ethyl 4-oxobutanoate

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 0-5° C. mechanically-stirred solution in diethyl ether (100 mL) of succinaldehydic acid ethyl ester (10.0 g, 77 mmol) was added bromine (3.9 g, 151 mmol) over 2.5 hours. The reaction mixture was stirred for an additional 1.25 hours and the ether was distilled at atmospheric pressure. The remaining yellow oil was distilled (6.0-6.5 mm Hg, bp 95-101° C.) to give 3-bromosuccinaldehydic acid ethyl ester (10.7 g, 66%). the ether was distilled at atmospheric pressure The remaining yellow oil was distilled (6.0-6.5 mm Hg, bp 95-101° C.)

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

実験手順: A suspension of N-benzylglycinamide (35.5 g, 0.22 mol) and ethyl 4-oxobutanoate (31 g, 0.24 mol) in toluene (370 ml) was refluxed for 6 hours in a Dean-Stark apparatus. After cooling, the mixture was extracted twice with 10% sulphuric acid (200+100 ml); the aqueous extracts were neutralized with sodium hydrogen carbonate and extracted twice with toluene (250 ml of each time). The organic solution was washed with water (100 ml), dried (MgSO4) and evaporated under vacuum to afford an oil which was triturated with a mixture of diethyl ether-light petroleum (1:2) to give 45 g (75%), of the title compound as a yellow solid, m.p. 60°-62° C. NMR (CDCl3): deltaH =7.5 (bs, 1H, NH); 7.30 (bs, 5H, PhH); 4.5-4.25 (ABX, 1H, CH--M); 4.13 (q, J=6.9 Hz, 2H, OCH2); 4.00 and 3.53 (ABq, J= 12.4 Hz, 2H, PhCH2); 3.37 and 3.02 (ABX, J=14.9 Hz, 2H, NCH2CO); 2.65-2.30 (c.a., 2H, CH2CH2CO); 2.20-1.15 (c.a., 2H, CH2CH2CO); 1.24 (t, J=6.9 Hz, 3H, CH3). MS (E.I., 70 eV, 1.5 mA) m/z=276 (M+), 231 (M--OEt)+, 185 (M--PhCH2)+, 175 (M--C5H9O2)+, 91 (PhCH2)+. was refluxed for 6 hours in a Dean-Stark apparatus After cooling the mixture was extracted twice with 10% sulphuric acid (200+100 ml) extracted twice with toluene (250 ml of each time) The organic solution was washed with water (100 ml) dried (MgSO4) evaporated under vacuum to afford an oil which was triturated with a mixture of diethyl ether-light petroleum (1:2) to give 45 g (75%)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-[4-(3-chloro-propoxy)-phenyl]-3-methyl-4-oxo-butyric acid ethyl ester (7 g, 22 mmol), K2CO3 (9.3 g, 67 mmol), NaI (330 mg, 2.2 mmol), and (R)-methyl-pyrrolidinium benzenesulfonate (11 g, 47 mmol) in CH3CN (160 mL) was heated under argon at 80° C. for 36 h. The reaction mixture was concentrated at reduced pressure and partitioned between saturated aqueous sodium bicarbonate solution and methylene chloride. The aqueous layer was extracted twice with methylene chloride and the combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude material. The crude material was purified by ISCO (80 g siliga gel column) chromatography using 2% to 9% methanol in methylene chloride to 10% methanol containing 2.5 mL ammonium hydroxide in methylene chloride to afford a pure product. The pure product was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4), filtered, and concentrated to give 3-methyl-4-{4-R-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4-oxo-butyric acid ethyl ester (8.39 g, quantitative yield), MS m/z 362 (M+H). The reaction mixture was concentrated at reduced pressure partitioned between saturated aqueous sodium bicarbonate solution and methylene chloride The aqueous layer was extracted twice with methylene chloride the combined organics was washed with brine dried (Na2SO4) filtered concentrated to provide a crude material The crude material was purified by ISCO (80 g siliga gel column) chromatography to afford a pure product washed with saturated aqueous sodium bicarbonate solution, brine dried (Na2SO4) filtered concentrated

