反应详情

温度

10 °C

A solution of 4-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazole (700 g, 2.74 mol) in THF (1.4 L) was cooled to 15° C. and isopropylmagnesium chloride lithium chloride complex (1.3M in THF, 3.8 L, 4.94 mol) was added slowly while maintaining the reaction temperature below 25° C. The mixture was stirred for 3 hr at 20° C. and a 10° C. solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (610 g, 3.28 mol) in THF (1.4 L) was added dropwise while maintaining an internal temperature below 20° C. The resulting green/brown hazy solution as stirred for 1 hr between 10° C. and 20° C. after which time it was cooled to 10° C. Water (5.6 L) cooled to 10° C. was added slowly to the reaction mixture so that the reaction temperature stayed below 25° C. Celite (1.4 kg) was added followed by 2-methyltetrahydrofuran (7 L) and the mixture was stirred for 15 min at 20° C. The mixture was filtered through Celite and the filter pad was rinsed with 2-methyltetrahydrofuran (8 L). The organic phase was separated and washed with brine (5.6 L) then concentrated under vacuum to a low stir volume. The material was diluted with EtOH (3 L) and reconcentrated. This material was re-dissolved in EtOH (3.5 L) and water (4.2 L) was added over 30 min with strong stirring. The resulting slurry was stirred at 15° C. for 1 hr, filtered and washed with 4 volumes of water. The resulting cake was blown dry then further dried in a vacuum oven at 40° C. to yield 0.4 kg (48%) of Ex 1-Step 1 product as a white solid: APCI MS m/z 303.2 (M+1); 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, J=8.9, 5.6, 2H), 7.70 (s, 1H), 7.03 (dd, J=8.8, 8.8, 2H), 3.90 (s, 3H), 1.29 (s, 12H).

1. temperaturewhile maintaining the reaction temperature below 25° C
2. additionwas added dropwise
3. temperaturewhile maintaining an internal temperature below 20° C
4. additionwas added slowly to the reaction mixture so that the reaction temperature
5. customstayed below 25° C
6. additionCelite (1.4 kg) was added
7. stirringthe mixture was stirred for 15 min at 20° C
8. filtrationThe mixture was filtered through Celite
9. washthe filter pad was rinsed with 2-methyltetrahydrofuran (8 L)
10. customThe organic phase was separated
11. washwashed with brine (5.6 L)
12. concentrationthen concentrated under vacuum to a low stir volume
13. additionThe material was diluted with EtOH (3 L)
14. dissolutionThis material was re-dissolved in EtOH (3.5 L)
15. additionwater (4.2 L) was added over 30 min with strong stirring
16. stirringThe resulting slurry was stirred at 15° C. for 1 hr
17. filtrationfiltered
18. washwashed with 4 volumes of water
19. customThe resulting cake was blown dry
20. customthen further dried in a vacuum oven at 40° C.
21. customto yield 0.4 kg (48%) of Ex 1-Step 1 product as a white solid