3-phenylmethoxypropanoyl chloride

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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: equipped with a mechanical stirrer, a condenser, a dropping funnel After 1 or 2 minutes at about 30°-35° C stirring When the addition 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. After stirring at room temperature for two hours to stand at room temperature overnight gradually poured into a 3-l beaker equipped with a mechanical stirrer at about 10°-15° C After stirring for a few minutes the aqueous phase is separated extracted with toluene (three 150-ml portions) washed with a 15% phosphate buffer pH 6.5 (two 250-ml portions) dried over Na2SO4 concentrated to dryness

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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: equipped with a mechanical stirrer, a condenser, a dropping funnel After 1 or 2 minutes at about 30°-35° C stirring When the addition 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. After stirring at room temperature for two hours to stand at room temperature overnight gradually poured into a 3-l beaker equipped with a mechanical stirrer at about 10°-15° C After stirring for a few minutes the aqueous phase is separated extracted with toluene (three 150-ml portions) washed with a 15% phosphate buffer pH 6.5 (two 250-ml portions) dried over Na2SO4 concentrated to dryness

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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: equipped with a mechanical stirrer, a condenser, a dropping funnel After 1 or 2 minutes at about 30°-35° C stirring When the addition 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. After stirring at room temperature for two hours to stand at room temperature overnight gradually poured into a 3-l beaker equipped with a mechanical stirrer at about 10°-15° C After stirring for a few minutes the aqueous phase is separated extracted with toluene (three 150-ml portions) washed with a 15% phosphate buffer pH 6.5 (two 250-ml portions) dried over Na2SO4 concentrated to dryness