反应详情

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0 °C

A Grignard reagent was prepared from 3,5-dibromobenzene (150 g, 0.78 mol), and dried Mg (18.9 g, 0.78 mol) in ether (600 ml), followed by slowly dropwise adding a 100 ml ether solution of ethylene oxide (100 g, 2.27 mol) to the reagent under -50° C. cooling, heating the mixture up to room temperature, stirring the reaction solution for one hour, adding it into 6N hydrochloric acid (500 ml), extracting the resulting product with toluene, washing the extraction solution successively with a saturated aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, adding an aqueous HBr (47%) (500 ml) to the residue, refluxing the mixture for 7 hours, and distilling under reduced pressure using Vigoureux tube, to obtain a colorless, transparent liquid, 3,5-difluorophenetylbromide (41 g, 0.19 mol) (b.p. 52° to 53° C. under 2 Torr). The yield of this product from 3,5-difluorobromobenzene was 23.8%. A Grignard reagent was prepared from the product (20.0 g, 90.5 mmol) and dried Mg (2.2 g, 90.5 mmol) in ether (150 ml), cooling the agent down to 0° C., dropwise adding thereto a 130 ml ether solution of commercially available cyclohexanedione monoethylene ketal (14.2 g, 90.9 mmol), heating the reaction solution up to room temperature, stirring it for 3 hours, adding the reaction solution to 6N HCl (500 ml), extracting the product with toluene, washing the extract successively with a saturated, aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, adding to the residue (20 g), toluene (100 ml) and Amberlist (1 g), refluxing the mixture for 5 hours while removing water formed by the reaction, by means of Dean Stark, adding ethyleneglycol (2 g), further refluxing for 2 hours, adding water (100 ml) to the reaction solution, washing the organic layer successively with a saturated aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, purifying the residue according to column chromatography using toluene/ethyl acetate (4:1) as a developing solvent, hydrogenating the resulting purified substance in ethanol in the presence of 5% Pd/C catalyst (1.02 g), filtering off the catalyst, distilling off under reduced pressure, refluxing the resulting concentrate in formic acid (80 ml) for 3 hours, adding water (200 ml), extracting the product with toluene, washing the extraction liquid successively with a saturated aqueous solution of sodium bicarbonate and water, drying the toluene layer over magnesium sulfate, and distilling off toluene to obtain 4-(3,5-difluorophenylethyl)-1-cyclohexanone (10.1 g, 42.4 mmol). The yield of this product from 3,5-difluorobromobenzene was 46.6%.

1. additiondropwise adding
2. extractionextracting the product with toluene
3. washwashing the
4. extractionextract successively with a saturated, aqueous solution of sodium bicarbonate and water
5. dry with materialdrying over magnesium sulfate
6. distillationdistilling off the solvent
7. additionadding to the residue (20 g), toluene (100 ml) and Amberlist (1 g)
8. temperaturerefluxing the mixture for 5 hours
9. customwhile removing water
10. customformed by the reaction, by means of Dean Stark
11. temperaturefurther refluxing for 2 hours
12. washwashing the organic layer successively with a saturated aqueous solution of sodium bicarbonate and water
13. dry with materialdrying over magnesium sulfate
14. distillationdistilling off the solvent
15. custompurifying the residue
16. custompurified substance in ethanol in the presence of 5% Pd/C catalyst (1.02 g)
17. filtrationfiltering off the catalyst
18. distillationdistilling off under reduced pressure
19. temperaturerefluxing the resulting
20. concentrationconcentrate in formic acid (80 ml) for 3 hours
21. additionadding water (200 ml)
22. extractionextracting the product with toluene
23. washwashing
24. extractionthe extraction liquid successively with a saturated aqueous solution of sodium bicarbonate and water
25. dry with materialdrying the toluene layer over magnesium sulfate
26. distillationdistilling off toluene