194422-71-4Relevant academic research and scientific papers
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.
Racemisation process
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, (2008/06/13)
A process for the racemization of an enantiomerically-enriched compound of formula (3), comprises treatment of enantiomerically-enriched (3) with a base to obtain anion (4), optionally in protonated form, which is then combined with CH2 =CH--Y1 to form racemic (3), STR1 wherein Ar=aryl or heteroaryl; Ak=C1-20 alkyl; X=CN, CO2 R, CONR1 R2, and COR; Y and Y1 are independently selected from CN, CO2 R, CONR1 R2 and R, R1 and R2 are independently selected from H and C1-20 alkyl; optionally as a salt thereof. This racemization process can be used as part of an efficient synthesis of enantiomerically-enriched verapamil or aminoglutethimide.
