diethyl 2-tert-butylpropanedioate

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

実験手順: To a stirred solution of sodium ethoxide (prepared from 2.55 g of sodium, 10 mmol) in ethanol (60 ml), was added diethyl tert-butylmalonate (20 g, 92 mmol). The mixture was heated up to reflux. Urea (5.83 g, 97 mmol) in hot ethanol (50 ml) was added and the mixture was refluxed for 6 hr. The mixture was then evaporated in vacuo and the residue was dissolved in water (80 ml). The solution was washed with ether and the water layer was cooled in an ice bath and acidified by the addition of conc. hydrochloric acid. The precipitate was filtered, washed with cold water and n-hexane, and dried in vacuo to give 8.22 g (48%) of a white solid. m.p. 247-248° C.; 1H NMR (200 MHz, DMSO-d6) δ 1.00 (9H, s), 2.83 (1H, s), 11.11 (2H, s). The mixture was heated up to reflux the mixture was refluxed for 6 hr The mixture was then evaporated in vacuo the residue was dissolved in water (80 ml) The solution was washed with ether the water layer was cooled in an ice bath acidified by the addition of conc. hydrochloric acid The precipitate was filtered washed with cold water and n-hexane dried in vacuo

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Diisobutylaluminum hydride (35.2 mL of a 1.0 M solution in toluene, 35.2 mmol) was added over 5 min to a solution of 2-tert-butyl-malonic acid diethyl ester (3.81 g, 17.6 mmol) in dichloromethane (33 mL) at −78° C. The reaction mixture was stirred at that temperature for 3.5 h, and then was quenched with saturated aqueous ammonium chloride (30 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially, and the mixture was allowed to warm to 25° C. over 1.5 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford crude product (2.34 g, 13.6 mmol, 77%). This material was dissolved in ethanol (40 mL) at 25° C. and 4-fluorobenzylamine (1.55 mL, 13.6 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.71 g, 27.2 mmol) were added sequentially. The mixture was stirred at 25° C. for 36 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-70% ethyl acetate in hexanes) to afford rac-2-[(4-fluoro-benzylamino)-methyl]-3-methyl-butyric acid ethyl ester (1.25 g, 4.44 mmol, 33%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.96 (9H, s), 1.28 (3H, t, J=7.0 Hz), 2.39 (1H, dd, J1=3.5 Hz, J2=11.4 Hz), 2.46 (1H, dd, J1=3.9 Hz, J2=9.5 Hz), 2.73 (1H, dd, J1=3.7 Hz, J2=11.7 Hz), 3.71 (2H, d, J=13.2 Hz), 3.78 (1H, d, J=13.4 Hz), 4.14-4.20 (2H, m), 6.95-7.00 (2H, m), 7.22-7.26 (2H, m). was quenched with saturated aqueous ammonium chloride (30 mL) The cold bath was removed 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL) The organic layer was dried over sodium sulfate was concentrated in vacuo to afford crude product (2.34 g, 13.6 mmol, 77%) The mixture was stirred at 25° C. for 36 h was concentrated in vacuo The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL) The combined organic layers were dried over sodium sulfate were concentrated in vacuo The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-70% ethyl acetate in hexanes)

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The commercially available 2-tert-butyl-malonic acid diethyl ester (1 g, 4.6 mmol) is dissolved in EtOH (7 mL). A 1N NaOH solution (5.06 mL, 5.06 mmol) is added and the resulting mixture is stirred at 40° C. overnight. Next, the mixture is acidified to pH=1 with HCl. Extraction with EtOAc gives an organic phase that is dried over MgSO4, filtered and evaporated to give the desired product. Extraction with EtOAc gives an organic phase that is dried over MgSO4 filtered evaporated

