ethyl 3-(benzylamino)-3-oxopropanoate

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

Procedure: Sodium hydride (a 60% of dispersion in oil) (189 mg) is suspended in 1,2-dimethoxyethane (20 ml), and the mixture is cooled with ice-water. A solution of ethyl (N-benzylcarbamoyl)acetate (1.002 g) in 1,2-dimethoxyethane (23 ml) is added dropwise to the mixture. The mixture is stirred for 30 minutes. Then, 2-methylthio-1,3-dithiolium iodide (1.309 g) is added to the mixture, and the mixture is stirred at room temperature for 2 hours and then at 40° C. to 50° C. for one hour. After cooling, the mixture is poured into ice-water, and the aqueous solution is extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove the solvent. The residue thus obtained is treated in the same manner as described in Example 22-(2), whereby ethyl 2-(1,3-dithiol-2-ylidene)-2-(N-benzylcarbamoyl)acetate (595 mg) is obtained. the mixture is stirred at room temperature for 2 hours at 40° C. to 50° C. for one hour After cooling the aqueous solution is extracted with ethyl acetate The extract is washed with water dried evaporated to remove the solvent The residue thus obtained is treated in the same manner

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

Procedure: Ethyl (N-benzylcarbamoyl)acetate (39.00 g) and carbon disulfide (14.03 g) are dissolved in dimethylsulfoxide (390 ml). A solution of potassium hydroxide (21.52 g) in water (39 ml) is added dropwise to the mixture at 20° to 40° C. The mixture is stirred at the same temperature for 30 minutes, and then cis-1,2-dichloroethylene (17.84 g) is added dropwise thereto. The mixture is stirred at 50° C. for 5 hours. Cis-1,2-dichloroethylene (3.24 g) is further added to the mixture 3 hours after the commencement of the reaction. After cooling, the mixture is poured into water, and the aqueous solution is extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate=2:1), and then recrystallized from a mixture of n-hexane and ethyl acetate, whereby ethyl 2-(1,3-dithiol-2-ylidene)-2-(N-benzylcarbamoyl)acetate (33.77 g) is obtained as pale yellow prisms. Yield: 62.8%. The mixture is stirred at 50° C. for 5 hours after the commencement of the reaction After cooling the aqueous solution is extracted with ethyl acetate The extract is washed with water dried evaporated to remove the solvent The residue is purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate=2:1) recrystallized from a mixture of n-hexane and ethyl acetate

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

Procedure: A mixture of benzylamine (43.24 g) and methylene chloride (300 ml) is cooled with ice-water, and a solution of ethoxycarbonylacetyl chloride (29.63 g) in methylene chloride (150 ml) is added dropwise thereto. The mixture is stirred at the same temperature for 2 hours. The mixture is filtered to remove precipitates (benzylamine hydrochloride). The filtrate is washed with 2% hydrochloric acid and a saturated sodium chloride solution, dried and then evaporated to remove the solvent. The residue is recrystallized from a mixture of ether and n-hexane, whereby ethyl (N-benzylcarbamoyl)acetate (42.15 g) is obtained as colorless needles. Yield: 96.8%. The mixture is filtered to remove precipitates (benzylamine hydrochloride) The filtrate is washed with 2% hydrochloric acid a saturated sodium chloride solution, dried evaporated to remove the solvent The residue is recrystallized from a mixture of ether and n-hexane

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

Procedure: A mixture of benzylamine (43.24 g) and methylene chloride (300 ml) is cooled with ice-water, and a solution of ethoxycarbonylacetyl chloride (29.63 g) in methylene chloride (150 ml) is added dropwise thereto. The mixture is stirred at the same temperature for 2 hours. The mixture is filtered to remove precipitates (benzylamine hydrochloride). The filtrate is washed with 2% hydrochloric acid and a saturated sodium chloride solution, dried and then evaporated to remove the solvent. The residue is recrystallized from a mixture of ether and n-hexane, whereby ethyl (N-benzylcarbamoyl)acetate (42.15 g) is obtained as colorless needles. Yield: 96.8%. The mixture is filtered to remove precipitates (benzylamine hydrochloride) The filtrate is washed with 2% hydrochloric acid a saturated sodium chloride solution, dried evaporated to remove the solvent The residue is recrystallized from a mixture of ether and n-hexane

