* 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.
A. 1-Benzylpyrrolidine-3-methanol To a mixture of methyl 1-benzylpyrrolidine-3-carboxylate (11.67 g, 50 mmol) and tetrahydrofuran, at 0° C. was added lithium aluminum hydride (3.795 g, 100 mmol). The reaction was warmed to room temperature and refluxed for 24 hours. After cooling to 0° C., the reaction was quenched with saturated sodium sulfate and warmed to room temperature. Tetrahyrofuran (50 mL) and solid sodium sulfate were added to the mixture. After stirring for 1 hour, the mixture was filtered and the filtrate was concentrated and vacuum dried for 3 days to give the title compound as a colorless oil (8.49 g, 88percent). 1H-NMR (300 MHz, DMSO-d6): 7.21-7.31 (m, 5H), 4.50 (t, J=5.3 Hz, 1H), 3.51 (s, 2H), 3.20-3.31 (m, 2H), 2.35-2.50 (m, 4H), 2.10-2.27 (m, 1H), 1.70-1.85 (m, 1H), 1.27-1.43 (m, 1H). IS-MS, m/e: 192.4 (m+1).
Reference：
[1] Patent: US6635657, 2003, B1,
2
[ 51535-00-3 ]
[ 17012-21-4 ]
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,
3
[ 93102-05-7 ]
[ 292638-85-8 ]
[ 17012-21-4 ]
Yield
Reaction Conditions
Operation in experiment
1420 g
With trifluoroacetic acid In dichloromethane at 0 - 20℃; Large scale
To a 250 mL multi-vial was added 1530.0 g (6.5 mol) of benzylmethoxymethyltrimethylsilylmethylamine,31.80 g (3.7 mol)Methyl acrylate and 38 mL of dichloromethane,A solution of 44.0 g (0.4 mol) of trifluoroacetic acid at a mass concentration of 10percent was slowly added dropwise at 0 ° C,After completion of the dropwise addition, the mixture was stirred at room temperature overnight, and the mixture was concentrated under reduced pressure,The residueRespectively, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution,Combined organic phase,The organic phase passes through anhydrous sulfuric acidSodium drying, filtration,The filtrate was concentrated under reduced pressure,To obtain 1420.0 g of crude 1-benzylpyrrolidine-3-carboxylate as a crude product 100percent.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 19, p. 4861 - 4866
[2] Organic Process Research and Development, 2009, vol. 13, # 2, p. 292 - 296
[3] Synthesis, 2006, # 16, p. 2646 - 2648
[4] Synlett, 2015, vol. 26, # 13, p. 1815 - 1818
[5] Chemical & Pharmaceutical Bulletin, 1985, vol. 33, # 7, p. 2762 - 2766
[6] Tetrahedron Letters, 2011, vol. 52, # 26, p. 3266 - 3270
[7] Patent: CN104817549, 2017, B, . Location in patent: Paragraph 0036-0038
4
[ 93102-06-8 ]
[ 292638-85-8 ]
[ 17012-21-4 ]
Reference：
[1] Chemistry Letters, 1984, p. 1117 - 1120
5
[ 50-00-0 ]
[ 53215-95-5 ]
[ 292638-85-8 ]
[ 17012-21-4 ]
Yield
Reaction Conditions
Operation in experiment
10.4 g
Stage #1: With N,N,N',N'-tetramethylguanidine In tetrahydrofuran at 20℃; for 1.5 h; Stage #2: With trifluoroacetic acid In tetrahydrofuran
Paraformaldehyde (1.72 g, 54.3 mmol) was charged in the reactor followed by 100 mL THF and Benzyl-trimethylsilanylmethyl-amine (5) (10 g, 51.7 mmol). 1,1,3,3-tetramethylguanidine (119 mg, 130 μ, 1.03 mmol) was added to the suspension. The reaction mixture was stirred at RT for 1.5 h during which a clear solution was obtained. This solution was added dropwise over 30 min to a mixture consisting of TFA (301 mg, 203 μ, 2.59 mmol) and methyl acrylate (4.95 g, 56.9 mmol). After completion of the reaction (IPC by GC or HPLC, ca 3-5 h), the reaction mixture was concentrated under reduced pressure. The oily residue was dissolved in 25 mL MTBE and was washed twice washed with 60 mL water (60.0 g, 60 mL), then with 30 mL half saturated NaHC03 aq and 25 mL half saturated NaClaq. The organic phase was dried over MgS04, filtered and concentrated under reduced pressure to give 10.4 g of product (21) (89percent yield).
