Production of (R)-aminoglutethimide:: A new route from 1-chloro-4-nitrobenzene

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 find hydrogenation step to (R)-amino-glutethimide 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.