed anhydride by treatment with ethyl chloroformate and triethylamine, and subsequently condensed with amine (IV) to provide the corresponding amide (VI). Then, the N-tert-butoxycarbonyl group was eliminated with HCl to give the piperidine (VII), which was finally alkylated with halide (VIII) in the presence of K2CO3 in DMF to furnish the title compound.

参考文献 中间体
合成目标
【1】 Baker, S.R.; et al.; Synthesis and pharmacological evaluation of benzamides as selective 5-HT4 receptor agonists. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abs P 270.
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) 19349 4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine 7144-05-0 C6H14N2 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 19351 N-[(E)-benzylidene]-N-(4-piperidinylmethyl)amine; N-[(E)-benzylidene](4-piperidinyl)methanamine C13H18N2 详情 详情
(IV) 19352 4-Aminomethyl-1-N-Boc-piperidine; tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate 144222-22-0 C11H22N2O2 详情 详情
(V) 12419 4-Amino-5-chloro-2-methoxybenzoic acid 7206-70-4 C8H8ClNO3 详情 详情
(VI) 19354 tert-butyl 4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]-1-piperidinecarboxylate C19H28ClN3O4 详情 详情
(VII) 19355 4-amino-5-chloro-2-methoxy-N-(4-piperidinylmethyl)benzamide C14H20ClN3O2 详情 详情
(VIII) 19356 benzyl 4-chlorobutyl sulfone; benzyl(4-chlorobutyl)dioxo-lambda(6)-sulfane 14633-43-3 C11H15ClO2S 详情 详情

合成路线52

该中间体在本合成路线中的序号：(A)

4-(Aminomethyl)piperidine (I) was protected as the benzylideneimine (III) by condensation with benzaldehyde (II). Further acylation of (III) at the secondary amino group by treatment with di-tert--butyl dicarbonate gave, after acid hydrolysis of the imine, the N-Boc-piperidine (IV). The benzoic acid derivative (V) was activated as the mixed anhydride by treatment with ethyl chloroformate and triethylamine, and subsequently condensed with amine (IV) to provide the corresponding amide (VI). Then, the N-tert-butoxycarbonyl group was eliminated with HCl to give the piperidine (VII), which was finally alkylated with halide (VIII) in the presence of K2CO3 in DMF to furnish the title compound).

参考文献 中间体
合成目标
【1】 Baker, S.R.; et al.; Synthesis and pharmacological evaluation of benzamides as selective 5-HT4 receptor agonists. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abs P 270.
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) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(A) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(I) 19349 4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine 7144-05-0 C6H14N2 详情 详情
(II) 19351 N-[(E)-benzylidene]-N-(4-piperidinylmethyl)amine; N-[(E)-benzylidene](4-piperidinyl)methanamine C13H18N2 详情 详情
(III) 21110 benzylhydrosulfide; phenylmethanethiol 100-53-8 C7H8S 详情 详情
(IV) 21111 benzyl(3-chloropropyl)dioxo-lambda(6)-sulfane; benzyl 3-chloropropyl sulfone C10H13ClO2S 详情 详情
(V) 21112 [1-[3-(benzylsulfonyl)propyl]-4-piperidinyl]methylamine; [1-[3-(benzylsulfonyl)propyl]-4-piperidinyl]methanamine C16H26N2O2S 详情 详情
(VI) 12419 4-Amino-5-chloro-2-methoxybenzoic acid 7206-70-4 C8H8ClNO3 详情 详情

合成路线53

该中间体在本合成路线中的序号：(IV)

Reduction of 3-furaldehyde (I) under Wolff-Kishner conditions provided the desired 3-methylene-2,3-dihydrofuran (II) along with minor amounts of 3-methylfuran (III), which were used in the next step without previous separation. The asymmetric carbonyl-ene reaction of (II) with benzaldehyde (IV) using (R)-1,1'-binaphthol and titanium isopropoxide furnished the target (R)-2-(3-furyl)-1-phenylethanol (V). Condensation of the sodium alkoxide of (V) with 4-fluorobenzotrifluoride (VI) gave rise to ether (VII). Carboxylic acid (VIII) was then obtained by oxidative cleavage of the furan derivative (VII) with RuCl3/NaIO4. Coupling of acid (VIII) with methylamine gave amide (IX). Finally, amide reduction employing borane in THF yielded the title compound.

参考文献 中间体
合成目标
【1】 Miles, W.H.; et al.; Enantioselective synthesis of (S)- and (R)-fluoxetine hydrochloride. Tetrahedron 2001, 57, 50, 9925.
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) 47247 3-Furaldehyde 498-60-2 C5H4O2 详情 详情
(II) 55641 3-methylene-2,3-dihydrofuran C5H6O 详情 详情
(III) 55642 3-Methylfuran 930-27-8 C5H6O 详情 详情
(IV) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(V) 55643 (1R)-2-(3-furyl)-1-phenyl-1-ethanol C12H12O2 详情 详情
(VI) 52131 4-Fluorobenzotrifluoride; alpha,alpha-4-Tetrafluorotoluene 402-44-8 C7H4F4 详情 详情
(VII) 55644 (1R)-2-(3-furyl)-1-phenylethyl 4-(trifluoromethyl)phenyl ether; 3-{(2R)-2-phenyl-2-[4-(trifluoromethyl)phenoxy]ethyl}furan C19H15F3O2 详情 详情
(VIII) 55645 (3R)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propanoic acid C16H13F3O3 详情 详情
(IX) 55646 (3R)-N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propanamide C17H16F3NO2 详情 详情

合成路线54

该中间体在本合成路线中的序号：(VI)

The cyclization of methyl acetoacetate (I), 2-methoxybenzaldehyde (II) and thiourea (III) by means of HCl in refluxing ethanol gives the tetrahydropyrimidine (IV), which is finally cyclized with chloroacetic acid (V) and benzaldehyde (VI) by means of sodium acetate in a refluxing mixture of acetic acid and acetic anhydride.

参考文献 中间体
合成目标
【1】 Kelicen, P.; Ertan, M.; Demirdamar, R.; Krebs, B.; Tozkoparan, B.; Lage, M.; Condensed heterocyclic compounds: Synthesis and antiinflammatory activity of novel thiazolo[3,2-a]pyrimidines. Arch Pharm 1998, 331, 6, 201.
【2】 Assandri, A.; et al.; Pharmacokinetics of a new antihypertensive pyrrolyl pyridazinamine (MDL-899) in the rat and the dog. Arzneim-Forsch Drug Res 1985, 35, 2, 508.
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) 11791 methyl 3-oxobutanoate; Methyl acetoacetate 105-45-3 C5H8O3 详情 详情
(II) 12568 2-Methoxybenzaldehyde; o-Methoxybenzaldehyde 135-02-4 C8H8O2 详情 详情
(III) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(IV) 27432 methyl 4-(2-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate C14H16N2O3S 详情 详情
(V) 11847 2-Chloroacetic acid; Chloroacetic Acid 79-11-8 C2H3ClO2 详情 详情
(VI) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情

合成路线55

该中间体在本合成路线中的序号：

The esterification of 2-aminopropionic acid (I) with SOCl2 and methanol gives the methyl ester (II), whih is treated with benzaldehyde and TEA in dichloromethane yielding the benzylideneimine (III). The alkylation of (III) with N-(3-iodopropyl)phthalimide (IV) by means of LDA in THF affords the substituted pentanoate (V), which is treated with 1N HCl to give 2-amino-2-methyl-5-(phthalimido)pentanoic acid methyl ester (VI). The cyclization of (VI) by means of hydrazine and sodium methoxide in methanol yields the racemic 3-amino-3-methylpiperidin-2-one (VII), which is submitted to optical resolution with optically active binaphthyl phosphoric acid to afford 3(R)-amino-3-methy-piperidin-2-one (VIII). The reaction of (VIII) with 4-nitrophthalic anhydride (IX) in dioxane gives the amide (X), which is heated under vacuum to give the phthalimide (XI). The oxidation of (XI) with mCPBA in carbon tetrachloride yields the piperidinedione (XII), which is finally reduced at the nitro group by the usual methods.

