Benzo(B)Thiophene → Benzo[b]thiophen-2-yl(5-bromo-2-fluorophenyl)methanol

Participants

Reaction Conditions

Reaction Steps

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)].

Provenance & Evidence