Potassium Phosphate, Tribasic → 4'-(6-chloro-2-(((3R,5S,6R)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-2-fluoro-[1,1'-biphenyl]-4-carbonitrile

Temperature

80 °C

Placed 4-bromo-3-fluorobenzonitrile (15 mg, 0.075 mmol) and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (6 mg, 0.012 mmol) into a reaction vessel in a dry-glove box. Then 6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano-[3,2-d][1,3]dioxin-7-yl)oxy)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (45 mg, 0.062 mmol) was added as a solution in anhydrous dioxane (0.50 mL) which had been degassed. To this mixture was added a solution of degassed, aqueous 1N K3PO4 (0.19 mL, 0.19 mmol). The reaction vessel was sealed and heated to 80° C. with stirring. After 16 hours, the mixture was allowed to cool to room temperature, then diluted with DCM (2.0 mL) and water (1.0 mL), and vigorously stirred for 30 minutes. The organic layer was separated and concentrated under reduced pressure. The resultant oil was dissolved in DCM (1.0 mL), and SiliaMetS® Dimercaptotriazine (100 mg) was added. The resulting suspension was stirred for 2 hours at 35° C. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The resultant residue was dissolved in DCM (0.50 mL) and TFA (0.50 mL) and stirred at room temperature. After 3 hours the mixture was concentrated under reduced pressure. The resultant oil was dissolved in methanol (0.50 mL), then a 5N aqueous solution of NaOH (0.10 mL) was added and the mixture was allowed to stir at room temperature. After 15 minutes the solution was acidified with a few drops of formic acid and diluted with DMSO. The resulting mixture was filtered to remove solids and purified via reverse phase preparatory HPLC using MeCN/water/formic acid as the mobile phase. The fractions containing product were combined and concentrated under reduced pressure to provide the title compound as a white solid. LC-MS: calculated for C25H20ClFN4O4 494.12, observed m/e: 495.12 (M+H)+ (Rt 0.48/2 min).

1. customhad been degassed
2. additionTo this mixture was added a solution
3. customof degassed
4. customThe reaction vessel was sealed
5. temperatureto cool to room temperature
6. stirringvigorously stirred for 30 minutes
7. customThe organic layer was separated
8. concentrationconcentrated under reduced pressure
9. dissolutionThe resultant oil was dissolved in DCM (1.0 mL)
10. additionSiliaMetS® Dimercaptotriazine (100 mg) was added
11. stirringThe resulting suspension was stirred for 2 hours at 35° C
12. temperatureAfter cooling to room temperature
13. filtrationthe mixture was filtered
14. concentrationconcentrated under reduced pressure
15. dissolutionThe resultant residue was dissolved in DCM (0.50 mL)
16. stirringTFA (0.50 mL) and stirred at room temperature
17. concentrationAfter 3 hours the mixture was concentrated under reduced pressure
18. dissolutionThe resultant oil was dissolved in methanol (0.50 mL)
19. additiona 5N aqueous solution of NaOH (0.10 mL) was added
20. stirringto stir at room temperature
21. waitAfter 15 minutes the solution was acidified with a few drops of formic acid
22. additiondiluted with DMSO
23. filtrationThe resulting mixture was filtered
24. customto remove solids
25. custompurified via reverse phase preparatory HPLC
26. additionThe fractions containing product
27. concentrationconcentrated under reduced pressure

ORD record

ord-05f43e98629a4a68a3141e76ccaff530

Source dataset

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09382243B2