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 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.
Yamada
S
S
Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Osaka, Japan.
Yoshioka
R
R
Shibatani
T
T
D003460:Crystallization; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000302:isolation & purification; D013237:Stereoisomerism; D013696:Temperature; D013841:Thiazepines / Q000737:chemistry* / Q000302:isolation & purification*
C106746:1,5-benzothiazepine; C110555:5-(2-(dimethylamino)ethyl)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one; D013841:Thiazepines; D004110:Diltiazem