* 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.
Stage #1: With dimethylsulfide; borane In toluene at 0 - 110℃; for 16 h; Heating / reflux Stage #2: With sodium hydrogencarbonate In water; toluene at -10 - 20℃; for 2 h; Heating / reflux
Example A: Synthesis of (l-benzvl-pyrrolidin-3-vlmethvl)-methyl-amineStep a: Synthesis of l-(benzyl-pyrrolidin-3-yI)-methanolA solution of the compound l-benzyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (1.0 eq.) (commercially available) in toluene was cooled to 0°C under inert atmosphere. To the mixture was added solution of borane (3.75 eq.) in dimethyl sulphideand refluxed the mixture for 16 hours at 100°-110°C. The resulting reaction mixture was cooled to room temperature and subsequently to -5° to -10°C followed by the addition of sodium bicarbonate solution dropwise. The mixture was slowly brought to room temperature and subsequently refluxed the reaction mixture for 2 hours. The mixture was cooled and organic layer was separated. Aqueous layer was extracted with toluene. The combined toluene layers were washed with water and brine solution. The organic solvent was evaporated under reduced pressure to furnish the title compound. Yield: 99.14percent.
61%
With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether for 2.5 h; Heating / reflux
Compound b was prepared by a similar procedure to Wu's (J. Org. Chem. 1961, 1519.) except using THF to dissolve methyl l-benzyl-5-oxo-3pyrrolidinecarboxylate: [0388] A solution of methyl 1-benzyl-5-oxo-3pyrrolidinecarboxylate (a) (8.00 g, 34.30 mmol) in 10 mL of anhydrous THF was slowly added to a slurry of powdered lithium aluminum hydride (1.82 g, 48.01 mmol) in 30 mL of absolute ether. The addition was made over a period of 0.5 hour with efficient stirring so as to maintain a moderate reflux rate. When the addition was complete, refluxing and stirring was continued for 2 hours, after which the reaction mixture was left at room temperature. The mixture was quenched with 3 mL of water, and stirred for 2 hours. The white precipitate was filtered and washed with 2.x.30 mL of ether. The solid was extracted with Soxhlet type apparatus in EtOH for 8 hours. Th EtOH was removed. The residue was washed with Et2O (3.x.20 mL). The Et2O solutions were combined, dried over MgSO4, and concentrated. The residue was distilled under vacuum. The fraction at 137-145° C./1 mmHg was collected to give compound b (4.0 g) as a colorless oil.
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 9, p. 2005 - 2009
[2] Tetrahedron Letters, 1999, vol. 40, # 19, p. 3673 - 3676
[3] European Journal of Organic Chemistry, 2005, # 4, p. 673 - 682
[4] Journal of Medicinal Chemistry, 1999, vol. 42, # 25, p. 5254 - 5265
[5] Organic Letters, 1999, vol. 1, # 5, p. 799 - 801
[6] Patent: US2003/229226, 2003, A1, . Location in patent: Page 14
[7] Patent: WO2004/14910, 2004, A1, . Location in patent: Page 69-70
[8] Patent: EP307140, 1989, A1,
5
[ 51535-00-3 ]
[ 17012-21-4 ]
Yield
Reaction Conditions
Operation in experiment
3%
With hydrogenchloride; sodium hydroxide In tetrahydrofuran; dichloromethane
EXAMPLE 218 1-[1-(Anthracene-9-carbonyl)-piperidin-4-yl]-pyrrolidine-3-carboxylic acid diethylamide To a solution of 1-benzyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (30 mmol, 7 g) in anhydrous tetrahydrofuran (40 ml) was added borane-tetrahydrofuran solution (1M, 50 mmol, 50 mL) at ambient temperature. When gas evolution had subsided the solution was heated under reflux for 75 min then stirred for 16 hr at ambient temperature. Hydrochloric acid (6M) was added dropwise (ca. 5 mL) and the mixture was stirred at ambient temperature for 1 hr before removing the solvent under vacuum. The residue was dissolved in dichloromethane and the solution was washed with dilute sodium hydroxide solution. The dichloromethane solution was then extracted with dilute hydrochloric acid (*3), the extracts combined, made basic by addition of sodium hydroxide and extracted with dichloromethane (*3). The combined organic extract was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The product was purified by chromatography on silica gel eluding with 5percent methanol-dichloromethane to give 1-benzyl-pyrrolidine-3-carboxylic acid methyl ester (200 mg, 3percent). MS: 220.2 [M+H]+
