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

Chem Pharm Bull (Tokyo). 1997 Dec;45(12):1922-7. doi: 10.1248/cpb.45.1922.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Crystallization
  • Diltiazem / analogs & derivatives*
  • Diltiazem / isolation & purification
  • Stereoisomerism
  • Temperature
  • Thiazepines / chemistry*
  • Thiazepines / isolation & purification*

Substances

  • 1,5-benzothiazepine
  • 5-(2-(dimethylamino)ethyl)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one
  • Thiazepines
  • Diltiazem