ethyl 3-bromo-2-oxobutanoate

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

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

Procedure: The 2-oxo-butyric acid ethyl ester prepared above was dissolved in chloroform (100 mL) and bromine (20.964 g, 131.19 mmol) was added dropwise at room temperature. The reaction mixture was allowed to stir for 18 h. Concentration of the reaction mixture under reduced pressure provided 12.0 g of the title compound as an orange oil. 1H NMR (CDCl3) δ 4.39 (q, 2H), 4.32 (q, 1H), 1.88 (d, 3H), 1.39 (t, 3H).

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

Procedure: Part A: N-(4-methoxyphenyl)-2,4-dichlorobenzenecarboxamidine (15.0 gram, 50.8 mmol) is dissolved in 2-propanol and ethyl 3-bromo-2-oxobutanoate (23.5 g, 2 molar equivalents) and NaHCO3 (8.5 gram, 2 molar equivalents) are successively added. The resulting mixture is heated at reflux temperature for 40 hours and allowed to attain room temperature. The 2-propanol is removed in vacuo, ethyl acetate is added to the residue and the resulting organic layer is washed with NaHCO3 (5% aqueous solution). The ethylacetate layer is collected, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil is purified by column chromatography (diethyl ether/petroleum ether=1/3 (v/v), silicagel) to give ethyl 2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxy-phenyl)-1H-imidazole-4-carboxylate (8.61 g, 42% yield) as a solid. 1H-NMR (200 MHz, CDCl3): δ 7.33 (d, J=8 Hz, 1H), 7.27 (d, J=2 Hz, 1H), 7.18 (dd, J=8 Hz, J=2 Hz, 1H), 7.03 (dt, J=8 Hz, J=2 Hz, 2H), 6.85 (dt, J=8 Hz, J=2 Hz, 2H), 4.42 (q, J=7 Hz, 2H), 3.80 (s, 3H), 2.43 (s, 3H), 1.43 (t, J=7 Hz, 3H). The resulting mixture is heated at reflux temperature for 40 hours to attain room temperature The 2-propanol is removed in vacuo, ethyl acetate is added to the residue the resulting organic layer is washed with NaHCO3 (5% aqueous solution) The ethylacetate layer is collected dried over Na2SO4 filtered concentrated in vacuo The resulting oil is purified by column chromatography (diethyl ether/petroleum ether=1/3 (v/v), silicagel)

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

Procedure: Part C: 2,4-Dichloro-N-(4-(trifluoromethyl)phenyl)benzenecarboxamidine (15.0 g, 0.0450 mol) is dissolved in 2-propanol and ethyl 3-bromo-2-oxobutanoate (20.8 g, 2 molar equivalent) and NaHCO3 are successively added. The resulting mixture is heated at reflux temperature for 40 hours and allowed to attain room temperature. The 2-propanol is removed in vacuo, ethyl acetate is added to the residue and the resulting organic layer is washed with NaHCO3 (5% aqueous solution). The ethylacetate layer is collected, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil is purified by column chromatography (diethyl ether/petroleum ether=1/3 (v/v), silicagel) and further purified by crystallisation from cyclohexane to give ethyl 2-(2,4-dichlorophenyl)-5-methyl-1-(4-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxylate (10.45 g, 52% yield) as a yellow solid. Melting point: 160-162° C. The resulting mixture is heated at reflux temperature for 40 hours to attain room temperature The 2-propanol is removed in vacuo, ethyl acetate is added to the residue the resulting organic layer is washed with NaHCO3 (5% aqueous solution) The ethylacetate layer is collected dried over Na2SO4 filtered concentrated in vacuo The resulting oil is purified by column chromatography (diethyl ether/petroleum ether=1/3 (v/v), silicagel) further purified by crystallisation from cyclohexane

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

Procedure: Part C: 2,4-Dichloro-N-(4-(trifluoromethyl)phenyl)benzenecarboxamidine (15.0 g, 0.0450 mol) is dissolved in 2-propanol and ethyl 3-bromo-2-oxobutanoate (20.8 g, 2 molar equivalent) and NaHCO3 are successively added. The resulting mixture is heated at reflux temperature for 40 hours and allowed to attain room temperature. The 2-propanol is removed in vacuo, ethyl acetate is added to the residue and the resulting organic layer is washed with NaHCO3 (5% aqueous solution). The ethylacetate layer is collected, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil is purified by column chromatography (diethyl ether/petroleum ether=1/3 (v/v), silicagel) and further purified by crystallisation from cyclohexane to give ethyl 2-(2,4-dichlorophenyl)-5-methyl-1-(4-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxylate (10.45 g, 52% yield) as a yellow solid. Melting point: 160-162° C. The resulting mixture is heated at reflux temperature for 40 hours to attain room temperature The 2-propanol is removed in vacuo, ethyl acetate is added to the residue the resulting organic layer is washed with NaHCO3 (5% aqueous solution) The ethylacetate layer is collected dried over Na2SO4 filtered concentrated in vacuo The resulting oil is purified by column chromatography (diethyl ether/petroleum ether=1/3 (v/v), silicagel) further purified by crystallisation from cyclohexane

