Stereoselective synthesis of (S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl) propanenitrile

摘要

S)-3-(Methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile (1) is a key intermediate in the preparation of PF-00951966,(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 β-hydroxy amide 11b in good yield (73%) and high stereoselectivity (de 98%, ee <99%) after recrystallization and (b) S _N2 substitution reaction with methylamine to provide diamine 14 with inversion of configuration at the 1′-position in high yield (80%), after efficient purification using a simple acid/base extraction protocol.