2-(4-chlorophenoxy)ethanol

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:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 25.0 g (0.145 mole) of 2-(4-chlorophenoxy)ethanol (Lancaster Synthesis Inc., Windham, N.H. 03087) in 64.6 g (0.640 mole) of triethylamine and 40 ml of methylene chloride was added in a thin stream to a solution of 83.3 g (0.580 mole) of dimethylsulfamoyl chloride (Aldrich) in 60 ml of methylene chloride stirred at ambient temperature in a water bath. The reaction mixture was stirred for 8 days at ambient temperature. The solids were removed by filtration and the filtrate was evaporated under reduced pressure to yield a viscous residue. The residue was partitioned between water and ethyl ether (300 ml each). The organic layer was washed with two 200 ml portions of 2N hydrochloric acid. Once with 200 ml of water, dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield a viscous residue. The residue was treated with 65.0 g (0.63 mole) of triethylamine and the reaction mixture was stirred for 5 days at ambient temperature. The solids were removed by filtration and the filtrate was evaporated under reduced pressure and the viscous residue was partitioned between water and ethyl ether (450 ml each). The organic layer was washed with four 300 ml portions of water (pH neutral to pH paper), dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield a brown viscous oily residue. The oil was purified by chromatography (4.5×90 cm glass column; 500 g of silica gel; methylene chloride). Fractions containing the title compound were combined and the solvent evaporated under reduced pressure to yield a viscous oil. The oil was dissolved in 150 ml of isopropyl ether and filtered to remove some insolubles. The filtrate was concentrated to a viscous oil. The oil was triturated with isopropyl ether-petroleum ether (bp range 30°-60° C.), cooled (refrigerator) and the resulting solid was collected by filtration. The solid was recrystallized from isopropyl ether to give 18.5 g (45%) of white solid, mp 54°-57° C. The reaction mixture was stirred for 8 days at ambient temperature The solids were removed by filtration the filtrate was evaporated under reduced pressure to yield a viscous residue The residue was partitioned between water and ethyl ether (300 ml each) The organic layer was washed with two 200 ml portions of 2N hydrochloric acid Once with 200 ml of water, dried over magnesium sulfate the solvent evaporated under reduced pressure to yield a viscous residue the reaction mixture was stirred for 5 days at ambient temperature The solids were removed by filtration the filtrate was evaporated under reduced pressure the viscous residue was partitioned between water and ethyl ether (450 ml each) The organic layer was washed with four 300 ml portions of water (pH neutral to pH paper) dried over magnesium sulfate the solvent evaporated under reduced pressure to yield a brown viscous oily residue The oil was purified by chromatography (4.5×90 cm glass column; 500 g of silica gel; methylene chloride) Fractions containing the title compound the solvent evaporated under reduced pressure to yield a viscous oil filtered to remove some insolubles The filtrate was concentrated to a viscous oil The oil was triturated with isopropyl ether-petroleum ether (bp range 30°-60° C.) cooled (refrigerator) the resulting solid was collected by filtration The solid was recrystallized from isopropyl ether

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

Procedure: To a stirred solution of 45.0 g (0.347 mole) of methylsulfamoyl chloride prepared above in 100 ml of methylene chloride was added in a thin stream a solution of 25.0 g (0.145 mole) of 2-(4-chlorophenoxy)ethanol (Lancaster Synthesis, Inc., Windham, N.H. 03087) in 30 ml (0.369 mole) of pyridine and 100 ml of methylene chloride and the reaction mixture was stirred at ambient temperature for 3 days. The solids were removed by filtration and the filtrate was evaporated under reduced pressure to yield a brown viscous residue. The residue was partitioned between water and ethyl ether (400 ml each). The organic layer was washed twice with 300 ml portions of water, dried over magnesium sulfate (MgSO4) and the solvent evaporated under reduced pressure to yield a solid residue. The solid was triturated with 100 ml of isopropyl ether and the solid was recollected by filtration. The solid was recrystallized from isopropyl ether to give 12.9 g (34%) of title compound as a white solid, m.p. 101°-104° C. The solids were removed by filtration the filtrate was evaporated under reduced pressure to yield a brown viscous residue The residue was partitioned between water and ethyl ether (400 ml each) The organic layer was washed twice with 300 ml portions of water dried over magnesium sulfate (MgSO4) the solvent evaporated under reduced pressure to yield a solid residue The solid was triturated with 100 ml of isopropyl ether the solid was recollected by filtration The solid was recrystallized from isopropyl ether

