Cyanoacetic acid → 3-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-(isopropylamino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-3-oxopropanenitrile

Temperature

60 °C

To a solution of 2-cyanoacetic acid (8.3 mg, 0.097 mmol) in DMA (0.3 mL) at room temperature was added DIPEA (33.9 μL, 0.194 mmol), followed by HATU (36.9 mg, 0.097 mmol). This mixture was stirred for 5 min, then was treated with a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (33.5 mg, 0.065 mmol) in DMA (0.35 mL). The reaction mixture was heated at 60° C. for 30 min. The reaction mixture was purified directly by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 55% to 80% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (5.5 mg, 14%). 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.27 (m, 6H), 1.96 (m, 2H), 2.12 (m, 2H), 2.75 (t, J=5.9 Hz, 0.8H), 2.85 (m, 1.2H), 3.01 (m, 2H), 3.39 (m, 2H), 3.75 (t, J=5.8 Hz, 1.2H), 3.89 (t, J=5.9 Hz, 0.8H), 4.00 (m, 2H); 4.14 (m, 1H), 4.48 (m, 1H), 4.50 (s, 0.8H), 4.60 (s, 1.2H), 6.88 (m, 1H), 6.98 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 471.5.

1. customThe reaction mixture was purified directly by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column

ORD record

ord-b2ff1bce4a51452c80c644818105d016

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09181249B2