(3S)-N-cyclopropyl-3-[[(2R)-3-(cyclopropylmethylsulfonyl)-2-[[(1S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl]amino]propanoyl]amino]-2-oxopentanamide

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred suspension of (3S)—N-cyclopropyl-3-((R)-3-((cyclopropylmethyl)sulfonyl)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)propanamido)-2-hydroxypentanamide [63.2 g; 118 mmol] in a mixture of acetonitrile (1150 mL) and dichloromethane (1150 mL) previously cooled in a cold water bath, was added DMP (69.86 g; 164.7 mmol; 140 mol %) in portions. The resulting reaction mixture was stirred for 4 h at ambient temperature. The reaction mixture was concentrated in vacuo to distill about 1 L of solvent and the remaining solution was added to a mixture of 1M aqueous sodium thiosulfate (800 mL) and saturated aqueous sodium bicarbonate (800 mL). Ethyl acetate (1.6 L) was added and the biphasic mixture stirred for 1.5 h. The layers were separated and the organic phase was washed with water, a mixture of water and a solution of sodium chloride in water and finally a solution of sodium chloride in water. The organic phase was dried (MgSO4) and concentrated to a wet solid which was suspended in hexane. The resulting slurry was stirred overnight, filtered and the solid was washed with hexane. Drying provided 53.6 g (85%) of the title compound. Recrystallization of this material alone with 4 g of crude (S)—N-cyclopropyl-3-((R)-3-((cyclopropylmethyl)sulfonyl)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)propanamido)-2-oxopentanamide from another lot (57.6 g total) using hot IPA (1700 mL) gave 52 g of a white solid after washing with cold IPA and hexane, followed by drying over P2O5 in a vacuum oven at 40° C. LC-MS, positive ion mode: m/z=536 [M+H]+ (100%); 19F-NMR (CDCl3) δ, ppm: −74.54 (s); −110.09 (s). previously cooled in a cold water bath was added DMP (69.86 g; 164.7 mmol; 140 mol %) in portions The resulting reaction mixture The reaction mixture was concentrated in vacuo to distill about 1 L of solvent the remaining solution was added to a mixture of 1M aqueous sodium thiosulfate (800 mL) and saturated aqueous sodium bicarbonate (800 mL) Ethyl acetate (1.6 L) was added the biphasic mixture stirred for 1.5 h The layers were separated the organic phase was washed with water a mixture of water The organic phase was dried (MgSO4) concentrated to a wet solid which The resulting slurry was stirred overnight filtered the solid was washed with hexane Drying