ethyl 2,3-diaminobenzoate

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Iodopropane (2.0 mL, 20 mmol) was added to a solution of ethyl 2,3-diaminobenzoate (prepared according to the method of WO 97/10219, page 81, Example 51(1)) (3 g, 16.67 mmol) in N,N-dimethylformamide (20 mL), and the solution stirred at 50° C. for 3 hours. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (200 mL) and water (50 mL), and the layers separated. The organic layer was washed with water (5×50 mL), dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using ethyl acetate:pentane (5:95 to 90:10) to afford the title compound as a yellow oil, 1.4 g. prepared The mixture was concentrated under reduced pressure the residue partitioned between ethyl acetate (200 mL) and water (50 mL) the layers separated The organic layer was washed with water (5×50 mL) dried over magnesium sulphate concentrated in vacuo The crude product was purified by column chromatography on silica gel

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Iodopropane (2.0 mL, 20 mmol) was added to a solution of ethyl 2,3-diaminobenzoate (prepared according to the method of WO 97/10219, page 81, Example 51(1)) (3 g, 16.67 mmol) in N,N-dimethylformamide (20 mL), and the solution stirred at 50° C. for 3 hours. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (200 mL) and water (50 mL), and the layers separated. The organic layer was washed with water (5×50 mL), dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using ethyl acetate:pentane (5:95 to 90:10) to afford the title compound as a yellow oil, 1.4 g. prepared The mixture was concentrated under reduced pressure the residue partitioned between ethyl acetate (200 mL) and water (50 mL) the layers separated The organic layer was washed with water (5×50 mL) dried over magnesium sulphate concentrated in vacuo The crude product was purified by column chromatography on silica gel

