【药物名称】Spirapril, TI-211-950(hydrochloride), Sch-33844(HCl), Setrilan, Sandopril, Renormax
化学结构式(Chemical Structure):
参考文献No.4335
标题:7-Carboxyalkylaminoacyl-1,4-dithia-7-azaspiro[4.4]-nonane-8-carboxylic acids
作者:Smith, E.M.; Neustadt, B.R.; Gold, E.H. (Schering Corp.)
来源:JP 1989163197; US 4470972
合成路线图解说明:

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.

合成路线图解说明:

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No.77898
标题:Spirapril
作者:Prous, J.; Casta馿r, J.
来源:Drugs Fut 1987,12(9),860
合成路线图解说明:

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.

合成路线图解说明:

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No.98198
标题:Angiotensin converting enzyme inhibitors: Spirapril and related
作者:Swiss, G.F.; Neustadt, B.R.; McNamara, P.; Baum, T.; Smith, E.M.; Gold, E.H.; Sybertz, E.J.
来源:J Med Chem 1989,32(7),1600-6
合成路线图解说明:

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No.98200
标题:Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines
作者:Krapcho, J.; Turk, C.; Cushman, D.W.; Powell, J.R.; DeForrest, J.M.; Spitzmiller, E.R.; Karanewsky, D.S.; Duggan, M.; Rovnyak, G.; Schwartz, J.; et al.
来源:J Med Chem 1988,31(6),1148
合成路线图解说明:

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).

合成路线图解说明:

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.

合成路线图解说明:

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.

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