Azetidine → 1-(azetidin-1yl)-2-(2,6-difluoro-4-{2[(1S,2R)-2-{1-[5-(methoxylmethyl)pyrimidin-2yl]piperidin-4-yl}cyclopropyl]ethoxyl}phenyl)ethanone

To a solution of {2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy}phenyl]acetic acid (5.00 g, 10.8 mmol) in 8 ml anhydrous DMF at RT was added azetidine (0.928 g, 16.3 mmol) and N,N-diisopropylethylamine (3.78 ml, 21.7 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (6.18 g, 16.3 mmol) was added to the solution and the mixture stirred at RT for 4 hrs. The residue was purified by preparative biotage reverse phase (C-18) (100 g column), eluting with Acetonitrile/Water+0.1% formic acid (35% to 90%). The solid was purified by column chromatography on silica gel (Biotage 40M), eluting with EtOAc/hexanes (30% to 90%). The product was further purified by preparative biotage Reverse phase (C-18)(100 g), eluting with Acetonitrile/Water+0.1% formic acid (35% to 90%) to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 2H), 6.67 (d, J=9.4 Hz, 2H), 4.67 (t, J=13.9 Hz, 2H), 4.18 (m, 4H), 4.06 (m, 211), 3.85 (t, J=7.8 Hz, 2H), 3.38 (s, 2H), 3.23 (s, 3H), 2.85 (m, 2H), 2.20 (m, 211), 2.03 (m, 1H), 1.75 (t, J=14.2 Hz, 2H), 1.51 (m, 114), 1.21-1.25 (m, 3H), 0.87 (m, 1H), 0.57 (m, 2H), −0.08 (m, 1H). LC/MS (m/z): 501.4 (M+H)+. GPR119 Human EC50: 0.18 nM

1. customThe residue was purified by preparative biotage reverse phase (C-18) (100 g column)
2. washeluting with Acetonitrile/Water+0.1% formic acid (35% to 90%)
3. customThe solid was purified by column chromatography on silica gel (Biotage 40M)
4. washeluting with EtOAc/hexanes (30% to 90%)
5. customThe product was further purified by preparative biotage Reverse phase (C-18)(100 g)
6. washeluting with Acetonitrile/Water+0.1% formic acid (35% to 90%)

ORD-Eintrag

ord-e809f35430b14ba39cec12ec10619d00

Quelldatensatz

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09018224B2