Ammonium formate → HCID 89456413, compound

Temperature

70 °C

To a solution of Intermediate 17, 2,2,2-trifluoro-N-(3-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide (70 mg, 0.20 mmol) and ammonium formate (101 mg, 1.60 mmol) in MeOH (5 mL) under nitrogen was added 10% palladium on carbon (21 mg, 0.20 mmol). The mixture was heated at 70° C. for 3 hr before being cooled, 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)-3-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide as a red gum (64 mg). A solution of PyBOP (146 mg, 0.28 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (78 mg, 0.22 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)-3-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide (65 mg, 0.20 mmol) and DIPEA (56 μL, 0.32 mmol) in DCM (2 mL) was added and the mixture was stirred at room temperature for 30 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. Purification via silica gel column chromatography (0-100% Et2O/DCM) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(3-fluoro-4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a racemic mixture of four diastereoisomers in the form of a white solid (82 mg). This solid was re-dissolved in a mixture of DCM (12 mL) and TFA (2 mL) and the mixture was stirred at room temperature for 4 hr. The solvent was removed under reduced pressure. The residue was then re-dissolved in 7 N ammonia in MeOH (20 mL) and heated at 55° C. for 24 hr. The solvent was removed under reduced pressure and purification via silica gel column chromatography (0-5% 7 N ammonia in MeOH/DCM) gave two separate pairs of enantiomers of tert-butyl difluorophenyl)-4-(5-(3-fluoro-4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate. One pair of enantiomers 120 was obtained as a white solid (41 mg). 1H NMR (400 MHz, d4-MeOD) δ 7.60 (s, 1H), 7.53-7.43 (m, 1H), 7.15 (t, J=8.8 Hz, 2H), 4.48-4.30 (m, 1H), 3.83-3.72 (m, 3H), 3.57 (d, J=4.4 Hz, 1H), 3.59-3.45 (m, 1H), 3.37-3.29 (m, 2H), 3.14 (td, J=11.4, 5.2 Hz, 1H), 1.95-1.84 (m, 3H), 1.82-1.71 (m, 1H). LCMS (ES+) m/z 466 (M+1).

1. temperaturebefore being cooled
2. filtrationfiltered
3. concentrationconcentrated under reduced pressure
4. customThe residue was partitioned between water (10 mL) and DCM (50 mL)
5. customThe organic layer was separated
6. custompassed through a phase separation cartridge
7. concentrationconcentrated under reduced pressure

ORD record

ord-e909cc01d1a240c89f14efb8a61e7bef

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08614206B2