Process Development and Multikilogram-Scale Synthesis of a TRPV1 Antagonist

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• 作者：Ed Cleator ; Jeremy P. Scott ; Paulo Avalle ; Matthew M. Bio ; Sarah E. Brewer ; Antony J. Davies ; Andrew D. Gibb ; Faye J. Sheen ; Gavin W. Stewart ; Debra J. Wallace ; Robert D. Wilson.
• 刊名：Organic Process Research & Development
• 出版年：2013
• 出版时间：December 20, 2013
• 年：2013
• 卷：17
• 期：12
• 页码：1561-1567
• 全文大小：248K
• 年卷期：v.17,no.12(December 20, 2013)
• ISSN：1520-586X

文摘

The process development and multikilogram preparation of a TRPV1 antagonist, 1, is described. Pyrido[2,3-b]pyrazine 1 was prepared in a convergent manner by the coupling of two key fragments, glyoxal 2 and diamine 3. Glyoxal 2 was synthesized in six chemical steps in 20% overall yield, the key step being a challenging Grignard reaction to install the glyoxalate moiety. Diamine 3 was also prepared in six chemical steps in 46% overall yield, exploiting a regioselective nucleophilic aromatic substitution to obtain the key nitrodiamine intermediate 19.