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

The development of a short, safe and enantioselective route for the prepara tion of (R)-aminoglutethimide is described, The process was designed for ec onomic large-scale manufacture of the bulk drug substance to acceptable qua lity standards, to allow clinical evaluation of the single enantiomer over the existing racemate. (R)-Aminoglutethimide was prepared from 1-chloro-4-n itrobenzene using a six-stage synthetic sequence, via chemoresolution of ke y intermediate racemic 4-cyano-4-(4-nitrophenyl)hexanoic acid using (-)-cin chonidine, The process allowed for preparation of several kilograms of the precursor (R)-nitroglutethimide, to cGMP at pilot-plant scale, along with d emonstration of the find hydrogenation step to (R)-amino-glutethimide in th e laboratory, This route avoids the problems of hazardous nitration technol ogy, and therefore regio-isomer contamination of the product, associated wi th other procedures. The resolution chemistry described represents an impro vement on literature procedures, Optimisation of the asymmetric Michael add ition offers an attractive alternative approach.