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]+
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃; for 17h;
A solution of B1_3 (22.06 g,92.7 mmol) and methyl acrylate (C2, 11.54 g, 139.0 mmol) inDCM(100 mL) was cooled to 0 C.Asolutionof trifluoroacetic acid (12.71 g, 111.2 mmol) in DCM (50 mL) was added slowly by drop to the reactionmixture. The solution was warmed to room temperature and stirred for 17 h. NaHCO 3 saturatedsolution (150 mL) was added to the solution and stirred until no gas was produced. The mixture waspartitioned between water and DCM. The organic phase was washed with brine, dried over Na2SO4and concentrated to give the title compound (19.53 g, 96%). 1H-NMR (CDCl3) 7.35-7.23 (m, 5H),3.69 (s, 3H), 3.64 (s, 2H), 3.12-2.99 (m, 1H), 2.98-2.87 (m, 1H), 2.79-2.69 (m, 1H), 2.69-2.57 (m, 1H),2.58±2.48 (m, 1H), 2.17±2.04 (m, 2H). MS (ESI, pos, ion): 219.9 [M+ H]+.
96.8%
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃;
A solution of 3 (23.5g, 98.98mmol) and methyl acrylate (12.8g, 148.48mmol) in DCM (100 mL) was treated with TFA (13.5 g, 118.78 mmol) in DCM (50 mL) at 0C. The mixture was stirred at 0C for 0.5h, overnight at room temperature. The saturated aqueous NaHCO3 solution was added in the mixture, and it was stirred for 2h. The organic phase was washed with brine, dried with anhydrous Na2SO4, and concentrated in vacuo to give the compound 4 (21.01g, 96.8%).
1420 g
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃;Large scale;
To a 250 mL multi-vial was added 1530.0 g (6.5 mol) of benzylmethoxymethyltrimethylsilylmethylamine,31.80 g (3.7 mol)Methyl acrylate and 38 mL of dichloromethane,A solution of 44.0 g (0.4 mol) of trifluoroacetic acid at a mass concentration of 10% was slowly added dropwise at 0 C,After completion of the dropwise addition, the mixture was stirred at room temperature overnight, and the mixture was concentrated under reduced pressure,The residueRespectively, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution,Combined organic phase,The organic phase passes through anhydrous sulfuric acidSodium drying, filtration,The filtrate was concentrated under reduced pressure,To obtain 1420.0 g of crude 1-benzylpyrrolidine-3-carboxylate as a crude product 100%.
Paraformaldehyde (1.72 g, 54.3 mmol) was charged in the reactor followed by 100 mL THF and Benzyl-trimethylsilanylmethyl-amine (5) (10 g, 51.7 mmol). 1,1,3,3-tetramethylguanidine (119 mg, 130 μ, 1.03 mmol) was added to the suspension. The reaction mixture was stirred at RT for 1.5 h during which a clear solution was obtained. This solution was added dropwise over 30 min to a mixture consisting of TFA (301 mg, 203 μ, 2.59 mmol) and methyl acrylate (4.95 g, 56.9 mmol). After completion of the reaction (IPC by GC or HPLC, ca 3-5 h), the reaction mixture was concentrated under reduced pressure. The oily residue was dissolved in 25 mL MTBE and was washed twice washed with 60 mL water (60.0 g, 60 mL), then with 30 mL half saturated NaHC03 aq and 25 mL half saturated NaClaq. The organic phase was dried over MgS04, filtered and concentrated under reduced pressure to give 10.4 g of product (21) (89% yield).
