4-氨基丁酸乙酯 盐酸盐

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

实验步骤: 4 ml of orthoformic acid triethyl ester and 6 ml of acetic acid are added to 0.84 g of 4-aminobutyric acid ethyl ester hydrochloride and 0.9 g of sodium azide and the whole is heated under reflux for 7 hours. After cooling, the reaction mixture is taken up in ethyl acetate and aqueous sodium bicarbonate solution, the organic phases are separated off and washed four times with aqueous sodium bicarbonate solution. After washing with water and brine, the ethyl acetate phase is dried over sodium sulphate and concentrated to form the title compound. the whole is heated under reflux for 7 hours After cooling aqueous sodium bicarbonate solution, the organic phases are separated off washed four times with aqueous sodium bicarbonate solution After washing with water and brine the ethyl acetate phase is dried over sodium sulphate concentrated

反应条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-amino-butyric acid ethyl ester hydrochloride (1 eq.) in THF was added TEA (2.5 eq.). The mixture was stirred 5 min at 20° C., then benzofuran-6-carbaldehyde (0.95 eq.) and MgSO4 (3 eq.) were added. The reaction was refluxed for 2 h, then cooled to 20° C. and filtered. The filtrate was added to a suspension of NaBH4 (2 to 6 eq.) in MeOH at −15° C. The reaction was stirred for 2 h at −15° C. The reaction was quenched with the addition of aqueous HCl 2N until pH=2. The aqueous layer was washed twice with EtOAc. The organic layers were discarded. Solid KOH was added to the aqueous layer. The crude was extracted three times with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure at 20° C. The crude was purified by chromatography on silica gel (elution with DCM/MeOH: 95/5) to afford 4-[(benzofuran-6-ylmethyl)-amino]-butyric acid ethyl ester. The reaction was refluxed for 2 h cooled to 20° C. filtered The reaction was stirred for 2 h at −15° C The reaction was quenched with the addition of aqueous HCl 2N until pH=2 The aqueous layer was washed twice with EtOAc Solid KOH was added to the aqueous layer The crude was extracted three times with EtOAc dried over MgSO4 filtered concentrated under reduced pressure at 20° C The crude was purified by chromatography on silica gel (elution with DCM/MeOH: 95/5)

反应条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-amino-butyric acid ethyl ester hydrochloride (1 eq.) in either MeOH or EtOH were added TEA (2.5 eq.), 6-formyl-indole-1-carboxylic acid tert-butyl ester (0.95 eq.) and MgSO4 (1.5 eq.). The reaction was stirred at 20° C. for 15 h, then cooled to −15° C. NaBH4 (2 to 6 eq.) was added portionwise. The reaction was stirred for 1 h at −15° C., then 1 h at 0° C. The reaction was quenched with the addition of cold water at 0° C. The crude was extracted three times with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure at 20° C. The crude was purified by chromatography on silica gel (elution with DCM/MeOH: 1/0 to 99/1) to afford 6-[(3-ethoxycarbonyl-propylamino)-methyl]-indole-1-carboxylic acid tert-butyl ester. cooled to −15° C The reaction was stirred for 1 h at −15° C. 1 h at 0° C The reaction was quenched with the addition of cold water at 0° C The crude was extracted three times with DCM dried over MgSO4 filtered concentrated under reduced pressure at 20° C The crude was purified by chromatography on silica gel (elution with DCM/MeOH: 1/0 to 99/1)

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

实验步骤: To a stirred mixture of ethyl 4-aminobutanoate hydrochloride (3.4 g) and phenoxyacetyl chloride (2.76 ml) in 50 ml of Et2O and 50 ml of water was added one portion of NaHCO3 (4 2 g). After 2 hr the layers were separated and the organic phase was washed (1N HCl, brine), dried (MgSO4), and filtered. Evaporation of the solvent under vacuum gave 3.1 g (53%) of the title compound as an oil. After 2 hr the layers were separated the organic phase was washed (1N HCl, brine) dried (MgSO4) filtered Evaporation of the solvent under vacuum

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

实验步骤: To a solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (84 mg, 0.189 mmol; Example 91, Step C), ethyl 4-aminobutyrate hydrochloride (127 mg, 0.756 mmol) and acetic acid (3 drops) in DCE/MeOH (3/1, 4.0 mL) was added sodium triacetoxyhydroborate (200 mg, 0.945 mmol) at 25° C. After being stirred at 25° C. for 18 h, the reaction was quenched by adding ice-cold saturated aqueous NaHCO3 solution and was extracted with DCM. The combined organic layers were washed (1×sat. aq. NaCl solution) and concentrated under reduced pressure. The residue was purified by reverse phase preparatory HPLC (acetonitrile in water with 0.1% TFA, gradient elution) to give the title compound as a white solid. the reaction was quenched by adding ice-cold saturated aqueous NaHCO3 solution was extracted with DCM The combined organic layers were washed (1×sat. aq. NaCl solution) concentrated under reduced pressure The residue was purified by reverse phase preparatory HPLC (acetonitrile in water with 0.1% TFA, gradient elution)

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

实验步骤: To a solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (84 mg, 0.189 mmol; Example 91, Step C), ethyl 4-aminobutyrate hydrochloride (127 mg, 0.756 mmol) and acetic acid (3 drops) in DCE/MeOH (3/1, 4.0 mL) was added sodium triacetoxyhydroborate (200 mg, 0.945 mmol) at 25° C. After being stirred at 25° C. for 18 h, the reaction was quenched by adding ice-cold saturated aqueous NaHCO3 solution and was extracted with DCM. The combined organic layers were washed (1×sat. aq. NaCl solution) and concentrated under reduced pressure. The residue was purified by reverse phase preparatory HPLC (acetonitrile in water with 0.1% TFA, gradient elution) to give the title compound as a white solid. the reaction was quenched by adding ice-cold saturated aqueous NaHCO3 solution was extracted with DCM The combined organic layers were washed (1×sat. aq. NaCl solution) concentrated under reduced pressure The residue was purified by reverse phase preparatory HPLC (acetonitrile in water with 0.1% TFA, gradient elution)

