反应详情

温度

-10 °C

Ethyl bromide (5 ml) is added dropwise into a 2 l five-necked flask equipped with a mechanical stirrer, a condenser, a dropping funnel, a thermometer and an Argon inlet tube charged with magnesium turnings (26.6 g), anhydrous tetrahydrofuran (100 ml) and iodine (a few crystals). After 1 or 2 minutes, once the reaction begins, the mixture is stirred and diluted with anhydrous tetrahydrofuran (510 ml). Ethyl bromide (86.6 ml) is gradually added, over a period of 45 minutes keeping the temperature at about 30°-35° C. When the ethyl bromide has been added stirring is continued for an additional 30 minutes and the mixture is cooled to about -10° C. Then a solution of ethyl malonic acid monoethyl ester (87.7 g) in anhydrous tetrahydrofuran (80 ml) is slowly added dropwise (60 minutes) into the above mixture. When the addition is complete, the mixture is stirred for one hour at room temperature and for an additional hour at about 75° C. The mixture is then cooled to 15° C. and a solution of 3-benzyloxypropionyl chloride (108.8 g) in anydrous tetrahydrofuran (50 ml) is added drop by drop over a period of 15 minutes. After stirring at room temperature for two hours, the reaction mixture is allowed to stand at room temperature overnight and gradually poured into a 3-l beaker, equipped with a mechanical stirrer and a thermometer, containing 8% HCl (295 ml) and toluene (295 ml), keeping the temperature at about 10°-15° C. After stirring for a few minutes, the aqueous phase is separated and extracted with toluene (three 150-ml portions). The toluene extracts are combined, washed with a 15% phosphate buffer pH 6.5 (two 250-ml portions), dried over Na2SO4 and concentrated to dryness yielding 5-benzyloxy-3-oxo-2-ethyl-pentanoic acid ethyl ester (146.8 g). The ethylmalonic acid monoethyl ester used in this step has been prepared as follows:

1. customequipped with a mechanical stirrer, a condenser, a dropping funnel
2. customAfter 1 or 2 minutes
3. customat about 30°-35° C
4. stirringstirring
5. additionWhen the addition
6. stirringthe mixture is stirred for one hour at room temperature and for an additional hour at about 75° C
7. temperatureThe mixture is then cooled to 15° C.
8. stirringAfter stirring at room temperature for two hours
9. waitto stand at room temperature overnight
10. additiongradually poured into a 3-l beaker
11. customequipped with a mechanical stirrer
12. customat about 10°-15° C
13. stirringAfter stirring for a few minutes
14. customthe aqueous phase is separated
15. extractionextracted with toluene (three 150-ml portions)
16. washwashed with a 15% phosphate buffer pH 6.5 (two 250-ml portions)
17. dry with materialdried over Na2SO4
18. concentrationconcentrated to dryness