【药物名称】Zofenopril calcium, SQ-26900(K salt), SQ-26991, Zofepril, Zantipres, Teoula, Zopranol, Bifril, Zofenil, Zoprace
化学结构式(Chemical Structure):
参考文献No.13590
标题:Mercaptoacyl derivs. of substd. prolines
作者:Ondetti, M.A.; Krapcho, J. (Bristol-Myers Squibb Co.)
来源:US 4316906
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).

参考文献No.42231
标题:A process for the preparation of zofenopril calcium salt
作者:Giachetti, A.; Giorgi, R.; Mannucci, C.; Falezza, A. (Menarini Industrie Farma Riunite Srl)
来源:EP 1102745; JP 2002522417; WO 0007984
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).

参考文献No.57803
标题:Enzymatic resolution process hydrolyzing thio-ester
作者:Patel, R.N.; Howell, J.M.; Szarka, L.J. (Bristol-Myers Squibb Co.)
来源:US 5128263
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).

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.

Drug Information Express,Drug R&D,Chemical Database,Patent Search.
Copyright © 2006-2024 Drug Future. All rights reserved.Contact Us