参考文献 中间体
合成目标
【1】 Miyachi, H.; Koiso, Y.; Shirai, R.; Niwayama, S.; Liu, J.O.; Hashimoto, Y.; Tumor necrosis factor-alpha production enhancing activity of substituted 3'-methylthalidomide: Influence of substituents at the phthaloyl moiety on the activity and stereoselectivity. Chem Pharm Bull 1998, 46, 7, 1165.
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
(I) 31032 alanine 302-72-7 C3H7NO2 详情 详情
(II) 25315 methyl 2-aminopropanoate; Alanine, methyl ester 7625-53-8 C4H9NO2 详情 详情
(III) 31022 methyl 2-[[(E)-benzylidene]amino]propanoate C11H13NO2 详情 详情
(IV) 31023 2-(3-iodopropyl)-1H-isoindole-1,3(2H)-dione C11H10INO2 详情 详情
(V) 31024 methyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methyl-2-[[(E)-benzylidene]amino]pentanoate C22H22N2O4 详情 详情
(VI) 31025 methyl 2-amino-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methylpentanoate C15H18N2O4 详情 详情
(VII) 31026 3-amino-3-methyl-2-piperidinone C6H12N2O 详情 详情
(VIII) 31027 (3R)-3-amino-3-methyl-2-piperidinone C6H12N2O 详情 详情
(IX) 31028 5-nitro-2-benzofuran-1,3-dione 5466-84-2 C8H3NO5 详情 详情
(X) 31029 2-([[(3R)-3-methyl-2-oxopiperidinyl]amino]carbonyl)-5-nitrobenzoic acid C14H15N3O6 详情 详情
(XI) 31030 2-[(3R)-3-methyl-2-oxopiperidinyl]-5-nitro-1H-isoindole-1,3(2H)-dione C14H13N3O5 详情 详情
(XII) 31031 2-[(3R)-3-methyl-2,6-dioxopiperidinyl]-5-nitro-1H-isoindole-1,3(2H)-dione C14H11N3O6 详情 详情

合成路线56

该中间体在本合成路线中的序号：

The esterification of 2-aminopropionic acid (I) with SOCl2 and methanol gives the methyl ester (II), whih is treated with benzaldehyde and TEA in dichloromethane yielding the benzylideneimine (III). The alkylation of (III) with N-(3-iodopropyl)phthalimide (IV) by means of LDA in THF affords the substituted pentanoate (V), which is treated with 1N HCl to give 2-amino-2-methyl-5-(phthalimido)pentanoic acid methyl ester (VI). The cyclization of (VI) by means of hydrazine and sodium methoxide in methanol yields the racemic 3-amino-3-methylpiperidin-2-one (VII), which is submitted to optical resolution with optically active binaphthyl phosphoric acid to afford 3(S)-amino-3-methylpiperidin-2-one (VIII). The reaction of (VIII) with 4-nitrophthalic anhydride (IX) in dioxane gives the amide (X), which is heated under vacuum to give the phthalimide (XI). The oxidation of (XI) with mCPBA in carbon tetrachloride yields the piperidinedione (XII), which is finally reduced at the nitro group by the usual methods.

参考文献 中间体
合成目标
【1】 Miyachi, H.; Koiso, Y.; Shirai, R.; Niwayama, S.; Liu, J.O.; Hashimoto, Y.; Tumor necrosis factor-alpha production enhancing activity of substituted 3'-methylthalidomide: Influence of substituents at the phthaloyl moiety on the activity and stereoselectivity. Chem Pharm Bull 1998, 46, 7, 1165.
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
(I) 31032 alanine 302-72-7 C3H7NO2 详情 详情
(II) 25315 methyl 2-aminopropanoate; Alanine, methyl ester 7625-53-8 C4H9NO2 详情 详情
(III) 31022 methyl 2-[[(E)-benzylidene]amino]propanoate C11H13NO2 详情 详情
(IV) 31023 2-(3-iodopropyl)-1H-isoindole-1,3(2H)-dione C11H10INO2 详情 详情
(V) 31024 methyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methyl-2-[[(E)-benzylidene]amino]pentanoate C22H22N2O4 详情 详情
(VI) 31025 methyl 2-amino-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methylpentanoate C15H18N2O4 详情 详情
(VII) 31026 3-amino-3-methyl-2-piperidinone C6H12N2O 详情 详情
(VIII) 31033 (3S)-3-amino-3-methyl-2-piperidinone C6H12N2O 详情 详情
(IX) 31028 5-nitro-2-benzofuran-1,3-dione 5466-84-2 C8H3NO5 详情 详情
(X) 31034 2-([[(3S)-3-methyl-2-oxopiperidinyl]amino]carbonyl)-5-nitrobenzoic acid C14H15N3O6 详情 详情
(XI) 31035 2-[(3S)-3-methyl-2-oxopiperidinyl]-5-nitro-1H-isoindole-1,3(2H)-dione C14H13N3O5 详情 详情
(XII) 31036 2-[(3S)-3-methyl-2,6-dioxopiperidinyl]-5-nitro-1H-isoindole-1,3(2H)-dione C14H11N3O6 详情 详情

合成路线57

该中间体在本合成路线中的序号：(I)

Condensation of benzaldehyde (I) with hippuric acid (II) in the presence of NaOAc in boiling Ac2O furnished oxazolone (III). The title compound was then obtained by ring opening of (III) with piperidine (IV) in chloroform at 0 C, followed by chlorination with Cl2 gas.

参考文献 中间体
合成目标
【1】 Conway, S.C.; Perni, R.B. (Avid Corp.); 2-Benzoylamino-3-phenylpropenamide derivs. and methods of using the same. WO 9833501 .
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(II) 27236 2-(benzoylamino)acetic acid 495-69-2 C9H9NO3 详情 详情
(III) 27237 2-phenyl-4-[(Z)-benzylidene]-1,3-oxazol-5-one C16H11NO2 详情 详情
(IV) 10158 Piperidine 110-89-4 C5H11N 详情 详情

合成路线58

该中间体在本合成路线中的序号：(I)

Reaction of benzaldehyde (I) with trimethylsilyl cyanide and ZnI2 gave O-trimethylsilyl cyanohydrin (II). Subsequent condensation of (II) with 4-(methylthio)benzaldehyde (III) in the presence of lithium hexamethyldisilazide, followed by quenching of the intermediate (IV) with KHF2 and HCl, provided benzoin (V). This was oxidized either under Swern conditions, or with Bi2O3 in acetic to afford the corresponding benzil (VI). Condensation of (VI) with trifluoroacetaldehyde ethyl hemiacetal (VII) produced imidazole (VIII). Finally, oxidation of the sulfide group of (VIII) with hydrogen peroxide in AcOH provided the target sulfone.

参考文献 中间体
合成目标
【1】 Barta, T.E.; Collins, P.W.; Weier, R.M.; Stealey, M.A.; Antiinflammatory 4,5-diarylimidazoles as selective cyclooxygenase inhibitors. Bioorg Med Chem Lett 1998, 8, 24, 3443.
【2】 Weier, R.M.; Collins, P.W.; Stealey, M.A.; Barta, T.E.; Huff, R.M. (Pharmacia Corp.); 4,5-Substd. imidazolyl cpds. for the treatment of inflammation. EP 0772601; US 5620999; WO 9603387 .
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(II) 26578 2-phenyl-3-(trimethylsilyl)propanenitrile C12H17NSi 详情 详情
(III) 18815 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde 3446-89-7 C8H8OS 详情 详情
(IV) 26579 3-hydroxy-3-[4-(methylsulfanyl)phenyl]-2-phenyl-2-[(trimethylsilyl)methyl]propanenitrile C20H25NOSSi 详情 详情
(V) 26580 2-hydroxy-2-[4-(methylsulfanyl)phenyl]-1-phenyl-1-ethanone C15H14O2S 详情 详情
(VI) 26581 1-[4-(methylsulfanyl)phenyl]-2-phenyl-1,2-ethanedione C15H12O2S 详情 详情
(VII) 26582 1-ethoxy-2,2,2-trifluoro-1-ethanol 433-27-2 C4H7F3O2 详情 详情
(VIII) 26583 methyl 4-[5-phenyl-2-(trifluoromethyl)-1H-imidazol-4-yl]phenyl sulfide C17H13F3N2S 详情 详情

合成路线59

该中间体在本合成路线中的序号：

An related procedure was based on the formation of the intermediate stilbene sulfone (XII) by Wittig reaction. Thus, condensation of phosphonium salt (IX) with aldehyde (X) in the presence of LiOEt gave stilbene (XI) as a mixture of geometric isomers. Then, oxidation of the sulfide group of (XI) with Oxone provided stilbene sulfone (XII). Alternatively, phosphonium salt (XIV), prepared from benzyl chloride (XIII) and triphenyl phosphine, was condensed with benzaldehyde to yield (XII). The oxidation of stilbene (XII) with KMnO4 produced benzil (XV). Finally, cyclization of (XV) with hemiacetal (VII) furnished the title imidazole.

参考文献 中间体
合成目标
【1】 Barta, T.E.; Collins, P.W.; Weier, R.M.; Stealey, M.A.; Antiinflammatory 4,5-diarylimidazoles as selective cyclooxygenase inhibitors. Bioorg Med Chem Lett 1998, 8, 24, 3443.
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
(VII) 26582 1-ethoxy-2,2,2-trifluoro-1-ethanol 433-27-2 C4H7F3O2 详情 详情
(IX) 26584 benzyl(triphenyl)phosphonium iodide 15853-35-7 C25H22IP 详情 详情
(X) 18815 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde 3446-89-7 C8H8OS 详情 详情
(XI) 26585 methyl 4-[(Z)-2-phenylethenyl]phenyl sulfide C15H14S 详情 详情
(XII) 26586 methyl 4-[(Z)-2-phenylethenyl]phenyl sulfone C15H14O2S 详情 详情
(XIII) 26587 4-(chloromethyl)phenyl methyl sulfone C8H9ClO2S 详情 详情
(XIV) 26588 [4-(methylsulfonyl)benzyl](triphenyl)phosphonium chloride C26H24ClO2PS 详情 详情
(XV) 26589 1-[4-(methylsulfonyl)phenyl]-2-phenyl-1,2-ethanedione C15H12O4S 详情 详情

合成路线60

该中间体在本合成路线中的序号：(II)

The title compound was sinthesized by condensation of 2,6-dimethylpyridine (I) and benzaldehyde (II) in refluxing acetic anhydride.

