Acetic Acid → N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-{2-[(6-methyl-1,3-dihydro-2-benzofuran-5-yl)methyl]-1,3-dithian-2-yl}thiophene-3-sulfonamide

Participants

Reaction Conditions

Reaction Steps

To a mixture of N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-formylthiophene-3-sulfonamide described in Production Example 1-3 (4.9 g, 16 mmol) and dichloromethane (100 mL) was successively added boron trifluoride diethyl etherate (8.1 mL, 64 mmol) and 1,3-propanedithiol (1.9 mL, 19 mmol) under ice cooling, followed by stirring at room temperature for 90 minutes. Water was added under ice cooling to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with brine, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-(1,3-dithian-2-yl)thiophene-3-sulfonamide as a crude product. To a mixture of crude N-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-(1,3-dithian-2-yl)thiophene-3-sulfonamide and tetrahydrofuran (50 mL) was added dropwise n-butyl lithium (9.7 mL, 16 mmol, 1.6 M n-hexane solution) at −78° C., followed by stirring for 20 minutes at an internal temperature of −35° C. The reaction mixture was cooled to −78° C., and 5-(chloromethyl)-6-methyl-1,3-dihydro-2-benzofuran described in Production Example 1-6 (960 mg, 5.3 mmol) was added at that temperature and stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C., and a mixture of acetic acid (0.90 mL, 16 mmol) and tetrahydrofuran (7 mL) was added at that temperature. The reaction mixture was gradually returned to room temperature, water and an aqueous citric acid solution were added at that temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=4:1) to give the title compound (1.6 g, 54% yield).

Provenance & Evidence