Formic Acid → HCID 60167955, compound

Temperature

60 °C

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).

1. temperatureThe reaction mixture was cooled to 0° C. in an ice bath
2. customthe reaction was removed from the ice bath
3. temperatureto warm to room temperature
4. waitAfter 30 minutes
5. additionthe pH of the reaction mixture was adjusted to 6 through the addition of concentrated HCl
6. customThe reaction mixture was partitioned between EtOAc (100 mL) and water (50 mL)
7. extractionThe aqueous layer was extracted with EtOAc (2×100 mL)
8. washwashed with brine (1×50 mL)
9. dry with materialdried over Na2SO4
10. filtrationfiltered
11. customevaporated under reduced pressure
12. customThe resulting residue was purified by preparative HPLC reverse phase (C-18)
13. washeluting with a 10%-90% acetonitrile/water+0.05% TFA
14. customflush
15. customevaporated under reduced pressure

ORD record

ord-7b898c0ca5404a60aaf8f9719032f92d

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08796258B2