[0151] Following general procedure 5, to a cold (0 C.), stirred solution of amide (20) (32.7 g, 1 equiv.) in THF (70 mL) was added, dropwise, a solution of BH3-Me2S in THF (2 M, 140 mL, 2 equiv.). The resultant mixture was then heated to reflux for 2 h. The reaction was cooled to 0 C. and MeOH was added (25 mL). This mixture was stirred under reflux for 3 h and then cooled to rt. The solution was concentrated under reduced pressure and to the resultant residue was added ice (30 g) and 10 N NaOH until the pH of the mixture was adjusted to pH 9. The mixture was then extracted with CH2Cl2 (2×), dried (MgSO4) and concentrated under reduced pressure to afford the desired benzyl amine which was purified by distillation (bp 125-135 C., 1-2 mm Hg) of the benzyl amine. To a solution of the benzyl amine (219 mg, 1 equiv.) in CH2Cl2 (5 mL) was added a solution of BrCN in CH2Cl2 (1 M, 1.5 mL, 1.5 equiv.). The mixture was refluxed for 30 min, cooled to rt and concentrated under reduced pressure. The resultant residue was purified by flash chromatography (gradient elution 20% EtOAc in hexane to 50% EtOAc in hexane) to afford the desired methyl 1-cyano-3-pyrrolidinecarboxylate (21).[0164] Following general procedure 5, to a cold (0 C.), stirred solution of amide 20 (32.7 g, 1 equiv.) in TBF (70 mL) was added, dropwise, a solution of BH3.Me2S in TBF (2 M, 140 mL, 2 equiv.). The resultant mixture was then heated to reflux for 2 h. The reaction was cooled to 0 C. and MeOH was added (25 mL). This mixture was stirred under reflux for 3 h and then cooled to rt. The solution was concentrated under reduced pressure and to the resultant residue was added ice (30 g) and 10 N NaOH until the pH of the mixture was adjusted to pH 9. The mixture was then extracted with CH2Cl2 (2×), dried (MgSO4) and concentrated under reduced pressure to afford the desired amine which was purified by distillation (bp 125-135 C., 1-2 mm Hg) to yield the benzyl amine (32).
To a solution of methyl 1-benzyl-2-oxopyrrolidine-4- carboxylate (10.9 g) in THF (50 [ML)] was added 1.0 M borane in THF (84 mL) under ice-cooling and the mixture was refluxed for 1 hour. Decomposition of excess borane and boron complexes was effected by the dropwise addition of 30 mL of methanolic hydrogen chloride followed by refluxing for 1 hour. After removal of the solvents under reduced pressure another 30 mL of methanolic hydrogen chloride was added, and the mixture was refluxed an additional 1 hour. The solvents were again removed in vacuo and the residue was treated with saturated aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1) ) to give methyl 1-benzyl-3- pyrrolidinecarboxylate (4.8 g) as a pale yellow oil. A suspension of methyl [1-BENZYL-3-PYRROLIDINECARBOXYLATE] (4. [8] mg), [5%] palladium on carbon (300 mg) and ammonium formate (2.8 g) in methanol (50 [ML)-WATER] (5 mL) was refluxed for 2 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol (9: 1) ) to give methyl 3-pyrrolidinecarboxylate as a yellow oil. To a solution of methyl 3-pyrrolidinecarboxylate (1.7 g) in dichloromethane (20 mL) was added dimethylaminopyridine (161 mg) and [DI-TERT-BUTYLDICARBONATE] (3.4 g) at [0C] and the mixture was stirred for 13 hours. The mixture was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (2: 1) ) to give methyl 1-tert- [BUTOXYCARBONYL-3-PYRROLIDINECARBOXYLATE] (2.6 g) as a colorless oil. To a solution of acetonitrile (554 mg) in THF (30 mL) was added [N-BULI] (12.4 mmol) [AT-78C.] Further, methyl 1-tert-butoxycarbonyl-3-pyrrolidinecarboxylate (2.6 g) in THF (10 mL) was added and the mixture was stirred for 10 hours and the reaction was quenched with water. The mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (2: 1) ) to give [1-(1-TER-] [BUTOXYCARBONYLPYRROLIDIN-3-YL)-2-CYANOETHAN-1-ONE] (2.35 g) as a colorless oil. A solution of 2-chlorophenylaldehyde (1.4 g), 3-aminopyrazole (819 mg) and 1-(1-tert-butoxy- [CARBONYLPYRROLIDIN-3-YL)-2-CYANOETHAN-1-ONE] (2.35 g) in acetonitrile (10 mL) was heated under reflux for 1.5 hours. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (2.18 g) as colorless crystals. Anal. Calcd. For: [C22H24CLN502] : C, 62.04 ; H, 5.68 ; N, 16.44. Found: C, 61. 94 ; H, 5.69 ; N, 16.45. MS [(EI)] : 425 (M+). 1H-NMR [(400MHZ,] DMSO-d6) [8] [(PPM)] : 1.14 (9H, s), 2. [07] (lH, m), 2.32 (lH, m), 3.29-3. 58 (5H, m), 5.37 (1H, s), 7.22-7. 34 (4H, m), 7.42 (1H, d, J=8.3Hz), 9. 78(1H, s), 12. 20(1H, s).
