Trifluoroacetic acid → HCID 89908312, compound

Participants

Reaction Conditions

Reaction Steps

A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2, 70 mg, 0.143 mmol), tert-butyl azetidin-3-ylcarbamate (49.4 mg, 0.287 mmol), DIPEA (0.075 mL, 0.430 mmol) and iPrOH (1 mL) in a sealed vial was stirred at 120° C. for 2 h. The RM was treated with sat. aq. Na2CO3, extracted with EtOAc and the combined extracts were washed with brine (10 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 4 g, DCM/EtOH from 99:1 to 97:3). Fractions containing the desired intermediate were combined and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in DCM (1 mL), treated with TFA (0.216 mL, 2.80 mmol) and stirred at RT for 3 h. The RM was treated with sat. aq. Na2CO3, and extracted with EtOAc. The combined extracts were washed with brine (20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative HPLC (Condition 11). Fractions containing the product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure to give an aq. residue which was extracted with DCM. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as a white solid. HPLC (Condition 7) tR=5.545 min, UPLC-MS (Condition 3) tR=0.77 min, m/z=435.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.78-2.05 (m, 2H) 3.35-3.35 (m, 2H) 3.53-3.69 (m, 1H) 3.80-3.96 (m, 2H) 6.34-6.45 (m, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.74 (br. s, 1H) 7.87 (d, J=8.99 Hz, 2H) 8.00-8.10 (m, 1H) 8.66-8.78 (m, 1H) 10.24 (br. s, 1H).

Provenance & Evidence