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

実験手順: To a stirred solution of sodium ethoxide (prepared from 2.55 g of sodium, 10 mmol) in ethanol (60 ml), was added diethyl tert-butylmalonate (20 g, 92 mmol). The mixture was heated up to reflux. Urea (5.83 g, 97 mmol) in hot ethanol (50 ml) was added and the mixture was refluxed for 6 hr. The mixture was then evaporated in vacuo and the residue was dissolved in water (80 ml). The solution was washed with ether and the water layer was cooled in an ice bath and acidified by the addition of conc. hydrochloric acid. The precipitate was filtered, washed with cold water and n-hexane, and dried in vacuo to give 8.22 g (48%) of a white solid. m.p. 247-248° C.; 1H NMR (200 MHz, DMSO-d6) δ 1.00 (9H, s), 2.83 (1H, s), 11.11 (2H, s). The mixture was heated up to reflux the mixture was refluxed for 6 hr The mixture was then evaporated in vacuo the residue was dissolved in water (80 ml) The solution was washed with ether the water layer was cooled in an ice bath acidified by the addition of conc. hydrochloric acid The precipitate was filtered washed with cold water and n-hexane dried in vacuo

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

実験手順: To a stirred solution of sodium ethoxide (prepared from 2.55 g of sodium, 10 mmol) in ethanol (60 ml), was added diethyl tert-butylmalonate (20 g, 92 mmol). The mixture was heated up to reflux. Urea (5.83 g, 97 mmol) in hot ethanol (50 ml) was added and the mixture was refluxed for 6 hr. The mixture was then evaporated in vacuo and the residue was dissolved in water (80 ml). The solution was washed with ether and the water layer was cooled in an ice bath and acidified by the addition of conc. hydrochloric acid. The precipitate was filtered, washed with cold water and n-hexane, and dried in vacuo to give 8.22 g (48%) of a white solid. m.p. 247-248° C.; 1H NMR (200 MHz, DMSO-d6) δ 1.00 (9H, s), 2.83 (1H, s), 11.11 (2H, s). The mixture was heated up to reflux the mixture was refluxed for 6 hr The mixture was then evaporated in vacuo the residue was dissolved in water (80 ml) The solution was washed with ether the water layer was cooled in an ice bath acidified by the addition of conc. hydrochloric acid The precipitate was filtered washed with cold water and n-hexane dried in vacuo

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Diisobutylaluminum hydride (35.2 mL of a 1.0 M solution in toluene, 35.2 mmol) was added over 5 min to a solution of 2-tert-butyl-malonic acid diethyl ester (3.81 g, 17.6 mmol) in dichloromethane (33 mL) at −78° C. The reaction mixture was stirred at that temperature for 3.5 h, and then was quenched with saturated aqueous ammonium chloride (30 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially, and the mixture was allowed to warm to 25° C. over 1.5 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford crude product (2.34 g, 13.6 mmol, 77%). This material was dissolved in ethanol (40 mL) at 25° C. and 4-fluorobenzylamine (1.55 mL, 13.6 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.71 g, 27.2 mmol) were added sequentially. The mixture was stirred at 25° C. for 36 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-70% ethyl acetate in hexanes) to afford rac-2-[(4-fluoro-benzylamino)-methyl]-3-methyl-butyric acid ethyl ester (1.25 g, 4.44 mmol, 33%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.96 (9H, s), 1.28 (3H, t, J=7.0 Hz), 2.39 (1H, dd, J1=3.5 Hz, J2=11.4 Hz), 2.46 (1H, dd, J1=3.9 Hz, J2=9.5 Hz), 2.73 (1H, dd, J1=3.7 Hz, J2=11.7 Hz), 3.71 (2H, d, J=13.2 Hz), 3.78 (1H, d, J=13.4 Hz), 4.14-4.20 (2H, m), 6.95-7.00 (2H, m), 7.22-7.26 (2H, m). was quenched with saturated aqueous ammonium chloride (30 mL) The cold bath was removed 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL) The organic layer was dried over sodium sulfate was concentrated in vacuo to afford crude product (2.34 g, 13.6 mmol, 77%) The mixture was stirred at 25° C. for 36 h was concentrated in vacuo The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL) The combined organic layers were dried over sodium sulfate were concentrated in vacuo The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-70% ethyl acetate in hexanes)

