Tetrahydrofuran → 5-(4-amino-1-methyl-1H-pyrazol-5-yl)-8-oxabicyclo[3.2.1]octan-2-ol

Participants

Reaction Conditions

Reaction Steps

To a solution of 5-(4-fluoro-8-oxabicyclo[5.1.0]octan-4-yl)-1-methyl-4-nitro-1H-pyrazole (100 mg, 0.39 mmol) in THF (25 mL) and water (5 mL) was added 10% palladium on carbon (10 mg). The mixture was heated at 40° C. under an atmosphere of H2 (400 psi) for 3 hr. The mixture was filtered through Celite® washing with MeOH (30 mL) and concentrated under reduced pressure to give 5-(4-amino-1-methyl-1H-pyrazol-5-yl)-8-oxabicyclo[3.2.1]octan-2-ol as an orange solid (105 mg, quantitative). This solid (105 mg, 0.44 mmol) was dissolved in DCM (20 mL) and DIPEA (1 mL, 5.74 mmol) was added, followed by 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (161 mg, 0.45 mmol) and PyBOP (535 mg, 1.03 mmol). The reaction mixture was stirred at room temperature for 18 hr before being quenched with water (20 mL), extracted with DCM (100 mL), dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (80-100% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-hydroxy-8-oxabicyclo[3.2.1]octan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a colourless oil (635 mg, 54%). To a solution of this oil (160 mg, 0.28 mmol) in MeOH (5 mL) was added HCl in dioxane (4 M, 3.6 mL, 14.4 mmol). The reaction mixture was stirred at room temperature for 18 hr. The solvents were removed under reduced pressure before being purified via preparative HPLC, then dissolved in CHCl3/MeOH mixture (10 mL) and passed through an SCX cartridge, eluting with 3N NH3 in MeOH. The solvents were removed under reduced pressure to give 106 as a pale pink solid (31 mg, 24% over three steps). 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.25 (s, 1H), 7.32-7.26 (m, 1H), 7.02 (t, J=8.8 Hz, 2H), 6.12 (s, 2H), 4.59-4.55 (m, 1H), 4.12-4.05 (m, 1H), 3.85 (s, 3H), 2.42-2.33 (m, 1H), 2.22-1.89 (m, 6H), 1.62-1.56 (m, 1H), 1.50-1.45 (m, 1H). LCMS (ES+) m/z 462 (M+1).

Provenance & Evidence