Potassium Carbonate → HCID 74983249, compound

To a solution of 2,2,2-trifluoro-N-(5-hydroxy-4-methyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide (200 mg, 0.55 mmol) and ammonium formate (700 mg, 2.74 mmol) in MeOH (10 mL) under nitrogen was added 10% palladium on carbon (50 mg, 0.13 mmol). The mixture was heated at 65° C. for 2 hr before being cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between water (10 mL) and DCM (50 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure to give N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxy-4-methylazepan-4-yl)-2,2,2-trifluoroacetamide as a red gum (140 mg). A solution of PyBOP (330 mg, 0.62 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (160 mg, 0.45 mmol) in DCM (3 mL) was stirred at room temperature for 30 min. A solution of N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxy-4-methylazepan-4-yl)-2,2,2-trifluoroacetamide (140 mg, 0.41 mmol) and DIPEA (140 μL, 0.83 mmol) in DCM (2 mL) was added and the mixture was stirred at room temperature for 18 hr. Additional DCM (50 mL) was added and the mixture washed with water (20 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. The residue was dissolved in a mixture of THF (2 mL), MeOH (2 mL) and water (1 mL) and potassium carbonate (200 mg, 1.44 mmol) was added. The reaction mixture was heated at 60° C. for 18 hr, cooled to room temperature, filtered and concentrated under reduced pressure. The residue was then dissolved in DCM (3 mL) and trifluoroacetic acid (1 mL) added. The mixture was stirred at room temperature for 2 hr, concentrated under reduced pressure and purified via preparative HPLC to give 424 as the monoformate salt as a white solid (5 mg, 2% over three steps). 1H NMR (400 MHz, d4-MeOD) δ 8.56 (s, 1H), 7.57 (s, 1H), 7.53-7.44 (m, 1H), 7.15 (t, J=8.8 Hz, 2H), 3.86-3.72 (m, 5H), 3.45-3.35 (m, 2H), 3.26-3.14 (m, 1H), 2.15-1.90 (m, 4H), 1.46 (s, 3H). LCMS (ES+) m/z 478 (M+1)

1. washthe mixture washed with water (20 mL)
2. customThe organic layer was passed through a phase separation cartridge
3. concentrationconcentrated under reduced pressure
4. additionwas added
5. temperatureThe reaction mixture was heated at 60° C. for 18 hr
6. temperaturecooled to room temperature
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. dissolutionThe residue was then dissolved in DCM (3 mL)
10. additiontrifluoroacetic acid (1 mL) added
11. stirringThe mixture was stirred at room temperature for 2 hr
12. concentrationconcentrated under reduced pressure
13. custompurified via preparative HPLC

ORD record

ord-f8e5b3e042b240b5a831310a85fdde3f

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08614206B2