ethyl 3-ethoxy-3-iminopropanoate

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: Ethyl 3-ethoxy-3-iminopropionate, prepared as in Example 2(a), was reacted with 2-(3,4-diaminobenzyl)isoindole-1,3-dione under conditions similar to that set forth in Example 2(b) to provide ethyl 5-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-1H-benzoimidazol-2-ylacetate (71% yield); 1H-NMR (300 Mhz, DMSO-d6): 7.78-7.9 (m, 4H), 7.43-7.47 (m, 2H), 7.12 (d, 1H, J=9.43 Hz), 4.82 (s, 2H), 4.07 (q, 2H, J=7.2 Hz), 3.44 (s, 2H), 1.38 (t, 3H, J=7.2 Hz).

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,4-diaminobenzoic acid (9.4 g, 62 mmol), ethyl 3-ethoxy-3-iminopropionate and glacial acetic acid (15 mL) was stirred 30 minutes at 110° C. under nitrogen. The mixture was poured over crushed ice (50 mL) and stirred 30 minutes to give a dark yellow oil. The mixture was stirred while diethyl ether (25 mL) was added to give a gray precipitate. The precipitate was isolated by filtration, washed several times with diethyl ether and dried under vacuum to provide 2-ethoxycarbonylmethyl-1H-benzoimidazole-5-carboxylic acid (12.6 g, 83% yield); 1H-NMR (300 Mhz, DMSO-d6): 12.77 (broad s, 1H), 8.10 (s, 1H), 7.79 (d, 1H, J=8.4 Hz), 7.57 (d, 1H, J=8.4 Hz), 4.11 (q, 2H, J=7.1 Hz), 4.02 (s, 2H), 1.17 (t, 3H, J=7.1 Hz). The mixture was poured stirred 30 minutes to give a dark yellow oil was added to give a gray precipitate The precipitate was isolated by filtration washed several times with diethyl ether dried under vacuum

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

Procedure: Ethyl cyanoacetate (8 mL, 75 mmol) in anhydrous benzene (100 mL) was combined under nitrogen with anhydrous ethanol (6 mL, 105 mmol). The mixture was cooled to 10° C. (ice/acetone) and bubbled 20 minutes with dry hydrogen chloride gas. The mixture was slowly warmed to room temperature, sealed and stirred for approximately 18 hours. The mixture was diluted with diethyl ether (400 mL) and let stand for 5 hours at room temperature to give a crystalline solid. The solid was isolated by filtration, washed several times with anhydrous diethyl ether and dried to provide ethyl 3-ethoxy-3-iminopropionate (13.2 g, 90% yield) as a colorless, crystalline solid; 1H-NMR (300 Mhz, CDCL3): 7.84 (d, 1H, J=10.0 Hz), 7.19-7.36 (m, 5H), 7.00-7.06 (m, 2H), 4.10 (t, 2H, J=5.7 Hz), 2.73 (t, 2H, J=6.5 Hz), 1.89 (m, 4H). bubbled 20 minutes with dry hydrogen chloride gas sealed The mixture was diluted with diethyl ether (400 mL) let stand for 5 hours at room temperature to give a crystalline solid The solid was isolated by filtration washed several times with anhydrous diethyl ether dried

