2-chloro-5-fluorobenzaldehyde

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

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

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of thiazole-2-carboxamidine hydrochloride (0.13 g, 1.0 mmol), methyl acetoacetate (0.12 g, 1.0 mmol) and 2-chloro-5-fluorobenzaldehyde (0.16 g, 1.0 mmol) in CF3CH2OH (8 mL) was added potassium acetate (0.20 g, 2.0 mmol). The reaction mixture was either refluxed for 16 hrs or heated at 150° C. in microwave oven for 2 hours. After it was cooled to room temperature, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by column chromatography (ethyl acetate/petroleum ether is from ¼ to ½) to afford 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound B) as a yellow solid. MS: calc'd (MH+) 366, measured (MH+) 366. 1H NMR (DMSO-d6, 400 MHz): 6 ppm 9.98 (s, 1H), 7.97 (d, J=4.0 Hz, 1H), 7.90 (d, J=4.0 Hz, 1H), 7.41 (dd, J=8.0, 4.0 Hz, 1H), 7.35 (dd, J=8.0, 8.0 Hz, 1H), 7.18 (td, J=8.0, 4.0 Hz, 1H), 5.98 (s, 1H), 3.53 (s, 3H), 2.47 (s, 3H). The reaction mixture was either refluxed for 16 hrs After it was cooled to room temperature the reaction mixture was concentrated the residue was dissolved in ethyl acetate washed with brine The organic layer was dried over sodium sulfate concentrated the residue was purified by column chromatography (ethyl acetate/petroleum ether is from ¼ to ½)

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

Procedure: Sodium hydroxide (0.78 g) was dissolved in water (55 ml) and treated dropwise with acetone (55 ml) followed by a solution of 2-chloro-5-fluorobenzaldehyde (2.8 g) in acetone (10 ml). The reaction mixture was stirred at room temperature for 2 hours. Acetone was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and concentrated under reduced 5 pressure to obtain 4-(2-chloro-5-fluorophenyl)-3-buten-2-one (0.24 g). Acetone was distilled off under reduced pressure the residue was extracted with ethyl acetate The organic layer was washed successively with water and saturated brine concentrated under reduced 5 pressure

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

Procedure: A solution of 2-chloro-5-fluorotoluene (5.0 g) in acetic anhydride (40 ml) was treated dropwise with concentrated sulfuric acid (40 ml) with cooling on ice. Subsequently, a solution of chromic anhydride (9.3 g) in acetic anhydride (40 ml) was added dropwise over a period of 2 hours. At the same temperature, the mixture was stirred for 1 hour, and added to an ice-water. The mixture was extracted with diethyl ether and the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 ml), combined with water (4 ml) and concentrated sulfuric acid (4 ml), and heated with stirring at 100° C. for 30 minutes. After allowed to stand to cool, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to a column chromatography on a silica gel to obtain 2-chloro-5-fluorobenzaldehyde (1.6 g). with cooling on ice The mixture was extracted with diethyl ether the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine dried over magnesium sulfate The solvent was distilled off under reduced pressure the residue was dissolved in tetrahydrofuran (10 ml) heated with stirring at 100° C. for 30 minutes to cool the reaction mixture was extracted with ethyl acetate the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine dried over magnesium sulfate The solvent was distilled off

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

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

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of thiazole-2-carboxamidine hydrochloride (0.13 g, 1.0 mmol), methyl acetoacetate (0.12 g, 1.0 mmol) and 2-chloro-5-fluorobenzaldehyde (0.16 g, 1.0 mmol) in CF3CH2OH (8 mL) was added potassium acetate (0.20 g, 2.0 mmol). The reaction mixture was either refluxed for 16 hrs or heated at 150° C. in microwave oven for 2 hours. After it was cooled to room temperature, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by column chromatography (ethyl acetate/petroleum ether is from ¼ to ½) to afford 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound B) as a yellow solid. MS: calc'd (MH+) 366, measured (MH+) 366. 1H NMR (DMSO-d6, 400 MHz): 6 ppm 9.98 (s, 1H), 7.97 (d, J=4.0 Hz, 1H), 7.90 (d, J=4.0 Hz, 1H), 7.41 (dd, J=8.0, 4.0 Hz, 1H), 7.35 (dd, J=8.0, 8.0 Hz, 1H), 7.18 (td, J=8.0, 4.0 Hz, 1H), 5.98 (s, 1H), 3.53 (s, 3H), 2.47 (s, 3H). The reaction mixture was either refluxed for 16 hrs After it was cooled to room temperature the reaction mixture was concentrated the residue was dissolved in ethyl acetate washed with brine The organic layer was dried over sodium sulfate concentrated the residue was purified by column chromatography (ethyl acetate/petroleum ether is from ¼ to ½)

