Diisopropylethylamine → tert-butyl N-(2-(2,6-difluorophenyl)-4-((1-methyl-5-(2-((2,2,2-trifluoroacetyl)amino)-8-oxabicyclo[3.2.1]octan-5-yl)pyrazol-4-yl)carbamoyl)thiazol-5-yl)carbamate

Participants

Reaction Steps

To a solution of 2,2,2-trifluoro-N-(5-fluoro-2-hydroxy-5-(2-methyl-4-nitro-pyrazol-3-yl)cycloheptyl)acetamide (120 mg, 0.32 mmol) in THF (10 mL) and MeOH (10 mL) was added 10% palladium on carbon (12 mg). The reaction mixture was heated at 40° C. under a 400 psi atmosphere of hydrogen for 3 hr, cooled to room temperature, filtered through Celite®, washing with methanol (50 mL) and concentrated under reduced pressure. The procedure was repeated using the same conditions except with additional aqueous HCl (2 M, 2 mL). To a solution of the residue in DCM (20 mL) was added DIPEA (1.00 mL, 5.74 mmol), 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (123 mg, 0.46 mmol) and PyBOP (409 mg, 0.78 mmol) and the mixture was stirred at room temperature for 16 hr. The reaction was quenched with water (20 mL) and extracted with DCM (150 mL). The organic layer was washed saturated solution of NaHCO3 (30 mL) and water (30 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel chromatography (80-100% EtOAc/isohexane) gave tert-butyl N-(2-(2,6-difluorophenyl)-4-((1-methyl-5-(2-((2,2,2-trifluoroacetyl)amino)-8-oxabicyclo[3.2.1]octan-5-yl)pyrazol-4-yl)carbamoyl)thiazol-5-yl)carbamate as an off-white solid (58 mg, 27% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 10.39 (s, 1H), 8.33 (s, 1H), 7.39-7.33 (m, 1H), 7.18-7.10 (m, 2H), 5.91 (d, J=7.7 Hz, 1H), 4.89-4.83 (m, 1H), 4.47-4.38 (m, 1H), 3.86 (s, 3H), 2.47-2.38 (m, 1H), 2.27-1.90 (m, 7H), 1.55 (s, 9H).

Provenance & Evidence