First Generation Process for the Preparation of the DPP-IV Inhibitor Sitagliptin
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- 作者：Karl B. Hansen ; Jaume Balsells ; Spencer Dreher ; Yi Hsiao ; Michele Kubryk ; Michael Palucki ; Nelo Rivera ; Dietrich Steinhuebel ; Joseph D. Armstrong III ; David Askin ; and Edward J. J. Grabowski
- 刊名：Organic Process Research & Development
- 出版年：2005
- 出版时间：September 2005
- 年：2005
- 卷：9
- 期：5
- 页码：634 - 639
- 全文大小：82K
- 年卷期：v.9,no.5(September 2005)
- ISSN：1520-586X
文摘
A new synthesis of sitagliptin (MK-0431), a DPP-IV inhibitorand potential new treatment for type II diabetes, suitable forthe preparation of multi-kilogram quantities is presented. Thetriazolopyrazine fragment of sitagliptin was prepared in 26%yield over four chemical steps using a synthetic strategy similarto the medicinal chemistry synthesis. Key process developmentswere made in the first step of this sequence, the addition ofhydrazine to chloropyrazine, to ensure its safe operation on alarge scale. The beta-amino acid fragment of sitagliptin wasprepared by asymmetric reduction of the corresponding beta-ketoester followed by a two-step elaboration to an N-benzyloxybeta-lactam. Hydrolysis of the lactam followed by directcoupling to the triazolopiperazine afforded sitagliptin aftercleavage of the N-benzyloxy group and salt formation. Theoverall yield was 52% over eight steps.