Hydrochloric Acid → 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine

To a solution of tert-butyl 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (0.96 g, 2.56 mmol) in MeOH (3 mL) was added HCl in 1,4-dioxane (4 M, 12.8 mL, 51.2 mmol) and the solution was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure and the residue was dissolved in DCM (30 mL). The organic layer was washed with saturated aqueous NaHCO3 solution (30 mL), dried over Na2SO4 and the solvent removed under reduced pressure to give 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine. This amine was dissolved in MeOH/THF (1:1, 50 mL) and treated with formaldehyde (38% in water, 0.45 mL, 6.21 mmol). After 5 min, sodium cyanoborohydride (0.39 g, 6.21 mmol) was added portionwise and the resulting mixture stirred for 5 hr. Additional formaldehyde (38% in water, 0.45 mL, 6.21 mmol) and sodium cyanoborohydride (0.39 g, 6.21 mmol) were added and the resulting mixture was stirred for 60 hr. The solvents were removed under reduced pressure and the crude was purified via silica gel column chromatography (0-10% MeOH/DCM) to give 6,6-difluoro-N,N-dimethyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine as a yellow oil (0.64 g, 82% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.07-8.03 (m, 1H), 3.82 (s, 3H), 3.70-3.57 (m, 2H), 3.42-3.29 (m, 1H), 3.24-3.05 (m, 1H), 3.04-2.98 (m, 1H), 2.51-2.40 (m, 1H), 2.35-2.29 (m, 6H), 2.20-2.01 (m, 2H), 1.97-1.82 (m, 1H).

1. customThe solvents were removed under reduced pressure
2. dissolutionthe residue was dissolved in DCM (30 mL)
3. washThe organic layer was washed with saturated aqueous NaHCO3 solution (30 mL)
4. dry with materialdried over Na2SO4
5. customthe solvent removed under reduced pressure

ORD record

ord-bb6b4f8ac987493faaa70de82084f557

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08614206B2