Reference：
[1] Patent: US2003/187254, 2003, A1,
6
[ 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
7
[ 51535-00-3 ]
[ 122684-33-7 ]
Reference：
[1] European Journal of Organic Chemistry, 2005, # 4, p. 673 - 682
With sodium hydroxide; ammonium chloride; magnesium; In tetrahydrofuran; dichloromethane; water;
PREPARATION 106 4-[Bis(4-fluorophenyl)hydroxymethyl]-1-(phenylmethyl)-2-pyrrolidinone A Grignard solution was prepared by the addition of 96.3 g (0.55 mole) of 4-bromofluorobenzene in 150 ml of dry tetrahydrofuran to a mixture of 12.2 g (0.5 mole) of magnesium chips in 250 ml of tetrahydrofuran. After the reaction had subsided, the mixture was diluted with 350 ml of tetrahydrofuran and heated at reflux for 15 min to complete formation. The Grignard solution was added to a solution of 46.7 g (0.2 mole) of 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid methyl ester in 250 ml of tetrahydrofuran and the mixture was stirred at ambient temperature overnight. The solution was poured into 2.5 liters of a cold ammonium chloride solution. The layers were separated and the aqueous layer was extracted once with 500 ml of methylene chloride and once with 250 ml of methylene chloride. The combined organic layers were washed once with 250 ml of water, once with 250 ml of a 4% sodium hydroxide solution, once with 250 ml of water and once with 250 ml of brine, dried over sodium sulfate and concentrated under reduced pressure to give a gum as residue. The gum crystallized when saturated with petroleum ether. The solid was collected by filtration, washed with petroleum ether and recrystallized from 2-propanol to yield 39.4 g (50%) of the title compound as an off-white solid, m.p. 158-160 C. Analysis: Calculated for C24 H21 F2 NO2: C, 73.27; H, 5.38; N, 3.56. Found: C, 73.09; H, 5.38; N, 3.53.
With lithium hydroxide; In tetrahydrofuran; methanol; water; for 0.333333h;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, 97%).1H-NMR (DMSO-d6) delta; 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).
With lithium hydroxide monohydrate; water; In tetrahydrofuran; methanol; at 20℃; for 0.75h;
To a solution of methyl 1 -benzyl-5-oxo-pyrrolidine-3-carboxylate (5.0 g, 21.43 mmol) in 1 : 1 : 1 THF:water:MeOH (120 ml_) was added LiOH monohydrate (1.35 g, 32.17 mmol) and the reaction stirred at RT for 45 min. The mixture was concentrated in vacuo to a volume of -30 ml_, diluted with water (30 ml.) and washed with Et.2O (40 ml_). The aqueous layer was acidified to ~pH 1 with 6N HCI and extracted with DCM (2 x 40 ml_). The combined organic layers were dried over Na2S04and concentrated in vacuo to afford 4.67 g of 1 -benzyl-5-oxo-pyrrolidine-3-carboxylic acid as an off -white solid (86% purity, 85%) which was used in the next step without further purification LC-MS (METCR1410): 86% (UV), Rt= 0.84 min, m/z (ESI+)= 220.2 [M+H]+ H NMR (500 MHz, DMSO-ofe) delta 2.47 - 2.53 (m, 1 H), 2.59 (dd, J = 9.7, 16.9 Hz, 1 H), 3.17 - 3.25 (m, 1 H), 3.36 (dd, J= 5.5, 9.9 Hz, 1 H), 3.45 (dd, J= 8.9, 9.8 Hz, 1 H), 4.33 (d, J= 15.0 Hz, 1 H), 4.41 (d, J= 15.0 Hz, 1 H), 7.19 - 7.23 (m, 2H), 7.25 - 7.30 (m, 1 H), 7.32 - 7.36 (m, 2H)
Example A: Synthesis of (l-benzvl-pyrrolidin-3-vlmethvl)-methyl-amineStep a: Synthesis of l-(benzyl-pyrrolidin-3-yI)-methanolA solution of the compound l-benzyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (1.0 eq.) (commercially available) in toluene was cooled to 0C under inert atmosphere. To the mixture was added solution of borane (3.75 eq.) in dimethyl sulphideand refluxed the mixture for 16 hours at 100-110C. The resulting reaction mixture was cooled to room temperature and subsequently to -5 to -10C followed by the addition of sodium bicarbonate solution dropwise. The mixture was slowly brought to room temperature and subsequently refluxed the reaction mixture for 2 hours. The mixture was cooled and organic layer was separated. Aqueous layer was extracted with toluene. The combined toluene layers were washed with water and brine solution. The organic solvent was evaporated under reduced pressure to furnish the title compound. Yield: 99.14%.
