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

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%).

1. stirringthe mixture was stirred for 2 hr
2. stirringthe mixture was stirred for 3 hr
3. extractionthe mixture was extracted with ethyl acetate
4. washThe extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine
5. dry with materialdried over anhydrous magnesium sulfate
6. concentrationconcentrated under reduced pressure
7. customThe residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=3:1)
8. customto give
9. stirringThe obtained mixture was stirred at room temperature for 1 hr
10. concentrationconcentrated under reduced pressure
11. additionSaturated aqueous sodium hydrogen carbonate solution was added to the residue
12. extractionthe mixture was extracted with ethyl acetate
13. washThe extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine
14. dry with materialdried over anhydrous magnesium sulfate
15. concentrationconcentrated under reduced pressure
16. customThe residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=3:1)

ORD record

ord-cad28b98973849d99b911f3c14f551a4

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08933105B2