Production of (R)-Aminoglutethimide: A New Route from 1-Chloro-4-nitrobenzene

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• 作者：Michael J. Bunegar ; Ulrich C. Dyer ; Graham R. Evans ; Richard P. Hewitt ; Stephen W. Jones ; Neil Henderson ; Christopher J. Richards ; Sivadasan Sivaprasad ; Benjamin M. Skead ; Mark A. Stark ; and Eric Teal
• 刊名：Organic Process Research & Development
• 出版年：1999
• 出版时间：November 1999
• 年：1999
• 卷：3
• 期：6
• 页码：442 - 450
• 全文大小：139K
• 年卷期：v.3,no.6(November 1999)
• ISSN：1520-586X

文摘

The development of a short, safe and enantioselective route forthe preparation of (R)-aminoglutethimide is described. Theprocess was designed for economic large-scale manufacture ofthe bulk drug substance to acceptable quality standards, toallow clinical evaluation of the single enantiomer over theexisting racemate. (R)-Aminoglutethimide was prepared from1-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 processallowed for preparation of several kilograms of the precursor(R)-nitroglutethimide, to cGMP at pilot-plant scale, along withdemonstration of the final hydrogenation step to (R)-aminoglutethimide in the laboratory. This route avoids the problemsof hazardous nitration technology, and therefore regio-isomercontamination of the product, associated with other procedures.The resolution chemistry described represents an improvementon literature procedures. Optimisation of the asymmetricMichael addition offers an attractive alternative approach.