反应详情

温度

-55 °C

To a stirring solution of 48.6 g (0.48 moles) diisopropylamine in 520 ml tetrahydrofuran (THF) at -5° C. (ice/acetone bath) was added 185 ml of 2.6M n-butyllithium (0.48 moles) under nitrogen. The addition was complete after 30 minutes and the pale yellow solution was maintained at -5° to +5° C. for an additional 30 minutes. The ice/acetone bath was replaced by Dry Ice/acetone and when the internal temperature reached -55° C., 46.6 g (0.48 moles) 3,5-dimethylisoxazole was added dropwise over 20 minutes. This solution was allowed to stir an additional 30-40 minutes at -55° C. or lower. A solution containing 135 g (0.41 moles) 2-[4-(6-bromohexyloxy)phenyl]-4,5-dihydro-oxazole dissolved in 400 ml THF was added dropwise (via nitrogen pump) over 35 minutes. The temperature during the addition was kept below -50° C. by carefully controlling the rate of the addition. The heavy suspension was stirred for an additional hour. The Dry Ice bath was removed and the reaction was quenched by dropwise addition of 10 ml water. The reaction mixture was allowed to warm to about 5°-10° C. and then poured into 1 liter water and 1 liter ethyl acetate. The aqueous layer was set aside and the organic layer was washed once with water and brine. The extract was dried over magnesium sulfate and evaporated to near dryness under water vacuum. The crude crystalline product was dissolved in 600 ml warm acetonitrile, filtered thru a pad of solka floc and allowed to crystallize at room temperature. After two hours, the heavy crystalline precipitate was cooled to 10° C. and filtered to give 108 g (76%) 5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole, m.p. 97°-98° C., after drying 24 hrs at 60° C.

1. additionThe addition
2. temperaturethe pale yellow solution was maintained at -5° to +5° C. for an additional 30 minutes
3. customreached -55° C.
4. additionwas added dropwise (via nitrogen pump) over 35 minutes
5. additionThe temperature during the addition
6. customwas kept below -50° C.
7. additionthe rate of the addition
8. stirringThe heavy suspension was stirred for an additional hour
9. customThe Dry Ice bath was removed
10. customthe reaction was quenched by dropwise addition of 10 ml water
11. temperatureto warm to about 5°-10° C.
12. additionpoured into 1 liter water and 1 liter ethyl acetate
13. washthe organic layer was washed once with water and brine
14. dry with materialThe extract was dried over magnesium sulfate
15. customevaporated
16. dissolutionThe crude crystalline product was dissolved in 600 ml
17. temperaturewarm acetonitrile
18. filtrationfiltered
19. customto crystallize at room temperature
20. waitAfter two hours
21. temperaturethe heavy crystalline precipitate was cooled to 10° C.
22. filtrationfiltered