ethyl 2-isocyanato-3-phenylpropanoate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-isocyanato-3-phenylpropionic acid ethyl ester (6 g, 27.37 mmol) in DMF (50 ml) was added a solution of 4-aminobenzonitrile (3.23 g, 27.37 mmol) in DMF (30 ml) at 3° C. during 20 min. Stirring was continued for 7 d at room temperature, and additional 2-isocyanato-3-phenylpropionic acid ethyl ester (2.86 g) was added successively. The solvent was removed and the residue dissolved in ethyl acetate (100 ml), washed with water (20 ml), saturated aqueous KHSO4/K2SO4 solution (1:1, 2×20 ml) and with saturated aqueous NaCl solution (4×90 ml). The organic phase was dried (MgSO4), filtered and evaporated to give 12.20 g of the title compound which was used without further purification. MS 338.3 (M+1)+ The solvent was removed the residue dissolved in ethyl acetate (100 ml) washed with water (20 ml), saturated aqueous KHSO4/K2SO4 solution (1:1, 2×20 ml) and with saturated aqueous NaCl solution (4×90 ml) The organic phase was dried (MgSO4) filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-isocyanato-3-phenylpropionic acid ethyl ester (6 g, 27.37 mmol) in DMF (50 ml) was added a solution of 4-aminobenzonitrile (3.23 g, 27.37 mmol) in DMF (30 ml) at 3° C. during 20 min. Stirring was continued for 7 d at room temperature, and additional 2-isocyanato-3-phenylpropionic acid ethyl ester (2.86 g) was added successively. The solvent was removed and the residue dissolved in ethyl acetate (100 ml), washed with water (20 ml), saturated aqueous KHSO4/K2SO4 solution (1:1, 2×20 ml) and with saturated aqueous NaCl solution (4×90 ml). The organic phase was dried (MgSO4), filtered and evaporated to give 12.20 g of the title compound which was used without further purification. MS 338.3 (M+1)+ The solvent was removed the residue dissolved in ethyl acetate (100 ml) washed with water (20 ml), saturated aqueous KHSO4/K2SO4 solution (1:1, 2×20 ml) and with saturated aqueous NaCl solution (4×90 ml) The organic phase was dried (MgSO4) filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-isocyanato-3-phenylpropionic acid ethyl ester (6 g, 27.37 mmol) in DMF (50 ml) was added a solution of 4-aminobenzonitrile (3.23 g, 27.37 mmol) in DMF (30 ml) at 3° C. during 20 min. Stirring was continued for 7 d at room temperature, and additional 2-isocyanato-3-phenylpropionic acid ethyl ester (2.86 g) was added successively. The solvent was removed and the residue dissolved in ethyl acetate (100 ml), washed with water (20 ml), saturated aqueous KHSO4/K2SO4 solution (1:1, 2×20 ml) and with saturated aqueous NaCl solution (4×90 ml). The organic phase was dried (MgSO4), filtered and evaporated to give 12.20 g of the title compound which was used without further purification. MS 338.3 (M+1)+ The solvent was removed the residue dissolved in ethyl acetate (100 ml) washed with water (20 ml), saturated aqueous KHSO4/K2SO4 solution (1:1, 2×20 ml) and with saturated aqueous NaCl solution (4×90 ml) The organic phase was dried (MgSO4) filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-(4-tert-butylbenzyl)-1H-indol-5-amine (0.233 g, 0.84 mmol) and 2-isocyanato-3-phenyl-propionic acid ethyl ester (0.10 g, 0.8 mmol) in 10 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated and dissolved in 2:1:1 THF/MeOH/Water (10 mL). Lithium hydroxide monohydrate (0.30 g, 7.1 mmol) was added and the mixture was stirred at room temperature overnight. Most of the organic solvents were removed and the reaction mixture was made acidic (pH 6) with glacial acetic acid. The solid was collected and purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 minutes: 100% B; Hold 100% B 5 minutes. Flow Rate: 22.5 mL/min) The product was collected based on UV absorption and concentrated to give the title compound as an off-white solid (0.15 g, 40%): MS (ESI) m/z 470; MS (ESI) m/z 468. The reaction mixture was concentrated dissolved in 2:1:1 THF/MeOH/Water (10 mL) the mixture was stirred at room temperature overnight Most of the organic solvents were removed The solid was collected purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 minutes: 100% B; Hold 100% B 5 minutes. Flow Rate: 22.5 mL/min) The product was collected based on UV absorption concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-(4-tert-butylbenzyl)-1H-indol-5-amine (0.233 g, 0.84 mmol) and 2-isocyanato-3-phenyl-propionic acid ethyl ester (0.10 g, 0.8 mmol) in 10 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated and dissolved in 2:1:1 THF/MeOH/Water (10 mL). Lithium hydroxide monohydrate (0.30 g, 7.1 mmol) was added and the mixture was stirred at room temperature overnight. Most of the organic solvents were removed and the reaction mixture was made acidic (pH 6) with glacial acetic acid. The solid was collected and purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 minutes: 100% B; Hold 100% B 5 minutes. Flow Rate: 22.5 mL/min) The product was collected based on UV absorption and concentrated to give the title compound as an off-white solid (0.15 g, 40%): MS (ESI) m/z 470; MS (ESI) m/z 468. The reaction mixture was concentrated dissolved in 2:1:1 THF/MeOH/Water (10 mL) the mixture was stirred at room temperature overnight Most of the organic solvents were removed The solid was collected purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 minutes: 100% B; Hold 100% B 5 minutes. Flow Rate: 22.5 mL/min) The product was collected based on UV absorption concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-(4-tert-butylbenzyl)-1H-indol-5-amine (0.233 g, 0.84 mmol) and 2-isocyanato-3-phenyl-propionic acid ethyl ester (0.10 g, 0.8 mmol) in 