Formic Acid → (3R,3aR,6R,6aR)-6-[[6-chloro-5-[4-[4-(1,2,4-triazol-1-yl)phenyl]phenyl]-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol

Participants

Reaction Conditions

Reaction Steps

A mixture of formic acid (3 mL, 68.8 mmol), saturated aqueous KHSO4 (0.33 mL, 1.777 mmol), and (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-[4-(1,2,4-triazol-1-yl)phenyl]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 (1.15 g, 1.777 mmol). The reaction mixture was stirred at 60° C. overnight, and then cooled to 0° C. in an ice bath. The pH of the reaction mixture was adjusted to pH>11 through the addition of NaOH (2.75 g, 68.8 mmol) in water (5 mL). THE (5 mL) was added to the reaction mixture, and 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 pH 6 through the addition of concentrated HCl. The biphasic mixture was separated. The organic layer and the resulting white precipitate that had formed were concentrated under reduced pressure, redissolved in DMSO, and filtered before being purified by preparative HPLC Reverse phase (C-18), using a 19×100 mm Sunfire™ column and eluting with a 10%-90% acetonitrile/water gradient+0.05% TFA followed by a 90% acetonitrile/water+0.05% TFA flush. The desired fractions were combined, and evaporated under reduced pressure. The resulting residue was washed with MeOH and lyophilized from acetonitrile and water to afford the title compound as a white solid. LC-MS: calculated for C26H21ClN6O4 516.13 observed m/e: 516.85 (M+H)+ (Rt 1.11/2 min); 1H NMR δ (ppm) (CD3OD): 9.17 (s, 1H), 8.21 (s, 1H), 7.82-7.97 (m, 4H), 7.78-7.80 (m, 5H), 5.56 (qt, J=5.5 Hz, 1H), 4.98 (t, J=5.3 Hz, 1H), 4.49 (t, J=5 Hz, 11H), 4.28-4.32 (m, 1H), 4.19 (dd, J=6.0 Hz, 10.0 Hz, 1H), 4.12 (dd, J=5.0 Hz, 10.0 Hz, 1H), 3.92 (dd, J=7.0 Hz, 8.0 Hz, 1H), 3.62 (t, J=8.8 Hz, 1H).

Provenance & Evidence