title: Highly efficient asymmetric synthesis of sitagliptin.
abstract: A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity. Highly enantioselective hydrogenation of dehydrositagliptin 9, with as low as 0.15 mol % of Rh(I)/(t)Bu JOSIPHOS, affords sitagliptin, which is finally isolated as its phosphate salt with nearly perfect optical and chemical purity. This environmentally friendly, 'green' synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams. The efficiency of this cost-effective process, which has been implemented on manufacturing scale, results in up to 65% overall isolated yield.
authors.affiliation: Department of Process Research, Merck Research Laboratory, Rahway, New Jersey 07065, USA.
authors.forename: Karl B
authors.initials: KB
authors.lastname: Hansen
authors.forename: Yi
authors.initials: Y
authors.lastname: Hsiao
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.forename: Nelo
authors.initials: N
authors.lastname: Rivera
authors.forename: Andrew
authors.initials: A
authors.lastname: Clausen
authors.forename: Michele
authors.initials: M
authors.lastname: Kubryk
authors.forename: Shane
authors.initials: S
authors.lastname: Krska
authors.forename: Thorsten
authors.initials: T
authors.lastname: Rosner
authors.forename: Bryon
authors.initials: B
authors.lastname: Simmons
authors.forename: Jaume
authors.initials: J
authors.lastname: Balsells
authors.forename: Nori
authors.initials: N
authors.lastname: Ikemoto
authors.forename: Yongkui
authors.initials: Y
authors.lastname: Sun
authors.forename: Felix
authors.initials: F
authors.lastname: Spindler
authors.forename: Christophe
authors.initials: C
authors.lastname: Malan
authors.forename: Edward J J
authors.initials: EJ
authors.lastname: Grabowski
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Armstrong
mesh_terms: D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis*; D055772:Green Chemistry Technology / Q000191:economics / Q000379:methods*; D006865:Hydrogenation; D011719:Pyrazines / Q000138:chemical synthesis*; D000068900:Sitagliptin Phosphate; D013237:Stereoisomerism; D014230:Triazoles / Q000138:chemical synthesis*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D014230:Triazoles; D000068900:Sitagliptin Phosphate