反应详情

Methyl 3-hydroxy-5-[(phenylcarbonyl)oxy]benzoate (1.0 eq.), (R)-1-methoxy-2-propanol (1.25 eq.) and triphenylphosphine (1.25 eq.) were suspended in toluene (10 vol). Diisopropyl azodicarboxylate (1.25 eq.) was added at a batch temperature of between 0 and 5° C. over ˜2 h. The mixture was allowed to warm to room temperature and was stirred for further 30 min. at this temperature. The resulting suspension was filtered to remove the bulk of the triphenylphosphine oxide formed and the filter cake was washed with toluene (1.5 vol). To the combined toluene fractions containing the resulting methyl 3-[(1S)-2-methoxy-1-methylethoxy]-5-[(phenylcarbonyl)oxy]benzoate was added sodium methylate (0.8 eq.) at a batch temperature of between 20 and 30° C. and the mixture was stirred to 1 h. The solution of the resulting methyl 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]-benzoate was then extracted twice with KOH 0.25 M (3.5 vol each) at a batch temperature of between 0 and 5° C. KOH was then added (1 eq.) to hydrolyse the ester moiety and the batch was stirred for 1 h at a temperature of between 20 and 30° C. The pH of the aqueous phase is then adjusted to 1.5 using conc. hydrochloric at a batch temperature of <30° C. Crude 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid was subsequently extracted into MTBE (2×3 vol) before activated charcoal was added. The batch was stirred for 10 minutes and then filtered. The batch was reduced to 3 pot volumes by distillation at a batch temperature of <45° C. Toluene (4 vol) and heptane (1 vol) were added and vacuum distillation was continued at a batch temperature of <50° C. until no further MTBE was collected. The batch was cooled to a temperature of <40° C., seeded and further cooled to a batch temperature of between 28 and 32° C. The resulting suspension was stirred for 1 h at this temperature before being further cooled to 5 to 10° C. After 2 h stirring at 5 to 10° C. the batch was filtered and washed with cold toluene (1 vol.). Drying at <60° C. furnished 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid in >99% purity as colourless solid with a melting point of 95° C. in a typical yield between 65 and 70% from methyl 3-hydroxy-5-[(phenylcarbonyl)oxy]benzoate.

1. filtrationThe resulting suspension was filtered
2. customto remove the bulk of the triphenylphosphine oxide
3. customformed
4. washthe filter cake was washed with toluene (1.5 vol)
5. additionTo the combined toluene fractions containing the resulting methyl 3-[(1S)-2-methoxy-1-methylethoxy]-5-[(phenylcarbonyl)oxy]benzoate
6. stirringthe mixture was stirred to 1 h
7. extractionThe solution of the resulting methyl 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]-benzoate was then extracted twice with KOH 0.25 M (3.5 vol each) at a batch temperature of between 0 and 5° C
8. additionKOH was then added (1 eq.)
9. stirringthe batch was stirred for 1 h at a temperature of between 20 and 30° C
10. customis then adjusted to 1.5 using conc. hydrochloric at a batch temperature of <30° C
11. extractionCrude 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid was subsequently extracted into MTBE (2×3 vol)
12. additionwas added
13. stirringThe batch was stirred for 10 minutes
14. filtrationfiltered
15. distillationThe batch was reduced to 3 pot volumes by distillation at a batch temperature of <45° C
16. additionToluene (4 vol) and heptane (1 vol) were added
17. distillationvacuum distillation
18. customwas continued at a batch temperature of <50° C. until no further MTBE
19. customwas collected
20. temperatureThe batch was cooled to a temperature of <40° C.
21. temperaturefurther cooled to a batch temperature of between 28 and 32° C
22. stirringThe resulting suspension was stirred for 1 h at this temperature
23. temperaturebefore being further cooled to 5 to 10° C
24. stirringAfter 2 h stirring at 5 to 10° C. the batch
25. filtrationwas filtered
26. washwashed with cold toluene (1 vol.)
27. customDrying at <60° C.