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

実験手順: A mixture of 4-[4-(3-chloropropoxy)-3,5-difluorophenyl]-4-oxo-butyric acid ethyl ester (5 g, 14.9 mmol), K2CO3 (7.2 g, 52.1 mmol), NaI (220 mg, 1.4 mmol), and Benzenesulfonate; (R)-methylpyrrolidinium (8 g, 33 mmol) in CH3CN (110 mL) was heated under argon at 80° C. for 36 h. The reaction was concentrated and partitioned between saturated aqueous sodium bicarbonate solution and methylene chloride. The aqueous layer was extracted twice with methylene chloride and the combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude material (96% purity). The crude material was purified by ISCO (80 g silica gel column) chromatography using 2% to 9% methanol in methylene chloride to 10% methanol containing 0.1% ammonium hydroxide in methylene chloride. The isolated material was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4), filtered, and concentrated. The isolated material was crystallized with a mixture of methylene chloride, ether and hexane to obtain 4-{3,5-difluoro-4[3-(R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4-oxo-butyric acid ethyl ester (3.97 g, 70%, 99% purity), MS m/z=384 (M+H). The reaction was concentrated partitioned between saturated aqueous sodium bicarbonate solution and methylene chloride The aqueous layer was extracted twice with methylene chloride the combined organics was washed with brine dried (Na2SO4) filtered concentrated to provide a crude material (96% purity) The crude material was purified by ISCO (80 g silica gel column) chromatography The isolated material was dissolved in methylene chloride washed with saturated aqueous sodium bicarbonate solution, brine dried (Na2SO4) filtered concentrated The isolated material was crystallized with a mixture of methylene chloride, ether and hexane

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

実験手順: A suspension of N-benzylglycinamide (35.5 g, 0.22 mol) and ethyl 4-oxobutanoate (31g, 0.24 mol) in toluene (370 ml) was refluxed for 6 hours in a Dean-Stark apparatus. After cooling, the mixture was extracted twice with 10% sulphuric acid (200+100 ml); the aqueous extracts were neutralized with sodium hydrogen carbonate and extracted twice with toluene (250 ml each time). The organic solution was washed with water (100 ml), dried (MgSO4) and evaporated under vacuum to afford an oil which was triturated with a mixture of diethyl ether -light petroleum (1:2) to give 45 g (75%), of the title compound as a yellow solid, m.p. 60°-62° C. NMR (CDCl3): deltaH =7.5 (bs, 1H, NH); 7.30 (bs, 5H, PhH); 4.5-4.25 (ABX, 1H, CH--M); 4.13 (q, J=6.9 Hz, 2H, OCH2); 4.00 and 3.53 (ABq, J=12.4 Hz, 2H, PhCH2); 3.37 and 3.02 (ABX, J=14.9 Hz, 2H, NCH2CO); 2.65-2.30 (c.a., 2H, CH2CH2CO); 2.20-1.15 (c.a., 2H, CH2CH2CO); 1.24 (t, J=6.9 Hz, 3H, CH3). MS (E.I., 70 eV, 1.5 mA) m/z=276 (M+), 231 (M--OEt)+, 185 (M--PhCH2)+, 175 (M - C5H9O2)+, 91 (PhCH2)+. was refluxed for 6 hours in a Dean-Stark apparatus After cooling the mixture was extracted twice with 10% sulphuric acid (200+100 ml) extracted twice with toluene (250 ml each time) The organic solution was washed with water (100 ml) dried (MgSO4) evaporated under vacuum to afford an oil which was triturated with a mixture of diethyl ether -light petroleum (1:2) to give 45 g (75%)

