乙基丙二酸

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1-8 (0.068 g, 0.36 mmol), ethylmalonic acid (0.052 g, 0.40 mmol), BOP (0.24 g, 0.54 mmol), and NMM (0.16 mL, 1.4 mmol) in DMF (1.8 mL) was stirred at ambient temperature for 20 h. The mixture was diluted with ethyl acetate, washed with water, brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed on silica gel, eluting with 15% ethanol/EtOAc to give 1-9 as a colorless glass. washed with water, brine dried over MgSO4 removal of the solvent the residue was chromatographed on silica gel eluting with 15% ethanol/EtOAc

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1-8 (0.068 g, 0.36 mmol), ethylmalonic acid (0.052 g, 0.40 mmol), BOP (0.24 g, 0.54 mmol), and NMM (0.16 mL, 1.4 mmol) in DMF (1.8 mL) was stirred at ambient temperature for 20 h. The mixture was diluted with ethyl acetate, washed with water, brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed on silica gel, eluting with 15% ethanol/EtOAc to give 1-9 as a colorless glass. washed with water, brine dried over MgSO4 removal of the solvent the residue was chromatographed on silica gel eluting with 15% ethanol/EtOAc

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Using 3.7 g (23 retool) of 3-carboxy-1,2-benzisoxazole prepared in accordance with a known process [J. Amer. Chem. Soc., 97, 7305 (1975)], 3.34 g (25 mmol) of ethylmalonic acid and 6.4 g of 3,4-dihydropyran, 3-butyryl-1,2-benzisoxazole was obtained as colorless crystals by similar treatment to Example 28-(4). Analytical results of the crystals obtained: Yield: 3.5 g (85%). Melting point: 33°-35° C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In 50 ml of benzene, 2.6 g (57.5 mmol) of 60% sodium hydride were added to dipyranyl ethylmalonate which had been prepared from 5.7 g (43.2 mmol) of ethylmalonic acid, 9.0 g (107.1 mmol) of 3,4-dihydropyran and 1 droplet of concentrated sulfuric acid. At 40°-50° C., the ethylmalonate was converted to sodium dipyranyl malonate, to which a tetrahydrofuran solution of 3-(4-methylphenyl)isoxazole-5-carboxylic acid chloride synthesized above in the procedure (3) was added dropwise at room temperature. They were reacted for 3 hours. The reaction mixture was added with 10 ml of acetic acid and then heated under reflux for 6 hours. The mixture thus obtained was added into water and then extracted with benzene. The benzene extract was washed successively with an aqueous solution of sodium hydrogencarbonate and water. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. Hexane was added to the residue, and 3-(4-methylphenyl)-5-butyrylisoxazole precipitated as crystals was collected by filtration. Analytical results of the crystals obtained: Yield: 6.3 g (76.5%). Melting point: 86°-87° C. At 40°-50° C. synthesized above in the procedure (3) was added dropwise at room temperature They were reacted for 3 hours heated under reflux for 6 hours The mixture thus obtained extracted with benzene The benzene extract was washed successively with an aqueous solution of sodium hydrogencarbonate and water The organic layer was dried over anhydrous sodium sulfate the solvent was distilled off Hexane was added to the residue, and 3-(4-methylphenyl)-5-butyrylisoxazole precipitated as crystals was collected by filtration Analytical results of the crystals obtained

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 130 ml of benzene, were added 12.9 g (97.7 mmol) of ethylmalonic acid, 20.2 g (240.5 mmol) of 3,4-dihydropyran and 2 droplets of concentrated sulfuric acid. They were reacted for 1 hour under ice cooling, whereby dipyranyl ethylmalonate was prepared. The reaction mixture was added with 4.7 g (117.5 mmol) of 60% sodium hydride, followed by heating under stirring at 50° C. for 5 hours. A solution of 15.0 g (79.4 mmol) of 3-phenylisoxazole-5-carboxylic acid chloride, which had been synthesized above in the procedure (3), in 70 ml of tetrahydrofuran was added under ice cooling to the above-prepared reaction mixture. The mixture thus obtained was then subjected to a reaction at room temperature for 12 hours. The reaction mixture was added with 20 ml of acetic acid and then heated under reflux for 8 hours. The reaction mixture so obtained was poured into water and then extracted with benzene. The organic layer was washed successively with water, an aqueous solution of sodium hydrogencarbonate and saturated saline, and was then dried over anhydrous sodium sulfate. After the benzene was distilled off, hexane was added into the residue. Crystals precipitated was collected by filtration, so that 3-phenyl-5-butyrylisoxazole was obtained. Analytical results of the crystals obtained: Yield: 14.6 g (85.6%). Melting point: 90°-92° C. They were reacted for 1 hour under ice cooling by heating was added under ice cooling to the above-prepared reaction mixture The mixture thus obtained was then subjected to a reaction at room temperature for 12 hours heated under reflux for 8 hours The reaction mixture so obtained extracted with benzene The organic layer was washed successively with water an aqueous solution of sodium hydrogencarbonate and saturated saline, and was then dried over anhydrous sodium sulfate After the benzene was distilled off hexane was added into the residue Crystals precipitated was collected by filtration, so that 3-phenyl-5-butyrylisoxazole was obtained Analytical results of the crystals obtained

