反应详情

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 (30 mg, 0.049 mmol) in dichloromethane (450 μL, 0.1 M solution) was added triethylamine (20.6 μL, 0.148 mmol) followed by addition of 20% phosgene in toluene (6.2 μL, 0.059 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 stirred for 15 min at room temperature. 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-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl)-2,6-dimethylmorpholine-4-carboxamido)methyl)-4-fluoropyrrolidine-1-carboxylate (30 mg, 81%, over 2 steps). LC/MS (uplc): MH+ 751.5, 1.39 min.

1. additionwas added
2. customThe reaction mixture was quenched with H2O
3. extractionextracted with EtOAc
4. washThe organic layer was washed with NaHCO3 solution and brine
5. dry with materialdried over anhydrous sodium sulfate
6. filtrationfiltered
7. concentrationconcentrated
8. customAfter the volatile organic materials were removed in vacuo
9. customthe crude product was purified on preparative reverse phase HPLC
10. extractionwas then extracted with EtOAc
11. dry with materialThe organic layer was dried over anhydrous sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo