Highly efficient asymmetric synthesis of sitagliptin.
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.
Hansen
Karl B
KB
Department of Process Research, Merck Research Laboratory, Rahway, New Jersey 07065, USA.
Hsiao
Yi
Y
Xu
Feng
F
Rivera
Nelo
N
Clausen
Andrew
A
Kubryk
Michele
M
Krska
Shane
S
Rosner
Thorsten
T
Simmons
Bryon
B
Balsells
Jaume
J
Ikemoto
Nori
N
Sun
Yongkui
Y
Spindler
Felix
F
Malan
Christophe
C
Grabowski
Edward J J
EJ
Armstrong
Joseph D
JD
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*
D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D014230:Triazoles; D000068900:Sitagliptin Phosphate