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Using 3.7 g (23 mmol) of 3-carboxy-l,2-benzisoxazole prepared in accordance with a known process [J. Amer. Chem. Soc., 97, 7305 (1975)], 3.34 g (25 mmol) of ethylmalonic acid and 6.4 g of 3,4-dihydropyran, 3-butyryl-1,2-benzisoxazole was obtained as colorless crystals by similar treatment to Example 28-(4).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In 50 ml of benzene, 2.6 g (57.5 mmol) of 60% sodium hydride were added to dipyranyl ethylmalonate which had been prepared from 5.7 g (43.2 mmol) of ethylmalonic acid, 9.0 g (107.1 mmol) of 3,4-dihydropyran and 1 droplet of concentrated sulfuric acid. At 40°-50° C., the ethylmalonate was converted to sodium dipyranyl malonate, to which a tetrahydrofuran solution of 3-(4-methylphenyl)isoxazole-5-carboxylic acid chloride synthesized above in the procedure (3) was added dropwise at room temperature. They were reacted for 3 hours. The reaction mixture was added with 10 ml of acetic acid and then heated under reflux for 6 hours. The mixture thus obtained was added into water and then extracted with benzene. The benzene extract was washed successively with an aqueous solution of sodium hydrogencarbonate and water. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. Hexane was added to the residue, and 3-(4-methylphenyl)-5-butyrylisoxazole precipitated as crystals was collected by filtration. At 40°-50° C. synthesized above in the procedure (3) was added dropwise at room temperature They were reacted for 3 hours heated under reflux for 6 hours The mixture thus obtained extracted with benzene The benzene extract was washed successively with an aqueous solution of sodium hydrogencarbonate and water The organic layer was dried over anhydrous sodium sulfate the solvent was distilled off Hexane was added to the residue, and 3-(4-methylphenyl)-5-butyrylisoxazole precipitated as crystals was collected by filtration

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 130 ml of benzene, were added 12.9 g (97.7 mmol) of ethylmalonic acid, 20.2 g (240.5 mmol) of 3,4-dihydropyran and 2 droplets of concentrated suluric acid. They were reacted for 1 hour under ice cooling, whereby dipyranyl ethylmalonate was prepared. The reaction mixture was added with 4.7 g (117.5 mmol) of 60% sodium hydride, followed by heating under stirring at 50° C. for 5 hours. A solution of 15.0 g (79.4 mmol) of 3-phenylisoxazole-5-carboxylic acid chloride, which had been synthesized above in the procedure (3), in 70 ml of tetrahydrofuran was added under ice cooling to the above-prepared reaction mixture. The mixture thus obtained was then subjected to a reaction at room temperature for 12 hours. The reaction mixture was added with 20 ml of acetic acid and then heated under reflux for 8 hours. The reaction mixture so obtained was poured into water and then extracted with benzene. The organic layer was washed successively with water, an aqueous solution of sodium hydrogen- carbonate and saturated saline, and was then dried over anhydrous sodium sulfate. After the benzene was distilled off, hexane was added into the residue. Crystals precipitated was collected by filtration, so that 3-phenyl-5-butyrylisoxazole was obtained. They were reacted for 1 hour under ice cooling by heating was added under ice cooling to the above-prepared reaction mixture The mixture thus obtained was then subjected to a reaction at room temperature for 12 hours heated under reflux for 8 hours The reaction mixture so obtained extracted with benzene The organic layer was washed successively with water an aqueous solution of sodium hydrogen- carbonate and saturated saline, and was then dried over anhydrous sodium sulfate After the benzene was distilled off hexane was added into the residue Crystals precipitated was collected by filtration, so that 3-phenyl-5-butyrylisoxazole was obtained

