(S)-1-N-Boc-2-吡咯烷甲腈

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

实验步骤: 2.89 ml (20.8 mmol) trifluoroacetic acid anhydride was added to a solution of 4.05 g (18.9 mmol) BOC-L-prolyl-amide and 5.80 ml (41.6 mmol) triethyl amine in tetrahydrofuran at 0° C. The reaction was kept at rt for 2 h. 20 ml water was added, and the reaction was evaporated. The residue was dissolved in dichloromethane, and the organic phase was washed with 0.1 M HCl aq and 0.1 M NaOH aq. The organic phase was dried with anhydrous Na2SO4 and evaporated. Yield of crude product 3.64 g. The product was purified with a silica column using 25% ethyl acetate in petroleum ether as eluent. Yield 3.37 g (17.2 mmol, 91%). the reaction was evaporated The residue was dissolved in dichloromethane the organic phase was washed with 0.1 M HCl aq and 0.1 M NaOH aq. The organic phase was dried with anhydrous Na2SO4 evaporated The product was purified with a silica column

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

实验步骤: 2.89 ml (20.8 mmol) trifluoroacetic acid anhydride was added to a solution of 4.05 g (18.9 mmol) BOC-L-prolyl-amide and 5.80 ml (41.6 mmol) triethyl amine in tetrahydrofuran at 0° C. The reaction was kept at rt for 2 h. 20 ml water was added, and the reaction was evaporated. The residue was dissolved in dichloromethane, and the organic phase was washed with 0.1 M HCl aq and 0.1 M NaOH aq. The organic phase was dried with anhydrous Na2SO4 and evaporated. Yield of crude product 3.64 g. The product was purified with a silica column using 25% ethyl acetate in petroleum ether as eluent. Yield 3.37 g (17.2 mmol, 91%). the reaction was evaporated The residue was dissolved in dichloromethane the organic phase was washed with 0.1 M HCl aq and 0.1 M NaOH aq. The organic phase was dried with anhydrous Na2SO4 evaporated The product was purified with a silica column

反应条件: temp:93.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-2-Cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.55 mmol) in N,N-dimethyl-formamide (20 mL) is added sodium azide (174 mg, 2.68 mmol) and ammonium chloride (150 mg, 2.81 mmol). The solution is stirred at 93° C. over night. The solution is poured into 5% citric acid solution with ice, and the mixture is extracted with EtOAc. The organic extract is washed with brine, dried and concentrated under vacuum. The crude oil is used directly in the next step without further purification. M+H+=240. the mixture is extracted with EtOAc The organic extract is washed with brine dried concentrated under vacuum The crude oil is used directly in the next step without further purification

反应条件: temp:93.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-2-Cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.55 mmol) in N,N-dimethyl-formamide (20 mL) is added sodium azide (174 mg, 2.68 mmol) and ammonium chloride (150 mg, 2.81 mmol). The solution is stirred at 93° C. over night. The solution is poured into 5% citric acid solution with ice, and the mixture is extracted with EtOAc. The organic extract is washed with brine, dried and concentrated under vacuum. The crude oil is used directly in the next step without further purification. M+H+=240. the mixture is extracted with EtOAc The organic extract is washed with brine dried concentrated under vacuum The crude oil is used directly in the next step without further purification

反应条件: temp:93.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-2-Cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.55 mmol) in N,N-dimethyl-formamide (20 mL) is added sodium azide (174 mg, 2.68 mmol) and ammonium chloride (150 mg, 2.81 mmol). The solution is stirred at 93° C. over night. The solution is poured into 5% citric acid solution with ice, and the mixture is extracted with EtOAc. The organic extract is washed with brine, dried and concentrated under vacuum. The crude oil is used directly in the next step without further purification. M+H+=240. the mixture is extracted with EtOAc The organic extract is washed with brine dried concentrated under vacuum The crude oil is used directly in the next step without further purification

反应条件: temp:93.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-2-Cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.55 mmol) in N,N-dimethyl-formamide (20 mL) is added sodium azide (174 mg, 2.68 mmol) and ammonium chloride (150 mg, 2.81 mmol). The solution is stirred at 93° C. over night. The solution is poured into 5% citric acid solution with ice, and the mixture is extracted with EtOAc. The organic extract is washed with brine, dried and concentrated under vacuum. The crude oil is used directly in the next step without further purification. M+H+=240. the mixture is extracted with EtOAc The organic extract is washed with brine dried concentrated under vacuum The crude oil is used directly in the next step without further purification

反应条件: temp:93.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of (S)-2-Cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 2.55 mmol) in N,N-dimethyl-formamide (20 mL) is added sodium azide (174 mg, 2.68 mmol) and ammonium chloride (150 mg, 2.81 mmol). The solution is stirred at 93° C. over night. The solution is poured into 5% citric acid solution with ice, and the mixture is extracted with EtOAc. The organic extract is washed with brine, dried and concentrated under vacuum. The crude oil is used directly in the next step without further purification. M+H+=240. the mixture is extracted with EtOAc The organic extract is washed with brine dried concentrated under vacuum The crude oil is used directly in the next step without further purification

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

实验步骤: A solution of oxalyl chloride (11.0 ml, 0.126 mol) and DMF (11.4 ml, 0.138 mol) in MeCN (170 ml) was treated dropwise with a solution of N-Boc-L-proline amide (12.3 g, 0.57 mol) and pyridine (20.4 ml, 0.253 mol) in MeCN (30 ml) at 0° C. and stirred at this temperature for 15 minutes. The reaction mixture was diluted with EtOAc and washed with H2O (×3). The organic extract was dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was purified on a silica column eluting with a solvent gradient of pentane:EtOAc (80:20) gradually changing to (60:40) to afford the title compound (7.40 g, 66%). washed with H2O (×3) The organic extract was dried over anhydrous MgSO4 filtered The solvent was removed under reduced pressure The residue was purified on a silica column eluting with a solvent gradient of pentane:EtOAc (80:20)

