* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 5, p. 1151 - 1175
2
[ 51535-00-3 ]
[ 5733-86-8 ]
Yield
Reaction Conditions
Operation in experiment
97%
With lithium hydroxide In tetrahydrofuran; methanol; water for 0.333333 h; Heating / reflux
Methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate (2.00 g, 8.57 mmol) was dissolved in a mixed solvent of methanol (10 ml) and tetrahydrofuran (10 ml), followed by adding thereto a 2N aqueous lithium hydroxide solution (8.6 ml, 17.2 mmol), and the resulting mixture was heated under reflux for 20 minutes. After completion of the reaction, the reaction solution was ice-cooled, made into an acidic solution with an aqueous potassium hydrogensulfate solution, and then extracted with ethyl acetate. The ethyl acetate layer was concentrated, washed by repulping (ethyl acetate/hexane), and then dried to obtain 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid (1.83 g, 97percent).1H-NMR (DMSO-d6) δ; 2.56 (2H, m), 3.80 (1H, m), 3.15 (2H, m), 3.25 (2H, m), 4.36 (2H, q, J=8.6Hz), 7.27 (5H, m), 12.61 (1H, s).
Reference：
[1] Patent: EP1403255, 2004, A1, . Location in patent: Page 78
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 15, p. 2374 - 2385
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 377 - 379
[4] European Journal of Organic Chemistry, 2005, # 4, p. 673 - 682
[5] Patent: WO2006/123725, 2006, A1, . Location in patent: Page/Page column 64-65
3
[ 97-65-4 ]
[ 100-46-9 ]
[ 5733-86-8 ]
Yield
Reaction Conditions
Operation in experiment
82.9%
at 130℃; for 2.5 h; Inert atmosphere
A solution of itaconic acid (18 g, 0.138 mol)And thiamine (14.8 g, 0.138 mol) in a reaction flask,N2 protection,Heated to 130 ° C,Stirring slowly after melting,Reaction 2.5h,Stop heating,When cooled to 100 ° C,200 ml of a 10percent NaOH solution was added under stirring,Cooled to room temperature,The aqueous layer was washed with ethyl acetate,Was added dropwise to the aqueous layer with 10percent hydrochloric acid solution,A large number of white solid generation,To & lt; RTI ID = 0.0 & gt; 1,Washed to a pH of about 6,A white granular solid 25. lg,The yield was 82.9percentMp 143-145 ° C,HRMS = 220.0886 [M + H] & lt; + & gt ;.
Reference：
[1] Journal of Organic Chemistry, 2010, vol. 75, # 11, p. 3766 - 3774
[2] Journal of Fluorine Chemistry, 2010, vol. 131, # 2, p. 224 - 228
[3] Patent: CN104447733, 2016, B, . Location in patent: Paragraph 0055; 0056; 0057
[4] Chemical and Pharmaceutical Bulletin, 2004, vol. 52, # 1, p. 63 - 73
[5] Patent: EP1180513, 2002, A1, . Location in patent: Referential example 44
[6] Journal of the American Chemical Society, 1950, vol. 72, p. 1415
[7] Molecules, 2005, vol. 10, # 2, p. 367 - 375
4
[ 256451-31-7 ]
[ 5733-86-8 ]
Reference：
[1] Patent: US6436954, 2002, B1,
5
[ 617-52-7 ]
[ 5733-86-8 ]
Reference：
[1] European Journal of Organic Chemistry, 2005, # 4, p. 673 - 682
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 377 - 379
6
[ 5733-86-8 ]
[ 114214-69-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 5, p. 1151 - 1175
7
[ 5733-86-8 ]
[ 305329-97-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 5, p. 1151 - 1175
8
[ 5733-86-8 ]
[ 478832-05-2 ]
Reference：
[1] Patent: EP1403255, 2004, A1,
9
[ 5733-86-8 ]
[ 75-65-0 ]
[ 478832-03-0 ]
Yield
Reaction Conditions
Operation in experiment
51%
for 2 h; Heating / reflux
In tert-butyl alcohol (6 ml) was dissolved 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid (1.00 g, 4.56 mmol), and triethylamine (0.76 ml, 5.5 mmol) was added thereto. Then, a solution of diphenylphosphoryl azide (1.38 g, 5.02 mmol) in tert-butyl alcohol (4 ml) was added thereto, and the resulting mixture was refluxed for 2 hours. After completion of the reaction, the reaction solution was concentrated and the tert-butyl alcohol was removed as an azeotrope with toluene as much as possible. The residue was purified by a silica gel chromatography (eluent: ethyl acetate/hexane) to obtain tert-butyl 1-benzyl-5-oxo-3-pyrrolidinylcarbamate (480 mg, 51percent).1H-NMR (DMSO-d6) δ; 1.34 (9H, s), 2.23 (1H, dd, J=5.7, 16.8Hz), 2.61 (1H, dd, J=8.6, 16.8Hz), 3.01 (1H, dd, J=5.7, 9.9Hz), 3.43 (1H, dd, J=8.6, 9.9Hz), 4.03 (1H, m), 4.36 (2H, s), 7.30 (6H, m).