61%
With lithium aluminium tetrahydride; In tetrahydrofuran; diethyl ether; for 2.5h;Heating / reflux;
Compound b was prepared by a similar procedure to Wu's (J. Org. Chem. 1961, 1519.) except using THF to dissolve methyl l-benzyl-5-oxo-3pyrrolidinecarboxylate: [0388] A solution of methyl 1-benzyl-5-oxo-3pyrrolidinecarboxylate (a) (8.00 g, 34.30 mmol) in 10 mL of anhydrous THF was slowly added to a slurry of powdered lithium aluminum hydride (1.82 g, 48.01 mmol) in 30 mL of absolute ether. The addition was made over a period of 0.5 hour with efficient stirring so as to maintain a moderate reflux rate. When the addition was complete, refluxing and stirring was continued for 2 hours, after which the reaction mixture was left at room temperature. The mixture was quenched with 3 mL of water, and stirred for 2 hours. The white precipitate was filtered and washed with 2×30 mL of ether. The solid was extracted with Soxhlet type apparatus in EtOH for 8 hours. Th EtOH was removed. The residue was washed with Et2O (3×20 mL). The Et2O solutions were combined, dried over MgSO4, and concentrated. The residue was distilled under vacuum. The fraction at 137-145 C./1 mmHg was collected to give compound b (4.0 g) as a colorless oil.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 4.25h;
The (1-benzylpyrrolidin-3-yl)methanol can be prepared in the following way: 17.1 cm3 of a 1M lithium aluminum hydride solution in tetrahydrofuran are added to a solution of 2 g of 1-benzyl-5-oxopyrrolidine-3-carboxylic acid methyl ester in 40 cm3 of tetrahydrofuran, stirred at 0 C. under a nitrogen atmosphere. After stirring for 15 min at 0 C., the reaction medium is allowed to return to a temperature in the region of 20 C. and is stirred for 4 h. A mixture consisting of 0.65 cm3 of water and of 6.5 cm3 of tetrahydrofuran is added dropwise to the reaction medium. 0.65 cm3 of a 15% aqueous sodium hydroxide solution and 1.95 cm3 of water are then successively added. The medium is stirred at a temperature in the region of 20 C. until the formation of a filterable solid, to which two spatulas of magnesium sulfate are added. After filtration through an iena funnel, rinsing and concentrating to dryness under reduced pressure, 1.72 g of (1-benzylpyrrolidin-3-yl)methanol are obtained in the form of a colorless oil. Mass spectrum (EI): m/z 192+ (M+H)+.
With sodium hydroxide; In tetrahydrofuran; water;
Step A: 1-Benzyl-3-hydroxymethylpyrrolidine To a suspension of 0.50 g of lithium aluminum hydride in 35 mL of THF at 0 C. was added (dropwise via cannula) a solution of 2.00 g of methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate in 10 mL of THF. The cooling bath was removed and the mixture was stirred for 2.5 h at room temperature. The mixture was recooled to 0 C. and quenched by careful, sequential addition of 0.5 mL of water, 0.5 mL of 15% aqueous NaOH, and 1.5 mL of water. The mixture was stirred at room temperature for 1 h, at which point all solids were white, then filtered. The solids were washed thoroughly with Et2O, and the filtrate was dried over MgSO4 and concentrated to give 1.61 g of the title compound as a colorless oil.
