HCID 57929876, compound → HCID 68992238, compound

Temperature

-30 °C

In a dry three-neck flask, 3-bromo-2-(2,4-difluorophenyl)-8-methylimidazo[1,2-a]pyrazine (1.00 g, 3.09 mmol, prepared using General Procedure C.1 from 2-(2,4-difluorophenyl)-8-methylimidazo[1,2-a]pyrazine (prepared according to WO 2007/028051, Preparation #K.1) with NBS) was dissolved in THF (10 mL) under an atmosphere of nitrogen. The reaction mixture was cooled to about −30° C. and then i-PrMgCl (2.0 M in THF, 1.90 mL, 3.80 mmol) was added drop-wise. The reaction mixture was stirred at about −30° C. for about 15 min. In a separate dry flask, zinc chloride (0.57 g, 4.2 mmol) was dissolved in THF (5 mL) and cooled to about 0° C. The zinc chloride solution was added dropwise to the heteroaryl Grignard mixture. The reaction mixture was stirred at about −15° C. for about 30 min. A flask containing 6-iodo-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.85 g, 2.9 mmol; Preparation #H.1) and Pd(Ph3P)4 (0.14 g, 0.12 mmol, Strem) in DMF (10 mL) was stirred at about 80° C. until all of the solids were in solution. This solution was poured into the zincate suspension and the mixture was immediately heated to about 50° C. in an oil bath. After heating at about 50° C. for about 18 h, the mixture was cooled to ambient temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (50 mL), washed with water (5×100 mL), washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography using DCM/MeOH (gradient, 100:0 to 95:5) as eluent. The solid was then dissolved with heating in MeOH, sonicated, concentrated under reduced pressure to dryness under reduced pressure, then dried in a heated vacuum oven (about 60° C.) to afford a cream solid as the title compound (0.37 g, 29%): LC/MS (Table 1, Method a) Rt=2.85 min; MS m/z: 406.3 (M+H)+.

1. customIn a separate dry flask
2. temperaturecooled to about 0° C
3. stirringThe reaction mixture was stirred at about −15° C. for about 30 min
4. stirringwas stirred at about 80° C. until all of the solids
5. temperaturethe mixture was immediately heated to about 50° C. in an oil bath
6. temperatureAfter heating at about 50° C. for about 18 h
7. temperaturethe mixture was cooled to ambient temperature
8. concentrationThe reaction mixture was concentrated under reduced pressure
9. dissolutionThe residue was dissolved in DCM (50 mL)
10. washwashed with water (5×100 mL)
11. washwashed with brine (100 mL)
12. dry with materialdried over MgSO4
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. customThe crude material was purified by silica gel flash chromatography
16. dissolutionThe solid was then dissolved
17. temperaturewith heating in MeOH
18. customsonicated
19. concentrationconcentrated under reduced pressure to dryness under reduced pressure
20. customdried in a heated vacuum oven (about 60° C.)

ORD record

ord-22ce26e408244e3a99c4dbfbcd32d8a6

Source dataset

uspto-grants-2012_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08188083B2