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

实验步骤: A mixture of 600 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 394 mg of ethyl 4-aminobutyrate hydrochloride, 0.27 mL of triethylamine, and 6.0 mL of dichloromethane was stirred at room temperature for 2 hours. The reaction mixture was purified by silica gel column chromatography (hexane-chloroform) to obtain 442 mg of methyl 4-{2-[4-({[2-({3-[(4-ethoxy-4-oxobutyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a pale yellow solid. The reaction mixture was purified by silica gel column chromatography (hexane-chloroform)

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

实验步骤: A mixture of 1-benzyl-5-hydroxy-3-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.14 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. overnight, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. To the residue were then added HOBt (32 mg, 0.23 mmol), CH2Cl2 (3 mL), and EDC (50 mg, 0.26 mmol), and the resulting mixture was stirred for 10 min. 4-Amino-butyric acid ethyl ester HCl salt (39 mg, 0.23 mmol) and Hunig's base (0.1 mL, 0.52 mmol) were added, and the mixture was stirred for 48 h. The mixture was diluted with EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH) to give 38 mg of the title compound. MS: (+) m/z 516.37 (M+1). concentrated to approximately one-third of its original volume 1 M HCl was added the resulting suspension was extracted with EtOAc The organic layer was dried over MgSO4 concentrated the mixture was stirred for 48 h washed with 0.1 M HCl The organic layer was dried over MgSO4 concentrated The crude product was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH)

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

实验步骤: A mixture of 1-benzyl-5-hydroxy-3-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (51 mg, 0.123 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. overnight, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. To the residue were then added HOBt (27 mg, 0.20 mmol), CH2Cl2 (3 mL), and EDC (42 mg, 0.22 mmol), and the resulting mixture was stirred for 10 min. 4-Amino-butyric acid ethyl ester HCl salt (33 mg, 0.20 mmol) and Hunig's base (0.080 mL, 0.44 mmol) were added, and the mixture was stirred overnight. The mixture was diluted with EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-45% EtOAc/hexanes+1% AcOH) to give 20 mg of the title compound. MS: (+) m/z 516.37 (M+1). concentrated to approximately one-third of its original volume 1 M HCl was added the resulting suspension was extracted with EtOAc The organic layer was dried over MgSO4 concentrated the mixture was stirred overnight washed with 0.1 M HCl The organic layer was dried over MgSO4 concentrated The crude product was purified by silica gel chromatography (5-45% EtOAc/hexanes+1% AcOH)

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

实验步骤: A mixture of 1-benzyl-5-hydroxy-3-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (51 mg, 0.123 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. overnight, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. To the residue were then added HOBt (27 mg, 0.20 mmol), CH2Cl2 (3 mL), and EDC (42 mg, 0.22 mmol), and the resulting mixture was stirred for 10 min. 4-Amino-butyric acid ethyl ester HCl salt (33 mg, 0.20 mmol) and Hunig's base (0.080 mL, 0.44 mmol) were added, and the mixture was stirred overnight. The mixture was diluted with EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-45% EtOAc/hexanes+1% AcOH) to give 20 mg of the title compound. MS: (+) m/z 516.37 (M+1). concentrated to approximately one-third of its original volume 1 M HCl was added the resulting suspension was extracted with EtOAc The organic layer was dried over MgSO4 concentrated the mixture was stirred overnight washed with 0.1 M HCl The organic layer was dried over MgSO4 concentrated The crude product was purified by silica gel chromatography (5-45% EtOAc/hexanes+1% AcOH)

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

实验步骤: A mixture of 1-cyclohexylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.15 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. overnight, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. To the residue were then added HOBt (33 mg, 0.24 mmol), CH2Cl2 (3 mL), and EDC (53 mg, 0.28 mmol), and the resulting mixture was stirred for 10 min. 4-Amino-butyric acid ethyl ester HCl salt (41 mg, 0.24 mmol) and Hunig's base (0.1 mL, 0.56 mmol) were added, and the mixture was stirred for 48 h. The mixture was diluted with EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-30% EtOAc/hexanes+1% AcOH) to give 39 mg of the title compound. MS: (+) m/z 492.44 (M+1). concentrated to approximately one-third of its original volume 1 M HCl was added the resulting suspension was extracted with EtOAc The organic layer was dried over MgSO4 concentrated the mixture was stirred for 48 h washed with 0.1 M HCl The organic layer was dried over MgSO4 concentrated The crude product was purified by silica gel chromatography (5-30% EtOAc/hexanes+1% AcOH)

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

实验步骤: 1-Benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid (35 mg, 0.094 mmol) and HOBt (13 mg, 0.094 mmol) were added to 2 mL of CH2Cl2. EDC (25 mg, 0.13 mmol) was added, and the mixture was stirred for 10 min. 4-Amino-butyric acid ethyl ester HCl salt (16 mg, 0.094 mmol) and Hunig's base (0.033 mL, 0.19 mmol) were then added, and the mixture was stirred for 16 h. The mixture was diluted with EtOAc (40 mL) and washed with 0.1 M HCl and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-40% EtOAc/hexanes+2% AcOH) to give 13 mg of the title compound. MS: (+) m/z 486.39 (M+1). the mixture was stirred for 16 h washed with 0.1 M HCl and brine The organic layer was dried over MgSO4 concentrated The crude product was purified by silica gel chromatography (0-40% EtOAc/hexanes+2% AcOH)