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4.2 g (23 mmol) of ethyl 2,3-diaminobenzoate and 3.1 ml of concentrated acetic acid were dissolved in 100 ml of methanol. 4.5 g (30 mmol) of 4-nitrobenzaldehyde, dissolved in 150 ml of methanol, were then added dropwise over a period of 30 minutes. 6 g (30 mmol) of copper(II) acetate, dissolved in 150 ml of warm water, were then rapidly added dropwise, and the entire mixture was subsequently refluxed for 20 minutes. The reaction solution was cooled to 50° C. and 8.3 ml of concentrated hydrochloric acid were added. This was followed by careful dropwise addition of a solution of 8.6 g of sodium sulfide hydrate in 100 ml of water, and the entire mixture was stirred for another 15 minutes. The reaction solution was poured into ice-water and the resulting precipitate was filtered off with suction. The filtrate was made alkaline using aqueous sodium bicarbonate solution and extracted repeatedly with ethyl acetate. The ethyl acetate phase was separated off, dried and concentrated under reduced pressure. This gave 6.1 g of the intermediate. were then added dropwise over a period of 30 minutes were then rapidly added dropwise the entire mixture was subsequently refluxed for 20 minutes the resulting precipitate was filtered off with suction extracted repeatedly with ethyl acetate The ethyl acetate phase was separated off dried concentrated under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1 g (5.5 mmol) of ethyl 2,3-diaminobenzoate and 0.7 ml of concentrated acetic acid were dissolved in 13 ml of methanol. 1.24 g (7.2 mmol) of 4-imidazol-1-ylbenzaldehyde, dissolved in 25 ml of methanol, were then added dropwise over a period of 30 minutes. 1.4 g (7.2 mmol) of copper(II) acetate, dissolved in 19 ml of warm water, were then rapidly added dropwise, and the entire mixture was subsequently refluxed for 20 minutes. The reaction solution was cooled to 50° C. and 2.25 ml of 32% strength hydrochloric acid were added. This was followed by careful dropwise addition of a solution of 2.13 g of sodium sulfide hydrate in 15 ml of water, and the entire mixture was stirred for another 15 minutes. The reaction solution was poured into ice-water and the resulting precipitate was filtered off with suction. The filtrate was made alkaline using aqueous sodium bicarbonate solution and extracted repeatedly with ethyl acetate. The ethyl acetate phase was separated off, dried and concentrated under reduced pressure. This gave 1.7 g of the intermediate. were then added dropwise over a period of 30 minutes were then rapidly added dropwise the entire mixture was subsequently refluxed for 20 minutes the resulting precipitate was filtered off with suction extracted repeatedly with ethyl acetate The ethyl acetate phase was separated off dried concentrated under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.5 g (8.3 mmol) of ethyl 2,3-diaminobenzoate and 1.1 ml of concentrated acetic acid were dissolved in 50 ml of methanol. 1.6 g (10.8 mmol) of 4-nitrobenzaldehyde, dissolved in 150 ml of methanol, were then added dropwise over a period of 30 minutes. 2.2 g (10.8 mmol) of copper(II) acetate, dissolved in 100 ml of warm water, were then rapidly added dropwise, and the entire mixture was subsequently refluxed for 20 minutes. The reaction solution was cooled to 50° C. and 3 ml of 32% strength hydrochloric acid were added. This was followed by careful dropwise addition of a solution of 3.1 g of sodium sulfide hydrate in 50 ml of water, and the entire mixture was stirred for another 15 minutes. The reaction solution was poured into ice-water and the resulting precipitate was filtered off with suction. The filtrate was made alkaline using aqueous sodium bicarbonate solution and extracted repeatedly with ethyl acetate. The ethyl acetate phase was separated off, dried and concentrated under reduced pressure. This gave 2.2 g of the intermediate. were then added dropwise over a period of 30 minutes were then rapidly added dropwise the entire mixture was subsequently refluxed for 20 minutes the resulting precipitate was filtered off with suction extracted repeatedly with ethyl acetate The ethyl acetate phase was separated off dried concentrated under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1.5 g (8.3 mmol) of ethyl 2,3-diaminobenzoate and 1.1 ml of concentrated acetic acid were dissolved in 50 ml of methanol. 1.6 g (10.8 mmol) of 4-nitrobenzaldehyde, dissolved in 150 ml of methanol, were then added dropwise over a period of 30 minutes. 2.2 g (10.8 mmol) of copper(II) acetate, dissolved in 100 ml of warm water, were then rapidly added dropwise, and the entire mixture was subsequently refluxed for 20 minutes. The reaction solution was cooled to 50° C. and 3 ml of 32% strength hydrochloric acid were added. This was followed by careful dropwise addition of a solution of 3.1 g of sodium sulfide hydrate in 50 ml of water, and the entire mixture was stirred for another 15 minutes. The reaction solution was poured into ice-water and the resulting precipitate was filtered off with suction. The filtrate was made alkaline using aqueous sodium bicarbonate solution and extracted repeatedly with ethyl acetate. The ethyl acetate phase was separated off, dried and concentrated under reduced pressure. This gave 2.2 g of the intermediate. were then added dropwise over a period of 30 minutes were then rapidly added dropwise the entire mixture was subsequently refluxed for 20 minutes the resulting precipitate was filtered off with suction extracted repeatedly with ethyl acetate The ethyl acetate phase was separated off dried concentrated under reduced pressure

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

Procedure: To a solution of 3-ethoxycarbonyl-1,2-phenylenediamine (790 mg) in tetrahydrofuran (10 ml) was added 1,1′-thiocarbonyldiimidazole (1.02 g) in ice water bath and the mixture was stirred for 20 hours at ambient temperature. The reaction solvent was concentrated in vacuo and the residue was washed with chloroform and collected by vacuum filtration to give ethyl 2-mercapto-1H-benzimidazole-4-carboxylate (665 mg). The reaction solvent was concentrated in vacuo the residue was washed with chloroform collected by vacuum filtration

