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【结 构 式】 
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【药物名称】Zofenopril calcium, SQ-26900(K salt), SQ-26991, Zofepril, Zantipres, Teoula, Zopranol, Bifril, Zofenil, Zoprace 【化学名称】(4S)-N-[3-(Benzoylsulfanyl)-2(S)-methylpropionyl]-4-(phenylsulfanyl)-L-proline calcium salt 【CA登记号】81938-43-4, 81872-10-8 (free acid), 81938-40-1 (Na salt) 【 分 子 式 】C44H44CaN2O8S4 【 分 子 量 】897.18588 |
【开发单位】Bristol-Myers Squibb (Originator), FIRMA (Not Determined), Guidotti (Licensee), Menarini (Licensee) 【药理作用】Acute Myocardial Infarction, Treatment of, CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Angiotensin-I Converting Enzyme (ACE) Inhibitors |
合成路线1
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 |