Hydrochloric Acid → 2-chloro-3-(4,4-difluoro-3-methylene-3,4-dihydro-2H-pyrrol-5-yl)pyridine

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Reaction Steps

Under a nitrogen atmosphere, to a solution of diisopropylamine (30.8 g) in anhydrous tetrahydrofuran (300 mL) was added dropwise a 1.61 mol/L hexane solution (160 mL) of n-butyllithium at −78° C., and the mixture was stirred at the same temperature for 15 min. To the obtained solution was added a solution of 2-chloropyridine (30.9 g) in anhydrous tetrahydrofuran (30 mL) at the same temperature over 30 min, and the mixture was stirred for 2 hr. To the obtained suspension was added dropwise a solution of tert-butyl 3,3-difluoro-4-methylene-2-oxopyrrolidine-1-carboxylate (30.1 g) in anhydrous tetrahydrofuran (30 mL) at the same temperature, and the mixture was stirred for 3 hr. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=3:1) to give a mixture of tert-butyl [4-(2-chloropyridin-3-yl)-3,3-difluoro-2-methylene-4-oxobutyl]carbamate and tert-butyl 2-(2-chloropyridin-3-yl)-3,3-difluoro-2-hydroxy-4-methylenepyrrolidine-1-carboxylate (yield 23.8 g). To a solution of the obtained mixture (23.7 g) in acetic acid (70 mL) was added dropwise concentrated hydrochloric acid (18 mL). The obtained mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=3:1) to give the title compound as a yellow oil (yield 12.1 g, 2 step yield 41%).

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