2-(ethoxycarbonylamino)acetic acid

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

Procedure: A mixture of (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (173 mg, 0.488 mmol), 2-(ethoxycarbonylamino)acetic acid (86 mg, 0.488 mmol), EDCl (140 mg, 0.732 mmol), DIPEA (0.128 ml, 0.732 mmol) and HOAt (100 mg, 0.732 mmol) in DMF (2.5 ml) is allowed to stir at room temperature for 1 hour. The reaction mixture is diluted with water, and then the precipitated solid is collected on a funnel, washed with H2O, and dried under reduced pressure to give crude. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100) to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-(ethoxycarbonylamino)acetamido)butanoate (161 mg); HPLC retention time=1.16 minutes (condition B); MS (m+1)=447.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J=7.07 Hz, 3 H) 1.29 (t, J=7.07 Hz, 3 H) 2.50 (A of ABX, Jab=16.2 Hz, Jax=5.3 Hz, 1 H) 2.54 (B of ABX, Jab=16.2 Hz, Jbx=5.3 Hz, 1 H) 2.89 (A of ABX, Jab=13.6 Hz, Jax=7.8 Hz, 1 H) 2.99 (B of ABX, Jab=13.6 Hz, Jbx=6.6 Hz, 1 H) 3.80 (be d, J=5.8 Hz, 2 H) 4.12-4.23 (m, 4 H) 4.48-4.56 (m, 1 H) 5.15 (br s, 1 H) 6.64 (br d, J=8.8 Hz, 1 H) 7.25-7.27 (m, 2 H) 7.29-7.38 (m, 2 H) 7.43-7.46 (m, 1 H) 7.49-7.52 (m, 2 H) 7.55-7.56 (m, 1 H). the precipitated solid is collected on a funnel washed with H2O dried under reduced pressure to give crude The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100)

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

Procedure: A mixture of (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (173 mg, 0.488 mmol), 2-(ethoxycarbonylamino)acetic acid (86 mg, 0.488 mmol), EDCl (140 mg, 0.732 mmol), DIPEA (0.128 ml, 0.732 mmol) and HOAt (100 mg, 0.732 mmol) in DMF (2.5 ml) is allowed to stir at room temperature for 1 hour. The reaction mixture is diluted with water, and then the precipitated solid is collected on a funnel, washed with H2O, and dried under reduced pressure to give crude. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100) to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-(ethoxycarbonylamino)acetamido)butanoate (161 mg); HPLC retention time=1.16 minutes (condition B); MS (m+1)=447.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J=7.07 Hz, 3 H) 1.29 (t, J=7.07 Hz, 3 H) 2.50 (A of ABX, Jab=16.2 Hz, Jax=5.3 Hz, 1 H) 2.54 (B of ABX, Jab=16.2 Hz, Jbx=5.3 Hz, 1 H) 2.89 (A of ABX, Jab=13.6 Hz, Jax=7.8 Hz, 1 H) 2.99 (B of ABX, Jab=13.6 Hz, Jbx=6.6 Hz, 1 H) 3.80 (be d, J=5.8 Hz, 2 H) 4.12-4.23 (m, 4 H) 4.48-4.56 (m, 1 H) 5.15 (br s, 1 H) 6.64 (br d, J=8.8 Hz, 1 H) 7.25-7.27 (m, 2 H) 7.29-7.38 (m, 2 H) 7.43-7.46 (m, 1 H) 7.49-7.52 (m, 2 H) 7.55-7.56 (m, 1 H). the precipitated solid is collected on a funnel washed with H2O dried under reduced pressure to give crude The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100)

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

Procedure: A solution of ethyl chloroformate (3.689 g) in methylene chloride (10 ml) was added dropwise to a stirred solution of N-ethoxycarbonylglycine (4.998 g) and triethylamine (3.434 g) in methylene chloride (60 ml) under cooling in 5 minutes, and the stirring was continued for 5 minutes under cooling. To the solution of the mixed anhydride was added a solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.417 g) in chloroform (40 ml) and reacted in a similar manner to that of Example 17-(1). The reaction mixture was washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in ethanol (50 ml) and a solution of sodium hydroxide (1.6 g) in water (10 ml) was added dropwise to the solution with stirring under ice cooling in 5 minutes. After stirring for 30 minutes at room temperature, the solution was evaporated, and the residue was dissolved in a small amount of water. The solution was salted out and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and evaporated. The residue was dissolved in chloroform containing a small amount of ethanol and the solution was chromatographed on silica gel (50 g). The eluent with a mixture of chloroform and ethanol (30:1) gave a colorless solid of 3-[2-(N-ethoxycarbonylglycyl)hydrazino]-5-methyl-6-phenyl-1,2,4-triazine (1.872 g). under cooling in 5 minutes under cooling reacted in a similar manner to that of Example 17-(1) The reaction mixture was washed with water dried over magnesium sulfate evaporated under reduced pressure The residue was dissolved in ethanol (50 ml) a solution of sodium hydroxide (1.6 g) in water (10 ml) was added dropwise to the solution After stirring for 30 minutes at room temperature the solution was evaporated the residue was dissolved in a small amount of water extracted with ethyl acetate The extract was washed with a saturated aqueous solution of sodium chloride dried over magnesium sulfate evaporated The residue was dissolved in chloroform containing a small amount of ethanol the solution was chromatographed on silica gel (50 g) The eluent with a mixture of chloroform and ethanol (30:1)

