dimethyl 3-aminobenzene-1,2-dicarboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A mixture of 2.1 grams of dimethyl 3-aminophthalate, 1.4 grams of benzoylacetic acid and 2.9 grams of dicyclohexlcarbodiimide is dissolved in 15 ml of tetrahydrofuran and the mixture is stirred at room temperature for eighteen hours. The insoluble matter are removed by filtration, the filtrate is concentrated, and 1.9 grams of dimethyl 3-benzoylacetylaminophthalate, colorless crystals, melting point 100° to 103° C. is obtained. This (1.9 grams) is dissolved in 30 ml of methanol, heated to reflux for four hours with 0.48 grams of sodium hydride, cooled, adjusted to pH 3 with diluted hydrochloric acid, crystals separated out therefrom are collected by filtration and recrystallized from methanol to give 1.3 grams of methyl 3-benzoyl-4-hydroxy-2-quinolone-5-carboxylate, pale yellow needles, melting point 263° to 265° C. The insoluble matter are removed by filtration the filtrate is concentrated

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

Procedure: The compound 2 (205 g, 1.0 mol) was dissolved in 2 L of MeOH. Catalytic 10% Pd/C was added and the solution was hydrogenated under H2 (45 psi) on a Parr hydrogenation apparatus at room temperature overnight. Filtered through celite and evaporated to give a quantitative yield of 3-amino-phthalic acid dimethyl ester, 3. 1H NMR (300 MHz, DMSO-d6): 7.26 (t, J=7.33 Hz, 1H), 6.94 (d, J=8.34 Hz, 1H), 6.77 (d, J=8.33 Hz, 1H), 6.12 (s, 2H), 3.77 (s, 3H), 3.76 (s, 3H). 13C NMR: 51.51, 51.77, 110.50, 115.16, 118.56, 131.26, 133.16, 148.28, 167.12, 168.11. Filtered through celite evaporated

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

Procedure: To a stirred solution of 3-amino-phthalic acid dimethyl ester (3.14 g, 15 mmol) in methylene chloride (50 ml) under a nitrogen atmosphere were added valeraldehyde (2.0 ml, 18.75 mmol) and acetic acid (5.18 ml, 90 mmol). The mixture was stirred for 5 minutes followed by addition of sodium triacetoxyborohydride (6.36 g, 30 mmol). The reaction was stirred for 30 minutes, diluted with methylene chloride (50 ml), washed with water (2×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (100 ml), and, dried (MgSO4). The solvent was evaporated in vacuo to give 4.19 g of product (100%) that used without further purification. 1H NMR (DMSO-d6) d 7.31 (t, J=7.9 Hz, 1H), 6.81-6.75 (m, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.15 (bs, 2H), 1.68-1.60 (m, 2H), 1.45-1.32 (m, 4H), 0.89 (t, J=6.9 Hz, 3H). The reaction was stirred for 30 minutes washed with water (2×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (100 ml) dried (MgSO4) The solvent was evaporated in vacuo

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

Procedure: To a stirred solution of oxalyl chloride (1.75 ml, 20 mmol) in methylene chloride (20 ml) under a nitrogen atmosphere at −78° C. was added DMSO (1.42 ml, 20 mmol) in methylene chloride (10 ml) dropwise over 5 minutes. The mixture was stirred for 5 minutes followed by the dropwise addition of 2-methoxyethanol (1.58 ml, 20 mmol) in methylene chloride (10 ml) over 5 minutes. The mixture was stirred for 20 minutes followed by the dropwise addition of triethylamine (8.36 ml, 60 mmol) over 5 minutes. The resulting suspension was stirred for 30 minutes at −78° C. and then allowed to warm to room temperature. The reaction mixture was diluted with methylene chloride (20 ml). To this stirred mixture was added 3-amino-phthalic acid dimethyl ester (2.09 g, 10 mmol) and acetic acid (4.60 ml, 80 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 5 minutes followed by the addition of sodium triacetoxyborohydride (4.24 g, 20 mmol). The mixture was stirred for 3 h. The reaction mixture was diluted with methylene chloride (50 ml) and washed with water (3×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (100 ml), and dried (MgSO4). The solvent was evaporated in vacuo and the residue purified by chromatography (25% ethyl acetate/hexane) to give 2.24 g (84%) of product as an oil. 1H NMR (DMSO-d6) d 732 (t, J=8.0 Hz, 1H), 6.88-6.79 (m, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.62 (t, J=5.4 Hz, 2H), 3.41 (s, 3H), 3.35 (q, J=5.2 Hz, 2H). The mixture was stirred for 20 minutes The resulting suspension was stirred for 30 minutes at −78° C. The mixture was stirred at room temperature under a nitrogen atmosphere for 5 minutes The mixture was stirred for 3 h washed with water (3×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (100 ml) dried (MgSO4) The solvent was evaporated in vacuo the residue purified by chromatography (25% ethyl acetate/hexane)

