反应详情

To a 12-L three-necked round-bottom flask fitted with a mechanical stirrer and a thermocouple was charged solid potassium carbonate (709.4 g, 5.140 mol, 1.2 molar equivalents) and acetone (5300 mL). The mixture was stirred and 3-trifluoromethylphenol (694.4 g, 4.28 mol, 1.0 molar equivalent) was added dropwise via 500-mL addition funnel over one hour. The internal temperature rose from 19.6° C. to 28.1° C. during the addition. The addition funnel was rinsed with acetone (100 mL). The rinse was charged to the vessel. The mixture was stirred and methyl chloroacetate (786.3 g, 5.140 mol, 1.2 molar equivalents) was charged dropwise via 500-mL addition funnel over one hour. The addition funnel was rinsed with acetone (100 mL). The rinse was charged to the vessel. The resulting mixture was stirred and heated to reflux for no less than 15 hours. After completion of reaction, as judged by TLC, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (2000 mL) and water (2000 mL). Some solids did not dissolve but that did not prevent a clean layer separation. The layers were separated (pH of lower aqueous layer: 11). The upper organic layer was treated (slow addition) with 10% w/w aqueous citric acid (2000 mL). All solids dissolved and the layers were separated (pH of lower aqueous layer: 8). The organic layer was concentrated in vacuo (20 mmHg, bath at 30-35° C.). The resulting biphasic residue was dissolved in isopropyl acetate (3000 mL). The layers of the resulting biphasic mixture were separated (pH of lower aqueous layer: 8). The upper organic layer was concentrated in vacuo (20 mmHg, bath at 30-35° C.). The resulting residue was distilled under reduced pressure (boiling point: 126-130° C., 10 mmHg) to afford the title intermediate (861.93 g, 86% yield) as a colorless liquid.

1. customTo a 12-L three-necked round-bottom flask fitted with a mechanical stirrer
2. additionThe internal temperature rose from 19.6° C. to 28.1° C. during the addition
3. washThe addition funnel was rinsed with acetone (100 mL)
4. additionThe rinse was charged to the vessel
5. stirringThe mixture was stirred
6. washThe addition funnel was rinsed with acetone (100 mL)
7. additionThe rinse was charged to the vessel
8. stirringThe resulting mixture was stirred
9. temperatureheated
10. temperatureto reflux for no less than 15 hours
11. customAfter completion of reaction
12. dissolutionSome solids did not dissolve
13. customa clean layer separation
14. customThe layers were separated (pH of lower aqueous layer: 11)
15. additionThe upper organic layer was treated
16. addition(slow addition) with 10% w/w aqueous citric acid (2000 mL)
17. dissolutionAll solids dissolved
18. customthe layers were separated (pH of lower aqueous layer: 8)
19. concentrationThe organic layer was concentrated in vacuo (20 mmHg, bath at 30-35° C.)
20. dissolutionThe resulting biphasic residue was dissolved in isopropyl acetate (3000 mL)
21. customThe layers of the resulting biphasic mixture were separated (pH of lower aqueous layer: 8)
22. concentrationThe upper organic layer was concentrated in vacuo (20 mmHg, bath at 30-35° C.)
23. distillationThe resulting residue was distilled under reduced pressure (boiling point: 126-130° C., 10 mmHg)