反应详情

Another three-necked flask equipped with a thermometer, a nitrogen inlet and a magnetic stirrer was charged at room temperature with 6.7 g (0.0459 moles) of 1-(mercaptomethyl)cyclopropaneacetic acid and 48 ml of NMP under stirring and under nitrogen atmosphere to obtain a solution. 4.5 g of NaOH flakes (0.1125 moles) was added in one portion at room temperature followed by addition of 2.4 ml of water, and stirring was maintained for 1 hour to afford a suspension. The solution of compound (III) in about 50 ml THF, which was kept at 5° C., was added in portions at ambient temperature. After completing the addition, the mixture was stirred for 2 hours and reaction completion was checked by HPLC. 130 ml of toluene was added to the reaction mixture along with 130 ml of 5% sodium chloride solution, and the mixture was stirred for 20 minutes. Then, the layers were separated and the upper organic layer was washed with 130 ml of 5% sodium chloride solution, and the layers were separated. 84 ml of 0.5 M tartaric acid solution was added to the upper layer and the layers were separated. The upper layer was washed with 40 ml of water and again separated. The organic layer was distilled to dryness to afford an oily residue. 90 ml of toluene was added to the residue under stirring to obtain a solution. 3.1 ml of cyclooctylamine (0.0226 moles) was added and stirring was maintained for few minutes and the solution was seeded with crystalline montelukast acid cyclooctyl ammonium salt. Stirring was maintained at room temperature to afford a suspension, which was filtered off to obtain a cake. The cake was washed with toluene and dried at 40° C. in vacuum to afford 9.88 g of dry crude montelukast acid cyclooctyl ammonium salt in 70% yield, having 98% purity (according to HPLC). The crude montelukast cyclooctyl ammonium salt was crystallized from toluene containing about 2% of methanol to obtain a product having 99% purity (according to HPLC). 30 ml of dichloromethane was added followed by addition of 17 ml of 0.5M citric acid solution. The mixture was stirred at room temperature for half an hour to afford a two phase system. The layers were separated and the organic layer (containing the montelukast acid) was washed with 3×15 ml water, the layers were separated and the aqueous layer was removed. 20 ml of water was added under stirring followed by addition of 4 ml of 1M NaOH solution and stirring was maintained for about 5 minutes. The dichloromethane was distilled off at a temperature lower than 35° C. The pH was checked and 1 M NaOH solution was added drop-wise until the pH value was about 10.5. The aqueous layer (containing the desired end product) was freeze-dried to obtain 8.3 g of montelukast sodium in 99% yield having a purity of 99.8% (according to HPLC).

1. customAnother three-necked flask equipped with a thermometer, a nitrogen inlet and a magnetic stirrer
2. customto obtain a solution
3. stirringstirring
4. temperaturewas maintained for 1 hour
5. customto afford a suspension
6. customwas kept at 5° C.
7. additionwas added in portions at ambient temperature
8. additionthe addition
9. stirringthe mixture was stirred for 2 hours
10. customreaction completion
11. stirringthe mixture was stirred for 20 minutes
12. customThen, the layers were separated
13. washthe upper organic layer was washed with 130 ml of 5% sodium chloride solution
14. customthe layers were separated
15. addition84 ml of 0.5 M tartaric acid solution was added to the upper layer
16. customthe layers were separated
17. washThe upper layer was washed with 40 ml of water
18. customagain separated
19. distillationThe organic layer was distilled to dryness
20. customto afford an oily residue
21. stirringunder stirring
22. customto obtain a solution
23. stirringstirring
24. temperaturewas maintained for few minutes
25. stirringStirring
26. customto afford a suspension, which
27. filtrationwas filtered off
28. customto obtain a cake
29. washThe cake was washed with toluene
30. customdried at 40° C. in vacuum
31. customto afford 9.88 g
32. dry with materialof dry crude montelukast acid cyclooctyl ammonium salt in 70% yield
33. customThe crude montelukast cyclooctyl ammonium salt was crystallized from toluene containing about 2% of methanol
34. customto obtain a product
35. stirringThe mixture was stirred at room temperature for half an hour
36. customto afford a two phase system
37. customThe layers were separated
38. additionthe organic layer (containing the montelukast acid)
39. washwas washed with 3×15 ml water
40. customthe layers were separated
41. customthe aqueous layer was removed
42. addition20 ml of water was added
43. stirringunder stirring
44. additionfollowed by addition of 4 ml of 1M NaOH solution
45. stirringstirring
46. temperaturewas maintained for about 5 minutes
47. distillationThe dichloromethane was distilled off at a temperature lower than 35° C
48. addition1 M NaOH solution was added drop-wise until the pH value
49. additionThe aqueous layer (containing the desired end product)
50. customwas freeze-dried