反应详情

温度

25 °C

To a reactor was charged 1-(2-fluoro-6-trifluoromethyl-benzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione 1b (5.0 kg), 2-fluoro-3-methoxyphenylboronic acid (2.58 kg), and acetone (5.5 L). The mixture was agitated and a potassium hydroxide/water solution (2.658 kg/19.0 L) was charged. The reactor contents were degassed for 30-60 min, then the internal temperature was adjusted to 40° C. 1,1-(bis-di-t-butylphosphino)ferrocene palladium dichloride (11.4 g) was added to the reactor and the contents mixed with jacket temperature set to 45° C. until the reaction was complete (2.5 hr). The reaction mixture was cooled to 20-30° C. Celite (1.25 kg) was charged to the reactor and stirred for more than one hour and the mixture was filtered through a Celite pad (0.51 kg). The reactor and Celite cake were washed with acetone/water/KOH (2.6 L/7.5 L/0.38 kg). The filtered solutions were passed through a line filter and added over a period of 1-1.5 hr to a mixture of THF/AcOH/Water (15.0 L/7.53 L/5.0 L) maintained at 62° C. The reactor contents were cooled to 20° C. over 2-3 hr. The mixture was filtered and the cake washed with 60:40 water/MeOH (2×12.6 L) followed by methanol (2×16 L). The solid was dried in a vacuum oven at 65° C. for 18 hr to provide 5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1c (4.312 kg, 87% molar yield) as an off-white solid. LCMS (ESI) m/z 427.1 (MH+). If necessary, the material may be solubilized, re-treated with Celite, and crystallized as above to increase purity.

1. customThe reactor contents were degassed for 30-60 min
2. customwas adjusted to 40° C
3. addition1,1-(bis-di-t-butylphosphino)ferrocene palladium dichloride (11.4 g) was added to the reactor
4. additionthe contents mixed with jacket temperature
5. customset to 45° C. until the reaction
6. custom(2.5 hr)
7. additionCelite (1.25 kg) was charged to the reactor
8. stirringstirred for more than one hour
9. filtrationthe mixture was filtered through a Celite pad (0.51 kg)
10. washThe reactor and Celite cake were washed with acetone/water/KOH (2.6 L/7.5 L/0.38 kg)
11. filtrationfilter
12. additionadded over a period of 1-1.5 hr to a mixture of THF/AcOH/Water (15.0 L/7.53 L/5.0 L)
13. temperaturemaintained at 62° C
14. temperatureThe reactor contents were cooled to 20° C. over 2-3 hr
15. filtrationThe mixture was filtered
16. washthe cake washed with 60:40 water/MeOH (2×12.6 L)
17. customThe solid was dried in a vacuum oven at 65° C. for 18 hr