Stereoselective Synthesis of (S)-3-(Methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile
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- 作者：Manjinder S. Lall ; Garrett Hoge ; Tuan P. Tran ; William Kissel ; Sean T. Murphy ; Clarke Taylor ; Kim Hutchings ; Brian Samas ; Edmund L. Ellsworth ; Timothy Curran ; H. D. Hollis Showalter
- 刊名：The Journal of Organic Chemistry
- 出版年：2012
- 出版时间：May 18, 2012
- 年：2012
- 卷：77
- 期：10
- 页码：4732-4739
- 全文大小：415K
- 年卷期：v.77,no.10(May 18, 2012)
- ISSN：1520-6904
文摘
(S)-3-(Methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile (1) is a key intermediate in the preparation of PF-00951966,d(0);" class="ref">(1) a fluoroquinolone antibiotic for use against key pathogens causing community-acquired respiratory tract infections including multidrug resistant (MDR) organisms. The current work describes the development of a highly efficient and stereoselective synthesis of 1 in 10 steps with an overall yield of 24% from readily available benzyloxyacetyl chloride. Two key transformations in the synthetic sequence involve (a) catalytic asymmetric hydrogenation with chiral DM-SEGPHOS-Ru(II) complex to afford 尾-hydroxy amide 11b in good yield (73%) and high stereoselectivity (de 98%, ee >99%) after recrystallization and (b) SN2 substitution reaction with methylamine to provide diamine 14 with inversion of configuration at the 1鈥?position in high yield (80%), after efficient purification using a simple acid/base extraction protocol.