(a) 1-Benzyl-3-carbomethoxypyrrolidine This was prepared from 1-benzyl-3-carbomethoxy-5-pyrrolidinone by the procedure described by Kornet et al , J. Org. Chem. , 1968, 33 3637.
(b) 1-Methoxycarbonylmethyl-3-methoxycarbonylpyrrolidine. A solution of 1-benzyl-3-carbomethoxypyrrolidine (50g, 228 mmol) in methanol (300 ml) was subjected to hydrogenolysis over Pd(OH)2 (6g) on a Parr shaker for 7 hours. The suspension was filtered through celite and the solvent removed under vacuum to give 3-carbomethoxypyrrolidine (30 g) as a clear liquid.
With ammonium formate;5%-palladium/activated carbon; In methanol; water; for 2h;Heating / reflux;
To a solution of methyl 1-benzyl-2-oxopyrrolidine-4- carboxylate (10.9 g) in THF (50 [ML)] was added 1.0 M borane in THF (84 mL) under ice-cooling and the mixture was refluxed for 1 hour. Decomposition of excess borane and boron complexes was effected by the dropwise addition of 30 mL of methanolic hydrogen chloride followed by refluxing for 1 hour. After removal of the solvents under reduced pressure another 30 mL of methanolic hydrogen chloride was added, and the mixture was refluxed an additional 1 hour. The solvents were again removed in vacuo and the residue was treated with saturated aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1: 1) ) to give methyl 1-benzyl-3- pyrrolidinecarboxylate (4.8 g) as a pale yellow oil. A suspension of methyl [1-BENZYL-3-PYRROLIDINECARBOXYLATE] (4. [8] mg), [5%] palladium on carbon (300 mg) and ammonium formate (2.8 g) in methanol (50 [ML)-WATER] (5 mL) was refluxed for 2 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol (9: 1) ) to give methyl 3-pyrrolidinecarboxylate as a yellow oil. To a solution of methyl 3-pyrrolidinecarboxylate (1.7 g) in dichloromethane (20 mL) was added dimethylaminopyridine (161 mg) and [DI-TERT-BUTYLDICARBONATE] (3.4 g) at [0C] and the mixture was stirred for 13 hours. The mixture was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (2: 1) ) to give methyl 1-tert- [BUTOXYCARBONYL-3-PYRROLIDINECARBOXYLATE] (2.6 g) as a colorless oil. To a solution of acetonitrile (554 mg) in THF (30 mL) was added [N-BULI] (12.4 mmol) [AT-78C.] Further, methyl 1-tert-butoxycarbonyl-3-pyrrolidinecarboxylate (2.6 g) in THF (10 mL) was added and the mixture was stirred for 10 hours and the reaction was quenched with water. The mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (2: 1) ) to give [1-(1-TER-] [BUTOXYCARBONYLPYRROLIDIN-3-YL)-2-CYANOETHAN-1-ONE] (2.35 g) as a colorless oil. A solution of 2-chlorophenylaldehyde (1.4 g), 3-aminopyrazole (819 mg) and 1-(1-tert-butoxy- [CARBONYLPYRROLIDIN-3-YL)-2-CYANOETHAN-1-ONE] (2.35 g) in acetonitrile (10 mL) was heated under reflux for 1.5 hours. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (2.18 g) as colorless crystals. Anal. Calcd. For: [C22H24CLN502] : C, 62.04 ; H, 5.68 ; N, 16.44. Found: C, 61. 94 ; H, 5.69 ; N, 16.45. MS [(EI)] : 425 (M+). 1H-NMR [(400MHZ,] DMSO-d6) [8] [(PPM)] : 1.14 (9H, s), 2. [07] (lH, m), 2.32 (lH, m), 3.29-3. 58 (5H, m), 5.37 (1H, s), 7.22-7. 34 (4H, m), 7.42 (1H, d, J=8.3Hz), 9. 78(1H, s), 12. 20(1H, s).
