反应详情

To a yellow solution of (R)-4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 40, 1.64 g, 3.89 mmol), (R)-4-(4-((2-(tert-butyldimethylsilyloxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 67, 2.68 g, 4.09 mmol), DMAP (0.95 g, 7.78 mmol) and dichloromethane (41 ml) was added EDC (1.492 g, 7.78 mmol). After stirring for 16 hours, the mixture was diluted with saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, 330 g SiO2, isocratic 50% ethyl acetate in hexanes for 50 minutes, then 50→65% ethyl acetate in hexanes over 30 minutes followed by 65→100% ethyl acetate in hexanes over 20 min and then 0→10% methanol in ethyl acetate over 20 minutes) to afford the title product (3.25 g, yield: 79%).

1. customThe layers were separated
2. extractionthe aqueous layer was extracted with dichloromethane (×2)
3. washThe combined organic layers were washed with saturated aqueous sodium chloride
4. dry with materialdried over sodium sulfate
5. filtrationfiltered
6. concentrationconcentrated under reduced pressure
7. customThe concentrate was purified by column chromatography (ISCO, 330 g SiO2, isocratic 50% ethyl acetate in hexanes for 50 minutes
8. wait50→65% ethyl acetate in hexanes over 30 minutes followed by 65→100% ethyl acetate in hexanes over 20 min