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

Procedure: To a flask under a nitrogen atmosphere was added 6.1 g. of lithium aluminum hydride in 60 ml. of dry THF at -4° C. The resulting slurry was stirred and 20.0 g. (0.102 mole) of 4-chlorophenoxyacetic acid in 100 ml. of dry THF was added dropwise. The reaction was stirred overnight and was quenched by cautiously adding saturated aqueous sodium sulfate solution followed by ethyl acetate. The solid was removed by filtration and the aqueous phase was extracted twice with 50 ml. portions of ethyl acetate. The combined ethyl acetate solutions were washed with aqueous saturated sodium chloride solution (brine) and then dried using magnesium sulfate. Removal of the solvent resulted in 17.6 g. (94% yield) of 2-(4-chlorophenoxy)ethanol being isolated as a yellow oil. To a flask under a nitrogen atmosphere was added 6.1 g at -4° C The reaction was stirred overnight was quenched by cautiously adding saturated aqueous sodium sulfate solution The solid was removed by filtration the aqueous phase was extracted twice with 50 ml The combined ethyl acetate solutions were washed with aqueous saturated sodium chloride solution (brine) dried Removal of the solvent resulted in 17.6 g

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

Procedure: To a flask under a nitrogen atmosphere was added 6.1 g. of lithium aluminum hydride in 60 ml. of dry THF at -4° C. The resulting slurry was stirred and 20.0 g. (0.102 mole) of 4-chlorophenoxyacetic acid in 100 ml. of dry THF was added dropwise. The reaction was stirred overnight and was quenched by cautiously adding saturated aqueous sodium sulfate solution followed by ethyl acetate. The solid was removed by filtration and the aqueous phase was extracted twice with 50 ml. portions of ethyl acetate. The combined ethyl acetate solutions were washed with aqueous saturated sodium chloride solution (brine) and then dried using magnesium sulfate. Removal of the solvent resulted in 17.6 g. (94% yield) of 2-(4-chlorophenoxy)ethanol being isolated as a yellow oil. To a flask under a nitrogen atmosphere was added 6.1 g at -4° C The reaction was stirred overnight was quenched by cautiously adding saturated aqueous sodium sulfate solution The solid was removed by filtration the aqueous phase was extracted twice with 50 ml The combined ethyl acetate solutions were washed with aqueous saturated sodium chloride solution (brine) dried Removal of the solvent resulted in 17.6 g

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

Procedure: A process for the preparation of 2-(2-chloroethoxy)-benzenesulfonamide of formula I ##STR15## which process comprises the etherification of 4-chlorophenol of formula II ##STR16## with ethylene carbonate at a temperature between +130° C. and +150° C. and chlorination of the resulting 4-(2-hydroxyethoxy)-chlorobenzene of formula III ##STR17## with phosgene or thionyl chloride at a temperature between +70° C. and +90° C. to give 4-(2-chloroethoxy)-chlorobenzene of formula IV ##STR18## which is converted with chlorosulfonic acid, at a temperature between -20° C. and +60° C. and subsequent neutralizaion with sodium hydroxide to the sulfonic acid sodium salt of formula V ##STR19## which is hydrogenated at a temperature between +20° C. and +70° C. to the compound of formula VI ##STR20## which is subsequently reacted with phosgene at a temperature between +60° C. and +120° C. to the sulfonic acid chloride of formula VII ##STR21## which is reacted with ammonia at a temperature between 0° C. and +100° C. to the sulfonamide of formula I. at a temperature between +70° C. and +90° C.