1 kg N-Bn-pyrrolidine (21) from previous step (synthesis 43) (4414 mmol, 1 equiv.) was dissolved in 10 L methanol and hydrogenated at atmospheric pressure over 101 g Pd/C (95 mmol Pd, 0.02 equiv., 10% Degussa E101 N/D). After completion of the reaction, the catalyst was filtered and the solution was concentrated to ca 10 L. 2 L methanol were added and distilled at constant volume. A solution of 1.025 kg Boc20 (4603 mmol, 1.05 equiv) in 2.4 L methanol was added over 40 min keeping the temperature between 20-30C. After completion of the reaction (GC IPC), the reaction mixture was concentrated under reduced pressure (50C, 300 to 17 mbar) to give 998 g of (22) as a yellow oil. 4 L toluene was added and the solution was washed with 1.6 L of 0.5 M HClaq and 1.6 L of 5% NaHC03 aq. The organic phase was dried over Na2S04 and concentrated under reduced pressure (80 to 16 mbar, 50C) to give 975 g of crude product (22) as orange oil (98.6a% GC, 3.2% residual toluene).
Synthesis 44: 1 kg N-Bn-pyrrolidine (21) from previous step (synthesis 43) (4414 mmol, 1 equiv.) was dissolved in 10 L methanol and hydrogenated at atmospheric pressure over 101 g Pd/C (95 mmol Pd, 0.02 equiv., 10% Degussa E101 N/D). After completion of the reaction, the catalyst was filtered and the solution was concentrated to ca 10 L. 2 L methanol were added and distilled at constant volume. A solution of 1.025 kg Boc2O (4603 mmol, 1.05 equiv) in 2.4 L methanol was added over 40 min keeping the temperature between 20-30 C. After completion of the reaction (GC IPC), the reaction mixture was concentrated under reduced pressure (50 C., 300 to 17 mbar) to give 998 g of ( 22) as a yellow oil. 4 L toluene was added and the solution was washed with 1.6 L of 0.5 M HClaq and 1.6 L of 5% NaHCO3 aq. The organic phase was dried over Na2SO4 and concentrated under reduced pressure (80 to 16 mbar, 50 C.) to give 975 g of crude product ( 22) as orange oil (98.6a % GC, 3.2% residual toluene).
2-Pyrrolidin-3-ylmethyl-1H-pyrrolo[2,3-b]pyridine. (Compound 66); 8.83 g (91 mmol) methoxymethylamine. (HCl salt) was stirred in 200 ml anhydrous benzene (0 C., under N2). 46.2 ml trimethylaluminium/toluene (2.5M) was added and the mixture was stirred for 2.5 hours at 0 C. Compound 62 (6.73 g, 30.7 mmol) dissolved in 100 ml benzene was added and the resulting mixture was stirred for 1 hour at room temperature. To the mixture was added subsequently saturated NaHCO3 (0 C.) and ethyl acetate. The organic layer was washed three times with a 5% NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (MeOH/ethyl acetate (1/9)) to give 1-benzyl-pyrrolidine-3-carboxylic acid methoxy-methyl-amide (compound 63, 6.76 g, 88.7%).1H-NMR (400 MHz, CDCl3): δ 7.38-7.22 (m, 5H), 3.69-3.62 (m, 5H), 3.45-3.35 (m, 1H), 3.19-3.18 (2×s, 3H), 3.06-2.99 (m, 1H), 2.88-2.81 (m, 1H), 2.56-2.41 (m, 2H), 2.14-2.03 (m, 2H).
In dichloromethane; at 20℃; for 0.5h;Heating / reflux;
[0151] Following general procedure 5, to a cold (0 C.), stirred solution of amide (20) (32.7 g, 1 equiv.) in THF (70 mL) was added, dropwise, a solution of BH3-Me2S in THF (2 M, 140 mL, 2 equiv.). The resultant mixture was then heated to reflux for 2 h. The reaction was cooled to 0 C. and MeOH was added (25 mL). This mixture was stirred under reflux for 3 h and then cooled to rt. The solution was concentrated under reduced pressure and to the resultant residue was added ice (30 g) and 10 N NaOH until the pH of the mixture was adjusted to pH 9. The mixture was then extracted with CH2Cl2 (2×), dried (MgSO4) and concentrated under reduced pressure to afford the desired benzyl amine which was purified by distillation (bp 125-135 C., 1-2 mm Hg) of the benzyl amine. To a solution of the benzyl amine (219 mg, 1 equiv.) in CH2Cl2 (5 mL) was added a solution of BrCN in CH2Cl2 (1 M, 1.5 mL, 1.5 equiv.). The mixture was refluxed for 30 min, cooled to rt and concentrated under reduced pressure. The resultant residue was purified by flash chromatography (gradient elution 20% EtOAc in hexane to 50% EtOAc in hexane) to afford the desired methyl 1-cyano-3-pyrrolidinecarboxylate (21).
pyrrolidine-3-carboxylic acid methyl ester hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97.5%
With hydrogenchloride; palladium 10% on activated carbon; hydrogen; In 1,4-dioxane; methanol; at 50℃; for 5h;
A solution of 4a (5g, 22.80mmol) in MeOH (150 mL) and 4M HCl in dioxane (5.7mL, 22.80mmol) were treated with 10% Pd/C (500mg) of hydrogen at 50oC for 5h. The solid was filtered off and the filtrate was concentrated to give the compound 5a (3.68g, 97.5%).