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

Procedure: To a solution of ethyl 2,3-diaminobenzoate (4.72 g) and pyridine (2.49 g) in dichloroethane (50 ml) was added chloroacetyl chloride (3.11 g) in chloroform (10 ml) at −70° C. and the reaction mixture was stood overnight. After the reaction mixture was concentrated in vacuo, the residue was diluted with ethnaol (50 ml). To the solution was added p-toluenesulfonic acid (249 mg) and the reaction mixture was refluxed for 2 hours. After the reaction mixture was concentrated in vacuo, the reside was diluted with ethyl acetate and satureated sodium hydrogen carbonate aqueous solution. The organic layer was separated and washed with brine. The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give ethyl 2-chloromethyl-1H-benzimidazole-4-carboxylate (2.98 g). After the reaction mixture was concentrated in vacuo the residue was diluted with ethnaol (50 ml) To the solution was added p-toluenesulfonic acid (249 mg) the reaction mixture was refluxed for 2 hours After the reaction mixture was concentrated in vacuo the reside was diluted with ethyl acetate The organic layer was separated washed with brine The solution was dried over magnesium sulfate concentrated in vacuo The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,3-Butanedione (0.0776 mol) was added at room temperature to a solution of sodium pyrosulfite (0.1 mol) in water (75 ml). The mixture was heated to 70° C. and then added to a solution of ethyl 2,3-diaminobenzoate (0.0776 mol) in water (75 ml). The mixture was stirred at 100° C. for 12 hours, cooled, basified with K2CO3 10% and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (17.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc 93/7; 20-45 μm). The pure fractions were collected and the solvent was evaporated, yielding 12 g (67%) of ethyl 2,3-dimethyl-5-quinoxalinecarboxylate (interm. 6). cooled extracted with EtOAc The organic layer was separated dried (MgSO4) filtered the solvent was evaporated The residue (17.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc 93/7; 20-45 μm) The pure fractions were collected the solvent was evaporated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,3-Butanedione (0.0776 mol) was added at room temperature to a solution of sodium pyrosulfite (0.1 mol) in water (75 ml). The mixture was heated to 70° C. and then added to a solution of ethyl 2,3-diaminobenzoate (0.0776 mol) in water (75 ml). The mixture was stirred at 100° C. for 12 hours, cooled, basified with K2CO3 10% and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue (17.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc 93/7; 20-45 μm). The pure fractions were collected and the solvent was evaporated, yielding 12 g (67%) of ethyl 2,3-dimethyl-5-quinoxalinecarboxylate (interm. 6). cooled extracted with EtOAc The organic layer was separated dried (MgSO4) filtered the solvent was evaporated The residue (17.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc 93/7; 20-45 μm) The pure fractions were collected the solvent was evaporated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1 g (5.5 mmol) of ethyl 2,3-diaminobenzoate and 0.7 ml (11.3 mmol) of acetic acid were dissolved in 15 ml of ethanol. Then 0.77 g (7.2 mmol) of pyridine-4-carbaldehyde, dissolved in 25 ml of ethanol was added dropwise over the course of 30 minutes. A solution of 1.44 g (7.2 mmol) of copper(II) sulfate in 20 ml of water was then rapidly added dropwise. The mixture was boiled under reflux for 2 hours. The reaction solution was then allowed to cool to 50° C. 2.25 ml of 32% strength hydrochloric acid were then added. A solution of 2.13 g (8.9 mmol) of sodium sulfide hydrate and 25 ml of water was then cautiously added dropwise while hot. The mixture was stirred for 10 minutes. The reaction mixture was then poured into ice-water, and the resulting precipitate was filtered off. The filtrate was made alkaline with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with water, dried and concentrated in vacuo. 1.15 g of the product were obtained. was added dropwise over the course of 30 minutes under reflux for 2 hours the resulting precipitate was filtered off extracted with ethyl acetate The organic phase was washed with water dried concentrated in vacuo

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

Procedure: To a solution of ethyl 2,3-diaminobenzoate (3.0 g) in methanol (60 mL) was added 1 N hydrochloric acid (0.6 mL) and benzaldehyde (1.7 mL), and the mixture was stirred at room temperature for 1 hour. After evaporation of the solvent under a reduced pressure, to the solution of the obtained residue in dichloromethane was added silica gel. The solvent was evaporated under a reduced pressure, and the resulting residue was heated at 100° C. for 1 hour. By purifying the reaction mixture by a silica gel column chromatography (eluent:hexane/ethyl acetate), the title compound was obtained as crystal (1.8 g). After evaporation of the solvent under a reduced pressure to the solution of the obtained residue in dichloromethane was added silica gel The solvent was evaporated under a reduced pressure the resulting residue was heated at 100° C. for 1 hour By purifying the reaction mixture by a silica gel column chromatography (eluent:hexane/ethyl acetate)