(S)-甲基1-苄基吡咯烷-2-羧酸盐

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 4-bromobiphenyl (7.42 g, 31.87 mmol) in 40 mL THF was prepared, and 10 mL was added to Mg (0.85 g, 35.05 mmol) and one crystal of 12 in THF (10 mL). The Grignard reaction was initiated with the aid of gentle warming by a heat gun. After the iodine color had dissipated, the remaining 30 mL of bromide solution was added dropwise to the reaction mixture. After the reflux subsided, the solution was warmed over an oil bath (70° C.) for 30 minutes, then cooled to 0° C. N-benzyl-(S)-proline methyl ester (5, 2.18 g, 9.96 mmol) in THF (10 mL) was added. After the addition, the solution was allowed to warm to room temperature and stirred for another 8 hours. Saturated NH4Cl (150 mL) was added and the resulting mixture was diluted with Et2O (200 mL). The phases were separated and the organic phase was washed with H2O and brine, dried (MgSO4), and concentrated. The residue was purified over a short silica gel column using 5 to 20% EtOAc/pet ether to a give a white solid, which was recrystalized with CH2Cl2/pet ether to obtain white needles (4.106 g, 83%): mp 85-86° C., 1H NMR (300 MHz, CDCl3) δ 1.60-1.74 (m, 2 H), 1.76-1.88 (m, 1 H), 1.94-2.08 (m, 1 H), 2.40 (dd, J=16.6, 9.0 Hz, 1 H), 2.92-3.00 (m, 1 H), 3.10 (d, J=12.7 Hz, 1 H), 3.38 (d, J=12.5 Hz, 1 H), 4.06 (dd, J=9.3, 4.6 Hz, 1 H), 5.04 (s, 1 H), 7.04-7.60 (m, 14H), 7,68 (d, J=8.3 Hz, 2 H), 7.82 (d, J=8.3 Hz, 2 H). The Grignard reaction of gentle warming by a heat gun cooled to 0° C After the addition to warm to room temperature The phases were separated the organic phase was washed with H2O and brine dried (MgSO4) concentrated The residue was purified over a short silica gel column a give a white solid, which was recrystalized with CH2Cl2/pet ether

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Acetylchloride (9.26 mL, 130.28 mmol) was added dropwise to a stirred and cooled (0° C.) solution of (S)-proline (5 g, 43.42 mmol) in MeOH (86 mL). After the addition, the ice bath was removed and the stirring was continued for 15 h at room temperature. The solvent was then evaporated and the residual oil redissolved in dry CH3CN (70 mL). Et3N (18 mL, 130 mmol) and BnBr (6.20 mL, 52.10 mmol) were added to obtain a white suspension. After 12 h of stirring at room temperature, the CH3CN was evaporated, and the residue was partitioned between saturated NH4Cl (200 mL) and Et2O (200 mL). The phases were separated, the aqueous layer was extracted with Et2O (40 mL×2), and the combined organic phases were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified over silica gel using 5 to 10% EtOAc/pet ether to give a clear oil (6.37 g, 69%): 1H NMR (300 MHz, CDCl3) δ 1.70-2.20 (m, 4 H), 2.32-2.46 (m, 1 H), 3.00-3.10 (m, 1 H), 3.20-3.30 (m, 1 H), 3.56 (d, J=12.7 Hz, 1 H), 3.64 (s, 3 H), 3.88 (d, J=12.7 Hz, 1 H), 7.25-7.35 (m, 5 H). The spectroscopic data agrees with literature values (Corey, E. J., Link, J. O.; J. Org. Chem. 1991, 56, 442). After the addition the ice bath was removed The solvent was then evaporated the residual oil redissolved in dry CH3CN (70 mL) to obtain a white suspension After 12 h of stirring at room temperature the CH3CN was evaporated the residue was partitioned between saturated NH4Cl (200 mL) and Et2O (200 mL) The phases were separated the aqueous layer was extracted with Et2O (40 mL×2) the combined organic phases were washed with water and brine dried (MgSO4) concentrated The residue was purified over silica gel using 5 to 10% EtOAc/pet ether

