反应详情

温度

22.5 °C

To a reactor was charged a solution of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid ethyl ester 4a from the previous step. Reagent alcohol (6.0 L) was added and the temperature adjusted to 20° C. A solution of NaOH/water (440 g/6.0 L) was added and the reactor contents were stirred at 20-25° C. for two hours until reaction completion. Water (9.0 L) was added and the reactor contents were concentrated using vacuum distillation to a volume of approximately 15.0 L. Water (15.0 L) and methyl isobutyl ketone (9.0 L) was charged, the mixture was agitated, the layers were separated, and the aqueous layer was retained. A second wash with methyl isobutyl ketone may be performed if needed. Methyl isobutyl ketone (9.0 L) was added and the mixture concentrated by vacuum distillation to a volume of approximately 30 L and ethanol content less than 3%. The reactor contents were set to a temperature of 25-30° C. and sodium chloride (4507 g) and methyl isobutyl ketone (21.0 L) were charged to the reactor and agitated. The layers were separated and the organic layer was concentrated to ˜2-3 volumes methyl isobutyl ketone. The concentrated solution was filtered through Celite and a 0.3 μm line filter. The filtered solution was charged to a well-agitated reactor containing heptane (30.0 L) cooled to 10-20° C. The mixture was stirred for two hours, filtered, and the cake was washed with heptane (8 L). The product was dried in a vacuum oven for 24-48 hr at 70-75° C. to provide 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid sodium salt 5-1 as an off-white solid (2.46 kg, 64% yield). LCMS (ESI) m/z 632.2 (MH+)

1. customadjusted to 20° C
2. concentrationthe reactor contents were concentrated
3. distillationvacuum distillation to a volume of approximately 15.0 L
4. additionWater (15.0 L) and methyl isobutyl ketone (9.0 L) was charged
5. stirringthe mixture was agitated
6. customthe layers were separated
7. washA second wash with methyl isobutyl ketone
8. additionMethyl isobutyl ketone (9.0 L) was added
9. concentrationthe mixture concentrated by vacuum distillation to a volume of approximately 30 L and ethanol content less than 3%
10. customwere set to a temperature of 25-30° C. and sodium chloride (4507 g) and methyl isobutyl ketone (21.0 L)
11. additionwere charged to the reactor
12. stirringagitated
13. customThe layers were separated
14. concentrationthe organic layer was concentrated to ˜2-3 volumes methyl isobutyl ketone
15. filtrationThe concentrated solution was filtered through Celite
16. filtrationa 0.3 μm line filter
17. additionThe filtered solution was charged to a well-agitated reactor
18. additioncontaining heptane (30.0 L)
19. temperaturecooled to 10-20° C
20. stirringThe mixture was stirred for two hours
21. filtrationfiltered
22. washthe cake was washed with heptane (8 L)
23. customThe product was dried in a vacuum oven for 24-48 hr at 70-75° C.