反应详情

To a flask fitted with thermometer, condenser, overhead stirrer, pH probe and nitrogen line was added methyl-3,5-dihydroxybenzoate (1.0 eq), sodium phosphate mono-basic monohydrate (0.46 eq) and water (10.5 vols) under a nitrogen atmosphere. The temperature was adjusted to 20° C.±3° C. 10% w/w Sodium hydroxide was added to adjust the pH to pH 7.8±0.2. Benzoyl chloride (1.0 eq) was added drop-wise in small portions over 1-2 hours, and sodium hydroxide was added concurrently drop-wise in small portions over the same time period to maintain the reaction in a pH range of pH 7.8±0.2 and at a reaction temperature of 20° C.±3° C. The crude reaction mixture was agitated for a further 30 minutes, filtered, and then washed with 4 vols of a solution prepared from water (4 vols), sodium phosphate mono-basic monohydrate (0.05 eq), and adjusted to pH7.5 with 10% w/w sodium hydroxide. The crude solid was then washed with 4 vols of a solution prepared from water (4 vols), sodium phosphate mono-basic monohydrate (0.05 eq), and adjusted to pH6.5 with 10% w/w sodium hydroxide. The crude solid was then dissolved in iso-propyl acetate (8 vols) and water (2 vols) and the mixture agitated for at least 30 minutes to ensure the solid had dissolved. The mixture was filtered through a CUNO™ filter to remove a small amount of brown solid. The aqueous layer was separated off. Water (2 vols) was added to the organic layer and the batch agitated for at least 30 minutes. The aqueous layer was separated off and the organic layer was vacuum distilled, keeping the batch temperature below 40° C. to reduce the volume to 5-6 vols. Toluene was added then added (5 vols) and the mixture was vacuum distilled keeping the batch temperature below 40° C., reducing the volume to approximately 3.5 vols. The mixture was cooled to 15° C.±3° C. and agitated at this temperature for at least 30 minutes, then filtered, and the solid washed with toluene (1 vol). The product was dried at 20° C.-40° C. to give the desired product as a solid (corrected yield 40%-70%).

1. customTo a flask fitted with thermometer, condenser, overhead stirrer, pH probe and nitrogen line
2. customwas adjusted to 20° C.±3° C
3. temperatureto maintain
4. customthe reaction in a pH range of pH 7.8±0.2
5. customat a reaction temperature of 20° C.±3° C
6. customThe crude reaction mixture
7. filtrationfiltered
8. washwashed with 4 vols of a solution
9. washThe crude solid was then washed with 4 vols of a solution
10. dissolutionhad dissolved
11. filtrationThe mixture was filtered through a CUNO™
12. filtrationfilter
13. customto remove a small amount of brown solid
14. customThe aqueous layer was separated off
15. additionWater (2 vols) was added to the organic layer
16. stirringthe batch agitated for at least 30 minutes
17. customThe aqueous layer was separated off
18. distillationdistilled
19. customthe batch temperature below 40° C.
20. additionToluene was added
21. additionthen added (5 vols)
22. distillationdistilled
23. customthe batch temperature below 40° C.
24. temperatureThe mixture was cooled to 15° C.±3° C.
25. stirringagitated at this temperature for at least 30 minutes
26. filtrationfiltered
27. washthe solid washed with toluene (1 vol)
28. customThe product was dried at 20° C.-40° C.