反应详情

温度

20 °C

To a mixture of Intermediate 84 (1000 g, 1.0 eq, 1.0 wt) and tetrabutylammonium bromide (300 g, 0.2 eq, 0.3 wt) in toluene (9.5 L, 9.5 vol) was added 3,4-dichlorobenzyl bromide (0.71 L, 1.05 eq, 0.71 vol), followed by a line rinse with toluene (0.5 L, 0.5 vol). 5M sodium hydroxide (5 L, 5.36 eq, 5 vol) was added and the biphasic mixture was stirred vigorously for 4 hours 30 minutes at 20° C. and sampled for completion by HPLC. Reaction was complete at 3 hours 30 minutes. The mixture was settled and separated. The aqueous phase was back-extracted with toluene (5 L, 5 vol). The combined organic phases were washed with water (2×2 L, 2×2 vol) and concentrated by atmospheric distillation to 3.4 L/3.4 vol. The mixture was cooled to 20° C. over 30 minutes and diluted with propan-2-ol (10 L, 10 vol). 5-6M hydrochloric acid in propan-2-ol (1.4 L, 1.5 eq, 1.40 vol) was added over 10 minutes at 55° C. The solution was stirred at 60° C. for 20 minutes and seeded with a sample of the title compound (0.4 g, 0.0004 wt). The slurry was aged at 60° C. for 30 minutes, cooled to 3° C. over 3 hours 15 minutes and stirred at this temperature for 1 hour 30 minutes. Solids were collected by vacuum filtration, washed with chilled (5° C.) propan-2-ol/toluene (6 L, 5:1 v/v, 6 vol), followed by tert-butylmethylether (2×5 L, 2×5 vol) and dried in vacuo at 40° C. for 16 hours 30 minutes. Yield of the title compound obtained was 1497 g/86% theory yield/150% w/w yield.

1. washrinse with toluene (0.5 L, 0.5 vol)
2. aliquotsampled for completion by HPLC
3. customReaction
4. waitwas complete at 3 hours 30 minutes
5. customseparated
6. extractionThe aqueous phase was back-extracted with toluene (5 L, 5 vol)
7. washThe combined organic phases were washed with water (2×2 L, 2×2 vol)
8. concentrationconcentrated by atmospheric distillation to 3.4 L/3.4 vol. The mixture
9. temperaturewas cooled to 20° C. over 30 minutes
10. additiondiluted with propan-2-ol (10 L, 10 vol)
11. stirringThe solution was stirred at 60° C. for 20 minutes