Web Release Date: October 28,
Production of (R)-Aminoglutethimide: A New Route from 1-Chloro-4-nitrobenzene
and
Celltech-Chiroscience p.l.c., Cambridge Science Park, Milton Road, Cambridge, CB4 0WE, UK, Hickson and Welch Ltd., Wheldon Road, Castleford, West Yorkshire, WF10 2JT, UK, and Department of Chemistry, University of Wales, Cardiff, P.O. Box 912, Cardiff, CF1 3TB, Wales
Received for review January 19, 1999.
Abstract:
The development of a short, safe and enantioselective route for the preparation of (R)-aminoglutethimide is described. The process was designed for economic large-scale manufacture of the bulk drug substance to acceptable quality standards, to allow clinical evaluation of the single enantiomer over the existing racemate. (R)-Aminoglutethimide was prepared from 1-chloro-4-nitrobenzene using a six-stage synthetic sequence, via chemoresolution of key intermediate racemic 4-cyano-4-(4-nitrophenyl)hexanoic acid using (-)-cinchonidine. The process allowed for preparation of several kilograms of the precursor (R)-nitroglutethimide, to cGMP at pilot-plant scale, along with demonstration of the final hydrogenation step to (R)-aminoglutethimide in the laboratory. This route avoids the problems of hazardous nitration technology, and therefore regio-isomer contamination of the product, associated with other procedures. The resolution chemistry described represents an improvement on literature procedures. Optimisation of the asymmetric Michael addition offers an attractive alternative approach.
Download the full text: PDF | HTML