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Diisobutylaluminum hydride (35.2 mL of a 1.0 M solution in toluene, 35.2 mmol) was added over 5 min to a solution of 2-tert-butyl-malonic acid diethyl ester (3.81 g, 17.6 mmol) in dichloromethane (33 mL) at −78° C. The reaction mixture was stirred at that temperature for 3.5 h, and then was quenched with saturated aqueous ammonium chloride (30 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially, and the mixture was allowed to warm to 25° C. over 1.5 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford crude product (2.34 g, 13.6 mmol, 77%). This material was dissolved in ethanol (40 mL) at 25° C. and 4-fluorobenzylamine (1.55 mL, 13.6 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.71 g, 27.2 mmol) were added sequentially. The mixture was stirred at 25° C. for 36 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-70% ethyl acetate in hexanes) to afford rac-2-[(4-fluoro-benzylamino)-methyl]-3-methyl-butyric acid ethyl ester (1.25 g, 4.44 mmol, 33%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.96 (9H, s), 1.28 (3H, t, J=7.0 Hz), 2.39 (1H, dd, J1=3.5 Hz, J2=11.4 Hz), 2.46 (1H, dd, J1=3.9 Hz, J2=9.5 Hz), 2.73 (1H, dd, J1=3.7 Hz, J2=11.7 Hz), 3.71 (2H, d, J=13.2 Hz), 3.78 (1H, d, J=13.4 Hz), 4.14-4.20 (2H, m), 6.95-7.00 (2H, m), 7.22-7.26 (2H, m). was quenched with saturated aqueous ammonium chloride (30 mL) The cold bath was removed 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL) The organic layer was dried over sodium sulfate was concentrated in vacuo to afford crude product (2.34 g, 13.6 mmol, 77%) The mixture was stirred at 25° C. for 36 h was concentrated in vacuo The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL) The combined organic layers were dried over sodium sulfate were concentrated in vacuo The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-70% ethyl acetate in hexanes)

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The commercially available 2-tert-butyl-malonic acid diethyl ester (1 g, 4.6 mmol) is dissolved in EtOH (7 mL). A 1N NaOH solution (5.06 mL, 5.06 mmol) is added and the resulting mixture is stirred at 40° C. overnight. Next, the mixture is acidified to pH=1 with HCl. Extraction with EtOAc gives an organic phase that is dried over MgSO4, filtered and evaporated to give the desired product. Extraction with EtOAc gives an organic phase that is dried over MgSO4 filtered evaporated

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

実験手順: To a stirred solution of sodium ethoxide (prepared from 2.55 g of sodium, 10 mmol) in ethanol (60 ml), was added diethyl tert-butylmalonate (20 g, 92 mmol). The mixture was heated up to reflux. Urea (5.83 g, 97 mmol) in hot ethanol (50 ml) was added and the mixture was refluxed for 6 hr. The mixture was then evaporated in vacuo and the residue was dissolved in water (80 ml). The solution was washed with ether and the water layer was cooled in an ice bath and acidified by the addition of conc. hydrochloric acid. The precipitate was filtered, washed with cold water and n-hexane, and dried in vacuo to give 8.22 g (48%) of a white solid. m.p. 247-248° C.; 1H NMR (200 MHz, DMSO-d6) δ 1.00 (9H, s), 2.83 (1H, s), 11.11 (2H, s). The mixture was heated up to reflux the mixture was refluxed for 6 hr The mixture was then evaporated in vacuo the residue was dissolved in water (80 ml) The solution was washed with ether the water layer was cooled in an ice bath acidified by the addition of conc. hydrochloric acid The precipitate was filtered washed with cold water and n-hexane dried in vacuo

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The commercially available 2-tert-butyl-malonic acid diethyl ester (1 g, 4.6 mmol) is dissolved in EtOH (7 mL). A 1N NaOH solution (5.06 mL, 5.06 mmol) is added and the resulting mixture is stirred at 40° C. overnight. Next, the mixture is acidified to pH=1 with HCl. Extraction with EtOAc gives an organic phase that is dried over MgSO4, filtered and evaporated to give the desired product. Extraction with EtOAc gives an organic phase that is dried over MgSO4 filtered evaporated

