Water → HCID 86680001, compound

To a solution of 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol (500 mg, 1.78 mmol) in dry DMF (15 mL) cooled to 0° C. was added sodium hydride (60% in mineral oil, 107 mg, 2.67 mmol). After stirring for 15 min, iodomethane (0.17 mL, 2.67 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 90 min. Water (20 mL) was added and the mixture was extracted with EtOAc (200 mL), washed with water (6×20 mL) and brine (20 mL). The organic layer was separated, dried over MgSO4, and concentrated under reduced pressure to give 4-azido-5-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane as a yellow oil (484 mg). A solution of this oil (480 mg, 1.63 mmol) in THF/water (15 mL/3 mL) was treated with triphenylphosphine (426 mg, 1.63 mmol) and the reaction mixture was heated at 60° C. for 5 hr. EtOAc (100 mL) was added and the mixture was washed with saturated aqueous NaHCO3 solution (20 mL). The aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting oil was triturated in Et2O, the resulting solid was filtered off and the filtrate concentrated under reduced pressure to give a yellow oil. To a solution of this oil in dry DCM (20 mL) at 0° C. was added DIPEA (0.85 mL, 4.88 mmol) and trifluoroacetic anhydride (0.27 mL, 1.95 mmol) took place. The reaction mixture was allowed to warm to room temperature and stirred for 4 hr. Water (20 mL) was added and the mixture extracted with DCM (100 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (40-50% EtOAc/isohexane) gave 2,2,2-trifluoro-N-(5-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide as a yellow oil (530 mg). A solution of this oil (520 mg, 1.42 mmol) in MeOH (20 mL) was treated with ammonium formate (900 mg, 14.2 mmol) and 10% palladium on carbon (50 mg). The mixture was heated at 65° C. for 1 hr. After cooling to room temperature the catalyst was filtered off and the filtrate concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 solution (20 mL) and DCM (50 mL). The aqueous layer was extracted with DCM (3×50 mL) and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-methoxyazepan-4-yl)-2,2,2-trifluoroacetamide as an orange foam (486 mg, 82% over 4 steps). 1H NMR (400 MHz, CDCl3) δ 8.85 (br s, 1H), 7.17 (s, 1H), 4.64 (dd, J=14.5, 7.2 Hz, 1H), 3.65 (s, 3H), 3.57-3.36 (m, 2H), 3.41 (s, 3H), 3.15-3.05 (m, 1H), 2.93-2.85 (m, 1H), 2.61 (br s, 2H), 2.43-2.33 (m, 1H), 1.92-1.77 (m, 4H).

1. stirringstirred for 90 min
2. extractionthe mixture was extracted with EtOAc (200 mL)
3. washwashed with water (6×20 mL) and brine (20 mL)
4. customThe organic layer was separated
5. dry with materialdried over MgSO4
6. concentrationconcentrated under reduced pressure

ORD record

ord-42fa54a32e5440108acd33b9503078f4

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08614206B2