ethyl 5,5-diethoxy-3-oxopentanoate

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

Procedure: To a solution of 11.8 g of the compound obtained in Step B (50.8 mmol) in 76 mL of water there are added, dropwise at 0° C., 6.6 ml of aqueous 40% methylamine solution (76.2 mmol). The reaction mixture is stirred and gently reheated to ambient temperature over 5 hours. After returning to 0° C., 8.8 mL of aqueous 40% methylamine solution (102 mmol) and then 16.6 mL of aqueous 50% chloroacetaldehyde solution (127 mmol) are each added dropwise at a temperature of less than 10° C. The reaction mixture is stirred at ambient temperature for 16 hours and then diluted with ethyl acetate. The organic phase is washed with brine, dried over MgSO4 and concentrated to dryness. The crude product thereby obtained is purified by chromatography over silica gel using petroleum ether and ethyl acetate as eluants. The title product is obtained in the form of an oil. After returning to 0° C. each added dropwise at a temperature of less than 10° C The reaction mixture is stirred at ambient temperature for 16 hours The organic phase is washed with brine dried over MgSO4 concentrated to dryness The crude product thereby obtained is purified by chromatography over silica gel

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 16 mL of 3-ethoxy-3-oxomalonic acid (135 mmol) in 40 mL of tetrahydrofuran there are added, under argon, 21.9 g of powdered magnesium (90.4 mmol). The mixture obtained is then heated at 80° C. for 7 hours. After returning to ambient temperature, this mixture is transferred by cannula to a solution of 10 g of the compound obtained in Step A (61.7 mmol) in 64 mL of tetrahydrofuran to which there has previously been added, in portions, 11 g of carbonyldiimidazole (66 mmol). The reaction mixture is stirred for 3 days at ambient temperature. After concentration, the residue is taken up in a mixture of ethyl acetate and aqueous sodium hydrogen sulphate (NaHSO4) solution. The mixture is stirred vigorously until no more gas is evolved. After separation of the phases, the organic phase is washed successively with water, saturated aqueous NaHCO3 solution and finally brine. After drying over MgSO4 and concentrating to dryness, the title product is obtained in the form of an oil which is used in the next Step without being otherwise purified. The mixture obtained After returning to ambient temperature After concentration the residue is taken up in a mixture of ethyl acetate and aqueous sodium hydrogen sulphate (NaHSO4) solution The mixture is stirred vigorously until no more gas After separation of the phases the organic phase is washed successively with water, saturated aqueous NaHCO3 solution and finally brine After drying over MgSO4 concentrating to dryness

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 16 mL of 3-ethoxy-3-oxomalonic acid (135 mmol) in 40 mL of tetrahydrofuran there are added, under argon, 21.9 g of powdered magnesium (90.4 mmol). The mixture obtained is then heated at 80° C. for 7 hours. After returning to ambient temperature, this mixture is transferred by cannula to a solution of 10 g of the compound obtained in Step A (61.7 mmol) in 64 mL of tetrahydrofuran to which there has previously been added, in portions, 11 g of carbonyldiimidazole (66 mmol). The reaction mixture is stirred for 3 days at ambient temperature. After concentration, the residue is taken up in a mixture of ethyl acetate and aqueous sodium hydrogen sulphate (NaHSO4) solution. The mixture is stirred vigorously until no more gas is evolved. After separation of the phases, the organic phase is washed successively with water, saturated aqueous NaHCO3 solution and finally brine. After drying over MgSO4 and concentrating to dryness, the title product is obtained in the form of an oil which is used in the next Step without being otherwise purified. The mixture obtained After returning to ambient temperature After concentration the residue is taken up in a mixture of ethyl acetate and aqueous sodium hydrogen sulphate (NaHSO4) solution The mixture is stirred vigorously until no more gas After separation of the phases the organic phase is washed successively with water, saturated aqueous NaHCO3 solution and finally brine After drying over MgSO4 concentrating to dryness

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

Procedure: To a solution of 11.8 g of the compound obtained in Step B (50.8 mmol) in 76 mL of water there are added, dropwise at 0° C., 6.6 ml of aqueous 40% methylamine solution (76.2 mmol). The reaction mixture is stirred and gently reheated to ambient temperature over 5 hours. After returning to 0° C., 8.8 mL of aqueous 40% methylamine solution (102 mmol) and then 16.6 mL of aqueous 50% chloroacetaldehyde solution (127 mmol) are each added dropwise at a temperature of less than 10° C. The reaction mixture is stirred at ambient temperature for 16 hours and then diluted with ethyl acetate. The organic phase is washed with brine, dried over MgSO4 and concentrated to dryness. The crude product thereby obtained is purified by chromatography over silica gel using petroleum ether and ethyl acetate as eluants. The title product is obtained in the form of an oil. After returning to 0° C. each added dropwise at a temperature of less than 10° C The reaction mixture is stirred at ambient temperature for 16 hours The organic phase is washed with brine dried over MgSO4 concentrated to dryness The crude product thereby obtained is purified by chromatography over silica gel

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 16 mL of 3-ethoxy-3-oxomalonic acid (135 mmol) in 40 mL of tetrahydrofuran there are added, under argon, 21.9 g of powdered magnesium (90.4 mmol). The mixture obtained is then heated at 80° C. for 7 hours. After returning to ambient temperature, this mixture is transferred by cannula to a solution of 10 g of the compound obtained in Step A (61.7 mmol) in 64 mL of tetrahydrofuran to which there has previously been added, in portions, 11 g of carbonyldiimidazole (66 mmol). The reaction mixture is stirred for 3 days at ambient temperature. After concentration, the residue is taken up in a mixture of ethyl acetate and aqueous sodium hydrogen sulphate (NaHSO4) solution. The mixture is stirred vigorously until no more gas is evolved. After separation of the phases, the organic phase is washed successively with water, saturated aqueous NaHCO3 solution and finally brine. After drying over MgSO4 and concentrating to dryness, the title product is obtained in the form of an oil which is used in the next Step without being otherwise purified. The mixture obtained After returning to ambient temperature After concentration the residue is taken up in a mixture of ethyl acetate and aqueous sodium hydrogen sulphate (NaHSO4) solution The mixture is stirred vigorously until no more gas After separation of the phases the organic phase is washed successively with water, saturated aqueous NaHCO3 solution and finally brine After drying over MgSO4 concentrating to dryness