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

Procedure: A process for the preparation of 2-(2-chloroethoxy)-benzenesulfonamide of formula I ##STR15## which process comprises the etherification of 4-chlorophenol of formula II ##STR16## with ethylene carbonate at a temperature between +130° C. and +150° C. and chlorination of the resulting 4-(2-hydroxyethoxy)-chlorobenzene of formula III ##STR17## with phosgene or thionyl chloride at a temperature between +70° C. and +90° C. to give 4-(2-chloroethoxy)-chlorobenzene of formula IV ##STR18## which is converted with chlorosulfonic acid, at a temperature between -20° C. and +60° C. and subsequent neutralizaion with sodium hydroxide to the sulfonic acid sodium salt of formula V ##STR19## which is hydrogenated at a temperature between +20° C. and +70° C. to the compound of formula VI ##STR20## which is subsequently reacted with phosgene at a temperature between +60° C. and +120° C. to the sulfonic acid chloride of formula VII ##STR21## which is reacted with ammonia at a temperature between 0° C. and +100° C. to the sulfonamide of formula I. at a temperature between +70° C. and +90° C.

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

Procedure: To a solution of 2-(4-chlorophenoxy)ethanol (2.0 g, 11.6 mmol) in DCM (10 mL) was added Et3N (5 mL) and 4-methylbenzene-1-sulfonyl chloride (TsCl; 2.43 g, 12.8 mmol) sequentially. The reaction mixture was stirred at room temperature overnight and partitioned between water and ethyl acetate. The organic layer was washed with water, 5% sodium bicarbonate (NaHCO3), and brine and concentrated. The resulting residue was washed with hexane to afford the title compound quantitatively. partitioned between water and ethyl acetate The organic layer was washed with water, 5% sodium bicarbonate (NaHCO3), and brine concentrated The resulting residue was washed with hexane

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

Procedure: A solution of 25.0 g (0.145 mole) of 2-(4-chlorophenoxy)ethanol (Lancaster Synthesis Inc., Windham, N.H. 03087) in 64.6 g (0.640 mole) of triethylamine and 40 ml of methylene chloride was added in a thin stream to a solution of 83.3 g (0.580 mole) of dimethylsulfamoyl chloride (Aldrich) in 60 ml of methylene chloride stirred at ambient temperature in a water bath. The reaction mixture was stirred for 8 days at ambient temperature. The solids were removed by filtration and the filtrate was evaporated under reduced pressure to yield a viscous residue. The residue was partitioned between water and ethyl ether (300 ml each). The organic layer was washed with two 200 ml portions of 2N hydrochloric acid. Once with 200 ml of water, dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield a viscous residue. The residue was treated with 65.0 g (0.63 mole) of triethylamine and the reaction mixture was stirred for 5 days at ambient temperature. The solids were removed by filtration and the filtrate was evaporated under reduced pressure and the viscous residue was partitioned between water and ethyl ether (450 ml each). The organic layer was washed with four 300 ml portions of water (pH neutral to pH paper), dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield a brown viscous oily residue. The oil was purified by chromatography (4.5×90 cm glass column; 500 g of silica gel; methylene chloride). Fractions containing the title compound were combined and the solvent evaporated under reduced pressure to yield a viscous oil. The oil was dissolved in 150 ml of isopropyl ether and filtered to remove some insolubles. The filtrate was concentrated to a viscous oil. The oil was triturated with isopropyl ether-petroleum ether (bp range 30°-60° C.), cooled (refrigerator) and the resulting solid was collected by filtration. The solid was recrystallized from isopropyl ether to give 18.5 g (45%) of white solid, mp 54°-57° C. The reaction mixture was stirred for 8 days at ambient temperature The solids were removed by filtration the filtrate was evaporated under reduced pressure to yield a viscous residue The residue was partitioned between water and ethyl ether (300 ml each) The organic layer was washed with two 200 ml portions of 2N hydrochloric acid Once with 200 ml of water, dried over magnesium sulfate the solvent evaporated under reduced pressure to yield a viscous residue the reaction mixture was stirred for 5 days at ambient temperature The solids were removed by filtration the filtrate was evaporated under reduced pressure the viscous residue was partitioned between water and ethyl ether (450 ml each) The organic layer was washed with four 300 ml portions of water (pH neutral to pH paper) dried over magnesium sulfate the solvent evaporated under reduced pressure to yield a brown viscous oily residue The oil was purified by chromatography (4.5×90 cm glass column; 500 g of silica gel; methylene chloride) Fractions containing the title compound the solvent evaporated under reduced pressure to yield a viscous oil filtered to remove some insolubles The filtrate was concentrated to a viscous oil The oil was triturated with isopropyl ether-petroleum ether (bp range 30°-60° C.) cooled (refrigerator) the resulting solid was collected by filtration The solid was recrystallized from isopropyl ether