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 4-bromobiphenyl (7.42 g, 31.87 mmol) in 40 mL THF was prepared, and 10 mL was added to Mg (0.85 g, 35.05 mmol) and one crystal of I2 in THF (10 mL). The Grignard reaction was initiated with the aid of gentle warming by a heat gun. After the iodine color had dissipated, the remaining 30 mL of bromide solution was added dropwise to the reaction mixture. After the reflux subsided, the solution was warmed over an oil bath (70° C.), for 30 minutes, then cooled to 0° C. N-benzyl-(S)-proline methyl ester (5, 2.18 g, 9.96 mmol) in THF (10 mL) was added. After the addition, the solution was allowed to warm to room temperature and stirred for another 8 hours. Saturated NH4Cl (150 mL) was added and the resulting mixture was diluted with Et2O (200 mL). The phases were separated and the organic phase was washed with H2O and brine, dried (MgSO4), and concentrated. The residue was purified over a short silica gel column using 5 to 20% EtOAc/pet ether to a give a white solid, which was recrystalized with CH2Cl2/pet ether to obtain white needles (4.106 g, 83%): mp 85-86° C., 1H NMR (300 MHz, CDCl3) δ 1.60-1.74 (m, 2H), 1.76-1.88 (m, 1H), 1.94-2.08 (m, 1H), 2.40 (dd, J=16.6, 9.0 Hz, 1H), 2.92-3.00 (m, 1H), 3.10 (d, J=12.7 Hz, 1H), 3.38 (d, J=12.5 Hz, 1H), 4.06 (dd, J=9.3, 4.6 Hz, 1H), 5.04 (s, 1H), 7.04-7.60 (m, 14H), 7.68 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H). The Grignard reaction of gentle warming by a heat gun cooled to 0° C After the addition to warm to room temperature The phases were separated the organic phase was washed with H2O and brine dried (MgSO4) concentrated The residue was purified over a short silica gel column a give a white solid, which was recrystalized with CH2Cl2/pet ether

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Acetylchloride (9.26 mL, 130.28 mmol) was added dropwise to a stirred and cooled (0° C.) solution of (S)-proline (5 g, 43.42 mmol) in MeOH (86 mL). After the addition, the ice bath was removed and the stirring was continued for 15 h at room temperature. The solvent was then evaporated and the residual oil redissolved in dry CH3CN (70 mL). Et3N (18 mL, 130 mmol) and BnBr (6.20 mL, 52.10 mmol) were added to obtain a white suspension. After 12 h of stirring at room temperature, the CH3CN was evaporated, and the residue was partitioned between saturated NH4Cl (200 mL) and Et2O (200 mL). The phases were separated, the aqueous layer was extracted with Et2O (40 mL×2), and the combined organic phases were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified over silica gel using 5 to 10% EtOAc/pet ether to give a clear oil (6.37 g, 69%): 1H NMR (300 MHz, CDCl3) δ 1.70-2.20 (m, 4H), 2.32-2.46 (m, 1H), 3.00-3.10 (m, 1H), 3.20-3.30 (m, 1H), 3.56 (d, J=12.7 Hz, 1H), 3.64 (s, 3H), 3.88 (d, J=12.7 Hz, 1H), 7.25-7.35 (m, 5H). The spectroscopic data agrees with literature values (Corey, E. J., Link, J. O.; J. Org. Chem. 1991, 56, 442). After the addition the ice bath was removed The solvent was then evaporated the residual oil redissolved in dry CH3CN (70 mL) to obtain a white suspension After 12 h of stirring at room temperature the CH3CN was evaporated the residue was partitioned between saturated NH4Cl (200 mL) and Et2O (200 mL) The phases were separated the aqueous layer was extracted with Et2O (40 mL×2) the combined organic phases were washed with water and brine dried (MgSO4) concentrated The residue was purified over silica gel using 5 to 10% EtOAc/pet ether

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-proline methyl ester hydrochloride (5.8 g, 35 mmol) was suspended in DCM (40 mL), to it was added triethylamine (12 ml, 84 mmol). After stirring for 10 min, the precipitate formed was filtered off and washed with DCM (5 mL). To the filtrate was added benzyl bromide (5.0 ml, 42 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc and washed with water and brine, dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 25% EtOAc in hexane, to provide (S)-methyl 1-benzylpyrrolidine-2-carboxylate as colorless oil. MS (ESI, pos. ion) m/z: 220.0 (M+1). the precipitate formed was filtered off washed with DCM (5 mL) The reaction mixture was stirred at RT for 16 h washed with water and brine dried (Na2SO4) concentrated The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (120 g) eluting with a gradient of 0% to 25% EtOAc in hexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-praline methyl ester hydrochloride (5.8 g, 35 mmol) was suspended in DCM (40 mL), to it was added triethylamine (12 ml, 84 mmol). After stirring for 10 min, the precipitate formed was filtered off and washed with DCM (5 mL). To the filtrate was added benzyl bromide (5.0 ml, 42 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc and washed with water and brine, dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 25% EtOAc in hexane, to provide (S)-methyl 1-benzylpyrrolidine-2-carboxylate as colorless oil. MS (ESI, pos. ion) m/z: 220.0 (M+1). the precipitate formed was filtered off washed with DCM (5 mL) The reaction mixture was stirred at RT for 16 h washed with water and brine dried (Na2SO4) concentrated The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (120 g) eluting with a gradient of 0% to 25% EtOAc in hexane

