反应详情

温度

120 °C

To a solution of methyl 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (72 g, 159 mmol) in dimethyl sulfoxide (1057 mL) was added copper(I) iodide (60.4 g, 317 mmol) and isopropyl sulfinic acid sodium salt (41.3 g, 317 mmol). The mixture was evacuated and purged with N2 three times and then heated at 120° C. for 6 h, then cooled to 65° C. Stirring was continued at 65° C. overnight then cooled to room temperature and MeI (39.6 mL, 634 mmol) was added. After stirring for 1 h, the mixture was diluted with DCM (750 mL) and water (1 L), followed by vigorous stirring for 30 min. The mixture was then filtered over celite and washed with DCM. The two layers were separated and the aqueous layer was extracted twice with DCM. The DCM extracts were washed 2× brine, dried over Na2SO4, filtered and concentrated to afford a thick dark residue. To the residue was added MeOH (500 mL) and the solvent was removed under reduced pressure until a precipitate formed. This solution was then heated to reflux with stirring and then allowed to cool slowly overnight. The following day, the mixture was filtered and washed with MeOH (100 mL) to give 44 g of an off white solid. The filtrate was concentrated and the process was repeated to give an additional 20 g. The resulting off white solids were a mixture of product, the acid of the product, and some unreacted starting material. The 44 g crop was dissolved in DCM (500 mL) and washed with 2N NaOH (400 mL). The DCM was separated and the aqueous layer extracted 2 times with DCM (100 ml). The combined DCM extracts were dried over Na2SO4 and concentrated under reduced pressure to afford a light yellow residue. The same procedure was repeated with the 20 g crop. This process removed the acid from the mixture. The first residue was dissolved in DCM (100 mL) and this mixture was heated to reflux and hexanes (500 mL) was added. The mixture was again heated to reflux making sure all the material was in solution. The solution was allowed to stir at reflux without a condenser. This reduced the amount of DCM in the solution allowing the product to crystallize. Once solid material began to appear in the solution, the solution was allowed to slowly cool to room temperature then filtered and washed with hexanes. The same procedure was repeated with the other residue. The two solids were combined in a 1 L flask and the DCM/Hex procedure was repeated. The filter cake was transferred into a 1 L flask and dried under reduced pressure to afford methyl 3-methyl-6-[(1-methylethyl)sulfonyl]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (53 g, 69% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.99-8.05 (m, 2H), 7.92 (d, J=8.03 Hz, 1H), 7.76-7.84 (m, 2H), 4.09 (s, 6H), 3.83 (quin, J=6.78 Hz, 1H), 2.37 (s, 3H), 1.21 (s, 3H), 1.20 (s, 3H); MS (m/z) 482.1 (M+H+).

1. customThe mixture was evacuated
2. custompurged with N2 three times
3. temperaturecooled to 65° C
4. temperaturethen cooled to room temperature
5. stirringAfter stirring for 1 h
6. stirringby vigorous stirring for 30 min
7. filtrationThe mixture was then filtered over celite
8. washwashed with DCM
9. customThe two layers were separated
10. extractionthe aqueous layer was extracted twice with DCM
11. washThe DCM extracts were washed 2× brine
12. dry with materialdried over Na2SO4
13. filtrationfiltered
14. concentrationconcentrated
15. customto afford a thick dark residue
16. customthe solvent was removed under reduced pressure until a precipitate
17. customformed
18. temperatureThis solution was then heated
19. temperatureto reflux
20. stirringwith stirring
21. temperatureto cool slowly overnight
22. filtrationThe following day, the mixture was filtered
23. washwashed with MeOH (100 mL)
24. customto give 44 g of an off white solid
25. concentrationThe filtrate was concentrated
26. customto give an additional 20 g
27. additiona mixture of product
28. washwashed with 2N NaOH (400 mL)
29. customThe DCM was separated
30. extractionthe aqueous layer extracted 2 times with DCM (100 ml)
31. dry with materialThe combined DCM extracts were dried over Na2SO4
32. concentrationconcentrated under reduced pressure
33. customto afford a light yellow residue
34. customThis process removed the acid from the mixture
35. dissolutionThe first residue was dissolved in DCM (100 mL)
36. temperaturethis mixture was heated
37. temperatureto reflux
38. additionhexanes (500 mL) was added
39. temperatureThe mixture was again heated
40. temperatureto reflux
41. stirringto stir
42. temperatureat reflux without a condenser
43. customto crystallize
44. temperatureto slowly cool to room temperature
45. filtrationthen filtered
46. washwashed with hexanes
47. customThe two solids were combined in a 1 L flask
48. customThe filter cake was transferred into a 1 L flask
49. customdried under reduced pressure