Development and Manufacture of the Inosine Monophosphate Dehydrogenase Inhibitor Merimepodib, VX-497
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- 作者：Adam R. Looker ; Benjamin J. Littler ; Todd A. Blythe ; John R. Snoonian ; Graham K. Ansell ; Andrew D. Jones ; Phil Nyce ; Minzhang Chen ; Bobbianna J. Neubert
- 刊名：Organic Process Research & Development
- 出版年：2008
- 出版时间：July 2008
- 年：2008
- 卷：12
- 期：4
- 页码：666-673
- 全文大小：234K
- 年卷期：v.12,no.4(July 2008)
- ISSN：1520-586X
文摘
A process for the manufacture of merimepodib (VX-497), an inosine monophosphate dehydrogenase (IMPDH) inhibitor, has been developed and efficiently scaled to produce clinical supply. The process comprises five steps, incorporating simple and robust chemistry that ultimately yielded 96.5 kg with a purity of 100% (by HPLC analysis) and 99.7% w/w assay. Highlights of the process are the effective use of production-scale phosgene, manipulation of Schotten−Baumann reaction conditions to give a low pH procedure that avoids a critical impurity, and the use of online tools to better identify parameters of the API purification.