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

Procedure: A solution of 25.0 g (0.145 mole) of 2-(4-chlorophenoxy)ethanol (Lancaster Synthesis Inc., Windham, N.H. 03087) in 64.6 g (0.640 mole) of triethylamine and 40 ml of methylene chloride was added in a thin stream to a solution of 83.3 g (0.580 mole) of dimethylsulfamoyl chloride (Aldrich) in 60 ml of methylene chloride stirred at ambient temperature in a water bath. The reaction mixture was stirred for 8 days at ambient temperature. The solids were removed by filtration and the filtrate was evaporated under reduced pressure to yield a viscous residue. The residue was partitioned between water and ethyl ether (300 ml each). The organic layer was washed with two 200 ml portions of 2N hydrochloric acid. Once with 200 ml of water, dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield a viscous residue. The residue was treated with 65.0 g (0.63 mole) of triethylamine and the reaction mixture was stirred for 5 days at ambient temperature. The solids were removed by filtration and the filtrate was evaporated under reduced pressure and the viscous residue was partitioned between water and ethyl ether (450 ml each). The organic layer was washed with four 300 ml portions of water (pH neutral to pH paper), dried over magnesium sulfate and the solvent evaporated under reduced pressure to yield a brown viscous oily residue. The oil was purified by chromatography (4.5×90 cm glass column; 500 g of silica gel; methylene chloride). Fractions containing the title compound were combined and the solvent evaporated under reduced pressure to yield a viscous oil. The oil was dissolved in 150 ml of isopropyl ether and filtered to remove some insolubles. The filtrate was concentrated to a viscous oil. The oil was triturated with isopropyl ether-petroleum ether (bp range 30°-60° C.), cooled (refrigerator) and the resulting solid was collected by filtration. The solid was recrystallized from isopropyl ether to give 18.5 g (45%) of white solid, mp 54°-57° C. The reaction mixture was stirred for 8 days at ambient temperature The solids were removed by filtration the filtrate was evaporated under reduced pressure to yield a viscous residue The residue was partitioned between water and ethyl ether (300 ml each) The organic layer was washed with two 200 ml portions of 2N hydrochloric acid Once with 200 ml of water, dried over magnesium sulfate the solvent evaporated under reduced pressure to yield a viscous residue the reaction mixture was stirred for 5 days at ambient temperature The solids were removed by filtration the filtrate was evaporated under reduced pressure the viscous residue was partitioned between water and ethyl ether (450 ml each) The organic layer was washed with four 300 ml portions of water (pH neutral to pH paper) dried over magnesium sulfate the solvent evaporated under reduced pressure to yield a brown viscous oily residue The oil was purified by chromatography (4.5×90 cm glass column; 500 g of silica gel; methylene chloride) Fractions containing the title compound the solvent evaporated under reduced pressure to yield a viscous oil filtered to remove some insolubles The filtrate was concentrated to a viscous oil The oil was triturated with isopropyl ether-petroleum ether (bp range 30°-60° C.) cooled (refrigerator) the resulting solid was collected by filtration The solid was recrystallized from isopropyl ether