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

Procedure: A solution of 2,3-diaminopyridine (6.8 g, 62 mmol) and 3-bromo-2-oxo-butyric acid ethyl ester (13 g, 62 mmol) in 1,2-dimethoxyethane (150 ml) was refluxed for 2 h. Sodium carbonate (6.5 g, 62 mmol) was added and the mixture was refluxed for 2 h. The solids were isolated by filtration and washed with dichloromethane:methanol (10:1). The filtrate and washings were combined the solvents were removed under reduced pressure. The oily residue was washed with petroleum ether and was purified twice by column chromatography on silica gel using 1) dichloromethane:methanol (10:1) 2) ethyl acetate as eluent to give 4.6 g (34%) of the title compound. the mixture was refluxed for 2 h The solids were isolated by filtration washed with dichloromethane:methanol (10:1) were removed under reduced pressure The oily residue was washed with petroleum ether was purified twice by column chromatography on silica gel using 1) dichloromethane:methanol (10:1) 2) ethyl acetate as eluent

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

Procedure: A solution of 2,3-diaminopyridine (6.8 g, 62 mmol) and 3-bromo-2-oxo-butyric acid ethyl ester (13 g, 62 mmol) in 1,2-dimethoxyethane (150 ml) was refluxed for 2 h. Sodium carbonate (6.5 g, 62 mmol) was added and the mixture was refluxed for 2 h. The solids were isolated by filtration and washed with dichloromethane:methanol (10:1). The filtrate and washings were combined the solvents were removed under reduced pressure. The oily residue was washed with petroleum ether and was purified twice by column chromatography on silica gel using 1) dichloromethane:methanol (10:1) 2) ethyl acetate as eluent to give 4.6 g (34%) of the title compound. the mixture was refluxed for 2 h The solids were isolated by filtration washed with dichloromethane:methanol (10:1) were removed under reduced pressure The oily residue was washed with petroleum ether was purified twice by column chromatography on silica gel using 1) dichloromethane:methanol (10:1) 2) ethyl acetate as eluent

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

Procedure: A solution of 1,6-naphthyridin-5-amine (700 mg, 4.83 mmol) in tetrahydrofuran (25 mL) was added ethyl 3-bromo-2-oxobutanoate (1.51 g, 7.24 mmol). The mixture was stirred at reflux for 36 h. Then the mixture was concentrated under reduced pressure, and purified by column chromatography to give 740 mg of the product as a yellow solid. MS (ESI): m/z 256.1 [M+H]+. at reflux for 36 h Then the mixture was concentrated under reduced pressure purified by column chromatography

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

Procedure: A solution of 1,6-naphthyridin-5-amine (700 mg, 4.83 mmol) in tetrahydrofuran (25 mL) was added ethyl 3-bromo-2-oxobutanoate (1.51 g, 7.24 mmol). The mixture was stirred at reflux for 36 h. Then the mixture was concentrated under reduced pressure, and purified by column chromatography to give 740 mg of the product as a yellow solid. MS (ESI): m/z 256.1 [M+H]+. at reflux for 36 h Then the mixture was concentrated under reduced pressure purified by column chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a magnetically stirred solution of above imidamide from step A (2.45 g, 7 mmol) in 30 mL anhydrous toluene were added ethyl 3-bromo-2-oxobutanoate (1.48 g, 7 mmol) and Na2CO3 (0.74 g, 7 mmol). The contents were stirred at 100° C. for 12 hours. The reaction was brought to RT. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined extracts were dried over anhydrous MgSO4, filtered and evaporated under reduced pressure. Purification by column chromatography gave the ester as pale white solid (1.5 g, 46.4%). was brought to RT The reaction mixture was quenched with water extracted with ethyl acetate The combined extracts were dried over anhydrous MgSO4 filtered evaporated under reduced pressure Purification by column chromatography

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

Procedure: To a solution of 2-amino-3-chloro-5-(trifluoromethyl)pyridine (11.3 g, 57.5 mmol) in dioxane (200 mL) at room temperature was added dropwise 3-bromo-2-oxo-butyric acid ethyl ester (12.017 g, 57.49 mmol, the product of Step A). The reaction mixture was heated to reflux for 24 h, cooled, and the dioxane was removed under reduced pressure. Chromatography on silica gel eluting with a hexane/ethyl acetate gradient afforded 17.3 g of 8-chloro-3-methyl-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester as a solid. The reaction mixture was heated to reflux for 24 h cooled the dioxane was removed under reduced pressure

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

Procedure: To a solution of 2-amino-3-chloro-5-(trifluoromethyl)pyridine (11.3 g, 57.5 mmol) in dioxane (200 mL) at room temperature was added dropwise 3-bromo-2-oxo-butyric acid ethyl ester (12.017 g, 57.49 mmol, the product of Step A). The reaction mixture was heated to reflux for 24 h, cooled, and the dioxane was removed under reduced pressure. Chromatography on silica gel eluting with a hexane/ethyl acetate gradient afforded 17.3 g of 8-chloro-3-methyl-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester as a solid. The reaction mixture was heated to reflux for 24 h cooled the dioxane was removed under reduced pressure