反应详情

温度

62.5 °C

To a 20 L flask was charged 4-bromo-2-fluoro-6-(methylthio)benzoic acid (1400 g, 1.0 eq) followed by THF (14 L, 10 vol) under nitrogen. To this solution was added borane-dimethyl sulfide complex (802.41 g, 1000 mL) at 25-28° C. over a period of 30-45 min. The reaction temperature was raised to 60-65° C. over a period of 30-45 min and the temperature maintained until HPLC showed <1% of 4-bromo-2-fluoro-6-(methylthio)benzoic acid (˜3-4 h). On completion of the reaction the mixture was cooled to 10-15° C. over a period of 30-40 min. The reaction was then quenched with methanol (2.1 L, 1.5 vol) over a period of 1 to 1½ h at 10-15° C. The reaction mass was then concentrated under vacuum at 40-50° C./0.4 to 0.7 mbar to 1 to 1.5 volumes. The resultant mixture was dissolved in DCM (8.4 L, 6 vol). The organic layer was washed with an ammonium chloride solution (560 g NH4Cl in 2.8 L water, 2 vol). The phases were separated and the organic layer was washed with 10% NaHCO3 solution (2.8 L, 2 vol), saturated brine solution (2.1 L, 1.5 vol) and water (4.2 L, 3 vol). The organic layer was separated and dried over sodium sulfate (700 g). The sodium sulfate was removed by filtration and washed with DCM (2.8 L, 2 vol). The organic layer was concentrated under vacuum at 40-45° C./0.4 to 0.7 mbar to 1 to 1.2 vol to afford the product which was dried under vacuum at 45-50° C./0.4 to 0.7 mbar. The title product was obtained in 90% yield (1200 g) with 90.07 Area %.

1. additionTo this solution was added borane-dimethyl sulfide complex (802.41 g, 1000 mL) at 25-28° C. over a period of 30-45 min
2. temperaturethe temperature maintained until HPLC
3. customOn completion of the reaction the mixture
4. temperaturewas cooled to 10-15° C. over a period of 30-40 min
5. customThe reaction was then quenched with methanol (2.1 L, 1.5 vol) over a period of 1 to 1½ h at 10-15° C
6. concentrationThe reaction mass was then concentrated under vacuum at 40-50° C./0.4 to 0.7 mbar to 1 to 1.5 volumes
7. dissolutionThe resultant mixture was dissolved in DCM (8.4 L, 6 vol)
8. washThe organic layer was washed with an ammonium chloride solution (560 g NH4Cl in 2.8 L water, 2 vol)
9. customThe phases were separated
10. washthe organic layer was washed with 10% NaHCO3 solution (2.8 L, 2 vol), saturated brine solution (2.1 L, 1.5 vol) and water (4.2 L, 3 vol)
11. customThe organic layer was separated
12. dry with materialdried over sodium sulfate (700 g)
13. customThe sodium sulfate was removed by filtration
14. washwashed with DCM (2.8 L, 2 vol)
15. concentrationThe organic layer was concentrated under vacuum at 40-45° C./0.4 to 0.7 mbar to 1 to 1.2 vol
16. customto afford the product which
17. customwas dried under vacuum at 45-50° C./0.4 to 0.7 mbar