With sodium hydroxide; In tetrahydrofuran; water;
To a cold (0 C.) suspension of lithium aluminum hydride (2.44 g, 64 mmol) in THF (40 mL) was added methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate (5.00 g, 21 mmol). The reaction mixture was stirred at room temperature for 5 hrs. To the reaction mixture were added water (2.5 mL), 15% aqueous sodium hydroxide solution (2.5 mL), and water (7.5 mL), successively. The mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give (1-benzyl-3-pyrrolidinyl)methanol. (4.16 g, yield; quant.)
In tetrahydrofuran; water;
Preparation 26 To a suspension of lithium aluminum hydride (16.2 g) in tetrahydrofuran (1 l) was added 1-benzyl-4-methoxycarbonyl-2-oxopyrrolidine (50 g) under reflux for one hour and the mixture was refluxed for 2 hours. A solution of water (15.5 ml) and tetrahydrofuran (50 ml) was added to the mixture under reflux. After cooling, insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give 1-benzyl-3-hydroxymethylpyrrolidine (43.45 g). IR (Neat): 3350-3050 cm-1 NMR (DMSO-d6, delta): 1.1-1.9 (1H, m), 1.9-2.0 (1H, m), 2.0-2.6 (5H, m), 3.1-3.4 (2H, m), 3.50 (2H, s), 4.3-4.6 (1H, m), 7.23 (5H, s) MS: 191 (M+), 114 (M+ -77), 100 (M+ -91)
With lithium borohydride; In tetrahydrofuran; at 20℃;Inert atmosphere;
1-benzyl-4-(hydroxymethyl)pyrrolidin-2-one (19): To a solution of methyl-1-benzyl-5-oxo-3-pyrrolidinecarboxylate (1.5 g, 6.4 mmol) in dry THF (50 mL) under nitrogen was added LiBH4 (280 mg, 12.85 mmol), and the solution was stirred at room temp overnight. The reaction was quenched with 1M HCl and extracted with Et2O. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to provide 19 as a colorless oil, which crystallized upon standing (1.30 g, 99%).1H NMR (500 MHz; CDCl3): deltaH: 2.20 (1H, m, CH), 2.45 (2H, m, CH2C(O)), 3.04 (1H, m, CHH?N), 3.28 (1H, m, CHH?OH), 3.48 (2H, m, CHH?OH and CHH?N), 4.35 (2H, m, CH2Ar), 7.24 (5H, m, ArCH), 16.90 (1H, br. s, OH).13C NMR (125.77 MHz; CDCl3): deltaC: 27.10 (CH), 33.16 (CH2C(O)), 46.60 (NCH2), 49.34 (CH2Ar), 64.50 (CH2OH), 127.66, 127.84, 129.12, 129.94, 130.38 (all ArCH), 136.21 (ArC-CH2), 174.27 (C(O)).m/z (ESI): 228.19 [MNa+] (65%), 206.27 [MH+] (100).HRMS: C12H15NO2 requires: 205.1107, Found: 205.1103.
98.5%
With methanol; sodium tetrahydroborate; In water; at 0 - 5℃; for 4h;
Dissolve 1.46g (3eq) sodium borohydride in 15.5ml cold water in a 250ml multi-mouth bottle,3.0 g (12.87 mmol) of <strong>[51535-00-3]1-benzyl-5-oxopyrrolidine-3-carboxylic acid methyl ester</strong> 2 was dissolved in 38.5 ml of methanol to give a colorless clear solution which slowly dropped at a temperature of 0-5C. Aqueous sodium borohydride was added to the reaction flask and the reaction was continued at 0-5C. The reaction was continued at 0-5C. The end of the reaction was detected by TLC. The reaction was complete after 4 h. The pH was adjusted to 5-6 with 1M HCl, and the methanol was distilled off under reduced pressure. The residue was added with water, extracted three times with dichloromethane, and washed once with water. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to a viscous liquid, 1-benzyl-4-hydroxymethyl-pyrrolidine-2. - Ketone 3 2.60 g, yield 98.5%, purity 97%.