参考文献 中间体
合成目标
【1】 Endorn, R.; Velicelebi, G.; Cosford, N.D.; Allgeier, H.; Kuhn, R.; Varney, M.A.; Biollaz, M.; Auberson, Y.; Gasparini, F.; Johnson, E.C. (Novartis AG; SIBIA Neurosciences, Inc.); Pyridine derivs.. WO 9902497 .
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) 33693 2,6-dimethylpyridine 108-48-5 C7H9N 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情

合成路线61

该中间体在本合成路线中的序号：(III)

Quinoline (IV) was prepared by condensation of 2-(2-methoxyethyl)aniline (I), pyruvic acid (II) and benzaldehyde (III) in refluxing EtOH. After activation of (IV) as the imidazolide (V) by means of 1,1'-carbonyldiimidazole in DMF, its condensation with guanidine (VI) in the same solvent yielded the corresponding acyl guanidine.

参考文献 中间体
合成目标
【1】 Doebner, O.; Ueber alpha-alkylcinchoninsauren. Ber 1887, 20, 277-80.
【2】 Pfitzinger, W.; Chinolinederivate aus isatinsaure. J Prakt Chem 1886, 33, 100.
【3】 Kitamori, T.; Hosoya, J.; Mori, H.; Banno, H.; Kibayashi, K.; Yamashita, H.; Fujiwara, J.; MS-31-038. Drugs Fut 1999, 24, 12, 1306.
【4】 Fujiwara, J.; Mori, H.; Yamashita, H.; Kitamori, T.; Hosoya, J.; Banno, H. (Mitsui Chemicals, Inc.); Quinoline-4-carbonylguanidine derivates, process for producing the same and pharmaceutical compsns. containing the cpds.. EP 0726254; JP 1996277269; US 5627193 .
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) 27088 2-(2-methoxyethoxy)aniline C9H13NO2 详情 详情
(II) 24066 2-oxopropionic acid 127-17-3 C3H4O3 详情 详情
(III) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(IV) 27089 8-(2-methoxyethoxy)-2-phenyl-4-quinolinecarboxylic acid C19H17NO4 详情 详情
(V) 27090 1H-imidazol-1-yl[8-(2-methoxyethoxy)-2-phenyl-4-quinolinyl]methanone C22H19N3O3 详情 详情
(VI) 14790 Guanidine 113-00-8 CH5N3 详情 详情

合成路线62

该中间体在本合成路线中的序号：(VII)

The alkylation of phenylacetylene (I) with AlMe3 and ZnCl2CP2 gives the alpha-methylstyrene (II), which is treated with paraformaldehyde and BuLi to yield 3-phenyl-2-buten-1-ol (III). The reaction of (III) with NCS and DMS affords the butenyl chloride (IV), which is treated with trichlorosilane, TEA and CuCl to provide the allylic trichlorosilane (V). The condensation of (V) with benzaldehyde (VI) by means of the chiral catalyst (VII) and tetrabutylammonium iodide in dichloromethane gives the chiral diphenylcarbinol (VIII), which is submitted to hydroboration by means of 9-BBN and NaBO3 to yield the diol (IX). The selective, two step reduction of one phenyl group of (IX) with H2 over Rh/alumina and H2 over Pt/C affords the chiral cyclohexyl-butanediol derivative (X), which is oxidized by means of (COCl)2, DMSO and TEA in dichloromethane to provide the keto-aldehyde (XI). Finally, this compound is reductocondensed with 1-(2-methoxyphenyl)piperazine (XII) by means of NaBH(OAc)3 in 1,2-dichloroethane to give the target disubstituted piperazine.

参考文献 中间体
合成目标
【1】 Denmark, S.E.; Fu, J.; Asymmetric construction of quaternary centers by enantioselective allylation: Application to the synthesis of the serotonin antagonist lY426965. Org Lett 2002, 4, 11, 1951.
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) 20597 1-ethynylbenzene 536-74-3 C8H6 详情 详情
(II) 28450 1-isopropenylbenzene 98-83-9 C9H10 详情 详情
(III) 57208 (E)-3-phenyl-2-buten-1-ol C10H12O 详情 详情
(IV) 57209 1-[(E)-3-chloro-1-methyl-1-propenyl]benzene C10H11Cl 详情 详情
(V) 57210 trichloro[(E)-3-phenyl-2-butenyl]silane C10H11Cl3Si 详情 详情
(VI) 57211 (9aS,9bS)-5-[{5-[[(9aS,9bS)-5-oxooctahydro-5lambda~5~-dipyrrolo[1,2-c:2,1-e][1,3,2]diazaphosphol-5-yl](methyl)amino]pentyl}(methyl)amino]octahydro-5lambda~5~-dipyrrolo[1,2-c:2,1-e][1,3,2]diazaphosphol-5-one C23H44N6O2P2 详情 详情
(VII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VIII) 57212 (1S,2S)-2-methyl-1,2-diphenyl-3-buten-1-ol C17H18O 详情 详情
(IX) 57213 (1S,2S)-2-methyl-1,2-diphenyl-1,4-butanediol C17H20O2 详情 详情
(X) 57214 (1S,2S)-1-cyclohexyl-2-methyl-2-phenyl-1,4-butanediol C17H26O2 详情 详情
(XI) 57215 (3S)-4-cyclohexyl-3-methyl-4-oxo-3-phenylbutanal C17H22O2 详情 详情
(XII) 11882 1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine 35386-24-4 C11H16N2O 详情 详情

合成路线63

该中间体在本合成路线中的序号：(IV)

The bromination of 1,1,1-trifluoroacetone (I) according to McBee and Burton gives 3,3-dibromo-1,1,1-trifluoroacetone (II), which is hydrolyzed with aqueous NaOAc to the glyoxal (III). The cyclization of (III) with benzaldehyde (IV) and ammonia in methanol yields 2-phenyl-4-(trifluoromethyl)-1H-imidazole (V), which is converted into the carbonitrile (VI) by reaction with hot aqueous ammonium hydroxide. The reduction of (VI) with diisobutylaluminum hydride in THF affords the carbaldehyde (VII), which is finally condensed with N-tert-butylhydroxylamine (VIII) by means of NaHCO3 in hot ethanol.

参考文献 中间体
合成目标
【1】 Dhainaut, A.; et al.; Synthesis, structure, and neuroprotective properties of novel imidazolyl nitrones. J Med Chem 2000, 43, 11, 2165.
【2】 Dhainaut, A.; Lestage, P.; Lockhart, B.; Tizot, A.; Goldstein, S. (ADIR et Cie.); Nitrone derivs., process for their preparation and pharmaceutical compsns. containing them. CA 2274621; EP 0967207; FR 2780404; JP 2000026428; US 6034250 .
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) 35449 1,1,1-trifluoroacetone 421-50-1 C3H3F3O 详情 详情
(II) 35450 3,3-dibromo-1,1,1-trifluoroacetone 431-67-4 C3HBr2F3O 详情 详情
(III) 35451 3,3,3-trifluoro-2-oxopropanal C3HF3O2 详情 详情
(IV) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(V) 35452 2-phenyl-4-(trifluoromethyl)-1H-imidazole C10H7F3N2 详情 详情
(VI) 35435 (1R)-2-[12-[(2R)-2-(benzoyloxy)propyl]-2,4,6,7,9,11-hexamethoxy-3,10-dioxo-3,10-dihydro-1-perylenyl]-1-methylethyl benzoate C46H42O12 详情 详情
(VII) 35454 2-phenyl-1H-imidazole-4-carbaldehyde C10H8N2O 详情 详情
(VIII) 35455 N-(tert-butyl)hydroxylamine; 2-(hydroxyamino)-2-methylpropane C4H11NO 详情 详情

合成路线64

该中间体在本合成路线中的序号：(II)

Condensation of 3-aminopyridine (I) with benzaldehyde (II) in refluxing toluene with azeotropic removal of water produced imine (III), which was reduced to amine (IV) using ethanolic NaBH4. Subsequent alkylation of (IV) with methyl 4-bromomethyl-2-(2-methylphenyl)benzoate (V) in the presence of n-BuLi in cold THF yielded the tertiary amine (VI). Basic hydrolysis of the ester group of (VI), followed by EDC-promoted coupling of the resulting carboxylic acid (VII) with L-methionine methyl ester (VIII) afforded amide (IX). The title compound was finally obtained by saponification of the methyl ester group of (IX) by means of LiOH.

参考文献 中间体
合成目标
【1】 Wang, L.; Barr, K.J.; O'Connor, S.; et al.; Second-generation peptidomimetic inhibitors of protein farnesyltransferase demonstrating improved cellular potency and significant in vivo efficacy. J Med Chem 1999, 42, 18, 3701.
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) 33327 3-Pyridinylamine; 3-Aminopyridine; 3-Pyridinamine 462-08-8 C5H6N2 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 35752 N-[(Z)-benzylidene]-N-(3-pyridinyl)amine; N-[(Z)-benzylidene]-3-pyridinamine C12H10N2 详情 详情
(IV) 35753 N-benzyl-N-(3-pyridinyl)amine; N-benzyl-3-pyridinamine C12H12N2 详情 详情
(V) 35754 ethyl 5-(bromomethyl)-2'-methyl[1,1'-biphenyl]-2-carboxylate C17H17BrO2 详情 详情
(VI) 35755 ethyl 5-[[benzyl(3-pyridinyl)amino]methyl]-2'-methyl[1,1'-biphenyl]-2-carboxylate C29H28N2O2 详情 详情
(VII) 35756 5-[[benzyl(3-pyridinyl)amino]methyl]-2'-methyl[1,1'-biphenyl]-2-carboxylic acid C27H24N2O2 详情 详情
(VIII) 17950 D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride 21691-49-6 C6H13NO2S 详情 详情
(IX) 35757 methyl (2S)-2-[[(5-[[benzyl(3-pyridinyl)amino]methyl]-2'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate C33H35N3O3S 详情 详情

合成路线65

该中间体在本合成路线中的序号：(III)

Cyclocondensation of a mixture of benzylamine (I), ethyl propiolate (II) and benzaldehyde (III) in hot AcOH furnished dihydropyridine (IV). Photodimerization of this compound in a MeOH-THF solution gave rise to the cage dimer (V). Finally, reduction of the ester groups of (V) by means of LiAlH4 at low temperature produced the title tetraol compound.

