反应详情

温度

9.5 °C

To a stirred suspension of NaH (10.47 g, 60% by wt, 0.2616 mol) in THF (1.40 L), at 13.1° C. under argon, was added a solution of 4-bromo-3-hydroxybenzoic acid (28.11 g, 0.130 mol) in THF (400 ml) over 1.25 h maintaining the internal temperature in the range 4-15° C. After 1.5 h a solution of benzyl bromide (44.3 g, 0.2591 mol) in THF (70 ml) was added over 0.5 h. To the resulting suspension was added DMF (500 ml) and the mixture allowed to warm to room temperature. After a further 15 h extra DMF was added (1.5 L) to the suspension. After approximately 30 minutes the reaction mixture was essentially clear and TLC analysis (25% EtOAc/hexane) indicated that effectively all of the starting material had been consumed. The reaction mixture was quenched with dilute ammonium chloride (100 ml) and concentrated in vacuo. To the concentrate was added ethyl acetate (1.0 L) and dilute ammonium chloride (1.0 L) and the fractions separated. The aqueous fraction was back extracted with ethyl acetate (1×450 ml and 1×300 ml). The total organic fraction was dried over sodium sulphate, filtered and concentrated in vacuo. The resulting solid was crystallised from ethanol:water (9:1; vol:vol, 200 ml), heated at reflux, to which was added ethanol (65 ml) until all the material had dissolved. Water was then added dropwise (17 ml), followed by extra ethanol (8.0 ml). The resulting solution was allowed to slowly cool to ambient temperature. The resulting solid was filtered off and dried (44.54 g). This solid was then dissolved in hot ethanol (227 ml) and water (5.0 ml) added and then allowed to slowly cool to ambient temperature. The resulting crystals were filtered off, washed with cold ethanol (25 ml) and dried in a vacuum oven at 50° C. to give the title compound (36.79 g, yield 71.5%). mp=80.5-81.5° C.

1. temperatureto warm to room temperature
2. customhad been consumed
3. customThe reaction mixture was quenched with dilute ammonium chloride (100 ml)
4. concentrationconcentrated in vacuo
5. additionTo the concentrate was added ethyl acetate (1.0 L) and dilute ammonium chloride (1.0 L)
6. customthe fractions separated
7. extractionThe aqueous fraction was back extracted with ethyl acetate (1×450 ml and 1×300 ml)
8. dry with materialThe total organic fraction was dried over sodium sulphate
9. filtrationfiltered
10. concentrationconcentrated in vacuo
11. customThe resulting solid was crystallised from ethanol:water (9:1; vol:vol, 200 ml)
12. temperatureheated
13. temperatureat reflux, to which
14. additionwas added ethanol (65 ml) until all the material
15. dissolutionhad dissolved
16. additionWater was then added dropwise (17 ml)
17. temperatureto slowly cool to ambient temperature
18. filtrationThe resulting solid was filtered off
19. customdried (44.54 g)
20. dissolutionThis solid was then dissolved in hot ethanol (227 ml)
21. additionwater (5.0 ml) added
22. temperatureto slowly cool to ambient temperature
23. filtrationThe resulting crystals were filtered off
24. washwashed with cold ethanol (25 ml)
25. customdried in a vacuum oven at 50° C.