2-氨基乙酸苄酯盐酸盐

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

实验步骤: Boc-Val-OH (8.69 g, 40.0 mmol) and Gly-OBzl.HCl (8.07 g, 40.0 mmol) were dissolved in methylene chloride (100 ml), and the solution was maintained at 0° C. Triethylamine (6.13 ml, 44.0 mmol), HOBt (1-hydroxybenzotriazole, 6.74 g, 44.0 mmol), and WSC.HCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 8.44 g, 44.0 mmol) were added to the solution, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with water (50 ml), 5% citric acid aqueous solution (50 ml×twice), saturated brine (50 ml), 5% sodium hydrogencarbonate aqueous solution (50 ml×twice), and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, then the magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to obtain white crystals of Boc-Val-Gly-OBzl (13.2 g, 36.2 mmol). The reaction mixture was concentrated under reduced pressure the residue was dissolved in ethyl acetate (200 ml) The solution was washed with water (50 ml), 5% citric acid aqueous solution (50 ml×twice), saturated brine (50 ml), 5% sodium hydrogencarbonate aqueous solution (50 ml×twice), and saturated brine (50 ml) The organic layer was dried over anhydrous magnesium sulfate the magnesium sulfate was removed by filtration the filtrate was concentrated under reduced pressure The residue was recrystallized from ethyl acetate/n-hexane

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

实验步骤: To a 25 ml pear-shaped flask containing 2-(S-t-butylsulfanylmethyl)-3-(3-bromophenyl)propionic acid (0.22 g, 0.665 mmol) and THF (7 ml), at 0° C. were added dropwise a solution of glycine benzyl ester hydrochloride (0.134 g, 0.665 mmol) and a solution of triethylamine (93 μl, 67.3 mg, 0.665 mmol) in CH2Cl2 (7 ml), followed by dropwise additions of a solution of HOBT (0.102 g, 0.665 mmol) in THF (5 ml) and a solution of 1,3-dicyclohexyl carbodiimide (0.164 g, 0.796 mmol) in CH2Cl2 (6 ml). The ice/water cooling bath was removed and the mixture was stirred at room temperature overnight. After concentration under reduced pressure, the residue was partitioned between water and CH2Cl2, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography eluting with 0 to 50% ether in hexane to give 2-[3-(3-bromophenyl)-2-(S-t-butylsulfanylmethyl)propionylamino]acetic acid benzyl ester as a colorless viscous oil, 0.25 g, 79% yield. HPLC purity: 100%. 1H NMR (CDCl3) δ 1.29 (s, 9H), 2.51 (m, 1H), 2.64 (m, 1H), 2.85 (m, 3H), 4.02 (m, 2H), 5.16 (s, 2H), 5.95 (m, 1H), 7.12 (m, 2H), 7.35 (m, 7H); MS (ES+) [M+H+]: 478, 480; (ES−) [M−H+]: 476, 478. The ice/water cooling bath was removed After concentration under reduced pressure the residue was partitioned between water and CH2Cl2 the combined organic layers were washed with brine dried over sodium sulfate filtered concentrated under reduced pressure The crude product was purified by silica gel flash column chromatography eluting with 0 to 50% ether in hexane

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4.2 cm3 of triethylamine and 3.02 g of benzyl glycinate hydrochloride are added, at 20° C., to 3 g of 4-methylpiperazin-1-ylcarbonyl chloride hydrochloride in solution in 150 cm3 of tetrahydrofuran. After stirring for 16 hours at 60° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is taken up in 70 cm3 of dichloromethane. The organic phase is successively washed with twice 100 cm3 of a saturated aqueous sodium bicarbonate solution and 70 cm3 of water, and then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.9 g of benzyl N-(4-methylpiperazin-1-ylcarbonyl)-glycinate in the form of a white solid. the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) The organic phase is successively washed with twice 100 cm3 of a saturated aqueous sodium bicarbonate solution and 70 cm3 of water dried over magnesium sulfate filtered concentrated to dryness under reduced pressure (2.7 kPa)

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

实验步骤: To a suspension of Boc—(D)—Arg(Tos)—OH (1 g, 2.34 mmol) in CH2Cl2 (10 mL) was added DIEA (1 mL) at 0° C. To the clear solution was added Gly—OBn.HCl (0.52 g, 2.58 mmol) and BOP (1.2 g, 2.8 mmol). The solution was stirred for 4 h at 0° C. Solvents were evaporated and residue was dissolved in a mixture of EtOAc (100 mL) and water (20 mL). The organic layer was washed with sat. NaHCO3 (10 mL), water (10 mL), 1 N HCl (10 mL) and sat. NaCl (3×10 mL), dried with MgSO4, filtered and evaporated. The solid residue was purified by column chromatography on silica gel (EtOAc) to give 1.12 g of the title compound as a powder. ES—MS (M+H)+=576.3 Solvents were evaporated residue was dissolved in a mixture of EtOAc (100 mL) and water (20 mL) The organic layer was washed with sat. NaHCO3 (10 mL), water (10 mL), 1 N HCl (10 mL) and sat. NaCl (3×10 mL) dried with MgSO4 filtered evaporated The solid residue was purified by column chromatography on silica gel (EtOAc)