With thionyl chloride; In dichloromethane; for 24h;Heating;
To a solution of the above-mentioned compound IA (6 g, 27.4 mmol)30 ml of methylene chloride was added,Heated to boiling,Gradually dissolved,3.2ml (44.Ommol) of thionyl chloride was slowly added dropwise with stirring,Sustained response 24h,Natural cooling,Spin drying solvent,Add 20mL anhydrous acetone dissolved,No post-processing,Go directly to the next step.
With diphenylphosphoranyl azide; triethylamine; for 2h;Heating / reflux;
In tert-butyl alcohol (6 ml) was dissolved <strong>[5733-86-8]1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid</strong> (1.00 g, 4.56 mmol), and triethylamine (0.76 ml, 5.5 mmol) was added thereto. Then, a solution of diphenylphosphoryl azide (1.38 g, 5.02 mmol) in tert-butyl alcohol (4 ml) was added thereto, and the resulting mixture was refluxed for 2 hours. After completion of the reaction, the reaction solution was concentrated and the tert-butyl alcohol was removed as an azeotrope with toluene as much as possible. The residue was purified by a silica gel chromatography (eluent: ethyl acetate/hexane) to obtain tert-butyl 1-benzyl-5-oxo-3-pyrrolidinylcarbamate (480 mg, 51%).1H-NMR (DMSO-d6) delta; 1.34 (9H, s), 2.23 (1H, dd, J=5.7, 16.8Hz), 2.61 (1H, dd, J=8.6, 16.8Hz), 3.01 (1H, dd, J=5.7, 9.9Hz), 3.43 (1H, dd, J=8.6, 9.9Hz), 4.03 (1H, m), 4.36 (2H, s), 7.30 (6H, m).
Example 30 N-Benzylpyrrolidin-2-one-4-carboxylic acid. A mixture of isopropyl N-benzylpyrrolidin-2-one4-carboxylate (Example 33, 3.93 g) in dioxane (80 mL), aqueous KOH (2 N, 40 mL) and MeOH (60 mL) was stirred at room temperature for 1 hour. The mixture was then cooled with ice, acidified to pH=4 with H3PO4 and left in a refrigerator overnight. The precipitate was filtered and the filtrate was concentrated to give a yellow oil. The oil was contaminated with dioxane, and therefore was dissolved in aqueous KOH. The solution was extracted with CHCl3 (2*20 mL), and the aqueous layer was acidified with HCl (3 N). It was extracted with CHCl3 (4*30 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give N-benzylpyrrolidin-2-one-4carboxylic acid as a pale yellow oil (2.89 g): 1H NMR (300 MHz) delta 10.77 (br s, CO2H), 7.34 (m, 5 H), 5.17 (d, J=14.9 Hz, 1 H), 4.02 (dd, J=9.4, 3.2Hz, 1 H), 3.98 (d, J=14.1 Hz, 1 H), 2.12-2.71 (m, 4 H); 13C NMR (75 MHz) delta 176.47, 174.32, 135.25, 128.78, 128.46, 127.90, 58.63, 45.69, 29.57, 22.83; MS (FAB), m/e 220 (100, M+H), 174 (40); HRMS (FAB) m/e calcd for (C12H13NO3+H) 220.0974, found 220.0984.
