ethyl 2-dimethoxyphosphorylacetate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the solution of ethyl[bis(methyloxy)phosphoryl]acetate (1.980 mL, 11.99 mmol) in THF-DMF (60 mL, v/v=5:1) at 0° C. was added t-BuOK (1.458 g, 12.99 mmol) portion wise. The resultant mixture was stirred at room temperature for 30 minutes, then mixed with a solution of 2,4,6-trifluorobenzaldehyde (1.6 g, 9.99 mmol) in THF (10 mL) at 0° C. It was allowed to warm to room temperature and the mixture was stirred for 45 min. It was mixed with aqueous ammonium chloride and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by a flash column chromatography to give the title compound as a pale yellow oil (2.0 g, 87% yield). LCMS: rt=3.52 min, [M+H+]=231.1 extracted with ethyl acetate The organic layer was washed with brine dried over Na2SO4 filtered concentrated The residue was purified by a flash column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the solution of ethyl[bis(methyloxy)phosphoryl]acetate (1.980 mL, 11.99 mmol) in THF-DMF (60 mL, v/v=5:1) at 0° C. was added t-BuOK (1.458 g, 12.99 mmol) portion wise. The resultant mixture was stirred at room temperature for 30 minutes, then mixed with a solution of 2,4,6-trifluorobenzaldehyde (1.6 g, 9.99 mmol) in THF (10 mL) at 0° C. It was allowed to warm to room temperature and the mixture was stirred for 45 min. It was mixed with aqueous ammonium chloride and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by a flash column chromatography to give the title compound as a pale yellow oil (2.0 g, 87% yield). LCMS: rt=3.52 min, [M+H+]=231.1 extracted with ethyl acetate The organic layer was washed with brine dried over Na2SO4 filtered concentrated The residue was purified by a flash column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the solution of ethyl[bis(methyloxy)phosphoryl]acetate (1.980 mL, 11.99 mmol) in THF-DMF (60 mL, v/v=5:1) at 0° C. was added t-BuOK (1.458 g, 12.99 mmol) portion wise. The resultant mixture was stirred at room temperature for 30 minutes, then mixed with a solution of 2,4,6-trifluorobenzaldehyde (1.6 g, 9.99 mmol) in THF (10 mL) at 0° C. It was allowed to warm to room temperature and the mixture was stirred for 45 min. It was mixed with aqueous ammonium chloride and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by a flash column chromatography to give the title compound as a pale yellow oil (2.0 g, 87% yield). LCMS: rt=3.52 min, [M+H+]=231.1 extracted with ethyl acetate The organic layer was washed with brine dried over Na2SO4 filtered concentrated The residue was purified by a flash column chromatography

反応条件: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To an ice-cooled suspension of sodium hydride (38.5 mg) in THF (10 ml) was added ethyl (dimethoxyphosphoryl)acetate (206 mg), and the mixture was stirred at 24° C. for 40 minutes. To the mixture was added 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoronicotinaldehyde (250 mg) at 24° C., the reaction mixture was stirred at same temperature for 30 minutes. The reaction mixture was poured into a mixture of AcOEt and 5% aqueous NaCl. The separated organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (8.2 g) using a mixed solvent of CH2Cl2 and MeOH(100:1 to 35:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Title compound (111 mg, 36%) was obtained as oil. the reaction mixture was stirred at same temperature for 30 minutes The separated organic layer was washed with brine dried over sodium sulfate evaporated in vacuo The resulting residue was purified by column chromatography on silica gel (8.2 g) The fractions containing the objective compound were collected evaporated under reduced pressure