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

Procedure: To a stirred suspension of methyl-3-amino-2-(methoxycarbonyl)benzoate (17.0 g, 81 mmol) in a mixture of concentrated HCl (44 ml) and water (440 ml) at 4° C. was added a solution of NaNO2 (6.73 g, 97 mmol) in water (25 ml) dropwise at 4-5° C. Stirring was continued for 30 min at 4° C. The mixture was then carefully neutralized with sat. sodium carbonate to pH 6. A stirred solution of CuCN (9.46 g, 105 mmol) and KCN (6.38 g, 105 mmol) in water (150 ml) was warned to 6° C. The cold neutralized diazonium solution was then added in small portions at a time with vigorous stirring. The mixture was stirred at 60° C. for 1 hour and then cooled to room temperature. The mixture was extracted with dichloromethane (4×150 ml) and the combined dichloromethane extracts were washed with water (2×100 ml), brine (100 ml) and dried. The solvent was removed in vacuo and the product was purified by chromatography (dichloromethane) to afford 12.36 g (65%) of the product as a light yellow solid: 1 H NMR (CDCl3) δ 8.19 (d, J=7.9 Hz, 1H), 7.8.9 (d, J=7.4 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 4.03 (s, 3H), 3.94 (s, 3H). was warned to 6° C The mixture was stirred at 60° C. for 1 hour The mixture was extracted with dichloromethane (4×150 ml) the combined dichloromethane extracts were washed with water (2×100 ml), brine (100 ml) dried The solvent was removed in vacuo the product was purified by chromatography (dichloromethane)

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

Procedure: To a stirred suspension of methyl-3-amino-2-(methoxycarbonyl)benzoate (17.0 g, 81 mmol) in a mixture of concentrated HCl (44 ml) and water (440 ml) at 4° C. was added a solution of NaNO2 (6.73 g, 97 mmol) in water (25 ml) dropwise at 4-5° C. Stirring was continued for 30 min at 4° C. The mixture was then carefully neutralized with sat. sodium carbonate to pH 6. A stirred solution of CuCN (9.46 g, 105 mmol) and KCN (6.38 g, 105 mmol) in water (150 ml) was warned to 6° C. The cold neutralized diazonium solution was then added in small portions at a time with vigorous stirring. The mixture was stirred at 60° C. for 1 hour and then cooled to room temperature. The mixture was extracted with dichloromethane (4×150 ml) and the combined dichloromethane extracts were washed with water (2×100 ml), brine (100 ml) and dried. The solvent was removed in vacuo and the product was purified by chromatography (dichloromethane) to afford 12.36 g (65%) of the product as a light yellow solid: 1 H NMR (CDCl3) δ 8.19 (d, J=7.9 Hz, 1H), 7.8.9 (d, J=7.4 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 4.03 (s, 3H), 3.94 (s, 3H). was warned to 6° C The mixture was stirred at 60° C. for 1 hour The mixture was extracted with dichloromethane (4×150 ml) the combined dichloromethane extracts were washed with water (2×100 ml), brine (100 ml) dried The solvent was removed in vacuo the product was purified by chromatography (dichloromethane)

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

Procedure: To a solution of methyl-2-(methoxycarbonyl)-3-nitrobenzoate (23.8 g, 99.51 mmol) in ethyl acetate (200 ml) was added 10% Pd/C (1.8 g). The mixture was hydrogenated under 50 psi of hydrogen for 3 hours in a Parr Type Shaker. The mixture was filtered through Celite and the filtrate was concentrated in vacuo to yield an oil. The crude product was purified by flash chromatography (dichloromethane/ethyl acetate 95 to 5) to afford 18.1 g (87%) of the product as a brown oil: 1H NMR (CDCl3) δ 7.22 (t, J=7.6 Hz, 1H), 6.90 (d, J=7.2 Hz, 1H), 6.79 (d, J=8.7 Hz), 5.07 (b, 2H), 3.85 (s, 3H), 3.83 (s, 3H). The mixture was filtered through Celite the filtrate was concentrated in vacuo to yield an oil The crude product was purified by flash chromatography (dichloromethane/ethyl acetate 95 to 5)

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

Procedure: The compound 2 (205 g, 1.0 mol) was dissolved in 2 L of MeOH. Catalytic 10% Pd/C was added and the solution was hydrogenated under H2 (45 psi) on a Parr hydrogenation apparatus at room temperature overnight. Filtered through celite and evaporated to give a quantitative yield of 3-amino-phthalic acid dimethyl ester, 3. 1H NMR (300 MHz, DMSO-d6): 7.26 (t, J=7.33 Hz, 1H), 6.94 (d, J=8.34 Hz, 1H), 6.77 (d, J=8.33 Hz, 1H), 6.12 (s, 2H), 3.77 (s, 3H), 3.76 (s, 3H). 13C NMR: 51.51, 51.77, 110.50, 115.16, 118.56, 131.26, 133.16, 148.28, 167.12, 168.11. Filtered through celite evaporated