ethyl 4-(4-aminophenyl)butanoate

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

Procedure: A solution of 3-dimethylaminobenzoyl chloride (0.19 g, 1.01 mmol) in THF (6 ml) was added dropwise to a solution of 4-(4-aminophenyl)butyric acid ethyl ester (0.26 g, 1.24 mmol) and triethylamine (0.31 g, 3.11 mmol) in THF (8 ml) under ice cooling. The reaction solution was stirred at room temperature for 8 hours, then added with water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous ammonium chloride and saturated brine, then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=15:1) to obtain 4-[4-(3-dimethylamino-benzoylamino)-phenyl]-butyric acid ethyl ester as a brown oily substance (0.36 g, yield: 97.5%). extracted with ethyl acetate The ethyl acetate layer was washed with saturated aqueous ammonium chloride and saturated brine dried over sodium sulfate filtered concentrated under reduced pressure The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=15:1)

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

Procedure: By using 2-bromomethyl-5-fluorobenzoic acid ethyl ester and 4-(4-amino-phenyl)butyric acid ethyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 4-[4-(6-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid ethyl ester as an orange oily substance. used in Example 25, synthesis

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

Procedure: By using 2-bromomethyl-benzoic acid methyl ester and 4-(4-amino-phenyl)butyric acid ethyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 4-[4-(1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid ethyl ester (Compound 19) as a white powdery substance. used in Example 25, synthesis

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

Procedure: By using 2-bromomethyl-5-nitrobenzoic acid methyl ester and 4-(4-amino-phenyl)butyric acid ethyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 4-[4-(6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid ethyl ester. used in Example 25, synthesis

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

Procedure: By using 2-bromomethyl-5-nitrobenzoic acid methyl ester and 4-(4-amino-phenyl)butyric acid ethyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 4-[4-(6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid ethyl ester. used in Example 25, synthesis

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

Procedure: By using 2-bromomethyl-4-nitrobenzoic acid methyl ester and 4-(4-aminophenyl)butyric acid ethyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 4-[4-(5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid ethyl ester. used in Example 25, synthesis

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

Procedure: By using 2-bromomethyl-4-nitrobenzoic acid methyl ester and 4-(4-aminophenyl)butyric acid ethyl ester instead of 2-bromomethyl-6-nitro-benzoic acid methyl ester and aniline used in Example 25, synthesis was performed in the same manner as that of Example 25 to obtain 4-[4-(5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid ethyl ester. used in Example 25, synthesis

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

Procedure: Catalytic sulfuric acid was added to a solution of 4-(4-aminophenyl) butyric acid (6.0 g, 33.48 mmol) in EtOH. The reaction mixture was stirred at room temperature for 24 h. HCl (5 mL, 6N) was added and the reaction mixture was heated at reflux for 24 h. The reaction mixture was concentrated in vacuo and CH2Cl2 and water were added. The pH was adjusted to 7.0 with aqueous NaHCO3 (satd). The organic solution was washed with water (1×) and brine (1×), dried over MgSO4, filtered, and concentrated to afford 4-(4-amino-phenyl)-butyric acid ethyl ester (1.53 g). 1H NMR (400 MHz, CDCl3) δ 6.95 (d, 2H), 6.61 (d, 2H), 4.10 (q, 2H), 3.66 (bs, 2H), 2.53 (t, 2H), 2.29 (t, 2H), 1.88 (m, 2H), 1.24 (t, 3H). the reaction mixture was heated at reflux for 24 h The reaction mixture was concentrated in vacuo and CH2Cl2 and water were added The organic solution was washed with water (1×) and brine (1×) dried over MgSO4 filtered concentrated

