反应详情

温度

50 °C

To a nitrogen purged flask was charged palladium acetate (13.2 g, 59 mmoles, 0.04 eq), racemic BINAP (36.6 g, 59 mmoles, 0.04 eq), followed by 1.9 L toluene. The heterogeneous slurry was heated to 50° C. under nitrogen for 2 hours, cooled to 30° C., then the pyridyl chloride 41 (386.4 g, 1.45 moles, 1.0 eq) and Boc-2,6-difluoroaniline 42 (386.4 g, 1.69 moles, 1.2 eq), and K3PO4 (872 g, 4.1 moles, 2.8 eq) were added all at once followed by a 1.9 L toluene rinse. The heterogeneous reaction mixture was heated to 100° C. overnight and monitored by HPLC. When the reaction showed complete conversion to 43 by HPLC [Tret 41=17 min, Tret 43=20.5 min, Tret 44=17.6 min, monitored at 229 nm] (usually between 18–20 hours) the reaction was cooled to room temperature and the contents diluted with 1.94 L EtOAc. To this was added 1×1.94 L of 6N HCl, and both layers were filtered through celite. The celite wet cake was rinsed with 2×1.9 L EtOAc. The layers were separated and the organic layer washed with 1×1.9 L of brine, dried (MgSO4), filtered and concentrated to a brown, viscous oil. To remove the Boc-protecting group, the oil was dissolved in 1.94 L of methylene chloride and 388 mL TFA was added. The reaction was stirred overnight to facilitate Boc removal. The volatiles were removed in vacuo, EtOAc (1.9 L) and sufficient quantity of 1 or 6N NaOH was added until the pH was 2–7. Then a sufficient quantity of 5% NaHCO3 was added to bring the pH to 8–9. The organic layer was separated and washed with 1×5% NaHCO3, dried (MgSO4), filtered an concentrated to a brown oil/liquid. The crude oil/liquid was azeodried twice with a sufficient quantity of toluene. At times the free base precipitated out resulting in a slurry. The residue was dissolved in 500 mL toluene and 1.6 L 1N HCl/ether solution was added, which resulted in the solids crashing out. Heat was applied until the homogenized/solids broke up. If necessary, 200 mL of EtOAc can be added to facilitate the break up. After cooling, the solid 44 was isolated by vacuum filtration.

1. temperaturecooled to 30° C.
2. washrinse
3. temperatureThe heterogeneous reaction mixture was heated to 100° C. overnight
4. customby HPLC [Tret 41=17 min, Tret 43=20.5 min, Tret 44=17.6 min, monitored at 229 nm]
5. customusually between 18–20 hours
6. temperaturewas cooled to room temperature
7. additionthe contents diluted with 1.94 L EtOAc
8. additionTo this was added 1×1.94 L of 6N HCl
9. filtrationboth layers were filtered through celite
10. washThe celite wet cake was rinsed with 2×1.9 L EtOAc
11. customThe layers were separated
12. washthe organic layer washed with 1×1.9 L of brine
13. dry with materialdried (MgSO4)
14. filtrationfiltered
15. concentrationconcentrated to a brown, viscous oil
16. customTo remove the Boc-
17. dissolutionthe oil was dissolved in 1.94 L of methylene chloride
18. addition388 mL TFA was added
19. customBoc removal
20. customThe volatiles were removed in vacuo, EtOAc (1.9 L) and sufficient quantity of 1 or 6N NaOH
21. additionwas added until the pH was 2–7
22. additionThen a sufficient quantity of 5% NaHCO3 was added
23. customThe organic layer was separated
24. washwashed with 1×5% NaHCO3
25. dry with materialdried (MgSO4)
26. filtrationfiltered
27. concentrationan concentrated to a brown oil/liquid
28. customAt times the free base precipitated
29. customout resulting in a slurry
30. customwhich resulted in the solids
31. temperatureHeat
32. temperatureAfter cooling