Ammonium Chloride → HCID 90409113, compound

Temperature

50 °C

In a three-neck round-bottom flask equipped with a mechanic stirring, an internal thermal couple and an addition funnel, 1-(5-fluoropyridin-2-yl)-1H-imidazo[4,5-c]pyridine (70 g, 326 mmol) was suspended in THF (1.7 L) and then warmed to 50° C. to form a clear solution. The clear solution was cooled to −78° C. and a lot of solid precipitated out. Under N2, MeMgBr (3.0 mol/L in THF, 109 mL, 326 mmol) was added over 30 min while the internal temperature was maintained at <−70° C. After 20 min, the solution of Intermediate 12 (87 g, 359 mmol) in THF (100 mL) was added over 30 min with the internal temperature maintained at <−70° C. The rest of MeMgBr (3.0 mol/L in THF, 130 mL, 390 mmol) was then added over 30 min. The reaction was stirred at −78° C. for 1 hour. The cold bath was removed and the reaction solution was warmed to 0° C. With an ice/water bath, 2 mol/L HCl aqueous solution was slowly added to quench the reaction while the internal temperature was maintained at <5° C. Concentrated NH4Cl aqueous solution was then added until clear phase separation was obtained. The aqueous layer was extracted with EtOAc twice (300 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was recrystallized from hot EtOAc (250 mL)/MTBE (500 mL). The precipitated solid was collected by filtration, washed with cold MTBE (500 mL) to afford Intermediate 245 as a white solid (117 g, 82%). MS-EI (m/z): [M+H]+ observed: 437.0.

1. customIn a three-neck round-bottom flask equipped with a mechanic stirring
2. customto form a clear solution
3. temperatureThe clear solution was cooled to −78° C.
4. customa lot of solid precipitated out
5. temperaturewas maintained at <−70° C
6. temperaturemaintained at <−70° C
7. customThe cold bath was removed
8. temperaturethe reaction solution was warmed to 0° C
9. additionWith an ice/water bath, 2 mol/L HCl aqueous solution was slowly added
10. customto quench
11. customthe reaction while the internal temperature
12. temperaturewas maintained at <5° C
13. customwas obtained
14. extractionThe aqueous layer was extracted with EtOAc twice (300 mL)
15. dry with materialdried over Na2SO4
16. concentrationconcentrated
17. customThe crude product was recrystallized from hot EtOAc (250 mL)/MTBE (500 mL)
18. filtrationThe precipitated solid was collected by filtration
19. washwashed with cold MTBE (500 mL)

ORD record

ord-ad8d5e15c6d24eb0876435d9a7b8a11f

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09066946B2