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

实验步骤: A solution of 31-1 (0.75 g, 1.5 mmol) in 1:1:1 THF/MeOH/H2O (15 mL) was treated with LiOH·H2O (0.37 g, 8.8 mmol). After 45 min. the solution was concentrated, diluted with water, washed with EtOAc. The aqueous layer was acidified to pH 2-3 with 10% KHSO4 and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated to give an acid which was dissolved in acetonitrile (3 mL) and treated with glycine benzyl ester·HCl (0.1 g, 0.5 mmol), N-methylmorpholine (0.11 mL, 0.98 mmol), and BOP reagent (0.26 g, 0.58 mmol) for 24 h. The solution was concentrated, dissolved in water and EtOAc and the layers separated. The organic layer was dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 70% acetone/hexanes) gave 31-2 as a white solid. After 45 min. the solution was concentrated diluted with water washed with EtOAc extracted with EtOAc The organic layer was dried (Na2SO4) filtered evaporated to give an acid which The solution was concentrated dissolved in water EtOAc and the layers separated The organic layer was dried (Na2SO4) filtered evaporated

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

实验步骤: A solution of 31-1 (0.75 g, 1.5 mmol) in 1:1:1 THF/MeOH/H2O (15 mL) was treated with LiOH·H2O (0.37 g, 8.8 mmol). After 45 min. the solution was concentrated, diluted with water, washed with EtOAc. The aqueous layer was acidified to pH 2-3 with 10% KHSO4 and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated to give an acid which was dissolved in acetonitrile (3 mL) and treated with glycine benzyl ester·HCl (0.1 g, 0.5 mmol), N-methylmorpholine (0.11 mL, 0.98 mmol), and BOP reagent (0.26 g, 0.58 mmol) for 24 h. The solution was concentrated, dissolved in water and EtOAc and the layers separated. The organic layer was dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 70% acetone/hexanes) gave 31-2 as a white solid. After 45 min. the solution was concentrated diluted with water washed with EtOAc extracted with EtOAc The organic layer was dried (Na2SO4) filtered evaporated to give an acid which The solution was concentrated dissolved in water EtOAc and the layers separated The organic layer was dried (Na2SO4) filtered evaporated

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

实验步骤: To a mixture of 4-benzyloxy-1-dimethylcarbamoyl-isoquinoline-3-carboxylic acid (210 mg, 0.6 mmol), NEt3 (175 μl, 1.25 mmol), and CH2Cl2 (12 ml) cooled with an ice bath was added ClCO2iBu (83 μl, 0.63 mmol) with stirring. After stirring for 15 min glycine benzyl ester hydrochloride (127 mg, 0.63 mmol) was added and the mixture was stirred for another 15 min before the ice bath was removed. Stirring was then continued at ambient temperature for additional 1.5 h. Subsequently; the mixture was concentrated in vacuo. To the residue was added water (10 ml) and a few drops of aqueous 6N HCl. The mixture was extracted with EtOAc (15 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give a yellowish gum. Purification by flash column chromatography on silica gel using hexanes:EtOAc=7:3 as the eluent gave the title compound as a slightly yellowish gum (211 mg); MS-(+)-ion: M+1=498.1. cooled with an ice bath was added was removed Stirring the mixture was concentrated in vacuo To the residue was added water (10 ml) and a few drops of aqueous 6N HCl The mixture was extracted with EtOAc (15 ml) The organic phase was dried over MgSO4 concentrated in vacuo to give a yellowish gum Purification by flash column chromatography on silica gel

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

实验步骤: To a mixture of 4-benzyloxy-1-dimethylcarbamoyl-isoquinoline-3-carboxylic acid (210 mg, 0.6 mmol), NEt3 (175 μl, 1.25 mmol), and CH2Cl2 (12 ml) cooled with an ice bath was added ClCO2iBu (83 μl, 0.63 mmol) with stirring. After stirring for 15 min glycine benzyl ester hydrochloride (127 mg, 0.63 mmol) was added and the mixture was stirred for another 15 min before the ice bath was removed. Stirring was then continued at ambient temperature for additional 1.5 h. Subsequently; the mixture was concentrated in vacuo. To the residue was added water (10 ml) and a few drops of aqueous 6N HCl. The mixture was extracted with EtOAc (15 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give a yellowish gum. Purification by flash column chromatography on silica gel using hexanes:EtOAc=7:3 as the eluent gave the title compound as a slightly yellowish gum (211 mg); MS-(+)-ion: M+1=498.1. cooled with an ice bath was added was removed Stirring the mixture was concentrated in vacuo To the residue was added water (10 ml) and a few drops of aqueous 6N HCl The mixture was extracted with EtOAc (15 ml) The organic phase was dried over MgSO4 concentrated in vacuo to give a yellowish gum Purification by flash column chromatography on silica gel

