Sodium Bicarbonate → HCID 118195187, compound

Participants

Reaction Conditions

Reaction Steps

(S)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1, 92 mg, 0.2 mmol) and 2-(fluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (prepared as described in US20090571601) (316 mg 30% ig, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M NaHCO3 (0.3 mL, 0.6 mmol) was added, the RM was flushed with argon, heated to 90° C. and Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol) was added. The RM was heated for 2 h at 90° C. After cooling at RT, the RM was dissolved in EtOAc and water, and extracted with EtOAc. The combined extracts were dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was first purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH), treated with Si-Thiol (100 mg) in MeOH and further purified by reverse phase chromatography (MPLC, Lichroprep 15-25 μm column, water+0.1% formic acid/MeCN+0.1% formic acid, gradient 10% to 38% MeCN+0.1% formic acid). The combined pure fractions were neutralized with NaHCO3 and extracted with EtOAc. The combined organic phases were dried over Na2SO4 and evaporated to afford the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=4.96 min, UPLC-MS (Condition 3) tR=1.07 min, m/z=491.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.62 (m, 1H) 1.77-1.89 (m, 1H) 2.15-2.29 (m, 1H) 2.92-3.02 (m, 1H) 3.07-3.38 (m, 4H) 3.42-3.53 (m, 2H) 4.60 (t, J=5.08 Hz, 1H) 5.47 (s, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.58 (d, J=7.82 Hz, 1H) 7.77-7.92 (m, 3H) 8.02 (d, J=2.35 Hz, 1H) 8.64 (d, J=1.56 Hz, 1H) 8.75 (d, J=2.74 Hz, 1H) 10.16 (s, 1H).

Provenance & Evidence