4-Methylmorpholine → (S)-5-(4-Bromo-2-fluorophenylamino)-N-(2-hydroxy-propoxy)imidazo[1,5-a]pyrazine-6-carboxamide

Participants

Reaction Steps

To a solution of 5-(4-bromo-2-fluorophenylamino)imidazo[1,5-a]-pyrazine-6-carboxylic acid (100 mg, 0.28 mmol) in anhydrous DMF (1.5 mL) was added, in order, (S)-1-aminooxy-propan-2-ol hydrochloride (37.4 mg, 0.29 mmol, 1.03 eq.), HOBt (40.4 mg, 0.30 mmol, 1.05 eq.), EDCI (57.3 mg, 0.30 mmol, 1.05 eq.), and 4-methylmorpholine (0.15 mL, 1.36 mmol, 4.8 eq.). The reaction mixture was stirred at room temperature under N2 for 7 h and then diluted with ether (25 mL) and ethyl acetate (25 mL). The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0 to 40% methanol in ethyl acetate) to give an oil. Crystallization from DCM—ether—hexane afforded the desired product as a white solid (30.3 mg, 25.0%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 11.88 (broad s, 1H), 10.29 (broad s, 1H), 8.82 (s, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.65 (dd, J=10.6 Hz, 2.2 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 6.78 (t, J=8.4 Hz, 1H), 4.80 (d, J=4.0 Hz, 1H), 3.90-3.81 (m, 1H), 3.75-3.62 (m, 2H), 1.05 (d, J=6.4 Hz, 3H); LCMS (method D2): RT=1.516 min, [M+H]+=424/426.

Provenance & Evidence