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A suspension of 90.0 g (0.798 mol) of glycinamide hydrochloride (purity 98%) in 7.2 liter of n-propanol is heated to reflux, and 250 ml of solvent are distilled off. A 15% w/v solution of sodium tert-butoxide in n-propanol (260 ml, 0.35 mol) are added and an apparent pH of 5.5 is measured. Maintaining this apparent pH at 5.5 by automatic addition of a 15% w/v solution of sodium tert-butoxide in n-propanol, ethyl 4-oxobutanoate (purity 97%) (262.3 g, 1.955 mol) is added dropwise during four hours while keeping the reaction mixture at reflux, continuously distilling the solvent at about 400 ml/h and continuously adding n-propanol to the reaction mixture at about 400 ml/h. A total amount of 363 ml (0.476 mol) of sodium tert-butoxide 15% w/w solution in n-propanol is added. The mixture is stirred at reflux for additional 1.5 hours and then cooled to 65° C. A 7.5% w/w solution of ammonia in n-propanol (800 g) is slowly added to the mixture during 6 hours, and heating at 65° C. is continued for additional 18 hours. The reaction mixture is cooled to room temperature and the precipitate is filtered off. The clear solution is concentrated to a small volume (about 0.5 liter) under vacuum and stirred at 0° C. for 2 hours. The white precipitate is collected by suction filtration, washed with 50 ml of n-propanol and dried under vacuum at 60° C. for 12 hours to afford pure dimiracetam (65 g, 58.1%), melting at 154° C. HPLC purity: 99.7% is heated to reflux 250 ml of solvent are distilled off are added Maintaining this apparent pH at 5.5 is added dropwise during four hours at reflux continuously distilling the solvent at about 400 ml/h and continuously adding n-propanol to the reaction mixture at about 400 ml/h at reflux for additional 1.5 hours heating at 65° C. The reaction mixture is cooled to room temperature the precipitate is filtered off The clear solution is concentrated to a small volume (about 0.5 liter) under vacuum stirred at 0° C. for 2 hours The white precipitate is collected by suction filtration washed with 50 ml of n-propanol dried under vacuum at 60° C. for 12 hours

反応条件: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2.56 g (22.7 mmol) of glycinamide hydrochloride (purity 98%) in 200 ml of water is heated to 95° C. and the pH adjusted to 6.6 with Na2CO3 20% w/v in water. Then ethyl 4-oxobutanoate (purity 97%) (7.60 g, 56.6 mmol) are added dropwise during four hours maintaining the temperature at 95° C. and the pH at 6.6 by automated addition (pHstat) of Na2CO3 20% w/v in water. The solution is stirred at 95° C. for 1.5 hours and then concentrated to a small volume under vacuum. The obtained suspension is treated with 50 ml of isopropanol and the solvent is evaporated at atmospheric pressure. This operation is repeated once again. The residue is diluted with 50 ml of isopropanol and the resulting suspension heated to 60° C. and then filtered. The filtrate is concentrated to about 15 ml, cooled to room temperature and stirring continued for about 2 hours. The white precipitate is collected by suction filtration, washed with 4 ml of isopropanol and dried under vacuum at 60° C. for 12 hours, resulting in 1.8 g of crude dimiracetam (12.8 mmol, 55.5%). Recrystallization from isopropanol (10 volumes) affords 1.6 g (50%) of pure dimiracetam (>99.5% as determined from area % HPLC). Melting point: 154° C. concentrated to a small volume under vacuum The obtained suspension is treated with 50 ml of isopropanol the solvent is evaporated at atmospheric pressure The residue is diluted with 50 ml of isopropanol the resulting suspension heated to 60° C. filtered The filtrate is concentrated to about 15 ml cooled to room temperature stirring continued for about 2 hours The white precipitate is collected by suction filtration washed with 4 ml of isopropanol dried under vacuum at 60° C. for 12 hours

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

実験手順: To a 0-5° C. mechanically-stirred solution in diethyl ether (100 mL) of succinaldehydic acid ethyl ester (10.0 g, 77 mmol) was added bromine (3.9 g, 151 mmol) over 2.5 hours. The reaction mixture was stirred for an additional 1.25 hours and the ether was distilled at atmospheric pressure. The remaining yellow oil was distilled (6.0-6.5 mm Hg, bp 95-101° C.) to give 3-bromosuccinaldehydic acid ethyl ester (10.7 g, 66%). the ether was distilled at atmospheric pressure The remaining yellow oil was distilled (6.0-6.5 mm Hg, bp 95-101° C.)

