Potassium Phosphate, Tribasic → 6-(2'-Chloro-4'-((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)biphenyl-4-yl)-3,5-dimethylpyrazine-2-carboxamide

Participants

Reaction Conditions

Reaction Steps

To a degassed solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid (Intermediate 5-1; 562 mg, 2.07 mmol) in DME (60 mL), methanol (15 mL) and water (15 mL) was added tripotassium phosphate (660 mg, 3.11 mmol), 3-(4-bromo-3-chlorobenzyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate 23-1; 600 mg, 2.07 mmol) followed by (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCM adduct) (341 mg, 0.41 mmol). The resulting mixture was stirred at 80° C. under nitrogen for 90 minutes. The reaction mixture was allowed to cool to ambient temperature evaporated and partitioned between DCM (100 mL) and 0.5M HCl (100 mL), the suspension was filtered (difficult as most of the material was a sticky gum) and the resultant material retained. Organic phase separated off, dried by passing through a phase seperating cartridge. Removal of the solvent under reduced pressure gave crude product which was combined with previously filtered material for chromatography. The crude product was purified by preparative HPLC (Waters—Xbridge Prep C18 5 μm), using decreasingly polar mixtures of water (containing 0.1% formic acid) and {MeOH(3):MeCN(1)} as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-(2′-chloro-4′-((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)biphenyl-4-yl)-3,5-dimethylpyrazine-2-carboxamide (269 mg, 29.8%) as a colourless solid.

Provenance & Evidence