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

Procedure: Catalytic sulfuric acid was added to a solution of 4-(4-aminophenyl) butyric acid (6.0 g, 33.48 mmol) in EtOH. The reaction mixture was stirred at room temperature for 24 h. HCl (5 mL, 6N) was added and the reaction mixture was heated at reflux for 24 h. The reaction mixture was concentrated in vacuo and CH2Cl2 and water were added. The pH was adjusted to 7.0 with aqueous NaHCO3 (satd). The organic solution was washed with water (1×) and brine (1×), dried over MgSO4, filtered, and concentrated to afford 4-(4-amino-phenyl)-butyric acid ethyl ester (1.53 g). 1H NMR (400 MHz, CDCl3) δ 6.95 (d, 2H), 6.61 (d, 2H), 4.10 (q, 2H), 3.66 (bs, 2H), 2.53 (t, 2H), 2.29 (t, 2H), 1.88 (m, 2H), 1.24 (t, 3H). the reaction mixture was heated at reflux for 24 h The reaction mixture was concentrated in vacuo and CH2Cl2 and water were added The organic solution was washed with water (1×) and brine (1×) dried over MgSO4 filtered concentrated

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

Procedure: Catalytic sulfuric acid was added to a solution of 4-(4-aminophenyl) butyric acid (6.0 g, 33.48 mmol) in EtOH. The reaction mixture was stirred at room temperature for 24 h. HCl (5 mL, 6N) was added and the reaction mixture was heated at reflux for 24 h. The reaction mixture was concentrated in vacuo and CH2Cl2 and water were added. The pH was adjusted to 7.0 with aqueous NaHCO3 (satd). The organic solution was washed with water (1×) and brine (1×), dried over MgSO4, filtered, and concentrated to afford 4-(4-amino-phenyl)-butyric acid ethyl ester (1.53 g). 1H NMR (400 MHz, CDCl3) δ 6.95 (d, 2H), 6.61 (d, 2H), 4.10 (q, 2H), 3.66 (bs, 2H), 2.53 (t, 2H), 2.29 (t, 2H), 1.88 (m, 2H), 1.24 (t, 3H). the reaction mixture was heated at reflux for 24 h The reaction mixture was concentrated in vacuo and CH2Cl2 and water were added The organic solution was washed with water (1×) and brine (1×) dried over MgSO4 filtered concentrated

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

Procedure: Catalytic sulfuric acid was added to a solution of 4-(4-aminophenyl) butyric acid (6.0 g, 33.48 mmol) in EtOH. The reaction mixture was stirred at room temperature for 24 h. HCl (5 mL, 6N) was added and the reaction mixture was heated at reflux for 24 h. The reaction mixture was concentrated in vacuo and CH2Cl2 and water were added. The pH was adjusted to 7.0 with aqueous NaHCO3 (satd). The organic solution was washed with water (1×) and brine (1×), dried over MgSO4, filtered, and concentrated to afford 4-(4-amino-phenyl)-butyric acid ethyl ester (1.53 g). 1H NMR (400 MHz, CDCl3) δ 6.95 (d, 2H), 6.61 (d, 2H), 4.10 (q, 2H), 3.66 (bs, 2H), 2.53 (t, 2H), 2.29 (t, 2H), 1.88 (m, 2H), 1.24 (t, 3H). the reaction mixture was heated at reflux for 24 h The reaction mixture was concentrated in vacuo and CH2Cl2 and water were added The organic solution was washed with water (1×) and brine (1×) dried over MgSO4 filtered concentrated

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

Procedure: Catalytic sulfuric Acid was added to a solution of 4-(4-aminophenyl) butyric Acid (6.0 g, 33.48 mmol) in EtOH. The reaction mixture was stirred at room temperature for 24 h. HCl (5 mL, 6N) was added and the reaction mixture was heated at reflux for 24 h. The reaction mixture was concentrated in vacuo and CH2Cl2 and water were added. The pH was adjusted to 7.0 with aqueous NaHCO3 (satd). The organic solution was washed with water (1×) and brine (1×), dried over MgSO4, filtered, and concentrated to afford 4-(4-aminophenyl)-butyric Acid ethyl ester (1.53 g). H NMR (400 MHz, CDCl3) δ 6.95 (d, 2H), 6.61 (d, 2H), 4.10 (q, 2H), 3.66 (bs, 2H), 2.53 (t, 2H), 2.29 (t, 2H), 1.88 (m, 2H), 1.24 (t, 3H). the reaction mixture was heated at reflux for 24 h The reaction mixture was concentrated in vacuo and CH2Cl2 and water were added The organic solution was washed with water (1×) and brine (1×) dried over MgSO4 filtered concentrated