With 1,1'-carbonyldiimidazole; methylamine; In dichloromethane;
Stage A N-Methyl-(1-benzyl-2-oxo-4-pyrrolidinyl)carboxamide. 0.2 mole of (1-benzyl-2-oxo-4-pyrrolidinyl)carboxylic acid (described in Journal of Organic Chemistry, 1961; 26: p 1519) is dissolved in 200 cm3 of methylene chloride. The mixture is treated with 32.4 g of carbonyldiimidazole. It is left in contact for 1 hour and then a solution consisting of 20 g of methylamine and 200 cm3 of methylene chloride is added. The mixture is left in contact for 12 hours at room temperature, washed with water and then dried over magnesium sulfate. An oil which is the expected compound is obtained. Yield: 92%.
3-(1-Benzyl-2-oxopyrrolidin-4-yl)-3-oxopropanoate 1,1'-Carbonyldiimidazole (42.5 g, 0.262 mole) was added to a stirred solution of 1-benzyl-2-oxopyrrolidine-4-carboxylic acid (50.0 g, 0.228 mole) in dry tetrahydrofuran (550 mL) under nitrogen in five portions over 30 minutes (gas evolution). The mixture was warmed at 45 for 16 hours. Magnesium bis-(ethylmalonate) (81.0 g, 0.283 mole) was added (vigorous gas[evolution]). The reaction was heated at reflux three hours and cooled to room temperature. The solvent was removed under reduced pressure to give a foam which was dissolved in dichloromethane, washed with 1N HCl (600 mL), water (600 mL), dilute sodium bicarbonate (600 mL), and dried (MgSO4). The solvent was removed under reduced pressure to give 3-(1-benzyl-2-oxopyrrolidin-4-yl)-3-oxopropanoate (58.2 g, 88%) as an orange oil. NMR delta (CDCl3) 7.1 (5H,m), 4.31 (2H,d), 4.05 (2H,q), 3.38 (4H,m), 2.42-2.67 (2H,m), 1.20 (3H,t).
N,N-diethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 4-methyl-morpholine; sodium hydroxide; In tetrahydrofuran; dichloromethane; water;
N,N-Diethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine To a solution of 32.9 g (0.15 mole) <strong>[5733-86-8]5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid</strong> [J. Org. Chem., 26, 1519 (1961)] and 300 mL of dichloromethane was added 15.2 g (0.15 mole) of N-methylmorpholine. After 15 minutes the solution was cooled to -25 C. and 16.3 g (0.15 mole) of ethyl chloroformate was added. After an additional ten minutes, a solution of 13.5 g (0.18 mole) of diethylamine and 18 mL dichloromethane was added to the reaction. Carbon dioxide was evolved and after 1.5 h another 10 g (0.13 mole) of diethylamine in 10 mL of dichlormethane was added. The reaction was stirred four hours, washed with 1N sodium hydroxide, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was added to a suspension of 17.4 g (0.46 mole) of lithium aluminum hydride and 210 mL anhydrous tetrahydrofuran. The reaction was refluxed overnight then cooled to room temperature. The cooled solution was quenched by the successive addition of 17.4 mL water, 17.4 mL 15% sodium hydroxide, and 52.2 mL water. The resulting precipitate was filtered and washed with ethyl alcohol. The filtrate was concentrated under reduced pressure, taken up in dichloromethane and dried over magnesium sulfate. The solvent was removed under vacuum giving 25.8 g (69%) of N,N-diethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine as a yellow oil. This material was used in the next step without purification.
With 4-methyl-morpholine; In tetrahydrofuran; dichloromethane; water;
N,N-Diethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine To a solution of 32.9 g (0.15 mole) <strong>[5733-86-8]5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid</strong> [J. Org. Chem., 26, 1519 (1961)] and 300 ml of dichloromethane was added 15.2 g (0.15 mole) of N-methylmorpholine. After 15 minutes the solution was cooled to -25 C. and 16.3 g (0.15 mole) of ethyl chloroformate was added. After an additional ten minutes, a solution of 13.5 g (0.18 mole) of diethylamine and 18 ml dichloromethane was added to the reaction. Carbon dioxide was evolved and after 1.5 h another 10 g (0.13 mole) of diethylamine in 10 ml of dichloromethane was added. The reaction was stirred four hours, washed with 1N sodium hydroxide, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was added to a suspension of 17.4 g (0.46 mole) of lithium aluminum hydride and 210 ml anhydrous tetrahydrofuran. The reaction was refluxed overnight then cooled to room temperature. The cooled solution was quenched with 17.4 ml water, 17.4 ml 15% sodium hydroxide, and 52.2 ml water. The resulting precipitate was filtered and washed with ethyl alcohol. The filtrate was concentrated under reduced pressure, taken up in dichloromethane, dried over magnesium sulfate. The solvent was removed under vacuum giving 25.8 g (69%) of N,N-diethyl-1-(phenylmethyl)-3-pyrrolidinemethanamine as a yellow oil. This material was used in the next step without purification.
