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【结 构 式】 
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【药物名称】Perindopril, DW-7950(as erbumine), SED-9490(as erbumine), McN-A-2833, S-9490, Coverene Cor, Coverex, Aceon, Coversum, Coversyl 【化学名称】1-[(2S)-2-[(1S)-1-Carbethoxybutylamino]-1-oxopropyl]-(2S,3aS,7aS)-perhydroindol-2-carboxylic acid 【CA登记号】82834-16-0 【 分 子 式 】C19H32N2O5 【 分 子 量 】368.47729 |
【开发单位】Servier (Originator), Daiichi Pharmaceutical (Licensee), Egis (Licensee), Solvay (Licensee) 【药理作用】CARDIOVASCULAR DRUGS, Cerebrovascular Diseases, Treatment of, Heart Failure Therapy, Hypertension, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors |
合成路线1
S-9490 is synthesized by coupling (2S,3aS,7aS)-2-tert-butoxycarbonylperhydroindole (II) with N-[(S)-1-carbethoxybutyl-(S)-alanine (I).
| 【1】 Vincent, M.; et al.; Stereoselective synthesis of a new perhydroindole derivative of dural iminodiacid, a potent inhibitor of angiotensin converting enzyme. Tetrahedron Lett 1982, 23, 2, 1677. |
| 【2】 Mich, T.F.; Goel, O.P.; Mulhern, T.A.; Burk, M.J.; Hoekstra, M.S.; Ramsden, J.A. (Pfizer Inc.); Asymmetric synthesis of pregabalin. WO 0155090 . |
合成路线2
[U-14C]-Aniline (I) is converted to [U-14C]phenyldiazonium chloride (II), which is condensed in situ with ethyl 2-(ethoxyalyl)propionate (III) to give [U-14C]phenylhydrazone of ethyl pyruvate (IV). Cyclization of (IV) by polyphosphoric acid in xylene affords ethyl [U-14C-phenyl]indole-2-carboxylic acid (V). Catalytic hydrogenation of compound (V) in the presence of platinum gives ethyl [U-14C-cyclohexyl]-(RS)-perhydroindole-2-carboxylic acid (VI), which is saponified to the corresponding acid (VIII). Compound (VI) can also be prepared by reduction of compound (V) with tin and hydrochloric acid to give compound (VII), and hydrogenation of the latter in the presence of palladium. Compound (VIII) is reesterified to the benzyl ester (IX), which is condensed with N-[(S)-1-carbethoxybutyl]-(S)-alanine (X) in the presence of DCC and 1-hydroxy-1-benzotriazole. The resulting compound (X) is separated fom the mixture of isomers by silica gel column chromatography. Hydrogenolysis of the latter compound gives [U-14C-cyclohexyl]perindopril, which is isolated as the tert-bytylamine salt.
| 【1】 Pichat, L.; et al.; Syntheses du S-9490-3. J Label Compd Radiopharm 1988, 25, 5, 553. |
| 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) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 25897 | benzenediazonium chloride | C6H5ClN2 | 详情 | 详情 | |
| (III) | 27781 | diethyl 2-methyl-3-oxosuccinate | 5965-53-7 | C9H14O5 | 详情 | 详情 |
| (IV) | 27782 | ethyl 2-[(E)-2-phenylhydrazono]propanoate | C11H14N2O2 | 详情 | 详情 | |
| (V) | 27783 | Indole-2-carboxylic acid ethyl ester; 2-Carbethoxyindole; 1H-indole-2-carboxylic acid ethyl ester | 3770-50-1 | C11H11NO2 | 详情 | 详情 |
| (VI) | 27784 | ethyl octahydro-1H-indole-2-carboxylate | C11H19NO2 | 详情 | 详情 | |
| (VII) | 27785 | ethyl 2-indolinecarboxylate | C11H13NO2 | 详情 | 详情 | |
| (VIII) | 27789 | octahydro-1H-indole-2-carboxylic acid | C9H15NO2 | 详情 | 详情 | |
| (IX) | 27790 | benzyl octahydro-1H-indole-2-carboxylate | C16H21NO2 | 详情 | 详情 | |
| (X) | 27786 | (2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl]amino]propionic acid | C10H19NO4 | 详情 | 详情 | |
| (XI) | 27787 | benzyl (2S,3aS,7aS)-1-((2S)-2-[[(1S)-1-(ethoxycarbonyl)butyl]amino]propanoyl)octahydro-1H-indole-2-carboxylate | C26H38N2O5 | 详情 | 详情 |