Development of a Practical Synthesis of DPP IV Inhibitor LY2497282
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- 作者：Hannah Yu ; Rachel N. Richey ; James R. Stout ; Mark A. LaPack ; Ruilin Gu ; Vien V. Khau ; Scott A. Frank ; Joel P. Ott ; Richard D. Miller ; Michael A. Carr ; Tony Y. Zhang
- 刊名：Organic Process Research & Development
- 出版年：2008
- 出版时间：March 2008
- 年：2008
- 卷：12
- 期：2
- 页码：218 - 225
- 全文大小：400K
- 年卷期：v.12,no.2(March 2008)
- ISSN：1520-586X
文摘
A new synthetic route to LY2497282 (1), a potent and selective DPP IV inhibitor for the potential treatment of diabetes, suitable for the preparation of multikilogram quantities is described. The key step involved a stereoselective addition of the dianion of nicotinamide 8 to N-dibenzyl-protected α-amino aldehyde 12, which was derived from N-acetyl-protected amino ester 14 without epimerization. The desired Felkin-Anh nonchelation controlled anti-amino alcohol 11 was isolated with >99% HPLC area and >99% ee by crystallization. After removing the dibenzyl protecting group under transfer hydrogenation conditions, LY2497282 (1) was finally obtained in 39% overall yield with a six-step longest linear sequence starting from N-acetyl-protected amino ester 14.