94%
With hydrogenchloride; palladium 10% on activated carbon; hydrogen; In 1,4-dioxane; methanol; at 50℃; for 5h;
A solution of B1_4(19.50 g, 88.99 mmol), HCl dioxane solution (22.3 mL, 88.99 mmol) in methanol (150 mL) was treatedwith 10% Pd/C (1.95 g) and stirred at 50 C under hydrogen atmosphere for 5 h. The solid was filteredo and the filtrate was concentrated to give the title compound (13.85 g, 94%).
With hydrogenchloride; hydrogen;palladium 10% on activated carbon; In methanol; water;
Reference Example 134 To a solution of <strong>[17012-21-4]methyl 1-benzylpyrrolidine-3-carboxylate</strong> in methanol (50 ml) and 1 N hydrochloric acid (16.9 ml) was added palladium carbon (10%, 1.8 g), and the mixture was stirred overnight under a hydrogen atmosphere. The insolubles were removed by filtration, and then the solvent was distilled off under reduced pressure. Toluene was added thereto, and then the solvent was again distilled off under reduced pressure to give methyl pyrrolidine-3-carboxylate hydrochloride (2.71 g) as a yellow oily material. 1H-NMR (300 MHz, DMSO-d6) δ 1.95-2.25 (2H, m), 3.11-3.45 (5H, m), 3.66 (3H, s), 9.23 (2H, br).
With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; hydrogenchloride; methanol; dichloromethane; chloroform; acetonitrile;
RF 0.38 (19:1 dichloromethane-methanol) A solution of 1-benzyl-pyrrolidine-3-carboxylic acid methyl ester (109.6 mg, 0.5 mmol) in 2N hydrochloric acid (3 mL) and dioxane (1 mL) was heated to 80-90 C. for 1 h. The solvent was evaporated under vacuum and the residue redissolved in dioxane/methanol/toluene and evaporated under vacuum. The residue was then heated under reflux in chloroform containing an excess of thionyl chloride for 1 h and then the solvent was evaporated under vacuum. The residue was dissolved in anhydrous dichloromethane (5 mL) and diethylamine (300 μL) was added. After 20 minutes the solvent was evaporated and the residue dissolved in dichloromethane, washed with dilute sodium hydroxide, dried over anhydrous sodium sulfate and evaporated under vacuum. This material was dissolved in anhydrous acetonitrile (2 mL) and 2,2,2-trichloroethyl chloroformate (1.1 eq, 76 μL) was added at room temperature. After 1.5 h a further aliquot of the chloroformate (0.52 eq., 36 μL) was added. After 30 minutes thin layer chromatography (5% methanol-dichloromethane) indicated that the reaction was still incomplete so a further aliquot of the chloroformate (0.52 eq., 36 μL) and N,N-diisopropylethylamine (0.2 eq., 20 μL) was added. After 1 h the reaction was diluted with dichloromethane, washed with dilute sodium hydroxide, dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel eluding with 40:1 dichloromethane-methanol to give 3-diethylcarbamoyl-pyrrolidine-1-carboxylic acid 2,2,2-trichloro-ethyl ester (102.2 mg, 60%) MS: 345.2 [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]+
1-benzyl-pyrrolidine-3-carboxylic acid amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium methylate; sodium; formamide; In methanol; chloroform; N,N-dimethyl-formamide; isopropyl alcohol;
Step 1 1-Benzyl-pyrrolidine-3-carboxylic acid amide To a mixture of 4.4 g 1-benzyl-pyrrolidine-3-carboxylic acid methyl ester (M. J. Kornet, P. A. Thio, S. E. Tan, J. Organic Chemistry, 33:3637-3639(1968) and 3 g formamide in 10 mL of anhydrous DMF heated to 100 C., a solution of sodium methoxide, from 0.33 g of sodium dissolved in methanol, was added dropwise over 20 minutes. After stirring for 1 h at 100 C., the mixture was allowed to cool to room temperature and added to 100 mL of isopropanol. The mixture was concentrated to dryness. The residue was triturated with 200 mL of chloroform, filtered and concentrated to dryness under reduced pressure. The resulting oil was fairly homogeneous by TLC (development with 90:10 chloroform saturated with ammonia:methanol): 1H NMR (400 MHz, CDCl3): δ7.1 (5H), 4.3 (br s, 2 H), 3.5 (d, 2H), 3.4 (m, 1H), 2.6 (m, 2H), 2.5 (m, 1H), 2.25 (m, 1H), 1.9 (m, 1H).
