Optical resolution of a 1,5-benzothiazepine derivative, a synthetic intermediate of diltiazem, by preferential crystallization and diastereomeric salt formation

Article abstract of DOI:10.1248/cpb.45.1922

Practical preparation methods of an optically active intermediate of diltiazem, (+)-(2S,3S)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one [(+)-7], have been developed by the 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·AHS and (-)- 7·AHS of 94-98% ee by a preferential crystallization procedure. 2) (+)- (1R)-3-Bromocamphor-9-sulfonic acid [(+)-BCS] was found to be an efficient resolving agent for (±)-7 and the diastereomeric resolution provided (+)- 7·(+)-BCS·2H₂O salt in >43% yield and >97% ee by fractional crystallization. It is presumed that the crystal water of (+)-7·(+)- BCS·2H₂O plays an important role in the selective crystallization during this efficient resolution.

Full text of DOI:10.1248/cpb.45.1922

NII-Electronic Library Service

NII-Electronic Library Service

NII-Electronic Library Service

NII-Electronic Library Service

NII-Electronic Library Service

NII-Electronic Library Service