m-Chloroperbenzoic acid → 2,3-Dihydro-1,4-benzodioxin-6-ol

Temperature

20 °C

A 2000 L reactor was charged with dichloromethane (1303.4 kg) followed by 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (98.0 kg, 597 mol) and stirred until a homogeneous solution was obtained. 3-Chloroperoxybenzoic acid (144.3 kg, 836 mol) was added. The mixture was heated to reflux at a rate of 8-10° C./h, heated at reflux for a further 6 h and allowed to cool to 20° C. The resultant suspension was filtered through a 500 L Nutsche filter and the filter cake was washed with dichloromethane (391 kg). The filtrate and wash solution were transferred to a 2000 L reactor. A 7% by weight aqueous solution of sodium bicarbonate (212.7 kg) was added and the mixture was stirred for 0.5 h. The stirring was stopped and the phases were allowed to separate over 0.5 h. The aqueous layer was removed. The aqueous sodium bicarbonate washing procedure was repeated three times in total. The organic phase was concentrated to dryness under reduced pressure at a temperature<30° C. Methanol (116.1 kg) was added and the resultant mixture was cooled to 0° C. A 15.5% by weight aqueous solution of sodium hydroxide (234.3 kg) was added at a rate of 30-40 kg/h such that the mixture's temperature was maintained between 0-10° C. The mixture was stirred at this temperature for a further 2.25 h and the pH of the mixture was adjusted to 6-7 by the addition of 4 N hydrochloric acid (266.5 kg) such that the mixture's temperature was maintained between 0-10° C. The mixture was allowed to warm to ambient temperature and was extracted three times in total with methyl tert-butyl ether (145 kg for each extraction) by stirring for 0.5 h, stopping the stirring and allowing the phases to separate for 0.5 h. The combined organic extracts were washed three times in total with a 7% aqueous solution of sodium bicarbonate (212.7 kg for each wash) by stirring for 0.5 h, stopping the stirring, allowing the phases to separate for 0.5 h and removing the aqueous phase. The organic phase was then washed with a 30% by weight aqueous solution of sodium chloride (212.7 kg) by stirring for 0.5 h, stopping the stirring, allowing the phases to separate for 0.5 h and removing the aqueous phase. The organic phase was concentrated to dryness under reduced pressure at a temperature<45° C. Tetrahydrofuran (170 kg) was added and the resultant solution concentrated to dryness under reduced pressure at a temperature<45° C. Further tetrahydrofuran (17.1 kg) was added and the resultant solution concentrated to dryness under reduced pressure at a temperature<45° C. Tetrahydrofuran (122.5 kg) was added to afford a brown-red solution of 2,3-dihydro-1,4-benzodioxin-6-ol (86.3 kg, 95%) in tetrahydrofuran which was carried forward without further purification: purity (HPLC-UV at 220 nm) 95.7%.

1. customwas obtained
2. temperatureThe mixture was heated
3. temperatureto reflux at a rate of 8-10° C./h
4. temperatureheated
5. temperatureat reflux for a further 6 h
6. filtrationThe resultant suspension was filtered through a 500 L Nutsche
7. filtrationfilter
8. washthe filter cake was washed with dichloromethane (391 kg)
9. washThe filtrate and wash solution
10. customwere transferred to a 2000 L reactor
11. additionA 7% by weight aqueous solution of sodium bicarbonate (212.7 kg) was added
12. stirringthe mixture was stirred for 0.5 h
13. customto separate over 0.5 h
14. customThe aqueous layer was removed
15. concentrationThe organic phase was concentrated to dryness under reduced pressure at a temperature<30° C
16. additionMethanol (116.1 kg) was added
17. temperaturethe resultant mixture was cooled to 0° C
18. additionA 15.5% by weight aqueous solution of sodium hydroxide (234.3 kg) was added at a rate of 30-40 kg/h such that the mixture's temperature
19. temperaturewas maintained between 0-10° C
20. stirringThe mixture was stirred at this temperature for a further 2.25 h
21. additionthe pH of the mixture was adjusted to 6-7 by the addition of 4 N hydrochloric acid (266.5 kg) such that the mixture's temperature
22. temperaturewas maintained between 0-10° C
23. temperatureto warm to ambient temperature
24. extractionwas extracted three times in total with methyl tert-butyl ether (145 kg
25. extractionfor each extraction)
26. stirringby stirring for 0.5 h
27. customto separate for 0.5 h
28. washThe combined organic extracts were washed three times in total with a 7% aqueous solution of sodium bicarbonate (212.7 kg for
29. washeach wash)
30. stirringby stirring for 0.5 h
31. customto separate for 0.5 h
32. customremoving the aqueous phase
33. washThe organic phase was then washed with a 30% by weight aqueous solution of sodium chloride (212.7 kg)
34. stirringby stirring for 0.5 h
35. customto separate for 0.5 h
36. customremoving the aqueous phase
37. concentrationThe organic phase was concentrated to dryness under reduced pressure at a temperature<45° C
38. additionTetrahydrofuran (170 kg) was added
39. concentrationthe resultant solution concentrated to dryness under reduced pressure at a temperature<45° C
40. additionFurther tetrahydrofuran (17.1 kg) was added
41. concentrationthe resultant solution concentrated to dryness under reduced pressure at a temperature<45° C
42. additionTetrahydrofuran (122.5 kg) was added

ORD record

ord-d090081b84924853bee83f22d6f308b4

Source dataset

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08445696B2