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【结 构 式】

【分子编号】55626

【品名】(2S,4S)-4-(phenylsulfanyl)-2-pyrrolidinecarboxylic acid

【CA登记号】

【 分 子 式 】C11H13NO2S

【 分 子 量 】223.29576

【元素组成】C 59.17% H 5.87% N 6.27% O 14.33% S 14.36%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(V)

The protected hydroxyproline tosylate (I) was condensed with the sodium derivative of thiophenol (II) to produce thioether (III). After saponification of the methyl ester function of (III), the N-benzyloxycarbonyl group of (IV) was removed by means of HBr in refluxing HOAc, yielding cis-4-(phenylthio)-L-proline (V). Acylation of (V) with (S)-3-(benzoylthio)-2-methylpropionyl chloride (VI) afforded zofenopril (VII), which was finally converted to the corresponding calcium salt by treatment with calcium oxide in EtOH/H2O. The intermediate (S)-3-(benzoylthio)-2-methylpropionyl chloride (VI) was obtained by enzymatic resolution of racemic 3-(benzoylthio)-2-methylpropionic acid (VIII) with Pseudomonas fluorescens (Amano lipase P-30) to yield (S)-3-(benzoylthio)-2-methylpropionic acid (IX), which was activated with oxalyl chloride to afford the chiral acyl chloride (VI).

1 Ondetti, M.A.; Krapcho, J. (Bristol-Myers Squibb Co.); Mercaptoacyl derivs. of substd. prolines. US 4316906 .
2 Giachetti, A.; Giorgi, R.; Mannucci, C.; Falezza, A. (Menarini Industrie Farma Riunite Srl); A process for the preparation of zofenopril calcium salt. EP 1102745; JP 2002522417; WO 0007984 .
3 Patel, R.N.; Howell, J.M.; Szarka, L.J. (Bristol-Myers Squibb Co.); Enzymatic resolution process hydrolyzing thio-ester. US 5128263 .
4 Powell, J.R.; Cushman, D.W.; Krapcho, J.; Turk, C.; DeForrest, J.M.; Spitzmiller, E.R.; Karanewsky, D.S.; Duggan, M.; Rovnyak, G.; Schwartz, J.; et al.; Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines. J Med Chem 1988, 31, 6, 1148.
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) 55623 1-benzyl 2-methyl (2S,4R)-4-{[(4-methylphenyl)sulfonyl]oxy}-1,2-pyrrolidinedicarboxylate C21H23NO7S 详情 详情
(II) 12951 Benzenethiol; Phenylmercaptan; Phenylhydrosulfide 108-98-5 C6H6S 详情 详情
(III) 55624 1-benzyl 2-methyl (2S,4S)-4-(phenylsulfanyl)-1,2-pyrrolidinedicarboxylate C20H21NO4S 详情 详情
(IV) 55625 (2S,4S)-1-[(benzyloxy)carbonyl]-4-(phenylsulfanyl)-2-pyrrolidinecarboxylic acid C19H19NO4S 详情 详情
(V) 55626 (2S,4S)-4-(phenylsulfanyl)-2-pyrrolidinecarboxylic acid C11H13NO2S 详情 详情
(VI) 41584 S-[(2R)-3-chloro-2-methyl-3-oxopropyl] benzenecarbothioate C11H11ClO2S 详情 详情
(VII) 55627 (2S,4S)-1-[(2S)-3-(benzoylsulfanyl)-2-methylpropanoyl]-4-(phenylsulfanyl)-2-pyrrolidinecarboxylic acid C22H23NO4S2 详情 详情
(VIII) 55628 3-(benzoylsulfanyl)-2-methylpropanoic acid C11H12O3S 详情 详情
(IX) 35379 (2S)-3-(benzoylsulfanyl)-2-methylpropionic acid C11H12O3S 详情 详情
Extended Information