反应详情

温度

52 °C

To a reactor was charged a solution of 3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1e in isopropyl acetate (30.7 kg in 125.4 kg solution). Dimethylformamide (28.8 kg) was charged and the mixture was distilled under vacuum to remove the isopropyl acetate. Ethyl-4-bromobutyrate (11.8 kg) was charged to the reactor followed by diisopropylethylamine (8.87 kg). The reactor contents were heated to 52° C. and stirred until completion of reaction. The reactor was cooled to 22° C. and isopropyl acetate (144 kg) and water (144 kg) were added. The mixture was agitated and the layers allowed to settle. The water layer was removed and the organic layer was washed with water (144 kg). The organic layer was treated with a solution of 85% phosphoric acid/H2O (15.6 kg/173 kg). The mixture was agitated, allowed to settle, and the layers were separated. The organic layer was treated with a solution of 85% phosphoric acid/H2O (4.03 kg/28.8 kg). The mixture was agitated, allowed to settle, and the layers were separated. The aqueous phosphate layers were combined and washed with isopropyl acetate (28.8 kg). After layer separation, isopropyl acetate (144 kg) was added to the aqueous layer, followed by slow addition of a solution of potassium carbonate/water (35.1 kg/43.2 kg) while mixing. The layers were separated and the organic layer was concentrated by vacuum distillation. The solution was passed through a silica gel plug pre-conditioned with CH2Cl2 and the plug eluted using i-PrOAc/CH2Cl2 (31 kg/190 kg) in four portions. Appropriate portions were combined and the solution was concentrated initially by atmospheric pressure distillation followed by vacuum distillation. The concentrated 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 (86.4 kg total, ˜29.8 kg of 4a, 80% yield) was used in the next step. LCMS (ESI) m/z 660.2 (MH+)

1. distillationthe mixture was distilled under vacuum
2. customto remove the isopropyl acetate
3. additionEthyl-4-bromobutyrate (11.8 kg) was charged to the reactor
4. temperatureThe reactor was cooled to 22° C.
5. additionisopropyl acetate (144 kg) and water (144 kg) were added
6. stirringThe mixture was agitated
7. customThe water layer was removed
8. washthe organic layer was washed with water (144 kg)
9. additionThe organic layer was treated with a solution of 85% phosphoric acid/H2O (15.6 kg/173 kg)
10. stirringThe mixture was agitated
11. customthe layers were separated
12. additionThe organic layer was treated with a solution of 85% phosphoric acid/H2O (4.03 kg/28.8 kg)
13. stirringThe mixture was agitated
14. customthe layers were separated
15. washwashed with isopropyl acetate (28.8 kg)
16. customAfter layer separation, isopropyl acetate (144 kg)
17. additionwas added to the aqueous layer
18. additionfollowed by slow addition of a solution of potassium carbonate/water (35.1 kg/43.2 kg)
19. additionwhile mixing
20. customThe layers were separated
21. concentrationthe organic layer was concentrated by vacuum distillation
22. washthe plug eluted
23. concentrationthe solution was concentrated initially by atmospheric pressure distillation
24. distillationfollowed by vacuum distillation