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: General procedure D was used to deprotect 0.4 grams (2.05 mmols) of 28 in 21 mL of dichloromethane and trifluoroacetic acid. After work-up, the TFA salt of 28 was then coupled to 0.6 grams (2.05 mmols) of 4-octylbenzoic acid with 1.1 grams (2.05 mmols) of PyBOP and 1.1 grams (8.2 mmols) of N,N-diisopropylethylamine in 21 mL of dichloromethane according to general procedure E and heating at 50° C. After previously described work-up and purification procedures (column chromatography, 25% EtOAc in hexanes) 0.256 grams (0.82 mmols, 40%) of the title product was recovered.

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

实验步骤: General procedure D was used to deprotect 0.447 grams (2.3 mmols) of 28. After standard work-up procedures, general procedure E was used to couple 2.3 mmols of the TFA salt of 28 to 0.635 grams (2.3 mmols) of 4-undecylbenzoic acid at 50° C. After work-up, 0.334 grams (0.94 mmols, 41%) of the title product was isolated as a yellow solid by flash chromatography (25% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3) δ 7.24 (dd, J=12.2, 4.4 Hz, 2H), 7.04 (t, J=7.7 Hz, 2H), 4.97 (s, 1H), 3.88 (s, 1H), 3.31 (dt, J=18.1, 9.0 Hz, 1H), 2.77-2.64 (m, 1H), 2.63-2.54 (m, 1H), 2.24-2.12 (m, 1H), 1.60 (dt, J=15.1, 7.3 Hz, 4H), 1.29 (d, J=10.9 Hz, 14H), 0.88 (t, J=6.7 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 169.97, 146.29, 128.42, 128.18, 127.63, 127.17, 118.73, 49.51, 46.85, 46.20, 35.84, 31.91, 31.20, 30.27, 29.64, 29.61, 29.56, 29.46, 29.33, 29.23, 25.57, 22.68, 14.12.

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: General procedure D was used to deprotect 0.4 grams (2.05 mmols) of 28 using 21 mL of dichloromethane and trifluoroacetic acid. After standard work-up procedures, the TFA salt of 28 was coupled to 0.6 grams (2.05 mmols) of 4-dodecylbenzoic acid using 1.1 grams (2.05 mmols) of PyBOP and 1.1 grams (8.2 mmols) of N,N-diisopropylethylamine in 21 mL of dichloromethane according general procedure E and heating to 50° C. After previously described work-up and purification procedures (column chromatography, 25% EtOAc in hexanes), 0.17 grams (0.45 mmols, 22%) of the title product was recovered as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J=8.0 Hz, 2H), 7.22 (d, J=7.6 Hz, 2H), 4.96-4.84 (m, 1H), 3.73-3.63 (m, 1H), 5.62-3.52 (m, 1H), 2.68-2.58 (m, 2H), 2.39-2.26 (m, 1H), 2.24-2.10 (m, 1H), 2.06-1.96 (m, 1H), 1.67-1.55 (m, 1H), 1.39-1.18 (m, 18H), 0.87 (t, J=6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 170.18, 146.28, 128.40, 127.61, 127.17, 118.73, 49.51, 46.87, 35.84, 31.91, 31.20, 30.30, 29.65, 29.56, 29.46, 29.34, 29.23, 25.58, 22.68, 14.12.

反应条件: temp:-25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a flame dried flask was added 2 grams (9.3 mmols) of N-Boc proline followed by 93 ml, of dichloromethane and 4.24 grams (41.85 mmols) of triethylamine. The reaction mixture was then cooled to −25° C. and 2.5 grams (18.6 mmols) of iso-butylchloroformate was added dropwise. After stirring for 45 minutes at this low temperature, 0.83 grams (49 mmol) of ammonia was added to the reaction mixture as a 7N solution in methanol. The flask was allowed to warm to ambient temperature and stir for an additional 16 hours. After this time, the reaction mixture was evaporated to dryness and reconstituted in 200 mL of EtOAc. The organic layer was washed four 15 mL portions of 1N HCl, dried with MgSO4 and evaporated to dryness. The crude material was then immediately dehydrated to the nitrile according to general procedure E using 1.9 grams (18.88 mmols) of triethylamine and 2.34 grams (11.16 mmols) of trifluoroacetic anhydride in 93 mL of THF. After standard work-up and purification techniques (column chromatography, 25% EtOAc in hexanes), 0.91 grams (4.65 mmols, 50%) of the title product was recovered as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 4.53 (d, J=5.5 Hz, 0.5H), 4.48-4.38 (m, 0.5H), 3.57-3.41 (m, 1H), 3.41-3.22 (m, 1H), 2.31-1.92 (m, 4H), 1.47 (d, J=9.4 Hz, 9H). 13C NMR (75 MHz, CDCl3) δ 153.25, 119.38, 81.64, 47.39, 45.93, 31.86, 31.01, 28.52, 24.88, 24.04. To a flame dried flask to warm to ambient temperature After this time, the reaction mixture was evaporated to dryness The organic layer was washed four 15 mL portions of 1N HCl dried with MgSO4 evaporated to dryness