반응 #70155

반응 방정식

2-methyltetrahydrofuran

isopropylmagnesium chloride lithium chloride

4-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazole

2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

→

3-(4-fluorophenyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

용매

Water

THF

THF

반응 조건

후처리

1. 1
   온도while maintaining the reaction temperature below 25° C
2. 2
   workup.ADDITIONwas added dropwise
3. 3
   온도while maintaining an internal temperature below 20° C
4. 4
   workup.ADDITIONwas added slowly to the reaction mixture so that the reaction temperature
5. 5
   기타stayed below 25° C
6. 6
   workup.ADDITIONCelite (1.4 kg) was added
7. 7
   workup.STIRRINGthe mixture was stirred for 15 min at 20° C
8. 8
   여과The mixture was filtered through Celite
9. 9
   세척the filter pad was rinsed with 2-methyltetrahydrofuran (8 L)
10. 10
    기타The organic phase was separated
11. 11
    세척washed with brine (5.6 L)
12. 12
    농축then concentrated under vacuum to a low stir volume
13. 13
    workup.ADDITIONThe material was diluted with EtOH (3 L)
14. 14
    workup.DISSOLUTIONThis material was re-dissolved in EtOH (3.5 L)
15. 15
    workup.ADDITIONwater (4.2 L) was added over 30 min with strong stirring
16. 16
    workup.STIRRINGThe resulting slurry was stirred at 15° C. for 1 hr
17. 17
    여과filtered
18. 18
    세척washed with 4 volumes of water
19. 19
    기타The resulting cake was blown dry
20. 20
    기타then further dried in a vacuum oven at 40° C.
21. 21
    기타to yield 0.4 kg (48%) of Ex 1-Step 1 product as a white solid

실험 절차

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).

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