反应详情

The acid was synthesised as reported in US 2005/0054733A1 and described below 1-bromo-3,4-difluoro-2-methylbenzene (I67) (8.07 g, 39.0 mmol) was cooled to 0° C. in tetrahydrofuran (THF) (40 mL). Isopropylmagnesium chloride (29.2 mL, 58.5 mmol) was added dropwise and the solution stirred at room temperature overnight. The solution was cooled to 0° C. and gassed slowly with Carbon dioxide (excess) for 1 hour. The cooling was removed and gassing continues for 4 hours before allowing the solution to stand at room temperature overnight. Water (10 ml) was added and the solvents removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and 2N Hydrochloric acid (25 mL). The aqueous phase was extracted with ethyl acetate (5×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to a crude solid that was recrystalised from cyclohexane to afford product in 4.68 g.

1. customThe acid was synthesised
2. temperatureThe solution was cooled to 0° C.
3. customThe cooling was removed
4. waitgassing continues for 4 hours
5. waitto stand at room temperature overnight
6. additionWater (10 ml) was added
7. customthe solvents removed in vacuo
8. customThe residue was partitioned between ethyl acetate (50 mL) and 2N Hydrochloric acid (25 mL)
9. extractionThe aqueous phase was extracted with ethyl acetate (5×50 mL)
10. washThe combined organic extracts were washed with water (50 mL), brine (50 mL)
11. dry with materialdried over anhydrous magnesium sulfate
12. concentrationconcentrated in vacuo to a crude solid
13. customthat was recrystalised from cyclohexane
14. customto afford product in 4.68 g