With lithium borohydride; acetic acid; In tetrahydrofuran;
(i) 200 ml of a 2M solution of lithium borohydride in THF were added dropwise to a stirred solution of 100 g of <strong>[51535-00-3]methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate</strong> in 600 ml of THF under a nitrogen atmosphere. After 3 hours, the mixture was cooled to 10 C. and treated with 200 ml of 50% aqueous acetic acid. The solvents were removed under reduced pressure and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic extracts were dried and evaporated to dryness to give 92 g of 1-benzyl-4-(hydroxymethyl)-2-pyrrolidinone.
With sodium tetrahydroborate; In ethanol; at 0 - 25℃; for 4h;
NaBH4 (24.0 g, 634 mmol) was added to a solution of methyl 1-benzyl-5- oxopyrrolidine-3-carboxylate (50.0 g, 214 mmol) in ethanol (800 mL) at 0 C. The resulting solution was stirred for 4 h at 25 C. The reaction was quenched with water (50 mL). The mixture was concentrated under vacuum. The residue was diluted with water (200 mL). The resulting mixture was extracted with DCM (3 x 500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 10:1 dicholoromethane/methanol) to give 1-benzyl-4- (hydroxymethyl)pyrrolidin-2-one as colorless oil. MS (ESI, m/z): 206 [M+H].
With hydrogenchloride; sodium hydroxide; In tetrahydrofuran; dichloromethane;
EXAMPLE 218 1-[1-(Anthracene-9-carbonyl)-piperidin-4-yl]-pyrrolidine-3-carboxylic acid diethylamide To a solution of 1-benzyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (30 mmol, 7 g) in anhydrous tetrahydrofuran (40 ml) was added borane-tetrahydrofuran solution (1M, 50 mmol, 50 mL) at ambient temperature. When gas evolution had subsided the solution was heated under reflux for 75 min then stirred for 16 hr at ambient temperature. Hydrochloric acid (6M) was added dropwise (ca. 5 mL) and the mixture was stirred at ambient temperature for 1 hr before removing the solvent under vacuum. The residue was dissolved in dichloromethane and the solution was washed with dilute sodium hydroxide solution. The dichloromethane solution was then extracted with dilute hydrochloric acid (*3), the extracts combined, made basic by addition of sodium hydroxide and extracted with dichloromethane (*3). The combined organic extract was dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The product was purified by chromatography on silica gel eluding with 5% methanol-dichloromethane to give 1-benzyl-pyrrolidine-3-carboxylic acid methyl ester (200 mg, 3%). MS: 220.2 [M+H]+
Example 43 First, N-benzyl-pyrrolidine-3-methanol was prepared as follows. Methyl N-benzyl-5-oxo-pyrrolidine-3-carboxylate (11.66 g, 50 mmol) was dissolved in diethyl ether and cooled to 0 C. This solution was added to a 0 C. suspension of lithium aluminum hydride in diethyl ether under nitrogen atmosphere. After addition, the mixture was refluxed for 1 hr, and then cooled with an ice bath. To quench the reaction, sodium sulfate decahydrate was added and the mixture was stirred for 1 hr. After filtration, the filtrate was collected, and concentrated to dryness to give N-Benzyl- pyrrolidine-3-methanol. ESMS (C12H17NO): calcd. 191.13; obsd. 192.2 [M+H]+. Retention time (anal. HPLC: 10-70% MeCN/H2O over 5 min)=0.95 min.
PREPARATION 43 5-Oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid, methyl ester A solution of 158.2 g (1.0 mole) of dimethylitaconate and 107.2 g (1.0 mole) of benzylamine in 750 ml of methanol was let stand at ambient temperature over the weekend. The solution was filtered and the filtrate was concentrated under reduced pressure to give an oil as residue. The oil crystallized when it was triturated with petroleum ether (30-60 C.). The solid was collected by filtration and dried to yield 225.5 g (97%) of white powder. An analytical sample, m.p. 63-65 C. was prepared from isopropyl ether.
225.5 g (97%)
In methanol;
PREPARATION 105 5-Oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid methyl ester A solution of 158.2 g (1.0 mole) of dimethylitaconate and 107.2 g (1.0 mole) of benzylamine in 750 ml of methanol was let stand at ambient temperature over the weekend. The solution was filtered and the filtrate was concentrated under reduced pressure to give an oil as residue. The oil crystallized when it was triturated with petroleum ether (30-60 C.). The solid was collected by filtration and dried to yield 225.5 g (97%) of the title compound as a white powder. An analytical sample, m.p. 63-65 C., was prepared from 2-propyl ether.
