Sodium Carbonate → 7-Thiazol-2-yl-imidazo[1,2-a]pyridine

In a 500 mL round bottom flask, stir a suspension of 7-chloro-imidazo[1,2-a]pyridine (7.5 g, 49.2 mmol) in 250 mL 1,4-dioxane with bis(pinacolato)diboron (13.74 g, 54.1 mmol, 1.1 eq), potassium acetate (7.24 g, 73.8 mmol, 1.5 eq) and tricyclohexylphosphine (1.66 g. 5.9 mmol, 0.12 eq). Deoxygenate the resulting slurry with two cycles of evacuation and bubbling nitrogen through the slurry for 10 minutes each. Fit the flask with a reflux condenser and add tris(dibenzylidineacetone)dipalladium (0) (2.25 g, 2.45 mmol, 0.05 eq) and stir the mixture under nitrogen at 80° C. overnight. Filter the hot mixture over a ˜1 cm pad of celite, wash with 50 mL 1,4-dioxane, then concentrate the combined filtrate and wash to give a brown pasty solid. Suspend a portion of the solid (32.8 mmol) in 80 mL of dioxane, combine with 41.25 mL of 2 M aqueous sodium carbonate (82.5 mmol, 2.5 eq) and 2-bromothiazole (4.38 mL, 8.07 g, 49.2 mmol, 1.5 eq), then deoxygenate twice via evacuation and bubbling nitrogen through the suspension. Add tetrakis (triphenylphosphine) palladium (1.89 g, 1.64 mmol, 0.05 eq), fit the flask with a reflux condenser and stir the mixture under nitrogen at 100° C. overnight. Filter the dark brown-black hot mixture through a 1 cm pad of Celite®, wash with 50 mL dioxane, then apply the combined filtrate and wash equally to three 25 g SCX Mega Bond-Elut™ SCX cartridges (Varian) each pre-washed with 200 mL 1:1 CH2Cl2:MeOH. After loading with vacuum assist, wash each cartridge with 300 mL 1:1 CH2Cl2:MeOH, then elute with 160 mL 1:1 CH2Cl2:2 M NH3-MeOH. Concentrate the combined eluates in vacuo and purify through a 330 g silica gel cartridge using a 0 to 5% methanol gradient in dichloromethane. Concentrate the pooled clean fractions and dry to yield 3 g (45%) of 7-thiazol-2-yl-imidazo[1,2-a]pyridine as a tan solid. MS (ES) mm/z 202, (M+1).

1. customDeoxygenate the resulting slurry with two cycles of evacuation
2. custombubbling nitrogen through the slurry for 10 minutes each
3. stirringstir the mixture under nitrogen at 80° C. overnight
4. filtrationFilter the hot mixture over a ˜1 cm pad of celite
5. washwash with 50 mL 1,4-dioxane
6. concentrationconcentrate the combined filtrate
7. washwash
8. customto give a brown pasty solid
9. customdeoxygenate twice via evacuation
10. custombubbling nitrogen through the suspension
11. stirringstir the mixture under nitrogen at 100° C. overnight
12. filtrationFilter the dark brown-black hot mixture through a 1 cm pad of Celite®
13. washwash with 50 mL dioxane
14. washapply the combined filtrate and wash equally to three 25 g SCX Mega Bond-Elut™ SCX cartridges (Varian)
15. washeach pre-washed with 200 mL 1:1 CH2Cl2
16. washwash each cartridge with 300 mL 1:1 CH2Cl2
17. washMeOH, then elute with 160 mL 1:1 CH2Cl2
18. concentrationConcentrate the combined eluates in vacuo
19. custompurify through a 330 g silica gel cartridge
20. concentrationConcentrate the pooled clean fractions
21. customdry

ORD record

ord-b38e523d7b0c4cf8a2f40e9b018b4ffa

Source dataset

uspto-grants-2010_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07666879B2