194422-71-4Relevant articles and documents
Production of (R)-aminoglutethimide: A new route from 1 -chloro-4-nitrobenzene
Bunegar, Michael J.,Dyer, Ulrich C.,Evans, Graham R.,Hewitt, Richard P.,Jones, Stephen W.,Henderson, Neil,Richards, Christopher J.,Sivaprasad, Sivadasan,Skead, Benjamin M.,Stark, Mark A.,Teale, Eric
, p. 442 - 450 (1999)
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.
