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【结 构 式】

【分子编号】11359

【品名】(8S)-1,4-Dithia-7-azaspiro[4.4]nonane-8-carboxylic acid

【CA登记号】

【 分 子 式 】C7H11NO2S2

【 分 子 量 】205.30188

【元素组成】C 40.95% H 5.4% N 6.82% O 15.59% S 31.24%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(III)

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2

该中间体在本合成路线中的序号:(III)

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
Extended Information