反应详情

温度

27.5 °C

1.09 kg=0.75 L (1.1 equiv., d=1.453 g/ml) of 5-bromo-2-methoxy pyridine and 3.60 L (6 V) of anhydrous toluene, previously degassed under a nitrogen flow, were loaded into a reactor A previously dried under nitrogen. The mixture was heated to 25-30° C. and added with 5.70 kg (1.485 equiv.) of a solution of Isopropyl magnesium chloride lithium chloride complex (20% wt/wt) in THF over about 1 h. It was stirred at 25-30° C. for at least 8 hours (the reaction may be conducted overnight). The conversion was monitored via HPLC. When the reaction was complete, a mixture of 9.67 g of Pd(dppf)C12 (0.25 mol %), 0.60 kg equal to 0.50 l (1 equiv., d=1.2 g/ml) of 2-chloropyridine and 3.60 l (6 V) of anhydrous toluene, previously degassed under a nitrogen flow, was loaded into a reactor B, previously dried and kept under a flow of nitrogen. The mixture was stirred at 45-50° C. for 30 min. The suspension of Grignard reagent from reactor A was transferred into reactor B over approximately 1 hr, while keeping the T at 45-50° C. Upon completion, stirring was prosecuted for at least 4 hr at 45-50° C. The conversion was monitored in HPLC (>99%; HPLC purity A/A % of the product >94%). When the reaction was complete, the mixture was cooled to 25-30° C., added with 3.60 L (6 V) of purified water carefully, keeping the temperature at 20-25° C., over about 30 min.-1 hr. Stirring was prosecuted for 15 min. The biphasic mixture was filtered on paper and the solid residue was washed with 0.60 L (1 V) of toluene. The filtrate was loaded into the reactor C. The organic phase (containing the reaction product) was separated. 3.60 L (6 V) of purified water were added to the organic phase. Stirring was continued for 15 min, the mixture was left to decant and the phases were separated. The organic phase (containing the reaction product) was recovered. A solution of Hydrochloric acid 4 M, prepared by using 1.41 L (2.35 V) of concentrated hydrochloric acid and 2.06 L (3.44V) of purified water, was added to the organic phase. Stirring was continued for 15 min, the mixture was left to decant and the aqueous acid phase (the product was in aqueous phase) was separated. The acid aqueous phase (containing the product) was washed twice with 1.20 L (2×2V) of MTBE. The aqueous phase was separated and weighed. Determination of the yield in solution of 2-methoxy-5-(pyridine-2-yl)pyridine was made by external standard HPLC analysis (molar yield in solution: 90.3%):

1. customwere loaded into a reactor
2. customA previously dried under nitrogen
3. customthe reaction
4. custompreviously degassed under a nitrogen flow
5. customwas loaded into a reactor
6. customB, previously dried
7. stirringThe mixture was stirred at 45-50° C. for 30 min
8. additionThe suspension of Grignard reagent from reactor
9. customA was transferred into reactor
10. waitB over approximately 1 hr
11. customat 45-50° C
12. stirringUpon completion, stirring
13. waitwas prosecuted for at least 4 hr at 45-50° C
14. temperaturethe mixture was cooled to 25-30° C.
15. additionadded with 3.60 L (6 V) of purified water carefully
16. customat 20-25° C.
17. waitover about 30 min.-1 hr
18. stirringStirring
19. waitwas prosecuted for 15 min
20. filtrationThe biphasic mixture was filtered on paper
21. washthe solid residue was washed with 0.60 L (1 V) of toluene
22. additionThe organic phase (containing the reaction product)
23. customwas separated
24. addition3.60 L (6 V) of purified water were added to the organic phase
25. stirringStirring
26. waitwas continued for 15 min
27. waitthe mixture was left
28. customto decant
29. customthe phases were separated
30. additionThe organic phase (containing the reaction product)
31. customwas recovered
32. customA solution of Hydrochloric acid 4 M, prepared
33. additionwas added to the organic phase
34. stirringStirring
35. waitwas continued for 15 min
36. waitthe mixture was left
37. customto decant
38. customwas separated
39. additionThe acid aqueous phase (containing the product)
40. washwas washed twice with 1.20 L (2×2V) of MTBE
41. customThe aqueous phase was separated