反应详情

TFA (0.2 L) was added to a stirred solution of (2R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)pyridin-2-yl]-2-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide (intermediate 24, 0.82 Kg) in DCM (6.55 L) at room temperature. The resultant solution was cooled to 0° C. Sodium triacetoxy borohydride (0.423 Kg) was added portion-wise and the reaction stirred for 2-4 hr. MeOH (0.4 L) was added to the reaction then water (1.64 L) was added carefully, followed by 3M NaOH (4.0 L) to raise the pH to 12. The layers are separated and the DCM layer retained. The aqueous layer was washed with DCM (0.8 L) and the layers separated. The organic layers were combined and washed with saturated brine solution. The organic layer was dried over magnesium sulphate and concentrated on a rotary evaporator to give (5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide (Example 1) and 5S)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide (Example 5) in approximately mixture of 4:1, as a white foam (859.5 g). To a such mixture (0.8 Kg), TBME (6 L) was added and the resultant solution was filtered. The solution was stirred at room temperature overnight. The resulting suspension was filtered and the cake rinsed with TBME. (0.8 L) The damp solid was dried under vacuum to furnish the title compound, in approximately 97% purity as a white crystalline solid (446.4 g.).

1. temperatureto raise the pH to 12
2. customThe layers are separated
3. washThe aqueous layer was washed with DCM (0.8 L)
4. customthe layers separated
5. washwashed with saturated brine solution
6. dry with materialThe organic layer was dried over magnesium sulphate
7. concentrationconcentrated on a rotary evaporator