5-oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetonitrile;
5-Oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide To a solution of 16.4 g (75 mmole) of <strong>[5733-86-8]5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid</strong> in 150 mL of acetonitrile was added 13.8 g (85 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60 C. for one hour, cooled to room temperature and treated with 4.85 g (85 mmole) of cyclopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 18.3 g of 5-oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide, mp 94-96 C.
In acetonitrile;
5-Oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide To a solution of 16.4 g (75 mmole) of <strong>[5733-86-8]5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid</strong> in 150 ml of acetonitrile was added 13.8 g (85 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60 C. for one hour, cooled to room temperature and treated with 4.85 g (85 mmole) of cyclopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 18.3 g of 5-oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide, mp 94-96 C.
In acetonitrile;
5-Oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide To a solution of 16.4 g (75 mmole) of <strong>[5733-86-8]5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid</strong> in 150 ml of acetonitrile was added 13.8 g (85 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60 C. for one hour, cooled to room temperature and treated with 4.85 g (85 mmole) of cyclopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 18.3 g of 5-oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide, mp 94-96 C.
5-oxo-1-(phenylmethyl)-N-propyl-3-pyrrolidinecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With propylamine; In acetonitrile;
5-Oxo-1-(phenylmethyl)-N-propyl-3-pyrrolidinecarboxamide To a solution of 10.96 g (50 mmole) of <strong>[5733-86-8]5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid</strong> in 150 mL of acetonitrile was added 9.73 g (60 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60 C. for one hour, cooled to room temperature and treated with 4.13 g (70 mmole) of n-propylamine. After stirring for two hours, the solvent was removed in vacuo and the residue partitioned between ether and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 12.0 g of 5-oxo-1-(phenylmethyl)-N-propyl-3-pyrrolidinecarboxamide, mp 86-87 C.
With propylamine; In acetonitrile;
5-Oxo-1-(phenylmethyl)-N-propyl-3-pyrrolidinecarboxamide To a solution of 10.96 g (50 mmole) of <strong>[5733-86-8]5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid</strong> in 150 ml of acetonitrile was added 9.73 g (60 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60 C. for one hour, cooled to room temperature and treated with 4.13 g (70 mmole) of n-propylamine. After stirring for two hours, the solvent was removed in vacuo and the residue partitioned between ether and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated invacuo to give 12.0 g of 5-oxo-1-(phenyl-methyl)-N-propyl-3-pyrrolidinecarboxamide, mp 86-87 C.
5-oxo-1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetonitrile;
5-Oxo-1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide To a solution of 16.4 g (75.0 mmole) of <strong>[5733-86-8]5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid</strong> in 150 mL of acetonitrile was added 13.8 g (85.0 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60 C. for one hour, cooled to room temperature and treated with 5.0 g (85 mmole) of isopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate and evaporated in vacuo to give 18.6 g of 5-oxo-1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide, mp 122-124 C.
In acetonitrile;
EXAMPLE F N-(2-Propyl)-3-pyrrolidinemethanamine 5-Oxo-1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide To a solution of 16.4 g (75.0 mmole) of <strong>[5733-86-8]5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid</strong> in 150 ml of acetonitrile was added 13.8 g (85.0 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60 C. for one hour, cooled to room temperature and treated with 5.0 g (85 mmole) of isopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate and evaporated in vacuo to give 18.6 g of 5-oxo-1-(phenylmethyl)-N-(2-propyl)3-pyrrolidinecarboxamide, mp 122-124 C.
In acetonitrile;
5-Oxo-1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide To a solution of 16.4 g (75.0 mmole) of <strong>[5733-86-8]5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid</strong> in 150 ml of acetonitrile was added 13.8 g (85.0 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60 C. for one hour, cooled to room temperature and treated with 5.0 g (85 mmole) of isopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate and evaporated in vacuo to give 18.6 g to give 18.6 g of 5-oxo-1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide, mp 122-124 C.
