title: Stereoselective synthesis of (S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile.
abstract: (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(N)2 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.
authors.affiliation: Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States. manjinder.lall@pfizer.com
authors.forename: Manjinder S
authors.initials: MS
authors.lastname: Lall
authors.forename: Garrett
authors.initials: G
authors.lastname: Hoge
authors.forename: Tuan P
authors.initials: TP
authors.lastname: Tran
authors.forename: William
authors.initials: W
authors.lastname: Kissel
authors.forename: Sean T
authors.initials: ST
authors.lastname: Murphy
authors.forename: Clarke
authors.initials: C
authors.lastname: Taylor
authors.forename: Kim
authors.initials: K
authors.lastname: Hutchings
authors.forename: Brian
authors.initials: B
authors.lastname: Samas
authors.forename: Edmund L
authors.initials: EL
authors.lastname: Ellsworth
authors.forename: Timothy
authors.initials: T
authors.lastname: Curran
authors.forename: H D Hollis
authors.initials: HD
authors.lastname: Showalter
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D002384:Catalysis; D024841:Fluoroquinolones / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: C574745:(S)-3-(methylamino)-3-((R)-pyrrolidin-3-yl)propanenitrile; D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D009570:Nitriles; D011759:Pyrrolidines