3-Hydroxybenzaldehyde → N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(3-hydroxyphenyl)-methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide formate

Participants

Reaction Steps

NaBH3CN (28 mg, 0.45 mmol) was added to a solution of N-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.22 mmol) in MeOH (10 mL) and 3-hydroxybenzaldehyde (55 mg, 0.45 mmol). The resulting solution was stirred for at room temperature overnight. The reaction was then quenched by the addition of 0.2 mL of water. The resulting mixture was concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 2.5% MeOH in DCM. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (32.0% up to 36.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 32.0% in 2 min); Detector, UV 254/220 nm. This resulted in 25.7 mg (19%) of the formic acid salt of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(3-hydroxyphenyl)-methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide formate as a white solid. LCMS (Method 20) [M+H]+=554.2, RT=1.58 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.37 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.68-8.67 (m, 2H), 8.37 (s, 1H), 7.61 (dd, 1H, J=2.4, 8.8 Hz), 7.60 (d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.05 (t, 1H, J=73.2 Hz), 7.10-7.06 (m, 1H), 6.74-6.72 (m, 2H), 6.60 (d, 1H, J=7.2 Hz), 4.25 (t, 2H, J=6.0 Hz), 3.66 (s, 2H), 2.94 (t, 2H, J=6.0 Hz).

Provenance & Evidence