参考文献 中间体
合成目标
【1】 Wiese, M.; Billich, A.; Hilgeroth, A.; Synthesis and biological evaluation of the first N-alkyl cage dimeric 4-aryl-1,4-dihydropyridines as novel nonpeptidic HIV-1 protease inhibitors. J Med Chem 1999, 42, 22, 4729.
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) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(II) 35333 ethyl propiolate 623-47-2 C5H6O2 详情 详情
(III) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(IV) 40525 diethyl 1-benzyl-4-phenyl-1,4-dihydro-3,5-pyridinedicarboxylate C24H25NO4 详情 详情
(V) 40526 　 C48H50N2O8 详情 详情

合成路线66

该中间体在本合成路线中的序号：

4-(Aminomethyl)-1-benzyl-4-hydroxypiperidine (XV) was protected as the tert-butyl carbamate (XVI) and the benzyl group was subsequently cleaved by transfer hydrogenolysis employing ammonium formate and Pd/C yielding (XVII). Condensation of piperidine (XVII) with mesylate (VIII) in the presence of K2CO3 in boiling isopropanol furnished adduct (XVIII). After deprotection of the Boc group of (XVIII) with trifluoroacetic acid, reductive alkylation of the resulting amine (XIX) with benzaldehyde in the presence of NaBH3CN provided the N-benzyl amine (XX). Finally, a further reductive alkylation of (XX) with formaldehyde and NaBH3CN yielded the title compound.

参考文献 中间体
合成目标
【1】 Stanton, J.A.; Showell, G.A.; Neduvelil, J.G.; Bourrain, S.; Beer, M.S.; MacLeod, A.M.; 4-Hydroxy-1-[3-(5-(1,2,4-triazol-4-yl)-1H-indol-3-yl)propyl]piperidines: Selective h5-HT1D agonists for the treatment of migraine. Bioorg Med Chem Lett 1999, 9, 23, 3369.
【2】 Baker, R.; Bourrain, S.; Castro Pineiro, J.L.; Chambers, M.S.; Guiblin, A.R.; Hobbs, S.C.; Jelley, R.A.; Madin, A.; Matassa, V.G.; Reeve, A.J.; Russell, M.G.N.; Showell, G.A.; Sternfeld, F.; Street, L.J.; Van Niel, M.B. (Merck Sharp & Dohme Ltd.); Azetidine, pyrrolidine and piperidine derivs.. EP 0804434; JP 1998503768; US 5854268; WO 9604274 .
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
(VIII) 36539 3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl methanesulfonate C14H16N4O3S 详情 详情
(XV) 36544 4-(aminomethyl)-1-benzyl-4-piperidinol C13H20N2O 详情 详情
(XVI) 36545 tert-butyl (1-benzyl-4-hydroxy-4-piperidinyl)methylcarbamate C18H28N2O3 详情 详情
(XVII) 36546 tert-butyl (4-hydroxy-4-piperidinyl)methylcarbamate C11H22N2O3 详情 详情
(XVIII) 36547 tert-butyl (4-hydroxy-1-[3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]-4-piperidinyl)methylcarbamate C24H34N6O3 详情 详情
(XIX) 36548 4-(aminomethyl)-1-[3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]-4-piperidinol C19H26N6O 详情 详情
(XX) 36549 4-[(benzylamino)methyl]-1-[3-[5-(4H-1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]-4-piperidinol C26H32N6O 详情 详情

合成路线67

该中间体在本合成路线中的序号：(II)

The condensation of 3-methoxyacetophenone (I) with benzaldehyde (II) by means of NaOH in ethanol - water gives 3'-methoxychalcone (III), which by addition of HCN (KCN) in ethanol-acetic acid is transformed into 2-phenyl-4-(3-methoxyphenyl)-4-oxobutyronitrile (IV). The hydrolysis of (IV) with aqueous H2SO4 at 100 C affords the corresponding ketoacid (V), which is reduced with amalgamated zinc and 2N HCl yielding 2-phenyl-4-(3-methoxyphenyl)butyric acid (VI). The cyclization of (VI) by means of liquid HF yields 2-phenyl-6-methoxy-1,2,3,4-tetrahydro-1-naphthalenone (VII), which is finally condensed with 4-(2-pyrrolidinoethoxy)phenylmagnesium bromide in refluxing THF.

参考文献 中间体
合成目标
【1】 Thorpe, P.; Castañer, J.; Nafoxidine. Drugs Fut 1978, 3, 3, 211.
【2】 Duncan, G.W.; Lednicer, D.; US 3483293 .
【3】 Lednicer, D.; US 3274213 .
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) 18792 3-methoxyacetophenone; 1-(3-methoxyphenyl)-1-ethanone 586-37-8 C9H10O2 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 39791 (E)-1-(3-methoxyphenyl)-3-phenyl-2-propen-1-one C16H14O2 详情 详情
(IV) 39792 4-(3-methoxyphenyl)-4-oxo-2-phenylbutanenitrile C17H15NO2 详情 详情
(V) 39793 4-(3-methoxyphenyl)-4-oxo-2-phenylbutyric acid C17H16O4 详情 详情
(VI) 39794 4-(3-methoxyphenyl)-2-phenylbutyric acid C17H18O3 详情 详情
(VII) 39795 6-methoxy-2-phenyl-3,4-dihydro-1(2H)-naphthalenone C17H16O2 详情 详情
(VIII) 29184 bromo[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]magnesium C12H16BrMgNO 详情 详情

合成路线68

该中间体在本合成路线中的序号：(VI)

The alkylation of 4-methylimidazole (I) with N-(3-bromopropyl)phthalimide (II) produced a mixture of N-alkylated regioisomers (III) and (IV). After selective derivatization of the undesired 5-methyl isomer (III) with trityl chloride, the 4-methyl derivative was isolated by flash chromatography and subsequently subjected to phthaloyl group hydrazinolysis to yield amine (V). Reductive condensation of amine (V) with benzaldehyde (VI) in the presence of NaBH4 afforded the N-benzyl amine (VII).

参考文献 中间体
合成目标
【1】 Guzi, T.; Taveras, A.G.; Ferreira, J.A.; Desai, J.A.; Wang, J.J.S.; Lalwani, T.; Alvarez, C.; Afonso, A.; Girijavallabhan, V.M.; Mallams, A.K.; Doll, R.J.; Weinstein, J.; Cooper, A.B.; Chao, J.; Rane, D.F.; Aki, C.J.; Kelly, J.M. (Schering Corp.); Tricyclic farnesyl protein transferase inhibitors. EP 1140902; WO 0037459 .
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) 51586 4-Methylimidazole; 4-Methyl-1H-imidazole; 4-Methyl Imidazole 822-36-6 C4H6N2 详情 详情
(II) 15216 N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione 5460-29-7 C11H10BrNO2 详情 详情
(III) 51587 2-[3-(5-methyl-1H-imidazol-1-yl)propyl]-1H-isoindole-1,3(2H)-dione C15H15N3O2 详情 详情
(IV) 51588 2-[3-(4-methyl-1H-imidazol-1-yl)propyl]-1H-isoindole-1,3(2H)-dione C15H15N3O2 详情 详情
(V) 51589 3-(4-methyl-1H-imidazol-1-yl)-1-propanamine; 3-(4-methyl-1H-imidazol-1-yl)propylamine C7H13N3 详情 详情
(VI) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VII) 51590 N-benzyl-3-(4-methyl-1H-imidazol-1-yl)-1-propanamine; N-benzyl-N-[3-(4-methyl-1H-imidazol-1-yl)propyl]amine C14H19N3 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 alkylation of N-[1(S)-(5-oxotetrahydrofuran-2(R)-yl)-2-phenylethyl]carbamic acid tert-butyl ester (I) with benzaldehyde (II) by means of LDA in THF, followed by a treatment with Ac2O and TEA at 120 C, gives the benzylidene derivative (III), which is hydrogenated with H2 over Pd/C in methanol/ethyl acetate to yield N-[1(S)-[4(R)-benzyl-5-oxotetrahydrofuran-2(R)-yl]-2-phenylethyl]carbamic acid tert-butyl ester (IV). The hydrolysis of (IV) with NaOH in dimethoxyethane/water affords the hexanoic acid (V), which is finally condensed with the dipeptide L-leucyl-L-phenylalaninamide (VI) by means of EDC and HOBT in DMF to provide the target acylated dipeptide.