1-Benzyl-3-(hydroxymethyl)pyrrolidine oxalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 1,2-dimethoxyethane; chloroform; ethyl acetate;
PREPARATION 44 1-Benzyl-3-(hydroxymethyl)pyrrolidine oxalate [1:1] A solution of (60.0 g, 0.2553 mole)5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid methyl ester in dry dimethoxyethane was added to a mixture of dimethoxyethane and 47.0 g (1.23 mole) of lithium aluminum hydride. The reaction mixture was stirred 2 hrs at room temperature and then heated at reflux 2 hrs. The mixture was then stirred overnight at room temperature, then quenched by the slow addition of ethyl acetate. More ethyl acetate was added and the use of Celite allowed the solid material to be separated from filtrate by filtration. The filtrate was stripped to dryness and dissolved in chloroform. The chloroform layer was extracted with 10% sodium hydroxide. The chloroform layer was dried, filtered, and solvent removed to give an oil. A portion of the oil was converted to the oxalate salt. The salt was recrystallized from methanol-ethyl ether and dried at 80 C. in vacuo overnight to give 2.27 g, 39.4% yield of white, crystalline solid, m.p. 98-102 C. Analysis: Calculated for C14 H19 NO5: C, 59.78; H, 6.81; N, 4.98. Found: C, 59.43; H, 6.79; N, 4.95.
N-methyl-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide A mixture of 100 g (0.43 mole) of methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate [J. Org. Chem., 26, 1519 (1961)], 500 ml methanol and 100 g (3.2 mole) of methylamine was heated at 100 C. in a pressure reactor for 16 hours. The reaction mixture was cooled and the ammonia and methanol were removed under reduced pressure. The residue was taken up in dichloromethane and washed with 3*100 ml 1N sodium hydroxide. The organic layer was dried over magnesium sulfate and the solvent removed at reduced pressure to give 88.3 g of N-methyl-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide as a white solid, mp 82.5-83.0 C.
N-Ethyl-5-oxo-1-(phenylmethyl)-3-pyrrolidine-carboxamide A mixture of 200 g (0.86 mole) of methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate [J. Org. Chem., 26, 1519 (1961)], 1000 ml methanol and 200 g (4.4 mole) of ethylamine was heated at 100 C. in a pressure reactor for 17.2 hours. The reaction mixture was cooled and the excess ethylamine and methanol were removed under reduced pressure. The residue was taken up in dichloromethane and washed with 3*150 ml 1N sodium hydroxide. The organic layer was dried over magnesium sulfate and the solvent removed at reduced pressure to give 104.6 g of N-ethyl-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide as a white solid, mp 97-99 C.
2-[(3-pyrrolidinylmethyl)amino]ethanol N-(2-hydroxyethyl)-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In methanol; dichloromethane;
EXAMPLE G 2-[(3-pyrrolidinylmethyl)amino]ethanol N-(2-hydroxyethyl)-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide A mixture of 46.7 g (1200 mole) of methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate (J. Org. Chem., 26, 1519 (1961)], 36.7 g (1600 mole) 2-aminoethanol and 500 ml methanol were refluxed overnight. The reaction was cooled to room temperature and the solvent removed at reduced pressure. The residue was taken up in dichloromethane and extracted 3*100 1N sodium hydroxide. The aqueous layer was taken to pH 5, extracted with 3*150 ml dichloromethane, then taken to pH 8 and again extracted with 3*150 ml dichloromethane. The aqueous layer was concentrated at reduced pressure and the resulting slurry stirred in dichloromethane. The salts were filtered off. The combined organic layers were dried over magnesium sulfate, the solvent removed at reduced pressure to yield 47.9 g of N-(2-hydroxyethyl)-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide as an oil. This was used in the next step without further purification.