In acetonitrile;
5-Oxo-1-phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide To a solution of 16.4 g (75.0 mmole) of <strong>[5733-86-8]5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid</strong> in 150 ml of acetonitrile was added 13.8 g (85.0 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60 C. for one hour, cooled to room temperature and treated with 5.0 g (85 mmole) of isopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate and evaporated in vacuo to give 18.6 g to give 18.6 g of 5-oxo-1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide, mp 122-124 C.
5-oxo-1-(phenylmethyl)-N-propyl-3-pyrrolidinecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With propylamine; 1,1'-carbonyldiimidazole; In acetonitrile;
5-Oxo-1-(phenylmethyl)-N-propyl-3-pyrrolidinecarboxamide To a solution of 10.96 g (50 mmole) of <strong>[5733-86-8]5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid</strong> in 150 ml of acetonitrile was added 9.73 g (60 mmole) of carbonyldiimidazole. The reaction was heated to 60 C. for one hour, cooled to room temperature and treated with 4.13 g (70 mmole) of n-propylamine. After stirring for two hours, the solvent was removed in vacuo and the residue partitioned between ether and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated invacuo to give 12.0 g of 5-oxo-1-(phenylmethyl)-N-propyl-3-pyrrolidinecarboxamide, mp 86-87 C.
With thionyl chloride; sulfuric acid; acetic acid; In 1,4-dioxane; chloroform; water;
(1) 4-Acetyl-1-benzyl-2-pyrrolidone 10 ml of thionyl chloride and 30 ml of dioxane were added to 4.4 g of 1-benzyl-4-carboxy-2-pyrrolidone. The mixture was stirred under heating to 90 to 100 C. for 30 min and then the solvent and excess thionyl chloride were distilled off under reduced pressure to obtain and acid chloride residue. 2.5 g of magnesium ethoxide and 3.5 g of ethyl malonate were added to 40 ml of anhydrous ether and the mixture was refluxed for 1.5 h to obtain a solution. The solution of the acid chloride in ether prepared as above was added dropwise to this solution under stirring and under cooling with ice. After completion of the addition, the mixture was refluxed for 1 h. An excess amount of dilute sulfuric acid solution was added thereto under cooling with ice to make the solution weakly acidic. It was extracted with ether and dried. The solvent was distilled off. 10 ml of acetic acid, 45 ml of water and 1 ml of concentrated sulfuric acid were added to the residue and the mixture was refluxed for 5 h. The solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with 10% hydrochloric acid and then with saturated sodium hydrogen carbonate solution and dried. The solvent was distilled off to obtain 3.3 g of the desired compound in the form of an oil. NMR(CDCl3) delta ppm: 2.2(3H, s), 2.66(2H, d, J=7.2 Hz), 3.0~3.6(3H, m), 4.32, 4.52 (each 1H, d, J=14 Hz, AB-q), 7.29(5H, s).
5-oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1,1'-carbonyldiimidazole; In acetonitrile;
EXAMPLE E N-Cyclopropyl-3-pyrrolidinemethanamine 5-Oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide To a solution of 16.4 g (75 mmole) of <strong>[5733-86-8]5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid</strong> in 150 ml of acetonitrile was added 13.8 g (85 mmole) of carbonyldiimidazole. The reaction was heated to 60 C. for one hour, cooled to room temperature and treated with 4.85 g (85 mmole) of cyclopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated in vacuo to give 18.3 g of 5-oxo-1-(phenylmethyl)-N-cyclopropyl-3-pyrrolidinecarboxamide, mp 94-96 C. 1-(Phenylmethyl)-N-cyclopropyl-3-pyrrolidine-methanamine
5-oxo-1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetonitrile;
5-Oxo-1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide To a solution of 16.4 g (75.0 mmole) of <strong>[5733-86-8]5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid</strong> in 150 ml of acetonitrile was added 13.8 g (85.0 mmole) of 1,1-'carbonyldiimidazole. The reaction was heated to 60 C. for one hour, cooled to room temperature and treated with 5.0 g (85 mmole) of isopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate, and evaporated in vacuo to give 18.6 g of 5-oxo-1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide, mp 122-124 C.
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