Toluene → (3R,4R)-benzyl 3-(((2S,6R)-N-((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-2,6-dimethylmorpholine-4-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

To a solution of (3R,4R)-benzyl 3-(((R)-1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (110 mg, 0.186 mmol) in dichloromethane (1.9 mL, 0.1 M solution) was added triethylamine (78 μL, 0.558 mmol) followed by addition of 20% phosgene in toluene (66 mg, 0.223 mmol) at room temperature. After the resulting solution was stirred at room temperature for 15 min (LC/MS (uplc): MH+654.3, 1.37 min for (3S,4R)-benzyl 3-((((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)(chlorocarbonyl)amino)methyl)-4-fluoropyrrolidine-1-carboxylate), 2,6-dimethylmorpholine (64 mg, 0.558 mmol) was added and heat at 40° C. for overnight (in a seal tube). The reaction mixture was quenched with H2O and extracted with EtOAc. The organic layer was washed with NaHCO3 solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. After the volatile organic materials were removed in vacuo, the crude product was purified on preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired (3R,4R)-benzyl 3-(((2S,6R)—N—((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-2,6-dimethylmorpholine-4-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate (91 mg, 66.7%, over 2 steps). LC/MS (uplc): MH+733.5, 1.41 min.

Provenance & Evidence