反应详情

温度

55 °C

Methanesulfonic acid (S)-3-tert-butoxycarbonylamino-3-phenyl-propyl ester 1d (19.7 kg), 5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1c (16.5 kg), potassium carbonate (powder, 325 mesh, 13.4 kg) and DMF (101 L) were charged to a reactor. The mixture was stirred at 55° C. After reaction completion, the reactor was cooled to 20° C. and isopropyl acetate (132 L) was charged, followed by water (157 L). After agitation and settling, the layers were separated and the organic layer washed with water (87 L). After agitation and settling, the water layer was removed. To the organic layer was charged methanesulfonic acid (11.2 kg) and the reactor contents were heated to 60° C. for 1-2 hours. The reactor contents were cooled to 20° C. and a solution of potassium carbonate/water (26.8 kg/140 L) was added slowly, agitated, and then allowed to settle prior to separation of layers. The organic layer was treated with a solution of 85% phosphoric acid/H2O (22.6 kg/236 kg). The mixture was agitated, allowed to settle, and the layers were separated. The aqueous layer was washed with isopropyl acetate (2×167 kg) and the layers were separated. A solution of potassium carbonate/water (36.1 kg/139 kg) was added slowly to the aqueous layer. Isopropyl acetate (206 kg) was charged; the mixture was agitated and then allowed to settle. The aqueous layer was removed and the organic layer was concentrated to provide 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 (125.4 kg, 30.7 kg contained, 86% yield) for use in the next step. LCMS (ESI) m/z 546.2 (MH+)

1. customAfter reaction completion
2. temperaturethe reactor was cooled to 20° C.
3. customthe layers were separated
4. washthe organic layer washed with water (87 L)
5. customthe water layer was removed
6. additionTo the organic layer was charged methanesulfonic acid (11.2 kg)
7. temperaturethe reactor contents were heated to 60° C. for 1-2 hours
8. temperatureThe reactor contents were cooled to 20° C.
9. additiona solution of potassium carbonate/water (26.8 kg/140 L) was added slowly
10. stirringagitated
11. customto separation of layers
12. additionThe organic layer was treated with a solution of 85% phosphoric acid/H2O (22.6 kg/236 kg)
13. stirringThe mixture was agitated
14. customthe layers were separated
15. washThe aqueous layer was washed with isopropyl acetate (2×167 kg)
16. customthe layers were separated
17. additionA solution of potassium carbonate/water (36.1 kg/139 kg) was added slowly to the aqueous layer
18. additionIsopropyl acetate (206 kg) was charged
19. stirringthe mixture was agitated
20. customThe aqueous layer was removed
21. concentrationthe organic layer was concentrated