Trifluoroacetic acid → N-(4-(Chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3-(1H-pyrazol-5-yl)benzamide

Participants

Reaction Steps

1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (126 mg, 0.451 mmol) and PdCl2(PPh3)2 (15.84 mg, 23 μmol) were added to a mixture of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)benzamide (Stage 77.1, 110 mg, 0.226 mmol) and Na2CO3 (0.451 mL, 0.903 mmol) in DME (1.5 mL)/EtOH (0.3 mL) in a vial, which was sealed, purged with argon and the RM was subjected to MW irradiation at 125° C. for 30 min. The RM was filtered through Hyflo® and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, 12 g, n-hexane/EtOAc from 20% to 100% EtOAc). The resulting intermediate was dissolved in DCM (2 mL), treated TFA (0.314 mL, 4.07 mmol) and stirred at RT for 2 h. The solvent was evaporated off under reduced pressure to give a residue which was treated with sat. aq. Na2CO3 and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative HPLC (Condition 10). Fractions containing pure 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 EtOAc. The combined extracts were washed with brine, 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 98:2 to 92:8) to give the title product as a white solid. HPLC (Condition 7) tR=6.105 min, UPLC-MS (Condition 8) tR=0.91 min, m/z=465.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.81 (d, J=10.56 Hz, 2H) 3.24-3.38 (m, 2H) 3.81-3.91 (m, 2H) 4.99 (br.s, 1H) 5.04 (br.s, 1H) 6.26-6.36 (m, 1H) 6.72-6.87 (m, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.47-7.94 (m, 5H) 10.10 (s, 1H) 12.75-13.04 (m, 1H).

Provenance & Evidence