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 4-bromobiphenyl (7.42 g, 31.87 mmol) in 40 mL THF was prepared, and 10 mL was added to Mg (0.85 g, 35.05 mmol) and one crystal of 12 in THF (10 mL). The Grignard reaction was initiated with the aid of gentle warming by a heat gun. After the iodine color had dissipated, the remaining 30 mL of bromide solution was added dropwise to the reaction mixture. After the reflux subsided, the solution was warmed over an oil bath (70° C.) for 30 minutes, then cooled to 0° C. N-benzyl-(S)-proline methyl ester (5, 2.18 g, 9.96 mmol) in THF (10 mL) was added. After the addition, the solution was allowed to warm to room temperature and stirred for another 8 hours. Saturated NH4Cl (150 mL) was added and the resulting mixture was diluted with Et2O (200 mL). The phases were separated and the organic phase was washed with H2O and brine, dried (MgSO4), and concentrated. The residue was purified over a short silica gel column using 5 to 20% EtOAc/pet ether to a give a white solid, which was recrystalized with CH2Cl2/pet ether to obtain white needles (4.106 g, 83%): mp 85-86° C., 1H NMR (300 MHz, CDCl3) δ 1.60-1.74 (m, 2 H), 1.76-1.88 (m, 1 H), 1.94-2.08 (m, 1 H), 2.40 (dd, J=16.6, 9.0 Hz, 1 H), 2.92-3.00 (m, 1 H), 3.10 (d, J=12.7 Hz, 1 H), 3.38 (d, J=12.5 Hz, 1 H), 4.06 (dd, J=9.3, 4.6 Hz, 1 H), 5.04 (s, 1 H), 7.04-7.60 (m, 14H), 7,68 (d, J=8.3 Hz, 2 H), 7.82 (d, J=8.3 Hz, 2 H). The Grignard reaction of gentle warming by a heat gun cooled to 0° C After the addition to warm to room temperature The phases were separated the organic phase was washed with H2O and brine dried (MgSO4) concentrated The residue was purified over a short silica gel column a give a white solid, which was recrystalized with CH2Cl2/pet ether

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Acetylchloride (9.26 mL, 130.28 mmol) was added dropwise to a stirred and cooled (0° C.) solution of (S)-proline (5 g, 43.42 mmol) in MeOH (86 mL). After the addition, the ice bath was removed and the stirring was continued for 15 h at room temperature. The solvent was then evaporated and the residual oil redissolved in dry CH3CN (70 mL). Et3N (18 mL, 130 mmol) and BnBr (6.20 mL, 52.10 mmol) were added to obtain a white suspension. After 12 h of stirring at room temperature, the CH3CN was evaporated, and the residue was partitioned between saturated NH4Cl (200 mL) and Et2O (200 mL). The phases were separated, the aqueous layer was extracted with Et2O (40 mL×2), and the combined organic phases were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified over silica gel using 5 to 10% EtOAc/pet ether to give a clear oil (6.37 g, 69%): 1H NMR (300 MHz, CDCl3) δ 1.70-2.20 (m, 4 H), 2.32-2.46 (m, 1 H), 3.00-3.10 (m, 1 H), 3.20-3.30 (m, 1 H), 3.56 (d, J=12.7 Hz, 1 H), 3.64 (s, 3 H), 3.88 (d, J=12.7 Hz, 1 H), 7.25-7.35 (m, 5 H). The spectroscopic data agrees with literature values (Corey, E. J., Link, J. O.; J. Org. Chem. 1991, 56, 442). After the addition the ice bath was removed The solvent was then evaporated the residual oil redissolved in dry CH3CN (70 mL) to obtain a white suspension After 12 h of stirring at room temperature the CH3CN was evaporated the residue was partitioned between saturated NH4Cl (200 mL) and Et2O (200 mL) The phases were separated the aqueous layer was extracted with Et2O (40 mL×2) the combined organic phases were washed with water and brine dried (MgSO4) concentrated The residue was purified over silica gel using 5 to 10% EtOAc/pet ether

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-proline methyl ester hydrochloride (5.8 g, 35 mmol) was suspended in DCM (40 mL), to it was added triethylamine (12 ml, 84 mmol). After stirring for 10 min, the precipitate formed was filtered off and washed with DCM (5 mL). To the filtrate was added benzyl bromide (5.0 ml, 42 mmol). The reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc and washed with water and brine, dried (Na2SO4) and concentrated. The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 25% EtOAc in hexane, to provide (S)-methyl 1-benzylpyrrolidine-2-carboxylate as colorless oil. MS (ESI, pos. ion) m/z: 220.0 (M+1). the precipitate formed was filtered off washed with DCM (5 mL) The reaction mixture was stirred at RT for 16 h washed with water and brine dried (Na2SO4) concentrated The crude product was chromatographed through a Redi-Sep® pre-packed silica gel column (120 g) eluting with a gradient of 0% to 25% EtOAc in hexane