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

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 4-fluoroaniline (11.1 g, 100 mmol) in water (50 mL) and concentrated hydrochloric acid (19 mL) was cooled to −15° C. To this mixture was added a previously cooled (0° C.) solution of sodium nitrite (7.6 g, 110 mmol) in water (25 mL) over 5 min. Ice was added directly to the reaction to maintain the temperature below 5° C. After the addition was complete, the reaction was stirred at 0° C. for 15 min. Sodium acetate (41.0 g, 500 mmol) was added followed by ethyl 3-ethoxy-3-iminopropionate (15.9 g, 100 mmol). A yellow precipitate formed immediately. The suspension was stirred at 23° C. for 30 min., and then the solid was filtered and washed with water (40 mL). The still wet hydrazone was dissolved in pyridine (150 mL). A solution of copper (II) sulfate (49.7 g, 199 mmol) in water (150 mL) was added at once. The dark mixture was heated to 90° C. for 4 h. The majority of the pyridine (˜100 mL) was removed under vacuum. The residue was diluted with ethyl acetate (200 mL), water (100 mL) and 2 M sulfuric acid (80 mL). The resulting emulsion was filtered through Celite® diatomaceaous earth filter aid. The organic layer was washed with 2 M sulfuric acid (2×100 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting crude mixture was recrystallized from ethanol (80 mL) to obtain the title compound (15.1 g) as a pale red solid. To this mixture was added Ice was added directly to the reaction to maintain the temperature below 5° C After the addition A yellow precipitate formed immediately The suspension was stirred at 23° C. for 30 min. the solid was filtered washed with water (40 mL) The still wet hydrazone was dissolved in pyridine (150 mL) The dark mixture was heated to 90° C. for 4 h The majority of the pyridine (˜100 mL) was removed under vacuum The residue was diluted with ethyl acetate (200 mL), water (100 mL) and 2 M sulfuric acid (80 mL) The resulting emulsion was filtered through Celite® filter aid The organic layer was washed with 2 M sulfuric acid (2×100 mL) dried (MgSO4) concentrated under reduced pressure The resulting crude mixture was recrystallized from ethanol (80 mL)

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 4-fluoroaniline (11.1 g, 100 mmol) in water (50 mL) and concentrated hydrochloric acid (19 mL) was cooled to −15° C. To this mixture was added a previously cooled (0° C.) solution of sodium nitrite (7.6 g, 110 mmol) in water (25 mL) over 5 min. Ice was added directly to the reaction to maintain the temperature below 5° C. After the addition was complete, the reaction was stirred at 0° C. for 15 min. Sodium acetate (41.0 g, 500 mmol) was added followed by ethyl 3-ethoxy-3-iminopropionate (15.9 g, 100 mmol). A yellow precipitate formed immediately. The suspension was stirred at 23° C. for 30 min., and then the solid was filtered and washed with water (40 mL). The still wet hydrazone was dissolved in pyridine (150 mL). A solution of copper (II) sulfate (49.7 g, 199 mmol) in water (150 mL) was added at once. The dark mixture was heated to 90° C. for 4 h. The majority of the pyridine (˜100 mL) was removed under vacuum. The residue was diluted with ethyl acetate (200 mL), water (100 mL) and 2 M sulfuric acid (80 mL). The resulting emulsion was filtered through Celite® diatomaceaous earth filter aid. The organic layer was washed with 2 M sulfuric acid (2×100 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting crude mixture was recrystallized from ethanol (80 mL) to obtain the title compound (15.1 g) as a pale red solid. To this mixture was added Ice was added directly to the reaction to maintain the temperature below 5° C After the addition A yellow precipitate formed immediately The suspension was stirred at 23° C. for 30 min. the solid was filtered washed with water (40 mL) The still wet hydrazone was dissolved in pyridine (150 mL) The dark mixture was heated to 90° C. for 4 h The majority of the pyridine (˜100 mL) was removed under vacuum The residue was diluted with ethyl acetate (200 mL), water (100 mL) and 2 M sulfuric acid (80 mL) The resulting emulsion was filtered through Celite® filter aid The organic layer was washed with 2 M sulfuric acid (2×100 mL) dried (MgSO4) concentrated under reduced pressure The resulting crude mixture was recrystallized from ethanol (80 mL)

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

Procedure: A mixture of bis(2,4-dimethoxybenzyl)amine (8 g), ethyl 3-ethoxy-3-iminopropanoate (8.02 g), acetic acid (1.44 mL) and ethanol (420 mL) was refluxed overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (17 g). was refluxed overnight The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)

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

Procedure: A mixture of bis(2,4-dimethoxybenzyl)amine (8 g), ethyl 3-ethoxy-3-iminopropanoate (8.02 g), acetic acid (1.44 mL) and ethanol (420 mL) was refluxed overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (17 g). was refluxed overnight The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)