PREPARATION OF [4S-(4ALPHA,7ALPHA,10ABETA)]-4-AMINO-OCTAHYDRO-5-OXO-7H-PYRIDO 2,1-B] 1,3]THIAZEPINE-7-CARBOXYLIC ACID, METHYL ESTER AND SALTS THEREOF VIA NOVEL DISULFIDES

摘要

Protected N,N'-L-homocystinediyl-bis(6,6-dimethoxy-L-norleucine methyl ester) derivatives (I) are new. The protected N,N'-L-homocystinediyl-bis(6,6-dimethoxy-L-norleucine methyl ester) derivatives are of formula (I). [Image] P1a protecting group. Independent claims are also included for: (1) protected L-homocystine bis(6,6-dimethoxy-L-norleucine methyl ester) disalts of formula (II). (2) a process for preparing (I); (3) a process for preparing protected methyl [4S-(4alpha ,7alpha ,10abeta )]-4-amino-octahydro-5-oxo- 7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate derivatives of formula (III), comprising reacting (I) with a reagent that cleaves the disulfide bond and subjecting the product to acid-catalyzed cyclization: (4) a process for preparing methyl [4S-(4alpha ,7alpha ,10abeta )]-4-amino-octahydro-5-oxo- 7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (IV) comprising preparing (III) by process (3) and removing the protecting group; (5) a process for preparing [4S-(4alpha (R*),7alpha ,10abeta )]-octahydro-4-(2-mercapto-1-oxo -3-phenylpropylamino)-5- oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid (V), comprising: (a) preparing (IV) by process (4); (b) coupling (IV) with a 2-acylthio-3-phenylpropionic acid of formula (VI); and (c) treating the product of formula (VII) to remove the acyl group and convert the methyl ester group to a carboxylic acid group. [Image] [Image] [Image] [Image].