参考文献 中间体
合成目标
【1】 Hunt, P.A.; Harrison, T.; Castro Pineiro, J.L.; Nadin, A.J. (Merck Sharp & Dohme Ltd.); gamma-Secretase inhibitors. WO 0153255 .
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) 52631 1,1-dimethylethyl 1-(5-oxotetrahydro-2-furanyl)-2-phenylethylcarbamate C17H23NO4 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 52632 1,1-dimethylethyl 1-[5-oxo-4-(phenylmethylidene)tetrahydro-2-furanyl]-2-phenylethylcarbamate C24H27NO4 详情 详情
(IV) 52633 1,1-dimethylethyl 1-[5-oxo-4-(phenylmethyl)tetrahydro-2-furanyl]-2-phenylethylcarbamate C24H29NO4 详情 详情
(V) 52634 5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-hydroxy-6-phenyl-2-(phenylmethyl)hexanoic acid C24H31NO5 详情 详情
(VI) 52635 2-amino-N-[2-amino-2-oxo-1-(phenylmethyl)ethyl]-4-methylpentanamide C15H23N3O2 详情 详情

合成路线70

该中间体在本合成路线中的序号：(II)

In a related method, the 2-lithio derivative of 5-methoxy-1-(phenylsulfonyl)indole (I) is condensed with benzaldehyde (II) to produce carbinol (III). Subsequent oxidation of (III) to the corresponding ketone (IV) is accomplished by treatment with pyridinium dichromate (PDC) in the presence of pyridinium trifluoroacetate (PTFA). Finally, the N-phenylsulfonyl group of (IV) is deprotected by treatment with tetrabutylammonium fluoride.

参考文献 中间体
合成目标
【1】 Teller, S.; Pongratz, H.; Mahboobi, S.; et al.; Bis(1H-2-indolyl) methanones as a novel class of inhibitors of the platelet-derived growth factor receptor kinase. J Med Chem 2002, 45, 5, 1002.
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) 57928 5-methoxy-1-(phenylsulfonyl)-1H-indole; methyl 1-(phenylsulfonyl)-1H-indol-5-yl ether C15H13NO3S 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 57930 [5-methoxy-1-(phenylsulfonyl)-1H-indol-2-yl](phenyl)methanol C22H19NO4S 详情 详情
(IV) 57929 [5-methoxy-1-(phenylsulfonyl)-1H-indol-2-yl](phenyl)methanone C22H17NO4S 详情 详情

合成路线71

该中间体在本合成路线中的序号：(II)

Selective protection of the secondary amino group of 4-(aminomethyl)piperidine (I) was achieved via conversion to imine (III) upon condensation with benzaldehyde (II), followed by treatment with di-tert-butyl dicarbonate to afford carbamate (IV). Subsequent acid hydrolysis of the imine function of (IV) furnished the mono-protected diamine (V). Coupling of amine (V) with 3-methoxy-4-(3-o-tolylureido)phenylacetic acid (VI) using HATU furnished amide (VII). Acidic cleavage of the N-Boc protecting group of (VII) gave piperidine (VIII). Aziridine (X) was prepared from ethyl 2,3-dibromopropionate (IX) by treatment with ammonia in acetonitrile. Condensation of (X) with N-(benzyloxycarbonyloxy)succinimide produced the benzyl carbamate (XI). Regioselective ring opening of the aziridine (XI) with piperidine (VIII) yielded adduct (XII). The ethyl ester group of (XII) was finally hydrolyzed to the target carboxylic acid under basic conditions.

参考文献 中间体
合成目标
【1】 Astles, P.C.; et al.; Diamine containing VLA-4 antagonists. Bioorg Med Chem 2001, 9, 8, 2195.
【2】 McCarthy, C.; Morley, A.D.; Harris, N.V. (Rhone-Poulenc Rorer Ltd.); Substd. diamines and their use as cell adhesion inhibitors. WO 9954321 .
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) 19349 4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine 7144-05-0 C6H14N2 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 19351 N-[(E)-benzylidene]-N-(4-piperidinylmethyl)amine; N-[(E)-benzylidene](4-piperidinyl)methanamine C13H18N2 详情 详情
(IV) 49958 tert-butyl 4-([[(E)-benzylidene]amino]methyl)-1-piperidinecarboxylate C18H26N2O2 详情 详情
(V) 19352 4-Aminomethyl-1-N-Boc-piperidine; tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate 144222-22-0 C11H22N2O2 详情 详情
(VI) 39718 2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetic acid C17H18N2O4 详情 详情
(VII) 49959 tert-butyl 4-[[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]methyl]-1-piperidinecarboxylate C28H38N4O5 详情 详情
(VIII) 49960 2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]-N-(4-piperidinylmethyl)acetamide C23H30N4O3 详情 详情
(IX) 18341 ethyl 2,3-dibromopropanoate 3674-13-3 C5H8Br2O2 详情 详情
(X) 49961 ethyl 2-aziridinecarboxylate C5H9NO2 详情 详情
(XI) 49962 1-benzyl 2-ethyl 1,2-aziridinedicarboxylate C13H15NO4 详情 详情
(XII) 49963 ethyl 2-[[(benzyloxy)carbonyl]amino]-3-(4-[[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]methyl]-1-piperidinyl)propanoate C36H45N5O7 详情 详情

合成路线72

该中间体在本合成路线中的序号：(V)

Dilithiation of thiophene (I) employing an excess of BuLi in the presence of TMEDA produced the intermediate 2,5-dilithiothiophene (II). Addition of 4-fluorobenzaldehyde (III) to the organolithium compound (II) afforded the bis-carbinol adduct (IV). Alternatively, addition of benzaldehyde (V) to (II) provided adduct (VI). Boron trifluoride-catalyzed condensation of pyrrole (VII) with diol (IV) yielded the bis(alpha-pyrrolylbenzyl)thiophene (VIII). The dithiaporphyrin derivative (IX) was then obtained by condensation between (VIII) and (VI) in the presence of boron trifluoride. Finally, aromatic sulfonation of (IX) with hot sulfuric acid, followed by neutralization with NaOH furnished the title disulfonate disodium salt.

参考文献 中间体
合成目标
【1】 Hilmey, D.G.; et al.; Water-soluble, core-modified porphyrins as novel longer-wavelength-absorbing sensitizers for photodynamic therapy. II. Effects of core heteroatoms and meso-substituents on biological activity. J Med Chem 2002, 45, 2, 449.
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) 13297 Thiophene 110-02-1 C4H4S 详情 详情
(II) 54835 　 C4H2Li2S 详情 详情
(III) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(IV) 54836 (4-fluorophenyl){5-[(4-fluorophenyl)(hydroxy)methyl]-2-thienyl}methanol C18H14F2O2S 详情 详情
(V) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VI) 54837 {5-[hydroxy(phenyl)methyl]-2-thienyl}(phenyl)methanol C18H16O2S 详情 详情
(VII) 21674 1H-pyrrole 109-97-7 C4H5N 详情 详情
(VIII) 54838 2-((4-fluorophenyl){5-[(4-fluorophenyl)(1H-pyrrol-2-yl)methyl]-2-thienyl}methyl)-1H-pyrrole C26H20F2N2S 详情 详情
(IX) 54839 7,12-bis(4-fluorophenyl)-2,17-diphenyl-21,23-dithia-22,24-diazapentacyclo[16.2.1.1~3,6~.1~8,11~.1~13,16~]tetracosa-1,3(24),4,6,8,10,12,14,16(22),17,19-undecaene C44H26F2N2S2 详情 详情

合成路线73

该中间体在本合成路线中的序号：(XXI)

An alternative synthetic method employed the racemic amino acid (XXIX). The phenylpyruvic acid precursor (XXVII) was prepared from benzaldehyde (XXI) by several procedures. Condensation of benzaldehyde (XXI) with hydantoin (XXII) yielded the benzylidene hydantoin (XXIV), which was converted to (XXVII) by basic hydrolysis. Alternatively, aldehyde (XXI) was condensed with N-acetyl glycine or with the phosphonoacetate reagent (XXIII) to produce (XXV) or (XXVI), respectively. Basic hydrolysis of either (XXV) or (XXVI) led to the desired phenylpyruvic acid (XXVII). Dialkylation of keto acid (XXVII) with iodomethane and NaOH furnished the dimethyl derivative (XXVIII). Then, reductive amination of (XXVIII) with methylamine yielded the racemic amino acid (XXIX). Coupling of amino acid (XXIX) with the intermediate dipeptide (XIX) gave rise to tripeptide (XXX) as an epimeric mixture. After chromatographic isolation of the desired isomer, basic hydrolysis of the ethyl ester provided the title compound.