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

Procedure: A solution of ethyl chloroformate (3.689 g) in methylene chloride (10 ml) was added dropwise to a stirred solution of N-ethoxycarbonylglycine (4.998 g) and triethylamine (3.434 g) in methylene chloride (60 ml) under cooling in 5 minutes, and the stirring was continued for 5 minutes under cooling. To the solution of the mixed anhydride was added a solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.417 g) in chloroform (40 ml) and reacted in a similar manner to that of Example 17-(1). The reaction mixture was washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in ethanol (50 ml) and a solution of sodium hydroxide (1.6 g) in water (10 ml) was added dropwise to the solution with stirring under ice cooling in 5 minutes. After stirring for 30 minutes at room temperature, the solution was evaporated, and the residue was dissolved in a small amount of water. The solution was salted out and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and evaporated. The residue was dissolved in chloroform containing a small amount of ethanol and the solution was chromatographed on silica gel (50 g). The eluent with a mixture of chloroform and ethanol (30:1) gave a colorless solid of 3-[2-(N-ethoxycarbonylglycyl)hydrazino]-5-methyl-6-phenyl-1,2,4-triazine (1.872 g). under cooling in 5 minutes under cooling reacted in a similar manner to that of Example 17-(1) The reaction mixture was washed with water dried over magnesium sulfate evaporated under reduced pressure The residue was dissolved in ethanol (50 ml) a solution of sodium hydroxide (1.6 g) in water (10 ml) was added dropwise to the solution After stirring for 30 minutes at room temperature the solution was evaporated the residue was dissolved in a small amount of water extracted with ethyl acetate The extract was washed with a saturated aqueous solution of sodium chloride dried over magnesium sulfate evaporated The residue was dissolved in chloroform containing a small amount of ethanol the solution was chromatographed on silica gel (50 g) The eluent with a mixture of chloroform and ethanol (30:1)

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

Procedure: A solution of ethyl chloroformate (3.689 g) in methylene chloride (10 ml) was added dropwise to a stirred solution of N-ethoxycarbonylglycine (4.998 g) and triethylamine (3.434 g) in methylene chloride (60 ml) under cooling in 5 minutes, and the stirring was continued for 5 minutes under cooling. To the solution of the mixed anhydride was added a solution of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.417 g) in chloroform (40 ml) and reacted in a similar manner to that of Example 17-(1). The reaction mixture was washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in ethanol (50 ml) and a solution of sodium hydroxide (1.6 g) in water (10 ml) was added dropwise to the solution with stirring under ice cooling in 5 minutes. After stirring for 30 minutes at room temperature, the solution was evaporated, and the residue was dissolved in a small amount of water. The solution was salted out and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and evaporated. The residue was dissolved in chloroform containing a small amount of ethanol and the solution was chromatographed on silica gel (50 g). The eluent with a mixture of chloroform and ethanol (30:1) gave a colorless solid of 3-[2-(N-ethoxycarbonylglycyl)hydrazino]-5-methyl-6-phenyl-1,2,4-triazine (1.872 g). under cooling in 5 minutes under cooling reacted in a similar manner to that of Example 17-(1) The reaction mixture was washed with water dried over magnesium sulfate evaporated under reduced pressure The residue was dissolved in ethanol (50 ml) a solution of sodium hydroxide (1.6 g) in water (10 ml) was added dropwise to the solution After stirring for 30 minutes at room temperature the solution was evaporated the residue was dissolved in a small amount of water extracted with ethyl acetate The extract was washed with a saturated aqueous solution of sodium chloride dried over magnesium sulfate evaporated The residue was dissolved in chloroform containing a small amount of ethanol the solution was chromatographed on silica gel (50 g) The eluent with a mixture of chloroform and ethanol (30:1)