With sodium methylate; sodium; formamide; In methanol; N,N-dimethyl-formamide; isopropyl alcohol;
Step 1 1-Benzyl-pyrrolidine-3-carboxylic acid amide To a mixture of 4.4 g of 1-benzyl-pyrrolidine-3-carboxylic acid methyl ester (M. J. Kornet et al., J. Org. Chem., 33:3637-3639(1968)) and 3 g of formamide in 10 mL of anhydrous DMF heated to 100 C. was added a solution of sodium methoxide, from 0.33 g of sodium dissolved in methanol, dropwise over 20 min. After stirring for 1 h at 100 C., the mixture was allowed to cool to rt and added to 100 mL of isopropanol. The mixture was concentrated to dryness. The resulting residue was triturated with 200 mL of chloroform, filtered and concentrated to dryness under reduced pressure. The resulting oil was fairly homogeneous by TLC (development with 90:10 chloroform saturated with ammonia: methanol): 1H NMR (400 MHz, CDCl3): 7.1 (5H), 4.3 (br s, 2 H), 3.5 (d, 2H), 3.4 (m, 1H), 2.6 (m, 2H), 2.5 (m, 1H), 2.25 (m, 1H), 1.9 (m, 1H).
A. 1-Benzylpyrrolidine-3-methanol To a mixture of methyl 1-benzylpyrrolidine-3-carboxylate (11.67 g, 50 mmol) and tetrahydrofuran, at 0 C. was added lithium aluminum hydride (3.795 g, 100 mmol). The reaction was warmed to room temperature and refluxed for 24 hours. After cooling to 0 C., the reaction was quenched with saturated sodium sulfate and warmed to room temperature. Tetrahyrofuran (50 mL) and solid sodium sulfate were added to the mixture. After stirring for 1 hour, the mixture was filtered and the filtrate was concentrated and vacuum dried for 3 days to give the title compound as a colorless oil (8.49 g, 88%). 1H-NMR (300 MHz, DMSO-d6): 7.21-7.31 (m, 5H), 4.50 (t, J=5.3 Hz, 1H), 3.51 (s, 2H), 3.20-3.31 (m, 2H), 2.35-2.50 (m, 4H), 2.10-2.27 (m, 1H), 1.70-1.85 (m, 1H), 1.27-1.43 (m, 1H). IS-MS, m/e: 192.4 (m+1).
Methyl (+-)-3-pyrrolidinecarboxylate may be prepared in the following manner: 0.704 g of 10% palladium on carbon (Pd/C) and then 11.5 g of ammonium formate are successively added at a temperature in the region of 20 C., under an argon atmosphere, to 5 g (22.8 mmol) of methyl (+-)-1-(phenylmethyl)-3-pyrrolidinecarboxylate in solution in 100 cm3 of methanol. After stirring for 3 hours at the reflux temperature, the reaction mixture is filtered on Celite. The Celite is rinsed with 3 times 20 cm3 of methanol. The filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) to give 2.5 g of methyl (+-)-3-pyrrolidinecarboxylate in the form of a colorless oil. CI m/z 130 (MH+).