参考文献 中间体
合成目标
【1】 Zask, A.; Cheung, K.; Birnberg, G.; et al.; Synthesis and biological activity of analogs of the antimicrotubule agent HTI-286. Proc Am Assoc Cancer Res 2002, 43, Abst 3653.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIX) 55124 ethyl (E,4S)-4-[[(2S)-2-amino-3,3-dimethylbutanoyl](methyl)amino]-2,5-dimethyl-2-hexenoate C17H32N2O3 详情 详情
(XXI) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(XXII) 32482 2,4-imidazolidinedione 461-72-3 C3H4N2O2 详情 详情
(XXIII) 55126 methyl 2-(acetyloxy)-2-(diethoxyphosphoryl)acetate C9H17O7P 详情 详情
(XXIV) 55127 5-[(Z)-phenylmethylidene]-2,4-imidazolidinedione C10H8N2O2 详情 详情
(XXV) 55128 2-methyl-4-[(Z)-phenylmethylidene]-1,3-oxazol-5-one C11H9NO2 详情 详情
(XXVI) 55129 methyl (Z)-2-(acetyloxy)-3-phenyl-2-propenoate C12H12O4 详情 详情
(XXVII) 55130 2-Oxophenylpropionic acid; Alpha-keto-DL-phenylalanine; Benzylglyoxylic acid; Phenylpyruvic acid 156-06-9 C9H8O3 详情 详情
(XXVIII) 55131 3-methyl-2-oxo-3-phenylbutanoic acid C11H12O3 详情 详情
(XXIX) 55132 N-methyl-3-phenylvaline C12H17NO2 详情 详情
(XXX) 55133 ethyl (E,4S)-4-[((2S)-3,3-dimethyl-2-{[3-methyl-2-(methylamino)-3-phenylbutanoyl]amino}butanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate C29H47N3O4 详情 详情

合成路线74

该中间体在本合成路线中的序号：(I)

Benzaldehyde (I) is converted into the corresponding hydrazone (II) upon treatment with methylhydrazine in toluene. Condensation of hydrazone (II) with ethyl (ethoxymethylene)cyanoacetate (III) produces the hydrazinomethylene cyanoacetate (IV), which is further cyclized to the pyrazole (V) under acidic conditions (1). Heating of amino ester (V) with formamide gives rise to the pyrazolopyrimidinone (VI). This is finally alkylated with 2,6-difluorobenzyl chloride (VII) to furnish the title compound

参考文献 中间体
合成目标
【1】 Unverferth, K.; Lankau, H-J.; Arnold, T.; Synthesis and anticonvulsant activity of AWD 34-176. Drugs Fut 2002, 27, Suppl. A.
【2】 Lankau, H.-J.; Unverferth, K.; Tober, C.; Rundfeldt, C.; Arnold, T.; Dost, R.; Gasparic, A.; Bernöster, K. (AWD.pharma GmbH & Co. KG); 2,5-Dihydro-pyrazolo[3,4-d]pyrimidin-4-ones with an anticonvulsive action and methods for producing the same. WO 0218387 .
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) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(II) 62055 benzaldehyde N-methylhydrazone C8H10N2 详情 详情
(III) 43563 ethyl (E)-2-cyano-3-ethoxy-2-propenoate；(E)-ethyl 2-cyano-3-ethoxyacrylate 94-05-3 C8H11NO3 详情 详情
(IV) 62056 ethyl (E)-2-cyano-3-{1-methyl-2-[(E)-phenylmethylidene]hydrazino}-2-propenoate C14H15N3O2 详情 详情
(V) 62057 ethyl 3-amino-1-methyl-1H-pyrazole-4-carboxylate C7H11N3O2 详情 详情
(VI) 62058 2-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one C6H6N4O 详情 详情
(VII) 23150 2-(chloromethyl)-1,3-difluorobenzene 697-73-4 C7H5ClF2 详情 详情

合成路线75

该中间体在本合成路线中的序号：(VIII)

The condensation of 1,3,5-tribromobenzene (VII) with benzaldehyde (VIII) by means of BuLi in ethyl ether gives 3,5-dibromodiphenylmethanol (IX), which is reduced with Tes-H and BF3/Et2O to yield 3,5-dibromodiphenylmethane (X). The carbonylation of (X) with BuLi and DMF in THF affords the benzaldehyde (XI), which is reduced by means of NaBH4 in methanol to provide the benzyl alcohol (XII). The reaction of (XII) with CBr4 and PPh3 in dichloromethane gives the bromomethyl derivative (XIII), which is condensed with 1,3-propanesultam (XIV) by means of K2CO3 in refluxing acetonitrile to yield the adduct (XV). The reaction of (XV) with thalium acetate and palladium acetate in DMF affords the acetyl derivative (XVI), which is brominated with Br2 and AlCl3 in dioxane to provide the bromoacetyl compound (XVII). The condensation of (XVII) with the intermediate amine (VI) by means of TEA in acetonitrile gives the secondary amine (XVIII), which is protected with benzyl chloroformate (XIX) to yield the carbamate (XX). The carboxylation of (XX) by means of CO, EtOH, TEA and PdCl2(PPh3)2 in ethyl acetate affords the pyridine-2-carboxylate derivative (XXI), which is finally cyclized by means of NaOMe in THF to provide the target naphthyridine derivative.

参考文献 中间体
合成目标
【1】 Design and synthesis of 8-hydroxy-[1,6]naphthyridines as novel inhibitors of HIV-1 integrase in vitro and in infected cells. J Med Chem 2003, 46, 4, 453.
【2】 Young, S.D.; Guare, J.P.; Wai, J.S.; Payne, L.S.; Fisher, T.E.; Zhuang, L.; Embrey, M. (Merck & Co., Inc.); Aza- and polyaza-naphthalenyl ketones useful as HIV integrase inhibitors. WO 0236734 .
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) 61832 (2-chloro-3-pyridinyl)methanamine; (2-chloro-3-pyridinyl)methylamine C6H7ClN2 详情 详情
(VII) 26991 1,3,5-tribromobenzene 626-39-1 C6H3Br3 详情 详情
(VIII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(IX) 61833 (3,5-dibromophenyl)(phenyl)methanol C13H10Br2O 详情 详情
(X) 61834 1-benzyl-3,5-dibromobenzene C13H10Br2 详情 详情
(XI) 61835 3-benzyl-5-bromobenzaldehyde C14H11BrO 详情 详情
(XII) 61836 (3-benzyl-5-bromophenyl)methanol C14H13BrO 详情 详情
(XIII) 61837 1-benzyl-3-bromo-5-(bromomethyl)benzene C14H12Br2 详情 详情
(XIV) 61838 1lambda~6~-isothiazolidine-1,1-dione C3H7NO2S 详情 详情
(XV) 61839 2-(3-benzyl-5-bromobenzyl)-1lambda~6~-isothiazolidine-1,1-dione C17H18BrNO2S 详情 详情
(XVI) 61840 2-(3-acetyl-5-benzylbenzyl)-1lambda~6~-isothiazolidine-1,1-dione C19H21NO3S 详情 详情
(XVII) 61841 2-[3-benzyl-5-(2-bromoacetyl)benzyl]-1lambda~6~-isothiazolidine-1,1-dione C19H20BrNO3S 详情 详情
(XVIII) 61842 2-[3-benzyl-5-(2-{[(2-chloro-3-pyridinyl)methyl]amino}acetyl)benzyl]-1lambda~6~-isothiazolidine-1,1-dione C25H26ClN3O3S 详情 详情
(XIX) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(XX) 61843 benzyl 2-{3-benzyl-5-[(1,1-dioxo-1lambda~6~-isothiazolidin-2-yl)methyl]phenyl}-2-oxoethyl[(2-chloro-3-pyridinyl)methyl]carbamate C33H32ClN3O5S 详情 详情
(XXI) 61844 ethyl 3-({(2-{3-benzyl-5-[(1,1-dioxo-1lambda~6~-isothiazolidin-2-yl)methyl]phenyl}-2-oxoethyl)[(benzyloxy)carbonyl]amino}methyl)-2-pyridinecarboxylate C36H37N3O7S 详情 详情

合成路线76

该中间体在本合成路线中的序号：(II)

　

参考文献 中间体
合成目标
【1】 Baetz F,JunghansB 2006. Improved process for the preparation of sodium ibandronate, [l-hydroxy-3-(methylpentylamino) propylidene] bisphosphonic acid monosodium salt mmohydrate W0 2006045578（本专利申请人为F．Hoffmann-IA Roche AG, Switz）
【2】 Grassi S,Volante A. 2005. An improved process for the preparation of alkyl- and aryl-substituted-hydroxy-l,l-ethanediphosphonic acids and salts thereof by solvent-free reaction of carboxylic acids with pbosphoxous acid and phosphorus oxychloride. W0 2005063779(本专利申请人为Lyogen Limited, Cyprus)
【3】 Szabo CM, Matsumura Y, Fukrua S,et aL 2002. Inhibition of geranylgeranyl diphosphate synthase by bisphosphontes and diphosphates: a potential route to new bone antiresorption ru,d antiparasitic agents.J Med Che:m, 45 (11): 2185~2196
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) 15764 amylamine; 1-pentanamine; pentylamine 110-58-7 C5H13N 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 15766 N-pentyl-N-[(E)-benzylidene]amine; N-[(E)-benzylidene]-1-pentanamine C12H17N 详情 详情
(IV) 15767 N-Methylamylamine; N-methyl-N-pentylamine; N-methyl-1-pentanamine 25419-06-1 C6H15N 详情 详情

合成路线77

该中间体在本合成路线中的序号：(II)

　

参考文献 中间体
合成目标
【1】 Hegedues A, Hell Z. 2004. One-step preparation of l-substituted tetrahydroisoquinolines via the Pictet-Spengler reaction using zeolite catalysts. Tetrahedron Lett, 45(46):8553～8555
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) 18333 Phenethylamine; 2-Phenyl-1-ethanamine 64-04-0 C8H11N 详情 详情
(II) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(III) 66736 1-phenyl-1,2,3,4-tetrahydroisoquinoline 　 C15H15N 详情 详情

合成路线78

该中间体在本合成路线中的序号：(IV)

　