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Using 3.7 g (23 mmol) of 3-carboxy-1,2-benzisoxazole prepared in accordance with a known process [J. Amer. Chem. Soc., 97, 7305 (1975)], 3.34 g (25 mmol) of ethylmalonic acid and 6.4 g of 3,4-dihydropyran, 3-butyryl-1,2-benzisoxazole was obtained as colorless crystals by similar treatment to Example 28-(4).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In 50 ml of benzene, 2.6 g (57.5 mmol) of 60% sodium hydride were added to dipyranyl ethylmalonate which had been prepared from 5.7 g (43.2 mmol) of ethylmalonic acid, 9.0 g (107.1 mmol) of 3,4-dihydropyran and 1 droplet of concentrated sulfuric acid. At 40°-50° C., the ethylmalonate was converted to sodium dipyranyl malonate, to which a tetrahydrofuran solution of 3-(4-methylphenyl)isoxazole-5-carboxylic acid chloride synthesized above in the procedure (3) was added dropwise at room temperature. They were reacted for 3 hours. The reaction mixture was added with 10 ml of acetic acid and then heated under reflux for 6 hours. The mixture thus obtained was added into water and then extracted with benzene. The benzene extract was washed successively with an aqueous solution of sodium hydrogencarbonate and water. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. Hexane was added to the residue, and 3-(4-methylphenyl)-5-butyrylisoxazole precipitated as crystals was collected by filtration. At 40°-50° C. synthesized above in the procedure (3) was added dropwise at room temperature They were reacted for 3 hours heated under reflux for 6 hours The mixture thus obtained extracted with benzene The benzene extract was washed successively with an aqueous solution of sodium hydrogencarbonate and water The organic layer was dried over anhydrous sodium sulfate the solvent was distilled off Hexane was added to the residue, and 3-(4-methylphenyl)-5-butyrylisoxazole precipitated as crystals was collected by filtration

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 130 ml of benzene, were added 12.9 g (97.7 mmol) of ethylmalonic acid, 20.2 g (240.5 mmol) of 3,4-dihydropyran and 2 droplets of concentrated sulfuric acid. They were reacted for 1 hour under ice cooling, whereby dipyranyl ethylmalonate was prepared. The reaction mixture was added with 4.7 g (117.5 mmol) of 60% sodium hydride, followed by heating under stirring at 50° C. for 5 hours. A solution of 15.0 g (79.4 mmol) of 3-phenylisoxazole-5-carboxylic acid chloride, which had been synthesized above in the procedure (3), in 70 ml of tetrahydrofuran was added under ice cooling to the above-prepared reaction mixture. The mixture thus obtained was then subjected to a reaction at room temperature for 12 hours. The reaction mixture was added with 20 ml of acetic acid and then heated under reflux for 8 hours. The reaction mixture so obtained was poured into water and then extracted with benzene. The organic layer was washed successively with water, an aqueous solution of sodium hydrogen-carbonate and saturated saline, and was then dried over anhydrous sodium sulfate. After the benzene was distilled off, hexane was added into the residue. Crystals precipitated was collected by filtration, so that 3-phenyl-5-butyrylisoxazole was obtained. They were reacted for 1 hour under ice cooling by heating was added under ice cooling to the above-prepared reaction mixture The mixture thus obtained was then subjected to a reaction at room temperature for 12 hours heated under reflux for 8 hours The reaction mixture so obtained extracted with benzene The organic layer was washed successively with water an aqueous solution of sodium hydrogen-carbonate and saturated saline, and was then dried over anhydrous sodium sulfate After the benzene was distilled off hexane was added into the residue Crystals precipitated was collected by filtration, so that 3-phenyl-5-butyrylisoxazole was obtained

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 2.0 g (15 mmol) of ethyl-malonic acid, 4.7 mL (31 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 3.9 mL (32 mmol) of benzyl bromide in 100 mL of benzene was refluxed for 22 hours. After cooling, the reaction was washed with 150 mL of H2O. After separating layers, the organic phase was dried over MgSO4 and concentrated. The residue was purified on a 40M Biotage column using 24:1 v/v hexane/EtOAc as the eluant to afford the title compound as a colorless oil: RF: 0.40 (9:1 v/v hexane/EtOAc); 1H-NMR (500 MHz) δ 0.97 (t, J=7.4, 3H), 1.99 (quint, J=7.4, 2H), 3.39 (t, J=7.4, 1H), 5.17 (s, 2H), 7.29–7.36 (m, 10H). After cooling the reaction was washed with 150 mL of H2O After separating layers the organic phase was dried over MgSO4 concentrated The residue was purified on a 40M Biotage column