Formic Acid → 4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydro-furo[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]benzonitrile

Temperature

40 °C

A flask was charged with 4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-6-chloro-1-(2-trimethylsilylethoxymethyl)-imidazo[4,5-b]pyridin-5-yl]benzonitrile (209.8 mg, 0.397 mmol), formic acid (3.6 ml, 94 mmol), and saturated aqueous KHSO4 (0.4 ml). The reaction mixture was heated to 40° C. for 16 h. Then the reaction mixture was cooled to room temperature before being cooled to 0° C. in an ice bath. A 50% weight solution of aqueous NaOH (5.3 ml, 200.7 mmol) was added to the reaction mixture, which solidified after being removed from the ice bath and was allowed to warm to room temperature. The reaction mixture was diluted with THF (2.0 ml) and water (10.0 ml) to give a hazy biphasic mixture with a pH of 14 that was stirred at room temperature for 30 min. The pH was adjusted to 5 by the addition of 2 N aqueous HCl. The reaction mixture was partitioned between EtOAc (50 ml) and water (20 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over Na2SO4, filtered, and evaporated under reduced pressure to give a light pink residue. This material was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient, followed by a 100% acetonitrile+0.05% TFA flush. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C19H15ClN4O4 398.08 observed m/e: 399.09 (M+H)+ (Rt 1.07/2 min); 1H NMR δ (ppm) (CD3OD): 7.84 (s, 1H), 7.84 (qt, J=8.3 Hz, 4H), 5.54 (qt, J=5.3 Hz, 1H), 4.96 (t, J=5.2 Hz, 1H), 4.46 (t, J=5.0 Hz, 1H), 4.25-4.30 (m, 1H), 4.16 (dd, J=5.6 Hz, J=10.2, 1H), 4.11 (dd, J=4.7 Hz, J=10.2 Hz, 1H), 3.89 (dd, J=7.0 Hz, J=8.1 Hz, 1H), 3.59 (t, J=8.6 Hz, 1H).

1. temperatureThen the reaction mixture was cooled to room temperature
2. temperaturebefore being cooled to 0° C. in an ice bath
3. customafter being removed from the ice bath
4. temperatureto warm to room temperature
5. additionThe reaction mixture was diluted with THF (2.0 ml) and water (10.0 ml)
6. customto give a hazy biphasic mixture with a pH of 14 that
7. customThe reaction mixture was partitioned between EtOAc (50 ml) and water (20 ml)
8. extractionThe aqueous layer was extracted with EtOAc (2×50 ml)
9. washwashed with brine (1×30 ml)
10. dry with materialdried over Na2SO4
11. filtrationfiltered
12. customevaporated under reduced pressure
13. customto give a light pink residue
14. customThis material was purified by preparative HPLC reverse phase (C-18)
15. washeluting with a 20%-100% acetonitrile/water+0.05% TFA gradient
16. customflush
17. customevaporated under reduced pressure

ORD record

ord-952b5104670b4867b85642750fc6e792

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09290517B2