反应详情

温度

30 °C

To the resultant tributyl tin azide solution in methylene chloride, N-[(2′-cyanobiphenyl-4-yl)-methyl]-N-valeryl-(L)-valine methyl ester (28.3 g) and o-xylene (85 ml) were added and heated to reflux. The reaction mass was maintained at reflux for about 6 hours, 15 minutes and then cooled to about 30° C. 11.7 g of lithium hydroxide in water (198 ml) was added and stirred for about 10 hours at 28-30° C. Reaction completion was confirmed by thin layer chromatography and the organic and aqueous layers were separated. The aqueous layer was washed twice with toluene (2×28.3 ml). To the aqueous layer was added dichloromethane (28.3 ml) and the pH was adjusted to 6.7 using a 20% aqueous acetic acid (32 ml) solution. The aqueous layer was separated and washed with dichloromethane (28.3 ml). The aqueous layer was separated and 113.2 ml of dichloromethane was added. The pH of the reaction mass was adjusted to 5 using acetic acid (8.2 ml). The reaction mixture was stirred for 15 minutes and the organic and aqueous layers were separated. The aqueous layer was again extracted with dichloromethane (113.2 ml). The combined organic layers were washed with water (113.2 ml) and then with a solution of sodium chloride (5.7 g) in water (113.2 ml) followed by a further wash with water (113.2 ml). The organic layer was concentrated at atmospheric pressure and about 90% of the solvent was distilled off at 42° C. To the residual mass cyclohexane (56.6 ml) was added and concentrated under reduced pressure at about 55° C. to obtain a residue. The residue was cooled to 30° C.; 113.2 ml of cyclohexane was added to the residue and stirred for about 55 minutes at 28-30° C. The resultant solid was filtered and washed with cyclohexane (28.3 ml). The obtained solid was dried at about 50° C. for about 6 hours to give 22.3 g of the crude valsartan. (Purity by HPLC 98.75 area-%)

1. temperatureheated to reflux
2. temperatureThe reaction mass was maintained
3. temperatureat reflux for about 6 hours, 15 minutes
4. customReaction completion
5. customthe organic and aqueous layers were separated
6. washThe aqueous layer was washed twice with toluene (2×28.3 ml)
7. additionTo the aqueous layer was added dichloromethane (28.3 ml)
8. customThe aqueous layer was separated
9. washwashed with dichloromethane (28.3 ml)
10. customThe aqueous layer was separated
11. addition113.2 ml of dichloromethane was added
12. stirringThe reaction mixture was stirred for 15 minutes
13. customthe organic and aqueous layers were separated
14. extractionThe aqueous layer was again extracted with dichloromethane (113.2 ml)
15. washThe combined organic layers were washed with water (113.2 ml)
16. washa further wash with water (113.2 ml)
17. concentrationThe organic layer was concentrated at atmospheric pressure and about 90% of the solvent
18. distillationwas distilled off at 42° C
19. additionTo the residual mass cyclohexane (56.6 ml) was added
20. concentrationconcentrated under reduced pressure at about 55° C.
21. customto obtain a residue
22. temperatureThe residue was cooled to 30° C.
23. stirringstirred for about 55 minutes at 28-30° C
24. filtrationThe resultant solid was filtered
25. washwashed with cyclohexane (28.3 ml)
26. customThe obtained solid was dried at about 50° C. for about 6 hours