5-Oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidine carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; dichloromethane;
5-Oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidine carboxamide A mixture of 21.9 g (0.10 mole) methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate in 150 ml tetrahydrofuran, was cooled to 0 C. in an ice bath under nitrogen and 24.3 g (0.15 mole) carbonyl diimidazole was added. The reaction was stirred at 0 C. for 30 minutes, then at room temperature for 30 minutes. A solution of 13.6 g (0.10 mole) of <strong>[373-88-6]2,2,2-trifluoroethylamine hydrochloride</strong>, 15.2 g (0.10 mole) 1,8-diazabicyclo[5.4.0]undec-7-ene and 100 ml tetrahydrofuran was added. The reaction was stirred at room temperature overnight. The solvent was removed at reduced pressure. The residue was taken up in dichloromethane and washed 3*150 ml saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure. The product was purified by column chromatography on silica with ethyl acetate to give 8.50 g of 5-oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinecarboxamide, mp 110-112
With sodium hydroxide; In methanol; dichloromethane;
N-(2-Hydroxyethyl)-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide A mixture of 46.7 g (0.2 mole) of methyl 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate [J. Org. Chem., 26, 1519 (1961)], 36.7 g (0.6 mole) of 2-aminoethanol and 500 ml methanol was refluxed overnight. The reaction was cooled to room temperature and the solvent removed at reduced pressure. The residue was taken up in dichloromethane and extracted 3*100 ml 1N sodium hydroxide. The aqueous layer was taken to pH 5, extracted 3*150 ml dichloromethane, then taken to pH 8 and again extracted 3*150 ml dichloromethane. The aqueous layer was concentrated at reduced pressure and the resulting slurry stirred in dichloromethane. The salts were filtered off. The combined organic layers were dried over magnesium sulfate, the solvent removed at reduced pressure to Yield 47.9 g of N-(2-hydroxyethyl)-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxamide as an oil. This was used in the next step without further purification.
With hydrogenchloride; sodium hydroxide; ammonium formate; N-ethyl-N,N-diisopropylamine;palladium dihydroxide; In tetrahydrofuran; methanol; dichloromethane; water; ethyl acetate;
Step A 1-Benzyl-<strong>[85310-69-6]3-hydroxymethylpyrrolidine</strong> To a suspension of 0.50 g of lithium aluminum hydride in 35 mL of THF at 0 C. was added (dropwise via cannula) a solution of 2.00 g of methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate in 10 mL of THF. The cooling bath was removed and the mixture was stirred for 2.5 h at room temperature. The mixture was recooled to 0 C. and quenched by careful, sequential addition of 0.5 mL of water, 0.5 mL of 15% aqueous NaOH, and 1.5 mL of water. The mixture was stirred at room temperature for 1 h, at which point all solids were white, then filtered. The solids were washed thoroughly with Et2O, and the filtrate was dried over MgSO4 and concentrated to give 1.61 g of a colorless oil. To a solution of this oil (1.60 g) in 25 mL of methanol was added 1.58 g of ammonium formate, then 1.45 g of palladium hydroxide on carbon (20% Pd). The mixture was heated to reflux and stirred at this temperature for 45 min, then cooled and filtered through Celite, washing the solids thoroughly with methanol. The filtrate was concentrated to give 1.32 g of To ab 0 C. solution of 1.32 g of <strong>[85310-69-6]3-hydroxymethylpyrrolidine</strong> and 1.62 g of diisopropylethylamine in 35 mL of CH2Cl2 was added 1.43 g of benzyl chloroformate dropwise. The mixture was allowed to warm to room temperature over 3.5 h, then diluted with 100 mL of EtOAc and washed with 50 mL each of 1 N HCl, saturated NaHCO3, and brine. The organic phase was dried over MgSO4 and concentrated. The residue was purified by flash chromatography, eluding with a gradient system of 1:1 to 2:1 EtOAc-hexanes, to yield 674 mg of the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3): delta 7.28-7.40 (m, 5H), 5.13 (m, 2H), 3.44-3.66 (m, 4H), 3.32-3.43 (m, 2H), 3.18 (dd, J=10.3, 17.4 Hz, 1H), 2.34-2.47 (m, 1H), 1.97 (br s, 1H), 1.55-1.76 (m, 2H).
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