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

Procedure: A solution of benzylamine (1.10 g, 10.3 mmol) and ethyl malonyl chloride (1.29 mL, 10.3 mmol) in dichloromethane (10 mL) was treated with triethylamine (1.44 mL, 10.3 mmol). The solution was stirred at ambient temperature for 1 h and then diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×20 mL). The combined organic portions were dried over magnesium sulfate, filtered, and concentrated in vacuo to obtain the title compound as a yellow oil (2.27 g, 100%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.55 (br. s., 1H), 7.24-7.36 (m, 5H), 4.45 (d, J=5.6 Hz, 2H), 4.17 (q, J=7.2 Hz, 2H), 3.31 (s, 2H), 1.27 (t, J=7.2 Hz, 3H). MS(ES+) m/e 222 [M+H]+. extracted with ethyl acetate (3×20 mL) The combined organic portions were dried over magnesium sulfate filtered concentrated in vacuo

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

Procedure: Sodium hydride (a 60% of dispersion in oil) (189 mg) is suspended in 1,2-dimethoxyethane (20 ml), and the mixture is cooled with ice-water. A solution of ethyl (N-benzylcarbamoyl)acetate (1.002 g) in 1,2-dimethoxyethane (23 ml) is added dropwise to the mixture. The mixture is stirred for 30 minutes. Then, 2-methylthio-1,3-dithiolium iodide (1.309 g) is added to the mixture, and the mixture is stirred at room temperature for 2 hours and then at 40° C. to 50° C. for one hour. After cooling, the mixture is poured into ice-water, and the aqueous solution is extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove the solvent. The residue thus obtained is treated in the same manner as described in Example 22-(2), whereby ethyl 2-(1,3-dithiol-2-ylidene)-2-(N-benzylcarbamoyl)acetate (595 mg) is obtained. the mixture is stirred at room temperature for 2 hours at 40° C. to 50° C. for one hour After cooling the aqueous solution is extracted with ethyl acetate The extract is washed with water dried evaporated to remove the solvent The residue thus obtained is treated in the same manner

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

Procedure: Ethyl (N-benzylcarbamoyl)acetate (39.00 g) and carbon disulfide (14.03 g) are dissolved in dimethylsulfoxide (390 ml). A solution of potassium hydroxide (21.52 g) in water (39 ml) is added dropwise to the mixture at 20° to 40° C. The mixture is stirred at the same temperature for 30 minutes, and then cis-1,2-dichloroethylene (17.84 g) is added dropwise thereto. The mixture is stirred at 50° C. for 5 hours. Cis-1,2-dichloroethylene (3.24 g) is further added to the mixture 3 hours after the commencement of the reaction. After cooling, the mixture is poured into water, and the aqueous solution is extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate=2:1), and then recrystallized from a mixture of n-hexane and ethyl acetate, whereby ethyl 2-(1,3-dithiol-2-ylidene)-2-(N-benzylcarbamoyl)acetate (33.77 g) is obtained as pale yellow prisms. Yield: 62.8%. The mixture is stirred at 50° C. for 5 hours after the commencement of the reaction After cooling the aqueous solution is extracted with ethyl acetate The extract is washed with water dried evaporated to remove the solvent The residue is purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate=2:1) recrystallized from a mixture of n-hexane and ethyl acetate

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

Procedure: A mixture of benzylamine (43.24 g) and methylene chloride (300 ml) is cooled with ice-water, and a solution of ethoxycarbonylacetyl chloride (29.63 g) in methylene chloride (150 ml) is added dropwise thereto. The mixture is stirred at the same temperature for 2 hours. The mixture is filtered to remove precipitates (benzylamine hydrochloride). The filtrate is washed with 2% hydrochloric acid and a saturated sodium chloride solution, dried and then evaporated to remove the solvent. The residue is recrystallized from a mixture of ether and n-hexane, whereby ethyl (N-benzylcarbamoyl)acetate (42.15 g) is obtained as colorless needles. Yield: 96.8%. The mixture is filtered to remove precipitates (benzylamine hydrochloride) The filtrate is washed with 2% hydrochloric acid a saturated sodium chloride solution, dried evaporated to remove the solvent The residue is recrystallized from a mixture of ether and n-hexane

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

Procedure: A solution of benzylamine (1.10 g, 10.3 mmol) and ethyl malonyl chloride (1.29 mL, 10.3 mmol) in dichloromethane (10 mL) was treated with triethylamine (1.44 mL, 10.3 mmol). The solution was stirred at ambient temperature for 1 h and then diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×20 mL). The combined organic portions were dried over magnesium sulfate, filtered, and concentrated in vacuo to obtain the title compound as a yellow oil (2.27 g, 100%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.55 (br. s., 1H), 7.24-7.36 (m, 5H), 4.45 (d, J=5.6 Hz, 2H), 4.17 (q, J=7.2 Hz, 2H), 3.31 (s, 2H), 1.27 (t, J=7.2 Hz, 3H). MS(ES+) m/e 222 [M+H]+. extracted with ethyl acetate (3×20 mL) The combined organic portions were dried over magnesium sulfate filtered concentrated in vacuo