Reaction Steps
Combined formic acid (3 mL, 78 mmol), saturated aqueous KHSO4 (0.33 mL, 0.289 mmol), and (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-(4-pyrazol-1-ylphenyl)phenyl]-1-(2-trimethylsilylethoxymethyl)imidazo-[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (187 mg, 0.289 mmol). The reaction mixture was stirred at 60° C. overnight. The reaction mixture was cooled to 0° C. in an ice bath. The pH of the reaction mixture was adjusted to >11 by the addition of NaOH (3120 mg, 78 mmol) in water (5 mL). THF (5 mL) was added to the reaction mixture, then the reaction was removed from the ice bath and allowed to warm to room temperature. After 30 minutes, the pH of the reaction mixture was adjusted to 6 through the addition of concentrated HCl. The reaction mixture was partitioned between EtOAc (100 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (1×50 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting residue was purified by preparative HPLC reverse phase (C-18), using a 19×100 mm Sunfire™ column and eluting with a 10%-90% acetonitrile/water+0.05% TFA gradient followed by a 90% acetonitrile/water+0.05% TFA flush. The desired fractions were combined, evaporated under reduced pressure, and lyophilized from acetonitrile and water to give the title compound as a white solid. LC-MS: calculated for C27H22ClN5O4 515.14 observed m/e: 515.92 (M+H)+(Rt 1.16/2 min); 1H NMR δ (ppm) (CD3OD): 8.30 (d, J=2.5 Hz, 1H), 7.87 (m, 4H), 7.85 (s, 1H), 7.79 (m, 4H), 7.77 (d, J=1.5 Hz, 1H), 6.58 (t, J=2 Hz, 1H), 5.56 (qt, J=5 Hz, 11H), 4.99 (t, J=5.3 Hz, 1H), 4.49 (t, J=5.3 Hz, 1H), 4.28-4.31 (m, 1H), 4.19 (dd, J=5.5 Hz, 10.5 Hz, 1H), 4.12 (dd, J=4.5 Hz, 10 Hz, 1H), 3.92 (t, J=7.5 Hz, 1H), 3.62 (t, J=8.8 Hz, 1H).
