Spirapril, TI-211-950(hydrochloride), Sch-33844(HCl), Setrilan, Sandopril, Renormax, -Drug Synthesis Database

【结构式】

【药物名称】Spirapril, TI-211-950(hydrochloride), Sch-33844(HCl), Setrilan, Sandopril, Renormax

【化学名称】(8S)-7-[(S)-N-[(S)-1-Carboxy-3-phenylpropyl]alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid 1-ethyl ester

【CA登记号】83647-97-6, 94841-17-5 (HCl)

【分子式】C₂₂H₃₀N₂O₅S₂

【分子量】466.6228

【开发单位】Essex (Originator), Novartis (Originator), Schering-Plough (Originator), Pfizer (Licensee)

【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

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.

参考文献中间体

【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

合成路线2

The cyclization of 1-benzyloxycarbonyl-4-oxoproline methyl ester (I) with ethanedithiol (II) by means of p-toluenesulfonic acid in refluxing acetic acid gives methyl 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate (III), which is deprotected with 20% HBr to give methyl 1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate (IV). The condensation of (IV) with N-benzyloxycarbonyl alanine N-hydroxysuccinimide ester (V) affords the corresponding dipeptide methyl ester (VI), which is hydrolyzed with NaOH to the free acid (VII), and deprotected with 20% HBr as before to 7-alanyl-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid (VIII). Finally, this compound is condensed with ethyl 2-oxo-4-phenylbutyrate (IX) by means of sodium cyanoborohydride in methanol.

参考文献中间体

【1】 Smith, E.M.; Neustadt, B.R.; Gold, E.H. (Schering Corp.); 7-Carboxyalkylaminoacyl-1,4-dithia-7-azaspiro[4.4]-nonane-8-carboxylic acids. JP 1989163197; US 4470972 .
【2】 Prous, J.; Castaner, J.; Spirapril. Drugs Fut 1987, 12, 9, 860.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	27314	benzyl hydrogen sulfate		C₇H₈O₄S	详情	详情
(I)	27312	1-benzyl 2-methyl (2R)-4-oxo-1,2-cyclopentanedicarboxylate		C₁₅H₁₆O₅	详情	详情
(II)	27313	1,2-ethanedithiol	540-63-6	C₂H₆S₂	详情	详情
(III)	27315	7-benzyl 8-methyl (8R)-1,4-dithiaspiro[4.4]nonane-7,8-dicarboxylate		C₁₇H₂₀O₄S₂	详情	详情
(IV)	27316	methyl (8S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate		C₈H₁₃NO₂S₂	详情	详情
(V)	27317	benzyl (1S)-2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-1-methyl-2-oxoethylcarbamate		C₁₅H₁₆N₂O₆	详情	详情
(VI)	27318	methyl (8S)-7-((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate		C₁₉H₂₄N₂O₅S₂	详情	详情
(VII)	27319	(8S)-7-((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid		C₁₈H₂₂N₂O₅S₂	详情	详情
(VIII)	27320	(8S)-7-[(2S)-2-aminopropanoyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid		C₁₀H₁₆N₂O₃S₂	详情	详情
(IX)	20896	Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester	64920-29-2	C₁₂H₁₄O₃	详情	详情

合成路线3

The condensation of (IX) with alanine benzyl ester (X) with sodium cyanoboohydride as before gives N-[1-(ethoxycarbonyl)-3-phenylpropyl]alanine benzyl ester (XI), which is submitted to fractional crystallization with maleic acid yielding N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine benzyl ester (XII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol yielding the free acid (XIII). Finally, this compound is condensed with spirane (IV) through the N-hydroxysuccinimide ester, in the usual way.

参考文献中间体

【1】 Smith, E.M.; Neustadt, B.R.; Gold, E.H. (Schering Corp.); 7-Carboxyalkylaminoacyl-1,4-dithia-7-azaspiro[4.4]-nonane-8-carboxylic acids. JP 1989163197; US 4470972 .
【2】 Prous, J.; Castaner, J.; Spirapril. Drugs Fut 1987, 12, 9, 860.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	23808	Fumaric acid; (E)-2-butenedioic acid	110-17-8	C₄H₄O₄	详情	详情
(IV)	27316	methyl (8S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate		C₈H₁₃NO₂S₂	详情	详情
(IX)	20896	Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester	64920-29-2	C₁₂H₁₄O₃	详情	详情
(X)	10143	benzyl (2S)-2-aminopropanoate		C₁₀H₁₃NO₂	详情	详情
(XI)	27321	ethyl 2-[[(1S)-2-(benzyloxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate		C₂₂H₂₇NO₄	详情	详情
(XII)	15665	ethyl (2S)-2-[[(1S)-2-(benzyloxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate		C₂₂H₂₇NO₄	详情	详情
(XIII)	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4

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.

参考文献中间体

【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

Extended Information