反応条件: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To an ice-cooled suspension of sodium hydride (38.5 mg) in THF (10 ml) was added ethyl (dimethoxyphosphoryl)acetate (206 mg), and the mixture was stirred at 24° C. for 40 minutes. To the mixture was added 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoronicotinaldehyde (250 mg) at 24° C., the reaction mixture was stirred at same temperature for 30 minutes. The reaction mixture was poured into a mixture of AcOEt and 5% aqueous NaCl. The separated organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (8.2 g) using a mixed solvent of CH2Cl2 and MeOH(100:1 to 35:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Title compound (111 mg, 36%) was obtained as oil. the reaction mixture was stirred at same temperature for 30 minutes The separated organic layer was washed with brine dried over sodium sulfate evaporated in vacuo The resulting residue was purified by column chromatography on silica gel (8.2 g) The fractions containing the objective compound were collected evaporated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of ethyl dimethylphosphonoacetate (135 mg) in DMF (5 ml) at 0° was added 50% NaH/oil (33 mg), and the mixture stirred for 10 minutes. (E) 4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-methylbut-2-enyl bromide (600 mg) was added at the same temperature and allowed to reach room temperature in 30 minutes. The reaction was poured onto water and extracted with EtOAc. The organic layers were washed with water, dried over sodium sulfate, and evaporated to give the crude product which was purified by flash chromatography (CH2Cl2 followed by BtOAc) to obtain ethyl (E) 6-(4-methoxyethoxymethoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-(dimethylphosphono)-4-methyl-4-hexenoate as an oil. to reach room temperature in 30 minutes The reaction was poured onto water extracted with EtOAc The organic layers were washed with water dried over sodium sulfate evaporated to give the crude product which was purified by flash chromatography (CH2Cl2 followed by BtOAc)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of ethyl dimethylphosphonoacetate (135 mg) in DMF (5 ml) at 0° was added 50% NaH/oil (33 mg), and the mixture stirred for 10 minutes. (E)-4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy7-methyl -3-oxoisobenzofuran-5-yl)-2-methylbut-2-enyl bromide (600 mg) was added at the same temperature and allowed to reach room temperature in 30 minutes. The reaction was poured onto water and extracted with EtOAc. The organic layers were washed with water, dried over sodium sulfate, and evaporated to give the crude product which was purified by flash chromatography (CH2Cl2 followed by EtOAc) to obtain ethyl (E)-6-(4-methoxyethoxymethoxy -1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-(dimethylphosphono) -4-methyl-4-hexenoate as an oil. to reach room temperature in 30 minutes The reaction was poured onto water extracted with EtOAc The organic layers were washed with water dried over sodium sulfate evaporated to give the crude product which was purified by flash chromatography (CH2Cl2 followed by EtOAc)

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: An amount of 340.8 g of ethyl chloroacetate was mixed with 496 g of trimethyl phosphite in a reactor fitted with a thermometer, nitrogen inlet and a fractionation column (containing 5 mm Raschig rings as packing) topped with a variable reflux condenser. The reactor was heated to enable slow reflux in the column only followed by a slow increase in the temperature from 110 to 150 degrees C. over 10 hours and maintained at about this temperature. The pressure was reduced to 11 mm Hg and volatile material was removed on heating the reactor slowly from 50 to 140 degrees C. The yield of the pure product obtained was 85%. fitted with a thermometer, nitrogen inlet a fractionation column (containing 5 mm Raschig rings as packing) topped with a variable reflux condenser The reactor was heated to enable slow reflux in the column maintained at about this temperature was removed on heating the reactor slowly from 50 to 140 degrees C The yield of the pure product obtained

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the solution of ethyl[bis(methyloxy)phosphoryl]acetate (1.980 mL, 11.99 mmol) in THF-DMF (60 mL, v/v=5:1) at 0° C. was added t-BuOK (1.458 g, 12.99 mmol) portion wise. The resultant mixture was stirred at room temperature for 30 minutes, then mixed with a solution of 2,4,6-trifluorobenzaldehyde (1.6 g, 9.99 mmol) in THF (10 mL) at 0° C. It was allowed to warm to room temperature and the mixture was stirred for 45 min. It was mixed with aqueous ammonium chloride and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by a flash column chromatography to give the title compound as a pale yellow oil (2.0 g, 87% yield). LCMS: rt=3.52 min, [M+H+]=231.1 extracted with ethyl acetate The organic layer was washed with brine dried over Na2SO4 filtered concentrated The residue was purified by a flash column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the solution of ethyl[bis(methyloxy)phosphoryl]acetate (1.980 mL, 11.99 mmol) in THF-DMF (60 mL, v/v=5:1) at 0° C. was added t-BuOK (1.458 g, 12.99 mmol) portion wise. The resultant mixture was stirred at room temperature for 30 minutes, then mixed with a solution of 2,4,6-trifluorobenzaldehyde (1.6 g, 9.99 mmol) in THF (10 mL) at 0° C. It was allowed to warm to room temperature and the mixture was stirred for 45 min. It was mixed with aqueous ammonium chloride and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by a flash column chromatography to give the title compound as a pale yellow oil (2.0 g, 87% yield). LCMS: rt=3.52 min, [M+H+]=231.1 extracted with ethyl acetate The organic layer was washed with brine dried over Na2SO4 filtered concentrated The residue was purified by a flash column chromatography