Hydrochloric Acid → 2-(4'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-(trifluoromethyl)biphenyl-4-yl)acetic acid

Participants

Reaction Conditions

Reaction Steps

A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid (Intermediate 5-1; 278 mg, 1.02 mmol) and methyl 2-(3-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)phenyl)acetate (Intermediate 5-2; 300 mg, 0.82 mmol) and sodium carbonate (0.666 mL, 1.33 mmol), tetrakis(triphenylphosphine)palladium(0) (58.7 mg, 0.05 mmol) and lithium chloride (60.8 mg, 1.43 mmol) in DME (20 mL) was degassed and then stirred at 85° C. for 17 hours. The reaction mixture was The reaction mixture was acidified with 2M HCl and evaporated. The precipitate was collected by filtration, washed with water (20 mL) and dried under vacuum to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-(trifluoromethyl)biphenyl-4-yl)acetic acid (197 mg, 55.9%) as a brown solid, which was purified by flash silica chromatography, elution gradient 0 to 6% MeOH in DCM. Failed to purify material so was further purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-(trifluoromethyl)biphenyl-4-yl)acetic acid (197 mg, 55.9%) as a white solid.

Provenance & Evidence