反应详情

Potassium hydroxide (80 mL of a 10% aqueous solution) was added to a mixture of 5-tert-butyl-4-hydroxy-2-methylbenzaldehyde (99.0 g, 515 mmol) in water (180 mL) and THF (135 mL). This mixture was stirred at room temperature and a solution of dimethylthiocarbamoyl chloride (86.1 g) in THF (108 mL) added slowly over a 2 hour period with simultaneous addition of 10% KOH in order to hold the pH of the reaction mixture between 12.0 and 12.3. After approximately 70% of the dimethylthiocarbamoyl chloride-THF solution had been added, vacuum was applied to the reaction mixture to remove THF solvent and thus increase the rate of the bimolecular reaction. During the distillation, the simultaneous additions of 10% KOH and the dimethylthiocarbamoyl chloride-THF solution were continued while maintaining the pH range between 12.0 and 11.6 and the reaction temperature between 23-25° C. The distillation was continued for 10 minutes after all the dimethylthiocarbamoyl chloride-THF solution had been added and then stopped. Stirring at ambient pressure and temperature was continued for another 90 minutes. During this time the pH was stable between 11.6 and 11.75. A solution of ethyl acetate (150 mL) and heptane (150 mL) was added to the reaction mixture and after stirring and settling the layers were separated and the aqueous layer extracted with 1:1 heptane/ethyl acetate (150 mL). The combined organic extracts were extracted with 10% KOH (2×105 mL) and water (2×90 mL) and concentrated to an oil (210 gm). This was diluted with methanol (120 mL). The solution was warmed to 45° C. and water (20 mL) added. The solution was cooled to 25° C. and 50% NaOH (170 mg) was added. The resulting solution was concentrated to an oil (160 gm). This was redissolved in methanol (120 mL) at 50° C. and water (15 mL) added. The solution was cooled slowly with addition of dimethylthiocarbamic acid O-(2-tert-butyl-4-formyl-5-methylphenyl) ester seed crystals. Crystallization began at 43° C. The mixture was stirred and cooled over several hours to −5° C. The mixture was filtered and the solid washed with 4:1 methanol/water (75 mL) and vacuum dried at 40° C. overnight to give dimethylthiocarbamnic acid O-(2-tert-butyl-4-formyl-5-methylphenyl) ester (3a): 121.5 g (435 mmol, 84%): mp: 80-81° C.; assay (HPLC): 99.7 area %.

1. customto remove THF solvent
2. temperaturethus increase
3. customthe rate of the bimolecular reaction
4. distillationDuring the distillation
5. temperaturewhile maintaining the pH range between 12.0 and 11.6
6. custombetween 23-25° C
7. distillationThe distillation
8. additionafter all the dimethylthiocarbamoyl chloride-THF solution had been added
9. stirringStirring at ambient pressure and temperature
10. waitwas continued for another 90 minutes
11. additionA solution of ethyl acetate (150 mL) and heptane (150 mL) was added to the reaction mixture
12. stirringafter stirring
13. customwere separated
14. extractionthe aqueous layer extracted with 1:1 heptane/ethyl acetate (150 mL)
15. extractionThe combined organic extracts were extracted with 10% KOH (2×105 mL) and water (2×90 mL)
16. concentrationconcentrated to an oil (210 gm)
17. additionThis was diluted with methanol (120 mL)
18. temperatureThe solution was warmed to 45° C.
19. additionwater (20 mL) added
20. temperatureThe solution was cooled to 25° C.
21. addition50% NaOH (170 mg) was added
22. concentrationThe resulting solution was concentrated to an oil (160 gm)
23. dissolutionThis was redissolved in methanol (120 mL) at 50° C.
24. additionwater (15 mL) added
25. temperatureThe solution was cooled slowly with addition of dimethylthiocarbamic acid O-(2-tert-butyl-4-formyl-5-methylphenyl) ester seed crystals
26. customCrystallization
27. custombegan at 43° C
28. stirringThe mixture was stirred
29. temperaturecooled over several hours to −5° C
30. filtrationThe mixture was filtered
31. washthe solid washed with 4:1 methanol/water (75 mL) and vacuum
32. customdried at 40° C. overnight