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

实验步骤: To a mixture of 4-benzyloxy-1-methoxymethyl-isoquinoline-3-carboxylic acid (120 mg, 0.37 mmol), NEt3 (109 μl, 0.78 mmol), and CH2Cl2 (7 ml) cooled with an ice bath was added ClCO2iBu (52 μl, 0.39 mmol) with stirring. After stirring for 15 min glycine benzyl ester hydrochloride (79 mg, 0.39 mmol) was added and the mixture was stirred for another 15 min before the ice bath was removed. Stirring was then continued at ambient temperature for additional 1.5 h. Subsequently the mixture was concentrated in vacuo. To the residue was added water (10 ml) and a few drops of aqueous 6N HCl. The mixture was extracted with EtOAc (15 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give a yellowish gum. Purification by flash column chromatography on silica gel using hexanes:EtOAc=7:3 as the eluent gave the title compound as a yellow oil (141 mg); MS-(+)-ion: M+1=471.1. cooled with an ice bath was added was removed Stirring Subsequently the mixture was concentrated in vacuo To the residue was added water (10 ml) and a few drops of aqueous 6N HCl The mixture was extracted with EtOAc (15 ml) The organic phase was dried over MgSO4 concentrated in vacuo to give a yellowish gum Purification by flash column chromatography on silica gel

反应条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of Boc-D-Arg(Tos)OH (11.2 g, 26.1 mmol), HOBt (3.9 g, 28.7 g), glycine benzyl ester hydrochloride (5.2 g, 26.1 mmol) in 52 mL of DCM is added DIEA (4.5 mL, 26.1 mmol) followed by DCC (5.9 g, 28.7 mmol; dissolved in 5 mL of DCM). After stirring for 18 h, the reaction mixture is cooled to −10° C. and the precipitate is filtered off. The filtrate is extracted twice with 1N Hcl (50 mL), twice with 5% NaHCO3 (50 mL), brine (50 mL), dried (MgSO4), and concentrated in vacuo to give 15.2 g (100%) of Boc-D-Arg(Tos)Gly-Gly-OBn as a white solid. RP-HPLC: 18.9 min.;C18, 0-100% CH3CN over 25 min., 1.5 mL/min. the precipitate is filtered off The filtrate is extracted twice with 1N Hcl (50 mL), twice with 5% NaHCO3 (50 mL), brine (50 mL) dried (MgSO4) concentrated in vacuo

反应条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of Boc-D-Arg(Tos)OH (11.2 g, 26.1 mmol), HOBt (3.9 g, 28.7 g), glycine benzyl ester hydrochloride (5.2 g, 26.1 mmol) in 52 mL of DCM is added DIEA (4.5 mL, 26.1 mmol) followed by DCC (5.9 g, 28.7 mmol; dissolved in 5 mL of DCM). After stirring for 18 h, the reaction mixture is cooled to −10° C. and the precipitate is filtered off. The filtrate is extracted twice with 1N Hcl (50 mL), twice with 5% NaHCO3 (50 mL), brine (50 mL), dried (MgSO4), and concentrated in vacuo to give 15.2 g (100%) of Boc-D-Arg(Tos)Gly-Gly-OBn as a white solid. RP-HPLC: 18.9 min.;C18, 0-100% CH3CN over 25 min., 1.5 mL/min. the precipitate is filtered off The filtrate is extracted twice with 1N Hcl (50 mL), twice with 5% NaHCO3 (50 mL), brine (50 mL) dried (MgSO4) concentrated in vacuo

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

实验步骤: Boc-Val-OH (8.69 g, 40.0 mmol) and Gly-OBzl.HCl (8.07 g, 40.0 mmol) were dissolved in methylene chloride (100 ml), and the solution was maintained at 0° C. Triethylamine (6.13 ml, 44.0 mmol), HOBt (1-hydroxybenzotriazole, 6.74 g, 44.0 mmol), and WSC.HCl (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 8.44 g, 44.0 mmol) were added to the solution, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with water (50 ml), 5% citric acid aqueous solution (50 ml× twice), saturated brine (50 ml), 5% sodium hydrogencarbonate aqueous solution (50 ml× twice), and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, then the magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to obtain white crystals of Boc-Val-Gly-OBzl (13.2 g, 36.2 mmol). The reaction mixture was concentrated under reduced pressure the residue was dissolved in ethyl acetate (200 ml) The solution was washed with water (50 ml), 5% citric acid aqueous solution (50 ml× twice), saturated brine (50 ml), 5% sodium hydrogencarbonate aqueous solution (50 ml× twice), and saturated brine (50 ml) The organic layer was dried over anhydrous magnesium sulfate the magnesium sulfate was removed by filtration the filtrate was concentrated under reduced pressure The residue was recrystallized from ethyl acetate/n-hexane