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

Procedure: Sodium hydroxide (0.78 g) was dissolved in water (55 ml) and treated dropwise with acetone (55 ml) followed by a solution of 2-chloro-5-fluorobenzaldehyde (2.8 g) in acetone (10 ml). The reaction mixture was stirred at room temperature for 2 hours. Acetone was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and concentrated under reduced 5 pressure to obtain 4-(2-chloro-5-fluorophenyl)-3-buten-2-one (0.24 g). Acetone was distilled off under reduced pressure the residue was extracted with ethyl acetate The organic layer was washed successively with water and saturated brine concentrated under reduced 5 pressure

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

Procedure: A solution of 2-chloro-5-fluorotoluene (5.0 g) in acetic anhydride (40 ml) was treated dropwise with concentrated sulfuric acid (40 ml) with cooling on ice. Subsequently, a solution of chromic anhydride (9.3 g) in acetic anhydride (40 ml) was added dropwise over a period of 2 hours. At the same temperature, the mixture was stirred for 1 hour, and added to an ice-water. The mixture was extracted with diethyl ether and the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 ml), combined with water (4 ml) and concentrated sulfuric acid (4 ml), and heated with stirring at 100° C. for 30 minutes. After allowed to stand to cool, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to a column chromatography on a silica gel to obtain 2-chloro-5-fluorobenzaldehyde (1.6 g). with cooling on ice The mixture was extracted with diethyl ether the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine dried over magnesium sulfate The solvent was distilled off under reduced pressure the residue was dissolved in tetrahydrofuran (10 ml) heated with stirring at 100° C. for 30 minutes to cool the reaction mixture was extracted with ethyl acetate the organic layer was washed successively with aqueous sodium carbonate, water and saturated brine dried over magnesium sulfate The solvent was distilled off

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

Procedure: To a stirred solution of thiazole-2-carboxamidine hydrochloride (0.13 g, 1.0 mmol), methyl acetoacetate (0.12 g, 1.0 mmol) and 2-chloro-5-fluorobenzaldehyde (0.16 g, 1.0 mmol) in CF3CH2OH (8 mL) was added potassium acetate (0.20 g, 2.0 mmol). The reaction mixture was refluxed for 16 hours. After it was cooled to room temperature, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate and then washed with brine. The organic layer was dried over sodium sulfate. The solvent was concentrated, and the residue was purified by column chromatography (ethyl acetate/petroleum ether is from ¼ to ½) to afford 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound B) as a yellow solid. MS: calc'd (MH+) 366, measured (MH+) 366. 1H NMR (DMSO-d6, 400 MHz): δ ppm 9.98 (s, 1H), 7.97 (d, J=4.0 Hz, 1H), 7.90 (d, J=4.0 Hz, 1H), 7.41 (dd, J=8.0, 4.0 Hz, 1H), 7.35 (dd, J=8.0, 8.0 Hz, 1H), 7.18 (td, J=8.0, 4.0 Hz, 1H), 5.98 (s, 1H), 3.53 (s, 3H), 2.47 (s, 3H). The reaction mixture was refluxed for 16 hours the reaction mixture was concentrated the residue was dissolved in ethyl acetate washed with brine The organic layer was dried over sodium sulfate The solvent was concentrated the residue was purified by column chromatography (ethyl acetate/petroleum ether is from ¼ to ½)

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

Procedure: In water (55 ml) was dissolved sodium hydroxide (0.78 g), and to the mixture was added acetone (55 ml), and then added dropwise a solution of 2-chloro-5-fluorobenzaldehyde (2.8 g) in acetone (10 ml). The reaction solution was stirred at room temperature for 2 hours, and acetone was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and concentrated under reduced pressure to give 4-(2-chloro-5-fluorophenyl)-3-buten-2-one (0.24 g). acetone was evaporated under reduced pressure The residue was extracted with ethyl acetate the organic layer was washed with water and saturated brine concentrated under reduced pressure