反应详情

To a suspension of methyl 5-chloroimidazo[1,2-a]pyridine-8-carboxylate (1.115 g, 5.29 mmol) and tributyl({[(methyloxy)methyl]oxy}methyl)stannane (2.03 g, 5.56 mmol) in anhydrous toluene (10 mL) was added chloro(di-2-norbonylphosphino)(2′-dimethylamino-1,1′-biphenyl-2-yl)palladium (II) (300 mg, 0.535 mmol). The reaction vessel was sealed and heated in a Biotage Initiator microwave using initial absorption setting high to 170° C. for 1 hour. After cooling the reaction was poured onto a biphasic mixture of ethyl acetate (100 mL) and an aqueous potassium floride solution (2 g in 100 mL). The mixture was stirred rapidly and filtered through a pad of celite (10 g). The biphasic filtrate was separated and the aqueous layer back extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in DCM and purified on a silica cartridge (100 g) using a 0-15% methanol-DCM gradient over 60 min. The appropriate fractions were combined and evaporated in vacuo to give impure material which was subjected to a second chromatographic purification on silica (100 g) using a 0-100% ethyl acetate-DCM gradient over 40 min followed by a 0-15% methanol-DCM gradient over 40 min. The appropriate fractions were combined and evaporated in vacuo to give still impure methyl 5-({[(methyloxy)methyl]oxy}methyl)imidazo[1,2-a]pyridine-8-carboxylate (302 mg, purity by LCMS/UV ca 65%) which was used directly in the next step.

1. customThe reaction vessel was sealed
2. temperatureheated in a Biotage Initiator microwave
3. customabsorption
4. temperatureAfter cooling the reaction
5. additionwas poured onto a biphasic mixture of ethyl acetate (100 mL)
6. filtrationfiltered through a pad of celite (10 g)
7. customThe biphasic filtrate was separated
8. extractionthe aqueous layer back extracted with ethyl acetate (2×100 mL)
9. dry with materialThe combined organic extracts were dried (Na2SO4)
10. filtrationfiltered
11. concentrationconcentrated in vacuo
12. dissolutionThe residue was dissolved in DCM
13. custompurified on a silica cartridge (100 g)
14. customover 60 min
15. customevaporated in vacuo
16. customto give impure material which
17. customwas subjected to a second chromatographic purification on silica (100 g)
18. customover 40 min
19. waitfollowed by a 0-15% methanol-DCM gradient over 40 min
20. customevaporated in vacuo