反应详情

温度

-17.799999237060547 °C

Into a tetrahydrofuran (100 liters) solution of benzo[b]thiophene (17.4 kg) was dropwise added a n-hexane solution (56.2 kg) of n-butyl lithium (15.08%) in an argon atmosphere at −24.2 to −13.5° C., followed by stirring at −22.1 to −13.5° C. for 40 minutes. Into this solution was dropwise added a tetrahydrofuran (18 liters) solution of 5-bromo-2-fluorobenzaldehyde (25.5 kg) at −22.1 to −11.8° C., followed by stirring at −23.5 to −16.1° C. for 2 hours. To the reaction mixture were added water (100 liters), toluene (130 liters) and 38% hydrochloric acid (12.3 kg), and extraction was conducted. The organic layer was washed with water (130 liters) and then subjected to distillation at normal pressure to distill off the solvent until the residue became 100 liters. Toluene (130 liters) was added to the residue and the mixture was subjected to distillation at normal pressure to distil off the solvent until the residue became 100 liters. The operation of adding toluene to the residue and subjecting the mixture to distillation under reduced pressure to distill off the solvent, was repeated twice: Then, n-heptane (310 liters) was added to the residue, followed by heating to dissolve the residue. To the solution was added, as a seed crystal, about 26 g of the 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol produced in the same manner as that shown in the first step of Reference Example 1, followed by stirring at 1.2 to 5.0° C. for 13 hours. The separated-out crystals were collected by filtration, washed twice with a toluene-n-heptane (1:6) mixed solvent (26 liters), and subjected to vacuum drying to obtain, as white crystals, 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol [35.91 kg, yield: 84.8%, purity: 99% (HPLC)].

1. stirringby stirring at −23.5 to −16.1° C. for 2 hours
2. additionTo the reaction mixture were added
3. extractionwater (100 liters), toluene (130 liters) and 38% hydrochloric acid (12.3 kg), and extraction
4. washThe organic layer was washed with water (130 liters)
5. distillationsubjected to distillation at normal pressure
6. distillationto distill off the solvent until the residue
7. additionToluene (130 liters) was added to the residue
8. distillationthe mixture was subjected to distillation at normal pressure
9. customto distil off the solvent until the residue
10. distillationto distillation under reduced pressure
11. distillationto distill off the solvent
12. additionn-heptane (310 liters) was added to the residue
13. temperatureby heating
14. dissolutionto dissolve the residue
15. additionTo the solution was added, as a seed crystal, about 26 g of the 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol
16. customproduced in the same manner as
17. stirringby stirring at 1.2 to 5.0° C. for 13 hours
18. filtrationThe separated-out crystals were collected by filtration
19. washwashed twice with a toluene-n-heptane (1:6)
20. additionmixed solvent (26 liters)
21. customdrying