参考文献 中间体
合成目标
【1】 Li L, Tian QS, Wei WT, et al. 2003. Process for preparation of alvimopan and intermediates. 发明专利申请公开说明书， CN 1827598(Tianjiu Taipu Medicine Science and Technology Development Co, Ltd, Peop Rep China)
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) 16618 (3R,4R)-4-(3-isopropoxyphenyl)-1,3,4-trimethylhexahydropyridine; isopropyl 3-[(3R,4R)-1,3,4-trimethylhexahydro-4-pyridinyl]phenyl ether C17H27NO 详情 详情
(II) 67026 (3R,4R)-phenyl 4-(3-isopropoxyphenyl)-3,4-dimethylpiperidine-1-carboxylate 　 C23H29NO3 详情 详情
(III) 16620 3-[(3R,4R)-3,4-dimethylhexahydro-4-pyridinyl]phenol 119193-19-0 C13H19NO 详情 详情
(IV) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(V) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(VI) 49470 methyl 2-[hydroxy(phenyl)methyl]acrylate C11H12O3 详情 详情
(VII) 49475 methyl (E)-2-[(acetoxy)methyl]-3-phenyl-2-propenoate C13H14O4 详情 详情
(VIII) 49476 (E)-2-(hydroxymethyl)-3-phenyl-2-propenoic acid C10H10O3 详情 详情
(IX) 49480 2-benzyl-3-hydroxypropionic acid C10H12O3 详情 详情
(X) 49481 (2S)-2-benzyl-3-hydroxypropionic acid C10H12O3 详情 详情
(XI) 13601 benzyl 2-aminoacetate; Glycine benzyl ester hydrochloride 1738-68-7 C9H11NO2 详情 详情
(XII) 49477 benzyl 2-[[(2S)-2-benzyl-3-hydroxypropanoyl]amino]acetate C19H21NO4 详情 详情
(XIII) 49478 benzyl 2-([(2S)-2-benzyl-3-[(methylsulfonyl)oxy]propanoyl]amino)acetate C20H23NO6S 详情 详情
(XIV) 49479 benzyl 2-[[(2S)-2-benzyl-3-bromopropanoyl]amino]acetate C19H20BrNO3 详情 详情
(XV) 67027 benzyl 2-(2-benzyl-3-(4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl)propanamido)acetate 　 C32H38N2O4 详情 详情

合成路线79

该中间体在本合成路线中的序号：(VI)

　

参考文献 中间体
合成目标
【1】 Haycock-Lewandowski SJ, Wilder A, Ahman J. 2008. Development of a bulk enabling route to maraviroc (UK-427, 857), a CCR-5 receptor antagonist. Organic Process Research & Development, 12(6): 1094～1103.
【2】 Tung R. 2008. Preparation of deuterated triazolyl tropane derivatives as CCR5 receptor inhibitors. WO 2008063600.
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) 67255 (S)-methyl 3-amino-3-phenylpropanoate (2R,3S)-2,3-dihydroxysuccinate 　 C14H19NO8 详情 详情
(I) 67247 8-benzyl-8-azabicyclo[3.2.1]octan-3-one 28957-72-4 C14H17NO 详情 详情
(II) 67248 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime 76272-34-9 C14H18N2O 详情 详情
(III) 67249 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine 　 C14H20N2 详情 详情
(IV) 67251 N-(8-benzyl-8-azabicyclo[3.2.1]octan-3-yl)isobutyramide 376348-67-3 C18H26N2O 详情 详情
(V) 67252 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane 　 C20H28N4 详情 详情
(VI) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VII) 67253 3-(2-isopropyl-5-methyl-1H-pyrrol-1-yl)-8-azabicyclo[3.2.1]octane 　 C15H24N2 详情 详情
(VIII) 12963 Malonic acid 141-82-2 C3H4O4 详情 详情
(IX) 59224 3-(3-Aminophenyl)propionic acid; beta-Aminohydrocinnamic acid; DL-3-Amino-3-phenylpropionic acid; 3-Amino-3-phenylpropionic acid 614-19-7 C9H11NO2 详情 详情
(X) 67254 methyl 3-amino-3-phenylpropanoate 　 C10H13NO2 详情 详情
(XII) 67256 (S)-methyl 3-(((benzyloxy)carbonyl)amino)-3-phenylpropanoate 　 C18H19NO4 详情 详情
(XIII) 67257 (S)-3-(((benzyloxy)carbonyl)amino)-3-phenylpropanoic acid 　 C17H17NO4 详情 详情
(XIV) 67258 (S)-benzyl (3-hydroxy-1-phenylpropyl)carbamate 　　 C17H19NO3 详情 详情
(XV) 67259 (S)-benzyl (3-oxo-1-phenylpropyl)carbamate 　 C17H17NO3 详情 详情
(XVI) 67260 benzyl ((1S)-3-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-1-phenylpropyl)carbamate 　 C30H39N5O2 详情 详情
(XVII) 67261 (1S)-3-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-1-phenylpropan-1-amine 　 C22H33N5 详情 详情
(XVIII) 67262 4,4-difluorocyclohexanecarbonyl chloride 　 C7H9ClF2O 详情 详情
(XX) 67250 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine 　 C14H20N2 详情 详情

合成路线80

该中间体在本合成路线中的序号：(IV)

　

参考文献 中间体
合成目标
【1】 Price DA, Gayton S, Selby MD, et al. 2005. Initial synthesis of UK-427, 857(maraviroc). Tetrahedron Letters, 46(30): 5005～5007.
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) 67269 (S)-tert-butyl (3-oxo-1-phenylpropyl)carbamate 135865-78-0 C14H19NO3 详情 详情
(VI) 67261 (1S)-3-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-1-phenylpropan-1-amine 　 C22H33N5 详情 详情
(I) 67267 methyl 3-amino-3-phenylpropanoate 　 C10H13NO2 详情 详情
(II) 67268 (S)-methyl 3-((tert-butoxycarbonyl)amino)-3-phenylpropanoate 　 C15H21NO4 详情 详情
(IV) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(V) 67270 tert-butyl ((1S)-3-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-1-phenylpropyl)carbamate 　 C27H41N5O2 详情 详情
(VII) 67271 4,4-difluorocyclohexanecarboxylic acid 122665-97-8 C7H10F2O2 详情 详情

合成路线81

该中间体在本合成路线中的序号：(IX)

　

参考文献 中间体
合成目标
【1】 Lou S, Moquist PN, Schaus SE. 2007. Asymmetric allylboration of acyl imines catalyzed by chiral diols. Journal of the American Chemical Society, 129(49): 15398～15404.
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) 10507 Trimethyl-N-[(E)-benzylidene]silanamine; N-[(E)-Benzylidene]-N-(trimethylsilyl)amine 17599-61-0 C10H15NSi 详情 详情
(I) 67271 4,4-difluorocyclohexanecarboxylic acid 122665-97-8 C7H10F2O2 详情 详情
(II) 29841 Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride 79-37-8 C2Cl2O2 详情 详情
(IV) 67272 (E)-N-benzylidene-4,4-difluorocyclohexanecarboxamide 　 C14H15F2NO 详情 详情
(V) 67273 diisopropyl allylboronate 51851-79-7 C9H19BO2 详情 详情
(VI) 67274 3,3'-diphenyl-[1,1'-binaphthalene]-2,2'-diol 　 C32H22O2 详情 详情
(VII) 67275 (E)-4,4-difluoro-N-(1-phenylbut-3-en-1-ylidene)cyclohexanecarboxamide 　 C17H19F2NO 详情 详情
(VIII) 67276 (E)-4,4-difluoro-N-(3-oxo-1-phenylpropylidene)cyclohexanecarboxamide 　 C16H17F2NO2 详情 详情
(IX) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情

合成路线82

该中间体在本合成路线中的序号：(III)

Protection of 3-hydroxy-2-methylpyran-4-one (I) with PhCH2Br in the presence of K2CO3 in acetonitrile at 80 °C or in DMF yields 3-(benzyloxy)-2-methylpyran-4-one (II) , which, after deprotonation with LiHMDS in THF, is condensed with benzaldehyde (III) at –60 °C to afford 3-(benzyloxy)-2-(2-hydroxy-2-phenylethyl) pyran-4-one (IV). Sulfonylation of alcohol (IV) with MsCl and Et3N in THF followed by mesylate elimination by means of DBU in NMP gives alkene (V), which by oxidative cleavage with NaIO4 in the presence of RuCl3, optionally using H2S, in acetonitrile/AcOEt/water, and further oxidation of the obtained aldehyde with NaClO2 or NaClO in the presence of TEMPO, yields the pyrancarboxylic acid (VI). Condensation of the 4-pyranone (VI) with 3-aminopropane-1,2-diol (VII) in EtOH at 80 °C leads to the pyridone (VIII), which is then converted to the methyl ester (IX) using MeI and NaHCO3. Oxidative cleavage of the vicinal diol (IX) with NaIO4 and AcOH or H2SO4 in acetonitrile/water provides the pyridone-1-acetaldehyde hydrate (X), which by cyclization with 3(R)-amino-1-butanol (XI) by means of AcOH in MeOH at 90 °C or diglyme yields the pyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (XII). Bromination of compound (XII) with NBS in CH2Cl2 or NMP furnishes the bromopyridone derivative (XIII), which undergoes carbonylation with CO in the presence of 2,4-difluorobenzylamine (XIV) and Pd(PPh3)4/DIEA or Pd(OAc)2/DIEA/DPPB in DMSO at 90 °C to afford carboxamide (XV). Finally, compound (XV) is deprotected by debenzylation with H2 over Pd/C .
The pyrancarboxylic acid (VI) can also be prepared by oxidation of 3-(benzyloxy)-2-methylpyran-4-one (XVI) with SeO2 in bromobenzene at 160 °C to give aldehyde (XVII) and further oxidation with NaClO2 in the presence of NH2SO3H in acetone/H2O .