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

Procedure: A mixture of (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (173 mg, 0.488 mmol), 2-(ethoxycarbonylamino)acetic acid (86 mg, 0.488 mmol), EDCl (140 mg, 0.732 mmol), DIPEA (0.128 ml, 0.732 mmol) and HOAt (100 mg, 0.732 mmol) in DMF (2.5 ml) is allowed to stir at room temperature for 1 hour. The reaction mixture is diluted with water, and then the precipitated solid is collected on a funnel, washed with H2O, and dried under reduced pressure to give crude. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100) to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-(ethoxycarbonylamino)acetamido)butanoate (161 mg); HPLC retention time=1.16 minutes (condition B); MS (m+1)=447.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J=7.07 Hz, 3H) 1.29 (t, J=7.07 Hz, 3H) 2.50 (A of ABX, Jab=16.2 Hz, Jax=5.3 Hz, 1H) 2.54 (B of ABX, Jab=16.2 Hz, Jbx=5.3 Hz, 1H) 2.89 (A of ABX, Jab=13.6 Hz, Jax=7.8 Hz, 1H) 2.99 (B of ABX, Jab=13.6 Hz, Jbx=6.6 Hz, 1H) 3.80 (be d, J=5.8 Hz, 2H) 4.12-4.23 (m, 4H) 4.48-4.56 (m, 1H) 5.15 (br s, 1H) 6.64 (br d, J=8.8 Hz, 1H) 7.25-7.27 (m, 2H) 7.29-7.38 (m, 2H) 7.43-7.46 (m, 1H) 7.49-7.52 (m, 2H) 7.55-7.56 (m, 1H). the precipitated solid is collected on a funnel washed with H2O dried under reduced pressure to give crude The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100)

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

Procedure: A mixture of (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (173 mg, 0.488 mmol), 2-(ethoxycarbonylamino)acetic acid (86 mg, 0.488 mmol), EDCI (140 mg, 0.732 mmol), DIPEA (0.128 ml, 0.732 mmol) and HOAt (100 mg, 0.732 mmol) in DMF (2.5 ml) is allowed to stir at room temperature for 1 hour. The reaction mixture is diluted with water, and then the precipitated solid is collected on a funnel, washed with H2O, and dried under reduced pressure to give crude. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100) to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-(ethoxycarbonylamino)acetamido)butanoate (161 mg); HPLC retention time=1.16 minutes (condition B); MS (m+1)=447.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J=7.07 Hz, 3 H) 1.29 (t, J=7.07 Hz, 3 H) 2.50 (A of ABX, Jab=16.2 Hz, Jax=5.3 Hz, 1 H) 2.54 (B of ABX, Jab=16.2 Hz, Jbx=5.3 Hz, 1 H) 2.89 (A of ABX, Jab=13.6 Hz, Jax=7.8 Hz, 1 H) 2.99 (B of ABX, Jab=13.6 Hz, Jbx=6.6 Hz, 1 H) 3.80 (be d, J=5.8 Hz, 2 H) 4.12-4.23 (m, 4 H) 4.48-4.56 (m, 1 H) 5.15 (br s, 1 H) 6.64 (br d, J=8.8 Hz, 1 H) 7.25-7.27 (m, 2 H) 7.29-7.38 (m, 2 H) 7.43-7.46 (m, 1 H) 7.49-7.52 (m, 2 H) 7.55-7.56 (m, 1 H). the precipitated solid is collected on a funnel washed with H2O dried under reduced pressure to give crude The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100)

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

Procedure: A mixture of (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (173 mg, 0.488 mmol), 2-(ethoxycarbonylamino)acetic acid (86 mg, 0.488 mmol), EDCl (140 mg, 0.732 mmol), DIPEA (0.128 ml, 0.732 mmol) and HOAt (100 mg, 0.732 mmol) in DMF (2.5 ml) is allowed to stir at room temperature for 1 hour. The reaction mixture is diluted with water, and then the precipitated solid is collected on a funnel, washed with H2O, and dried under reduced pressure to give crude. The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100) to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-(ethoxycarbonylamino)acetamido)butanoate (161 mg); HPLC retention time=1.16 minutes (condition B); MS (m+1)=447.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25 (t, J=7.07 Hz, 3 H) 1.29 (t, J=7.07 Hz, 3 H) 2.50 (A of ABX, Jab=16.2 Hz, Jax=5.3 Hz, 1 H) 2.54 (B of ABX, Jab=16.2 Hz, Jbx=5.3 Hz, 1 H) 2.89 (A of ABX, Jab=13.6 Hz, Jax=7.8 Hz, 1 H) 2.99 (B of ABX, Jab=13.6 Hz, Jbx=6.6 Hz, 1 H) 3.80 (be d, J=5.8 Hz, 2 H) 4.12-4.23 (m, 4 H) 4.48-4.56 (m, 1 H) 5.15 (br s, 1 H) 6.64 (br d, J=8.8 Hz, 1 H) 7.25-7.27 (m, 2 H) 7.29-7.38 (m, 2 H) 7.43-7.46 (m, 1 H) 7.49-7.52 (m, 2 H) 7.55-7.56 (m, 1 H). the precipitated solid is collected on a funnel washed with H2O dried under reduced pressure to give crude The obtained residue is purified by silica gel flash column chromatography (heptane/EtOAc=100:0 to 0:100)