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 12.5 ml BuLi (1.6 M in hexane) was added a solution of 0.73 g acetone oxime in 8 ml THF at 0° C. After 30 minutes a solution of 1.0 g (S)-1-Benzyl-pyrrolidine-2-carboxylic acid methyl ester in 5 ml THF was added dropwise over a period of 20 minutes at this temperature. The resulting suspension was stirred for another 3 h at 0° C. before being cannulated into 21 ml 3 M HCl. The phases were separated; the aqueous phase was brought to pH8 using solid NaHCO3 and extracted with dichloromethane (3×) to give the crude product. Yield: 1.3 g mixture of E/Z isomers. The phases were separated extracted with dichloromethane (3×)

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 4-bromobiphenyl (7.42 g, 31.87 mmol) in 40 mL THF was prepared, and 10 mL was added to Mg (0.85 g, 35.05 mmol) and one crystal of I2 in THF (10 mL). The Grignard reaction was initiated with the aid of gentle warming by a heat gun. After the iodine color had dissipated, the remaining 30 mL of bromide solution was added dropwise to the reaction mixture. After the reflux subsided, the solution was warmed over an oil bath (70° C.), for 30 minutes, then cooled to 0° C. N-benzyl-(S)-proline methyl ester (5, 2.18 g, 9.96 mmol) in THF (10 mL) was added. After the addition, the solution was allowed to warm to room temperature and stirred for another 8 hours. Saturated NH4Cl (150 mL) was added and the resulting mixture was diluted with Et2O (200 mL). The phases were separated and the organic phase was washed with H2O and brine, dried (MgSO4), and concentrated. The residue was purified over a short silica gel column using 5 to 20% EtOAc/pet ether to a give a white solid, which was recrystalized with CH2Cl2/pet ether to obtain white needles (4.106 g, 83%): mp 85-86° C., 1H NMR (300 MHz, CDCl3) δ 1.60-1.74 (m, 2H), 1.76-1.88 (m, 1H), 1.94-2.08 (m, 1H), 2.40 (dd, J=16.6, 9.0 Hz, 1H), 2.92-3.00 (m, 1H), 3.10 (d, J=12.7 Hz, 1H), 3.38 (d, J=12.5 Hz, 1H), 4.06 (dd, J=9.3, 4.6 Hz, 1H), 5.04 (s, 1H), 7.04-7.60 (m, 14H), 7.68 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H). The Grignard reaction of gentle warming by a heat gun cooled to 0° C After the addition to warm to room temperature The phases were separated the organic phase was washed with H2O and brine dried (MgSO4) concentrated The residue was purified over a short silica gel column a give a white solid, which was recrystalized with CH2Cl2/pet ether

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Acetylchloride (9.26 mL, 130.28 mmol) was added dropwise to a stirred and cooled (0° C.) solution of (S)-proline (5 g, 43.42 mmol) in MeOH (86 mL). After the addition, the ice bath was removed and the stirring was continued for 15 h at room temperature. The solvent was then evaporated and the residual oil redissolved in dry CH3CN (70 mL). Et3N (18 mL, 130 mmol) and BnBr (6.20 mL, 52.10 mmol) were added to obtain a white suspension. After 12 h of stirring at room temperature, the CH3CN was evaporated, and the residue was partitioned between saturated NH4Cl (200 mL) and Et2O (200 mL). The phases were separated, the aqueous layer was extracted with Et2O (40 mL×2), and the combined organic phases were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified over silica gel using 5 to 10% EtOAc/pet ether to give a clear oil (6.37 g, 69%): 1H NMR (300 MHz, CDCl3) δ 1.70-2.20 (m, 4H), 2.32-2.46 (m, 1H), 3.00-3.10 (m, 1H), 3.20-3.30 (m, 1H), 3.56 (d, J=12.7 Hz, 1H), 3.64 (s, 3H), 3.88 (d, J=12.7 Hz, 1H), 7.25-7.35 (m, 5H). The spectroscopic data agrees with literature values (Corey, E. J., Link, J. O.; J. Org. Chem. 1991, 56, 442). After the addition the ice bath was removed The solvent was then evaporated the residual oil redissolved in dry CH3CN (70 mL) to obtain a white suspension After 12 h of stirring at room temperature the CH3CN was evaporated the residue was partitioned between saturated NH4Cl (200 mL) and Et2O (200 mL) The phases were separated the aqueous layer was extracted with Et2O (40 mL×2) the combined organic phases were washed with water and brine dried (MgSO4) concentrated The residue was purified over silica gel using 5 to 10% EtOAc/pet ether