参考文献 中间体
合成目标
【1】 Johns, B.A., Duan, M., Hakogi, T. (Shionogi & Co., Ltd.; GlaxoSmithKline, Inc.). Processes and intermediates for carbamoylpyridone HIV integrase inhibitors. CN 102245572, EP 2376453, JP 2012511574, KR 2011096574, US 2011263855, WO 2010068262.
【2】 Yoshida, H., Taoda, Y., Johns, B.A. (Shionogi & Co., Ltd.; GlaxoSmithKline, Inc.). Synthesis of carbamoylpyridone HIV integrase inhibitors and intermediates. CN 102245182, EP 2376080, JP 012511573, KR 2011094336, US 2011282055, WO 2010068253.
【3】 Johns, B.A., Kawasuji, T., Taishi, T., Taoda, Y. (Shionogi & Co., Ltd.). Polycyclic carbamoylpyridone derivative having HIV integrase inhibitory activity. EP 1874117, EP 2465580, JP 2008540343, JP 2009079058, US 200931821, US 8129385, US 2012115875, WO 2006116764.
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) 13671 Hydroxymethylpyrone; 3-Hydroxy-2-methyl-4H-pyran-4-one；Maltol;3-Hydroxy-2-methyl-4-pyrone 118-71-8 C6H6O3 详情 详情
(II) 12074 3-(Benzyloxy)-2-methyl-4H-pyran-4-one；3-(benzyloxy)-2-methylpyran-4-one 61049-69-2 C13H12O3 详情 详情
(III) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(IV) 68571 3-(benzyloxy)-2-(2-hydroxy-2-phenylethyl)-4H-pyran-4-one 　 C20H18O4 详情 详情
(V) 68572 (E)-3-(benzyloxy)-2-styryl-4H-pyran-4-one 　 C20H16O3 详情 详情
(VI) 68573 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid 　 C13H10O5 详情 详情
(VII) 12979 3-Amino-1,2-propanediol；3-aminopropane-1,2-diol 616-30-8 C3H9NO2 详情 详情
(VIII) 68574 3-(benzyloxy)-1-(2,3-dihydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 　 C16H17NO6 详情 详情
(IX) 68575 methyl 3-(benzyloxy)-1-(2,3-dihydroxypropyl)-4-oxo-1,4-dihydropyridine-2-carboxylate 　 C17H19NO6 详情 详情
(X) 68576 methyl 3-(benzyloxy)-1-(2,2-dihydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylate 　 C16H17NO6 详情 详情
(XI) 68577 3(R)-amino-1-butanol;(R)-3-aminobutan-1-ol 61477-39-2 C4H11NO 详情 详情
(XII) 68581 (4R,12aS)-7-(benzyloxy)-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione 　 C19H20N2O4 详情 详情
(XIII) 68580 (4R,12aS)-7-(benzyloxy)-9-bromo-4-methyl-3,4,12,12a-tetrahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-6,8-dione 　 C19H19BrN2O4 详情 详情
(XIV) 68578 2,4-difluorobenzylamine 72235-52-0 C7H7F2N 详情 详情
(XV) 68579 (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide 　 C27H25F2N3O5 详情 详情
(XVI) 12074 3-(Benzyloxy)-2-methyl-4H-pyran-4-one；3-(benzyloxy)-2-methylpyran-4-one 61049-69-2 C13H12O3 详情 详情
(XVII) 68582 3-(benzyloxy)-4-oxo-4H-pyran-2-carbaldehyde 　 C13H10O4 详情 详情

合成路线83

该中间体在本合成路线中的序号：(V)

2,5-Piperazinedione (I) is acylated with acetic anhydride at 110 oC in the presence of catalytic NaOAc to afford the diacetyl derivative (II). Claisen condensation of N,N’-diacetyl-2,5-piperazinedione (II) with 5-tert-butylimidazole-4-carbaldehyde (III) by means of Cs2CO3 in DMF at room temperature leads to the monoacetylated (imidazolylmethylene) piperazinedione (IV), which is finally condensed with benzaldehyde (V) in the presence of Cs2CO3 in DMF at 80 °C. In a related alternative method, diketopiperazine (II) is first condensed with benzaldehyde (V) in the presence of Cs2CO3 in DMF at room temperature, yielding the benzylidene piperazinedione (VI), which is subsequently condensed with the imidazole-aldehyde (III) by means of Cs2CO3 in hot DMF .

参考文献 中间体
合成目标
【1】 Hayashi, Y., Grodberg, J., Palladino, M. (Nereus Pharmaceuticals, Inc). Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins dehydrophenylahistins and analogs thereof. EP 1529044, JP 2006511534, WO 2004054498.
【2】 Palladino, M.A., Lloyd, G.K., Hayashi, Y., Nicholson, B. (Nereus Pharmaceuticals, Inc). Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof. EP 1711487, JP 2007520565, WO 2005077940.
【3】 Palladino, M., Lloyd, G.K., Hayashi, Y. (Nereus Pharmaceuticals, Inc). Analogs of dehydrophenylahistins and their therapeutic use. EP 1926724, US 2007078138, WO 2007035841.
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) 29800 2,5-piperazinedione；2,5-diketopiperazine;cycloglycylglycine；2,5-dioxopiperazine;cyclodiglycine;cyclo(glycylglycyl) 106-57-0 C4H6N2O2 详情 详情
(II) 19188 1,4-diacetyl-2,5-piperazinedione;N,N'-DIACETYLGLYCINE ANHYDRIDE;1,4-DIACETYL-PIPERAZINE-2,5-DIONE;1,4-DIACETYLTETRAHYDRO-2,5-PYRAZINEDIONE;1,4-DIACETYL-2,5-DIKETOPIPERAZINE;1,4-DIACETYL-2,5-DIOXOPIPERAZINE 3027-05-2 C8H10N2O4 详情 详情
(III) 69002 5-tert-butylimidazole-4-carbaldehyde;5-(1,1-dimethylethyl)-1H-Imidazole-4-carboxaldehyde;4-(1,1-dimethylethyl)-1H-Imidazole-5-carboxaldehyde 714273-83-3 C8H12N2O 详情 详情
(IV) 69003 (Z)-1-acetyl-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)piperazine-2,5-dione 　 C14H18N4O3 详情 详情
(V) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(VI) 19189 1-acetyl-3-[(Z)-benzylidene]-2,5-piperazinedione C13H12N2O3 详情 详情

合成路线84

该中间体在本合成路线中的序号：(XXII)

Condensation of benzaldehyde (XXII) with ethyl glycinate hydrochloride (XXIII) in the presence of Na2SO4 and Et3N in tert-butyl methyl ether gives ethyl[(benzylidene)amino]acetate (XXIV), which upon reaction with 1,4-dibromo-2-butene (XXV) in the presence of t-BuOLi in toluene yields racemic ethyl 1-amino-2-vinylcyclopropanecarboxylate (rac-[XXVI]). Resolution of rac-(XXVI) by treatment with (+)-dibenzoyltartaric acid in EtOAc gives ethyl 1(R)-amino-2(S)-vinylcyclopropanecarboxylate (+)-dibenzoyltartrate (XXVII) salt, which is finally treated with HCl in Et2O .
Alternatively, amino ester (rac-[XXVI]) can be prepared by condensation of ethyl ester (XXVIII) with 1,4-dibromo-2-butene (XXV) in the presence of t-BuOK in THF, followed by treatment of the resulting imine (rac-[XXIX]) with HCl in Et2O and then with NaHCO3 .

参考文献 中间体
合成目标
【1】 Llinas-Brunet, M., Bailey, M.D., Cameron, D. et al. (Boehringer Ingelheim [Canada] Ltd.). Hepatitis C inhibitor tri-peptides. CA 2338946, EP 1105413, EP 2028186, JP 2002522554, US 6323180, WO 2000009543.
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-(XXVI) 69285 racemic ethyl 1-amino-2-vinylcyclopropanecarboxylate 　 C8H13NO2 详情 详情
rac-(XXIX) 69287 racemic ethyl 1-((diphenylmethylene)amino)-2-vinylcyclopropanecarboxylate 　 C21H21NO2 详情 详情
(IX) 69270 (1R,2S)-ethyl 1-amino-2-vinylcyclopropanecarboxylate 746657-36-3 C8H13NO2 详情 详情
(XXII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(XXIII) 68234 ethyl glycinate hydrochloride；Glycine ethyl ester hydrochloride 623-33-6 C4H9NO2.HCl 详情 详情
(XXIV) 68235 (E)-ethyl 2-(benzylideneamino)acetate;2-(benzylideneamino)acetic acid ethyl ester；ethyl N-benzylideneglycinate；Benzylideneglycine ethyl ester；N-Benzylideneglycineethyl ester；ethyl(benzylideneamino)acetate 40682-54-0 C11H13NO2 详情 详情
(XXV) 18349 (E)-1,4-dibromo-2-butene；trans-1,4-dibromo-2-butene 821-06-7 C4H6Br2 详情 详情
(XXVII) 69286 ethyl 1(R)-amino-2(S)-vinylcyclopropanecarboxylate (+)-dibenzoyltartrate 213316-32-6 C8H13NO2 详情 详情
(XXVIII) 26772 ethyl 2-((diphenylmethylene)amino)acetate;N-(Diphenylmethylene)glycine ethyl ester;Ethyl N-(diphenylmethylene)glycinate;ethyl 2-[(dibenzylene)amino]acetate 69555-14-2 C17H17NO2 详情 详情
Extended Information