Sodium Carbonate → HCID 59137470, compound

Temperature

90 °C

A mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (53 mg, 0.25 mmol), 5-(5-bromo-2-(4-fluorophenyl)-1H-imidazol-4-yl)-3-methoxypyridin-2-amine (123 mg, 0.25 mmol; prepared similarly as per Example 2, Steps 2-3), and aqueous 2.0 M Na2CO3 solution (0.5 mL, 1.0 mmol) in DME (3 mL) was sparged with Ar for 5 min. A catalytic amount of Pd(PPh3)4 was added and the mixture was purged with Ar again. Then the reaction was heated to and maintained at 90° C. for 16 h. The reaction mixture was allowed cool to rt and partitioned between EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc (2×). The combined organic layers were dried (Na2SO4) and concentrated. The resulting residue was dissolved in dry MeOH (5 mL) and treated with Pd/C (10% w/w, 5.7 mg, 0.005 mmol). The reaction mixture was placed and maintained under a H2 atmosphere for 2 d. The reaction was then filtered through Celite, the filter cake was washed thoroughly with EtOAc. The combined filtrate was concentrated and the resulting residue was purified by flash chromatography (SiO2, 50:50-0:100 hexanes-EtOAc). The isolated material was treated with 3 N HCl at 60° C. for 1 h. The reaction was allowed to cool to rt and was directly purified on reverse phase HPLC, as after freeze drying, provided 6.0 mg of 5-(2-(4-fluorophenyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-4-yl)-3-methoxypyridin-2-amine as the TFA salt: LCMS (m/z): 369.0 (MH+), tR=0.44 min

1. customwas sparged with Ar for 5 min
2. additionA catalytic amount of Pd(PPh3)4 was added
3. customthe mixture was purged with Ar again
4. temperatureThen the reaction was heated to and
5. temperatureThe reaction mixture was allowed cool to rt
6. custompartitioned between EtOAc and water
7. customThe layers were separated
8. extractionthe aqueous phase was extracted with EtOAc (2×)
9. dry with materialThe combined organic layers were dried (Na2SO4)
10. concentrationconcentrated
11. dissolutionThe resulting residue was dissolved in dry MeOH (5 mL)
12. temperaturemaintained under a H2 atmosphere for 2 d
13. filtrationThe reaction was then filtered through Celite
14. washthe filter cake was washed thoroughly with EtOAc
15. concentrationThe combined filtrate was concentrated
16. customthe resulting residue was purified by flash chromatography (SiO2, 50:50-0:100 hexanes-EtOAc)
17. additionThe isolated material was treated with 3 N HCl at 60° C. for 1 h
18. temperatureto cool to rt
19. customwas directly purified on reverse phase HPLC
20. customas after freeze drying

ORD record

ord-8fb61e9297d5444996723c60206c4462

Source dataset

uspto-grants-2014_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08865732B2