10 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated and dissolved in 2:1:1 THF/MeOH/Water (10 mL). Lithium hydroxide monohydrate (0.30 g, 7.1 mmol) was added and the mixture was stirred at room temperature overnight. Most of the organic solvents were removed and the reaction mixture was made acidic (pH 6) with glacial acetic acid. The solid was collected and purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 minutes: 100% B; Hold 100% B 5 minutes. Flow Rate: 22.5 mL/min) The product was collected based on UV absorption and concentrated to give the title compound as an off-white solid (0.15 g, 40%): MS (ESI) m/z 470; MS (ESI) m/z 468. The reaction mixture was concentrated dissolved in 2:1:1 THF/MeOH/Water (10 mL) the mixture was stirred at room temperature overnight Most of the organic solvents were removed The solid was collected purified by semi-preparative HPLC (Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water (0.1% TFA buffer); Solvent B: Acetonitrile (0.1% TFA buffer); Solvent Gradient: Time 0: 0% B; 10 minutes: 100% B; Hold 100% B 5 minutes. Flow Rate: 22.5 mL/min) The product was collected based on UV absorption concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice-cold suspension of L-phenylalanine ethyl ester hydrochloride (25.0 g, 109 mmol) in methylene chloride (800 mL) a saturated solution of sodium bicarbonate (800 mL) was added and the mixture was vigorously stirred at 0° C. for 30 minutes. Stirring was stopped to allow the separation of the two layers and a solution of phosgene in toluene (20%, 100 mL, 190 mmol) was added directly into the organic layer. Stirring was resumed while keeping the mixture at 0° C. for one hour and at room temperature for one additional hour. The organic layer was separated, and washed sequentially with water and a saturated solution of sodium chloride, dried with sodium sulphate, filtered and evaporated to yield a colorless oil that slowly solidifies (22.7 g, 95% yield). was added Stirring the separation of the two layers Stirring at 0° C. for one hour at room temperature The organic layer was separated washed sequentially with water a saturated solution of sodium chloride, dried with sodium sulphate filtered evaporated to yield a colorless oil that

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an ice-cold suspension of L-phenylalanine ethyl ester hydrochloride (25.0 g, 109 mmol) in methylene chloride (800 mL) a saturated solution of sodium bicarbonate (800 mL) was added and the mixture was vigorously stirred at 0° C. for 30 minutes. Stirring was stopped to allow the separation of the two layers and a solution of phosgene in toluene (20%, 100 mL, 190 mmol) was added directly into the organic layer. Stirring was resumed while keeping the mixture at 0° C. for one hour and at room temperature for one additional hour. The organic layer was separated, and washed sequentially with water and a saturated solution of sodium chloride, dried with sodium sulphate, filtered and evaporated to yield a colorless oil that slowly solidifies (22.7 g, 95% yield). was added Stirring the separation of the two layers Stirring at 0° C. for one hour at room temperature The organic layer was separated washed sequentially with water a saturated solution of sodium chloride, dried with sodium sulphate filtered evaporated to yield a colorless oil that

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of compound 1 (0.255 g; 1.35 mmol) in anhydrous dichloromethane (8 mL) was treated with ethyl 2-isocyanato-3-phenylpropionate (0.325 g; 0.38 mmol) and stirred at room temperature overnight. The solvent was removed by evaporation, the residue was dissolved in ethanol (1 mL), 6N hydrochloric acid (0.5 mL) and water (0.5 mL) and the reaction mixture was heated to 50° C. After 3 h at 50° C., additional 6N hydrochloric acid (1 mL) was added and the reaction mixture was heated at 65° C. overnight. The reaction mixture was concentrated and the crude product was purified directly by column chromatography on silica gel using 1:1 ethyl acetate:hexane as the eluent to give 0.053 g of 5-Benzyl-3-(1-phenyl-cyclohexylmethyl)-imidazolidine-2,4-dione as a white solid. Mass Spec [M+H]+=363. The solvent was removed by evaporation the residue was dissolved in ethanol (1 mL) 6N hydrochloric acid (0.5 mL) and water (0.5 mL) and the reaction mixture was heated to 50° C After 3 h at 50° C. additional 6N hydrochloric acid (1 mL) was added the reaction mixture was heated at 65° C. overnight The reaction mixture was concentrated the crude product was purified directly by column chromatography on silica gel using 1:1 ethyl acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-isocyanato-3-phenylpropionic acid ethyl ester (6 g, 27.37 mmol) in DMF (50 ml) was added a solution of 4-aminobenzonitrile (3.23 g, 27.37 mmol) in DMF (30 ml) at 3° C. during 20 min. Stirring was continued for 7 d at room temperature, and additional 2-isocyanato-3-phenylpropionic acid ethyl ester (2.86 g) was added successively. The solvent was removed and the residue dissolved in ethyl acetate (100 ml), washed with water (20 ml), saturated aqueous KHSO4/K2SO4 solution (1:1, 2×20 ml) and with saturated aqueous NaCl solution (4×90 ml). The organic phase was dried (MgSO4), filtered and evaporated to give 12.20 g of the title compound which was used without further purification. MS 338.3 (M+1)+ The solvent was removed the residue dissolved in ethyl acetate (100 ml) washed with water (20 ml), saturated aqueous KHSO4/K2SO4 solution (1:1, 2×20 ml) and with saturated aqueous NaCl solution (4×90 ml) The organic phase was dried (MgSO4) filtered evaporated