合成路线: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: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.
参考文献标题:Spirapril
文献作者:Prous,J.; Castar,J.
参考来源:Drugs Fut 1987,12(9),860
合成路线: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.
参考文献标题:Angiotensin converting enzyme inhibitors: Spirapril and related
文献作者:Swiss,G.F.; Neustadt,B.R.; McNamara,P.; Baum,T.; Smith,E.M.; Gold,E.H.; Sybertz,E.J.
参考来源:J Med Chem 1989,32(7),1600-6
合成路线: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: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: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.
参考文献标题:Angiotensin-converting enzyme inhibitors.Mercaptan,carboxyalkyl dipeptide,and phosphinic acid inhibitors incorporating 4-substituted prolines
文献作者: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.
参考来源:J Med Chem 1988,31(6),1148
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