[0165] To a stirred solution of the benzyl amine (32) (10 g, 1 equiv.) in dichloroethane (220 mL) was added, dropwise, 1-chloroethylchloroformate (5.91 mL, 1.2 equiv.). The reaction was stirred at rt for 30 min followed by concentration of the mixture under reduced pressure. The residue was dissolved in MeOH (100 mL), refluxed for 20 min and then concentrated under reduced pressure. The residue was then dissolved in CHCl3 (80 mL) and Et3N (19.1 mL, 3 equiv.) and cooled to 0 C. To this mixture was added Boc2O (9.95 g, 1 equiv.) in CHCl3 (20 mL) and the reaction was stirred at rt for 16 h. This mixture was then concentrated under reduced pressure, dissolved in EtOAc and washed with 10% citric acid, H2O and brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution: 20% EtOAc in hexane to 33% EtOAc in hexane) to afford the Boc-protected amine. To a solution of the Boc-protected amine (2.29 g, 1 equiv.) in MeOH (24 mL) was added 1 N NaOH (12 mL, 1.2 equiv.). The mixture was stirred at rt for 3 days and then concentrated under reduced pressure. The residue was poured into a solution of 1 N HCl (10 mL) and 10% citric acid (20 mL). The mixture was extracted with EtOAc (3×) and the combined organic extracts were washed with H2O and brine, dried (MgSO4) and concentrated under reduced pressure to yield the acid (33).
STEP 1. 2-(1-BENZYLPYRROLIDIN-3-YL)PROPAN-2-OL To a cooled (0 C.) solution of methyl N-benzyl-3-pyrrolidinecarboxylate (1.013 g, 4.62 mmol, Tyger) in THF (50 mL) was added methylmagnesium bromide (3.0M solution in diethyl ether, 7.5 mL, 22.50 mmol) dropwise. After 30 min the mixture was warmed to rt for 2 h. The reaction was cooled (0 C.) and carefully quenched with saturated NH4Cl (50 mL) and then diluted with water (25 mL). The mixture was extracted with EtOAc (3*50 mL) and the combined organic layers were washed with brine and dried over Na2SO4. Concentration in vacuo gave a light-yellow oil. m/z: 220.0 [M+1].
To the solution of LDA (2M in THF, 61 mL, 123 mmol) in dry THF (98 mL) at -70C, a solution of methyl l -Benzyl-pyrrolidine-3-carboxylate (9 g, 41 mmol) in dry THF (65 ml) was added dropwise. The mixture was stirred at -70C for 90 minutes, then at -40C for 2 hours. The mixture was cooled to -70C and methyl chloroformate (9.54 mL, 123 mmol) in THF (65 mL) was added dropwise. The reaction was stirred at -70C for 30 minutes. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated NH4C1 solution at 0C. Layers were separated and the aqueous phase was washed with EtOAc. Mixed organic layers were washed with brine, dried (MgSO i) and concentrated. The crude product was purified by column chromatography on silica gel (EtOAc/hexane 4/6) to afford compound (13a) (7.19 g, 26 mmol, 63%). 1H NMR (300 MHz, CD3OD) δ 2.41 (t, J = 6.6 Hz, 2H), 2.66 (t, J = 6.6 Hz, 2H), 3.06 (s, 2H), 3.63 (s, 2H), 3.71 (s, 6H), 7.22-7.32 (m, 5H)
{benzyl[(trimethylsilyl)methyl]amino}methanol[ No CAS ]
[ 17012-21-4 ]
Yield
Reaction Conditions
Operation in experiment
In a separate reactor, 400 mL THF were charged (Tj=25 C.) followed by N-methylmorpholine (2.85 mL, 26 mmol, 0.05 equiv.), trifluoroacetic acid (TFA) (1 mL, 13 mmol, 0.025 equiv.) and methyl acrylate (56.5 mL, 621 mmol, 1.2 equiv.). The solution was heated to 50-55 C. and the solution from reactor A was added dropwise over ca 50 min. Ca 30 min after the end of addition (reaction complete as judged by IPC), the reactor was cooled to room temperature and the solution was concentrated to ca 500 mL. 250 mL heptane was added and the organic phase was washed twice with 250 mL water. The organic phase was dried over MgSO4, concentrated under reduced pressure (down to 10-20 mbar, 45 C.) to give 108 g of crude product ( 21) (90% yield).
With sodium carbonate; In dichloromethane; at 20℃;
To a 250 mL multi-vial was added 10.2 g (46.6 mmol)1-benzylpyrrolidine-3-carboxylate,15.8g(93.2 mmol) of benzyl chloroformate,14.8 g (140. Ommol) of sodium carbonate and 100 mL of dichloromethane, stirred at room temperature overnight,filter,The filtrate was washed with saturated sodium chloride solution,The organic phase was collected, the organic phase was concentrated under reduced pressure,The residue was purified by column chromatography(Baby gel column, eluent,Petroleum ether: ethyl acetate = 2: 1),To give 8. lg as a yellow oily pyrrolidine-1,3-dicarboxylic acid 1-benzyl3-methyl ester in a yield of 68%.
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