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

実験手順: A suspension of N-benzylglycinamide (35.5 g, 0.22 mol) and ethyl 4-oxobutanoate (31 g, 0.24 mol) in toluene (370 ml) was refluxed for 6 hours in a Dean-Stark apparatus. After cooling, the mixture was extracted twice with 10% sulphuric acid (200+100 ml); the aqueous extracts were neutralized with sodium hydrogen carbonate and extracted twice with toluene (250 ml of each time). The organic solution was washed with water (100 ml), dried (MgSO4) and evaporated under vacuum to afford an oil which was triturated with a mixture of diethyl ether-light petroleum (1:2) to give 45 g (75%), of the title compound as a yellow solid, m.p. 60°-62° C. NMR (CDCl3): deltaH =7.5 (bs, 1H, NH); 7.30 (bs, 5H, PhH); 4.5-4.25 (ABX, 1H, CH--M); 4.13 (q, J=6.9 Hz, 2H, OCH2); 4.00 and 3.53 (ABq, J= 12.4 Hz, 2H, PhCH2); 3.37 and 3.02 (ABX, J=14.9 Hz, 2H, NCH2CO); 2.65-2.30 (c.a., 2H, CH2CH2CO); 2.20-1.15 (c.a., 2H, CH2CH2CO); 1.24 (t, J=6.9 Hz, 3H, CH3). MS (E.I., 70 eV, 1.5 mA) m/z=276 (M+), 231 (M--OEt)+, 185 (M--PhCH2)+, 175 (M--C5H9O2)+, 91 (PhCH2)+. was refluxed for 6 hours in a Dean-Stark apparatus After cooling the mixture was extracted twice with 10% sulphuric acid (200+100 ml) extracted twice with toluene (250 ml of each time) The organic solution was washed with water (100 ml) dried (MgSO4) evaporated under vacuum to afford an oil which was triturated with a mixture of diethyl ether-light petroleum (1:2) to give 45 g (75%)

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

実験手順: A suspension of N-benzylglycinamide (35.5 g, 0.22 mol) and ethyl 4-oxobutanoate (31 g, 0.24 mol) in toluene (370 ml) was refluxed for 6 hours in a Dean-Stark apparatus. After cooling, the mixture was extracted twice with 10% sulphuric acid (200+100 ml); the aqueous extracts were neutralized with sodium hydrogen carbonate and extracted twice with toluene (250 ml of each time). The organic solution was washed with water (100 ml), dried (MgSO4) and evaporated under vacuum to afford an oil which was triturated with a mixture of diethyl ether-light petroleum (1:2) to give 45 g (75%), of the title compound as a yellow solid, m.p. 60°-62° C. NMR (CDCl3): deltaH =7.5 (bs, 1H, NH); 7.30 (bs, 5H, PhH); 4.5-4.25 (ABX, 1H, CH--M); 4.13 (q, J=6.9 Hz, 2H, OCH2); 4.00 and 3.53 (ABq, J= 12.4 Hz, 2H, PhCH2); 3.37 and 3.02 (ABX, J=14.9 Hz, 2H, NCH2CO); 2.65-2.30 (c.a., 2H, CH2CH2CO); 2.20-1.15 (c.a., 2H, CH2CH2CO); 1.24 (t, J=6.9 Hz, 3H, CH3). MS (E.I., 70 eV, 1.5 mA) m/z=276 (M+), 231 (M--OEt)+, 185 (M--PhCH2)+, 175 (M--C5H9O2)+, 91 (PhCH2)+. was refluxed for 6 hours in a Dean-Stark apparatus After cooling the mixture was extracted twice with 10% sulphuric acid (200+100 ml) extracted twice with toluene (250 ml of each time) The organic solution was washed with water (100 ml) dried (MgSO4) evaporated under vacuum to afford an oil which was triturated with a mixture of diethyl ether-light petroleum (1:2) to give 45 g (75%)