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Diisobutylaluminum hydride (35.2 mL of a 1.0 M solution in toluene, 35.2 mmol) was added over 5 min to a solution of 2-tert-butyl-malonic acid diethyl ester (3.81 g, 17.6 mmol) in dichloromethane (33 mL) at −78° C. The reaction mixture was stirred at that temperature for 3.5 h, and then was quenched with saturated aqueous ammonium chloride (30 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially, and the mixture was allowed to warm to 25° C. over 1.5 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford crude product (2.34 g, 13.6 mmol, 77%). This material was dissolved in ethanol (40 mL) at 25° C. and 4-fluorobenzylamine (1.55 mL, 13.6 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.71 g, 27.2 mmol) were added sequentially. The mixture was stirred at 25° C. for 36 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-70% ethyl acetate in hexanes) to afford rac-2-[(4-fluoro-benzylamino)-methyl]-3-methyl-butyric acid ethyl ester (1.25 g, 4.44 mmol, 33%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.96 (9H, s), 1.28 (3H, t, J=7.0 Hz), 2.39 (1H, dd, J1=3.5 Hz, J2=11.4 Hz), 2.46 (1H, dd, J1=3.9 Hz, J2=9.5 Hz), 2.73 (1H, dd, J1=3.7 Hz, J2=11.7 Hz), 3.71 (2H, d, J=13.2 Hz), 3.78 (1H, d, J=13.4 Hz), 4.14-4.20 (2H, m), 6.95-7.00 (2H, m), 7.22-7.26 (2H, m). was quenched with saturated aqueous ammonium chloride (30 mL) The cold bath was removed 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL) The organic layer was dried over sodium sulfate was concentrated in vacuo to afford crude product (2.34 g, 13.6 mmol, 77%) The mixture was stirred at 25° C. for 36 h was concentrated in vacuo The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL) The combined organic layers were dried over sodium sulfate were concentrated in vacuo The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-70% ethyl acetate in hexanes)

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Diisobutylaluminum hydride (35.2 mL of a 1.0 M solution in toluene, 35.2 mmol) was added over 5 min to a solution of 2-tert-butyl-malonic acid diethyl ester (3.81 g, 17.6 mmol) in dichloromethane (33 mL) at −78° C. The reaction mixture was stirred at that temperature for 3.5 h, and then was quenched with saturated aqueous ammonium chloride (30 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially, and the mixture was allowed to warm to 25° C. over 1.5 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford crude product (2.34 g, 13.6 mmol, 77%). This material was dissolved in ethanol (40 mL) at 25° C. and 4-fluorobenzylamine (1.55 mL, 13.6 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.71 g, 27.2 mmol) were added sequentially. The mixture was stirred at 25° C. for 36 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-70% ethyl acetate in hexanes) to afford rac-2-[(4-fluoro-benzylamino)-methyl]-3-methyl-butyric acid ethyl ester (1.25 g, 4.44 mmol, 33%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.96 (9H, s), 1.28 (3H, t, J=7.0 Hz), 2.39 (1H, dd, J1=3.5 Hz, J2=11.4 Hz), 2.46 (1H, dd, J1=3.9 Hz, J2=9.5 Hz), 2.73 (1H, dd, J1=3.7 Hz, J2=11.7 Hz), 3.71 (2H, d, J=13.2 Hz), 3.78 (1H, d, J=13.4 Hz), 4.14-4.20 (2H, m), 6.95-7.00 (2H, m), 7.22-7.26 (2H, m). was quenched with saturated aqueous ammonium chloride (30 mL) The cold bath was removed 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL) The organic layer was dried over sodium sulfate was concentrated in vacuo to afford crude product (2.34 g, 13.6 mmol, 77%) The mixture was stirred at 25° C. for 36 h was concentrated in vacuo The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL) The combined organic layers were dried over sodium sulfate were concentrated in vacuo The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-70% ethyl acetate in hexanes)