反应详情

To a degassed suspension of methyl 2-amino-6-chloro-3-pyridinecarboxylate (2.24 g, 12 mmol) and tributyl({[(methyloxy)methyl]oxy}methyl)stannane (4.82 g, 13.2 mmol) in anhydrous toluene (30 mL), split between two vessels, was added chloro(di-2-norbonylphosphino)(2′-dimethylamino-1,1′-biphenyl-2-yl)palladium (II) (325 mg, 0.598 mmol) to each vessel. The reaction vessels were sealed and heated in a Biotage Initiator using initial absorption normal to 170° C. for 1 hour. Analysis by LCMS indicated the reaction to be approximately 20-25% complete. The reaction was mixture was poured into a biphasic mixture of ethyl acetate (200 mL) and aqueous potassium flouride solution (3 g in 200 mL). The mixture was stirred rapidly for 10 min before filtering though celite (10 g). The filtrate was separated and the aqueous layer was back extracted with ethyl acetate (100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was dissolved in toluene (30 mL) and treated again with tributyl({[(methyloxy)methyl]oxy}methyl)stannane (4.82 g, 13.2 mmol) and chloro(di-2-norbonylphosphino)(2′-dimethylamino-1,1′-biphenyl-2-yl)palladium (II) (0.67 g, 1.195 mmol). The resulting mixture was split into two and degassed. The reaction vessels were sealed and heated in a Biotage Initiator using initial absorption normal to 170° C. for 1 hour. Analysis by LCMS indicated all starting material had been consumed. The reaction mixture was poured into a biphasic mixture of ethyl acetate (200 mL) and aqueous potassium flouride solution (3 g in 200 mL). The mixture was stirred rapidly and then filtered through a pad of celite (10 g). The resultant biphasic filtrate was separated and the aqueous layer was back extracted with ethyl acetate (150 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give a yellow slurry. This material was dissolved in DCM/methanol and purified by SPE on a sulphonic acid cartridge (SCX, 50 g) using first DCM/methanol followed by 2M ammonia/methanol. The appropriate fractions were combined and evaporated in vacuo to give crude product (2.1 g) which was dissolved in DCM and purified on silica (100 g) using a 0-50% ethyl acetate-cyclohexane gradient over 60 min. The appropriate fractions were combined and evaporated in vacuo to give a sticky yellow solid which was triturated with petroleum ether (40-60), collected by filtration and dried in vacuo to give the title compound (500 mg).

1. customsplit between two vessels
2. customThe reaction vessels
3. customwere sealed
4. temperatureheated in a Biotage Initiator
5. customabsorption normal to 170° C. for 1 hour
6. customthe reaction
7. filtrationbefore filtering though celite (10 g)
8. customThe filtrate was separated
9. extractionthe aqueous layer was back extracted with ethyl acetate (100 mL)
10. dry with materialThe combined organic extracts were dried (Na2SO4)
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. dissolutionThe residue was dissolved in toluene (30 mL)
14. customThe resulting mixture was split into two
15. customdegassed
16. customThe reaction vessels
17. customwere sealed
18. temperatureheated in a Biotage Initiator
19. customabsorption normal to 170° C. for 1 hour
20. customhad been consumed
21. additionThe reaction mixture was poured into a biphasic mixture of ethyl acetate (200 mL) and aqueous potassium flouride solution (3 g in 200 mL)
22. stirringThe mixture was stirred rapidly
23. filtrationfiltered through a pad of celite (10 g)
24. customThe resultant biphasic filtrate was separated
25. extractionthe aqueous layer was back extracted with ethyl acetate (150 mL)
26. dry with materialThe combined organic extracts were dried (Na2SO4)
27. filtrationfiltered
28. concentrationconcentrated in vacuo
29. customto give a yellow slurry
30. custompurified by SPE on a sulphonic acid cartridge (SCX, 50 g)
31. customevaporated in vacuo
32. customto give crude product (2.1 g) which
33. custompurified on silica (100 g)
34. customover 60 min
35. customevaporated in vacuo
36. customto give a sticky yellow solid which
37. customwas triturated with petroleum ether (40-60)
38. filtrationcollected by filtration
39. customdried in vacuo