OPTICAL RESOLUTION OF A 1,5-BENZOTHIAZEPINE DERIVATIVE, A SYNTHETIC INTERMEDIATE OF DILTIAZEM, BY PREFERENTIAL CRYSTALLIZATION AND DIASTEREOMERIC SALT FORMATION

Practical preparation methods of an optically active intermediate of d iltiazem, [2-(dimethyl-amino)ethyl]-2,3-dihydro-3-hydroxy-2- (4-methox yphenyl)-1,5-benzothiazepin-4(5H)-one [(+)-7], have bene developed by tbe use of physicochemical and chemical resolutions. 1) The salt of (/-)-7 with 3-amino-4-hydroxy-benzenesulfonic acid (AHS), was found to exist as a conglomerate and could be reproducibly resolved into (+)-7 AI-IS and (-)-7 AHS of 94-98% ee by a preferential crystallization pro cedure, 2) (+))-(1R)-3-Bromocamphor-9-sulfonic acid [(+)-BCS] was foun d to be an efficient resolving agent for (+/-)-7 and the diastereomeri c resolution provided (+)-7.(+)-BCS.2H(2)O salt in >43% yield and >97% ee by fractional crystallization. It is presumed that the crystal wat er of(+)-7.(+)-BCS.2H(2)O plays an important role in the selective cry stallization during this efficient resolution.