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【结 构 式】 
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【分子编号】11357 【品名】(2S)-1-[(Benzyloxy)carbonyl]-4-oxotetrahydro-1H-pyrrole-2-carboxylic acid 【CA登记号】 |
【 分 子 式 】C13H13NO5 【 分 子 量 】263.24996 【元素组成】C 59.31% H 4.98% N 5.32% O 30.39% |
合成路线1
该中间体在本合成路线中的序号：(XXIX)The Grignard condensation of N-(benzyloxycarbonyl)-4-oxo-L-proline (XXIX) with phenylmagnesium bromide gives the 4-hydroxy-4-phenylproline derivative (XXX), which is dehydrated with TFA yielding the dehydroproline (XXXI). The hydrogenation of (XXXI) with Li in liquid ammonia affords the previously reported trans-4-phenyl-L-proline (XIX), which is hydrogenated to the corresponding cyclohexyl derivative (XI) with H2 over PtO2.
| 【1】 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 |
|---|---|---|---|---|---|---|
| (XI) | 38567 | (2S,4S)-4-cyclohexyl-2-pyrrolidinecarboxylic acid | C11H19NO2 | 详情 | 详情 | |
| (XIX) | 38572 | (2S,4S)-4-phenyl-2-pyrrolidinecarboxylic acid | C11H13NO2 | 详情 | 详情 | |
| (XXIX) | 11357 | (2S)-1-[(Benzyloxy)carbonyl]-4-oxotetrahydro-1H-pyrrole-2-carboxylic acid | C13H13NO5 | 详情 | 详情 | |
| (XXX) | 38573 | (2S,4S)-1-[(benzyloxy)carbonyl]-4-hydroxy-4-phenyl-2-pyrrolidinecarboxylic acid | C19H19NO5 | 详情 | 详情 | |
| (XXXI) | 38574 | (2S)-1-[(benzyloxy)carbonyl]-4-phenyl-2,5-dihydro-1H-pyrrole-2-carboxylic acid | C19H17NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)A new synthesis of spirapril has been described: The cyclization of N-benzyloxycarbonyl-4-oxo-(S)-proline (I) with ethanedithiol by means of boron trifluoride ethearate in glacial acetic acid gives 7-(benzyloxycarbonyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (II), which is deprotected with HBr in acetic acid to yield 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (III). This compound is then condensed with N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (IV) by means of N-hydroxysuccinimide (NOS) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (DMCC) in DMF, or by means of N,N-disuccinimidyl carbonate and pyridine.
| 【1】 Swiss, G.F.; Neustadt, B.R.; McNamara, P.; Baum, T.; Smith, E.M.; Gold, E.H.; Sybertz, E.J.; Angiotensin converting enzyme inhibitors: Spirapril and related. J Med Chem 1989, 32, 7, 1600-6. |
| 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) | 11357 | (2S)-1-[(Benzyloxy)carbonyl]-4-oxotetrahydro-1H-pyrrole-2-carboxylic acid | C13H13NO5 | 详情 | 详情 | |
| (II) | 11358 | (8S)-7-[(Benzyloxy)carbonyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid | C15H17NO4S2 | 详情 | 详情 | |
| (III) | 11359 | (8S)-1,4-Dithia-7-azaspiro[4.4]nonane-8-carboxylic acid | C7H11NO2S2 | 详情 | 详情 | |
| (IV) | 11360 | (2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid; (S)-N-(1-Ethoxycarbonyl-3-phenylpropyl)-(S)-alanine | 82717-96-2 | C15H21NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)A new synthesis of spirapril has been reported: The cyclization of N-benzyloxycarbonyl-4-oxo-(S)-proline (I) with ethandithiol by means of boron trifluoride ethearate in dichloromethane gives 7-(benzyloxycarbonyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (II), which is treated with concentrated HCl to yield 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (III). The protection of (III) with tert-butoxycarbonyl chloride and with trimethylsilylethanol in the usual manner affords N-(tert-butoxycarbonyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxyli c acid 2-(trimethylsilyl)ethyl ester (IV), which is condensed with N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (V) by a first treatment with p-toluenesulfonic acid and a condensation step with dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HBT), giving spirapril 2-(trimethylsilyl)ethyl ester (VI). Finally, this ester is hydrolyzed with tetrabutylammonium fluoride trihydrate in DMF.
| 【1】 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) | 11357 | (2S)-1-[(Benzyloxy)carbonyl]-4-oxotetrahydro-1H-pyrrole-2-carboxylic acid | C13H13NO5 | 详情 | 详情 | |
| (II) | 11358 | (8S)-7-[(Benzyloxy)carbonyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid | C15H17NO4S2 | 详情 | 详情 | |
| (III) | 11359 | (8S)-1,4-Dithia-7-azaspiro[4.4]nonane-8-carboxylic acid | C7H11NO2S2 | 详情 | 详情 | |
| (IV) | 11364 | 7-(tert-butyl) 8-[2-(trimethylsilyl)ethyl] (8S)-1,4-dithia-7-azaspiro[4.4]nonane-7,8-dicarboxylate | C17H31NO4S2Si | 详情 | 详情 | |
| (V) | 11360 | (2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid; (S)-N-(1-Ethoxycarbonyl-3-phenylpropyl)-(S)-alanine | 82717-96-2 | C15H21NO4 | 详情 | 详情 |
| (VI) | 11366 | 2-(trimethylsilyl)ethyl (8S)-7-((2S)-2-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate | C27H42N2O5S2Si | 详情 | 详情 |