反应详情

温度

22.5 °C

To a reactor was charged a stock 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 (81.8 kg solution, containing ˜17.1 kg of 4a). A solution of NaOH/water (2.2 kg/70 L) was added and the reactor contents were stirred at 20-25° C. for five hours until reaction completion. The reactor contents were concentrated using vacuum distillation. Water (124 L) was added and the solution was passed through a 5 μm line filter. Methyl isobutyl ketone (120 L) was charged and the mixture heated to 55° C. Separate the layers and add methyl isobutyl ketone (120 L) to the aqueous layer at ambient temperature. Agitate the mixture and add 48% aqueous sodium hydroxide (33 kg). Separate the layers and wash the aqueous layer with methyl isobutyl ketone (51 L). Separate the layers and wash the combined methyl isobutyl ketone layers with an aqueous brine solution (15.4 kg NaCl/44 L water). Separate the layers and concentrate the organic layer to ˜2-3 volumes methyl isobutyl ketone. Filter the concentrated solution through a 0.2 μm filter. Charge the methyl isobutyl ketone solution to a well-agitated reactor containing heptane (171 L) cooled to 20° C. The mixture is stirred for two hours, filtered, and the cake is washed with heptane (10 L) 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 (13.2 kg, 78% yield). LCMS (ESI) m/z 632.2 (MH+)

1. concentrationThe reactor contents were concentrated
2. distillationvacuum distillation
3. additionWater (124 L) was added
4. filtrationfilter
5. additionMethyl isobutyl ketone (120 L) was charged
6. temperaturethe mixture heated to 55° C
7. customSeparate the layers
8. additionadd methyl isobutyl ketone (120 L) to the aqueous layer at ambient temperature
9. stirringAgitate the mixture
10. additionadd 48% aqueous sodium hydroxide (33 kg)
11. customSeparate the layers
12. washwash the aqueous layer with methyl isobutyl ketone (51 L)
13. customSeparate the layers
14. washwash the combined methyl isobutyl ketone layers with an aqueous brine solution (15.4 kg NaCl/44 L water)
15. customSeparate the layers
16. concentrationconcentrate the organic layer to ˜2-3 volumes methyl isobutyl ketone
17. filtrationFilter the concentrated solution through a 0.2 μm
18. filtrationfilter
19. additionCharge the methyl isobutyl ketone solution to a well-agitated reactor
20. additioncontaining heptane (171 L)
21. temperaturecooled to 20° C
22. stirringThe mixture is stirred for two hours
23. filtrationfiltered
24. washthe cake is washed with heptane (10 L)