Development of a Scalable Synthesis of Dipeptidyl Peptidase-4 Inhibitor ABT-279
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- 作者：Todd S. McDermott ; Lakshmi Bhagavatula ; Thomas B. Borchardt ; Kenneth M. Engstrom ; Jorge Gandarilla ; Brian J. Kotecki ; Albert W. Kruger ; Michael J. Rozema ; Ahmad Y. Sheikh ; Seble H. Wagaw ; Steven J. Wit
- 刊名：Organic Process Research & Development
- 出版年：2009
- 出版时间：November 20, 2009
- 年：2009
- 卷：13
- 期：6
- 页码：1145-1155
- 全文大小：247K
- 年卷期：v.13,no.6(November 20, 2009)
- ISSN：1520-586X
文摘
A convergent, scalable synthesis of dipeptidyl peptidase-4 inhibitor, ABT-279, has been developed and demonstrated on multikilogram scale. The cis-2,5-disubstituted pyrrolidine is generated by cyclization of a Boc-amine onto an alkynyl ketone followed by stereospecific reduction of the resulting acyliminium intermediate. The amine coupling partner was prepared by a novel Hofmann rearrangement promoted by 1,3-dibromo-5,5-dimethylhydantoin. The final product was isolated as the l-malic acid salt. The scale-up campaign consisted of 15 steps and delivered 42 kg of ABT-279 in 14% overall yield. A second-generation synthesis that addresses some of the issues encountered during scale-up was developed and demonstrated on kilogram scale.