methyl 2-fluoro-5-hydroxybenzoate

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

Procedure: The obtained 2-fluoro-5-hydroxybenzoic acid (3e) (780 mg, 5 mmol) was dissolved in 100 mL methanol. Thionyl chloride (0.8 mL, 10 mmol) was added dropwise under the condition of ice bath (0° C.) and stirring, and then refluxed for two hours. The reaction solution was concentrated, and then column chromatography (petroleum ether:ethyl acetate=2:1) was performed to isolate methyl 2-fluoro-5-hydroxybenzoate (3f), 833 mg white solid (yield 98%). 1H NMR (600 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.20-7.18 (m, 1H), 7.13-7.09 (m, 1H), 6.99-6.97 (m, 1H), 3.80 (s, 3H); ESI-MS m/z: calculated for 170.04. found 171.25 [M+H]+. refluxed for two hours The reaction solution was concentrated

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

Procedure: The obtained 2-fluoro-5-hydroxybenzoic acid (3e) (780 mg, 5 mmol) was dissolved in 100 mL methanol. Thionyl chloride (0.8 mL, 10 mmol) was added dropwise under the condition of ice bath (0° C.) and stirring, and then refluxed for two hours. The reaction solution was concentrated, and then column chromatography (petroleum ether:ethyl acetate=2:1) was performed to isolate methyl 2-fluoro-5-hydroxybenzoate (3f), 833 mg white solid (yield 98%). 1H NMR (600 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.20-7.18 (m, 1H), 7.13-7.09 (m, 1H), 6.99-6.97 (m, 1H), 3.80 (s, 3H); ESI-MS m/z: calculated for 170.04. found 171.25 [M+H]+. refluxed for two hours The reaction solution was concentrated

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

Procedure: In the presence of hydrazine hydrate/glacial acetic acid, phthalic anhydride (3a) with substituent R was transformed into R-substituted phthalhydrazide (3b), which subsequently generated substituted dichlorophthalazine compounds (3c) under the action of phosphorus pentachloride. In another aspect, under the action of hydrobromic acid, 2-fluoro-5-methoxybenzonitrile (3d) was converted to 2-fluoro-5-hydroxybenzoic acid (3e), which was esterificated with methanol to give methyl 2-fluoro-5-hydroxybenzoate (3f). Under the action of sodium hydride, the prepared dichlorophthalazine compounds with substituent R (3c) was reacted with methyl 2-fluoro-5-hydroxybenzoate (3f) to give methyl 5-((4-chloronaphthyridine-1-yl)oxy)-2-fluorobenzoate with substituent R (3g), 3g was transformed into methyl 2-fluoro-5-((4-oxo-3,4-dihydro-phthalazin-1-yl)oxy)benzoate (3h) in the presence of AcOH/NaOAc under the reflux condition, 3h was then hydrolyzed under alkali condition into substituent-contained 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (3i), which finally condensated with R′ substituted nitrogen heterocycles, e.g. piperazine, piperidine, 4-hydroxypiperidine, tetrahydropyridine and 1,4-diazacycloheptane in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), triethylamine and 1-hydroxy-7-azabenzotriazole (HOAt) to generate target compounds, wherein the definition of R and R′ is as described above.

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

Procedure: In the presence of hydrazine hydrate/glacial acetic acid, phthalic anhydride (3a) with substituent R was transformed into R-substituted phthalhydrazide (3b), which subsequently generated substituted dichlorophthalazine compounds (3c) under the action of phosphorus pentachloride. In another aspect, under the action of hydrobromic acid, 2-fluoro-5-methoxybenzonitrile (3d) was converted to 2-fluoro-5-hydroxybenzoic acid (3e), which was esterificated with methanol to give methyl 2-fluoro-5-hydroxybenzoate (3f). Under the action of sodium hydride, the prepared dichlorophthalazine compounds with substituent R (3c) was reacted with methyl 2-fluoro-5-hydroxybenzoate (3f) to give methyl 5-((4-chloronaphthyridine-1-yl)oxy)-2-fluorobenzoate with substituent R (3g), 3g was transformed into methyl 2-fluoro-5-((4-oxo-3,4-dihydro-phthalazin-1-yl)oxy)benzoate (3h) in the presence of AcOH/NaOAc under the reflux condition, 3h was then hydrolyzed under alkali condition into substituent-contained 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (3i), which finally condensated with R′ substituted nitrogen heterocycles, e.g. piperazine, piperidine, 4-hydroxypiperidine, tetrahydropyridine and 1,4-diazacycloheptane in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), triethylamine and 1-hydroxy-7-azabenzotriazole (HOAt) to generate target compounds, wherein the definition of R and R′ is as described above.

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

Procedure: To a solution of sodium hydride (1.7 g, 44.11 mmol) in tetrahydrofuran (50 mL) was added solution of 2-fluoro-5-hydroxy benzoic acid methyl ester (5 g, 29.41 mmol) in tetrahydrofuran (50 mL) under argon atmosphere and stirred for 15 minutes. A solution of 2-amino-5-bromothiazole (5.2 g, 29.41 mmol) in tetrahydrofuran (47 mL) was added dropwise over a period of 30 min and stirred at room temperature for 4 hrs. Reaction mixture was poured into ice cold water (300 mL) extracted with ethyl acetate (3×200 mL), combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Crude compound was purified by silica gel column chromatography using 40% ethyl acetate in hexane as eluent to afford pure 5-[(2-amino-5H-thiazol-5-yl)oxy]-2-fluoro-benzoic acid methyl ester. (2.5 g). stirred at room temperature for 4 hrs Reaction mixture extracted with ethyl acetate (3×200 mL) were washed with brine dried over anhydrous sodium sulfate filtered concentrated under reduced pressure Crude compound was purified by silica gel column chromatography

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

Procedure: To a solution of sodium hydride (1.7 g, 44.11 mmol) in tetrahydrofuran (50 mL) was added solution of 2-fluoro-5-hydroxy benzoic acid methyl ester (5 g, 29.41 mmol) in tetrahydrofuran (50 mL) under argon atmosphere and stirred for 15 minutes. A solution of 2-amino-5-bromothiazole (5.2 g, 29.41 mmol) in tetrahydrofuran (47 mL) was added dropwise over a period of 30 min and stirred at room temperature for 4 hrs. Reaction mixture was poured into ice cold water (300 mL) extracted with ethyl acetate (3×200 mL), combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Crude compound was purified by silica gel column chromatography using 40% ethyl acetate in hexane as eluent to afford pure 5-[(2-amino-5H-thiazol-5-yl)oxy]-2-fluoro-benzoic acid methyl ester. (2.5 g). stirred at room temperature for 4 hrs Reaction mixture extracted with ethyl acetate (3×200 mL) were washed with brine dried over anhydrous sodium sulfate filtered concentrated under reduced pressure Crude compound was purified by silica gel column chromatography

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

Procedure: The obtained 2-fluoro-5-hydroxybenzoic acid (3e) (780 mg, 5 mmol) was dissolved in 100 mL methanol. Thionyl chloride (0.8 mL, 10 mmol) was added dropwise under the condition of ice bath (0° C.) and stirring, and then refluxed for two hours. The reaction solution was concentrated, and then column chromatography (petroleum ether:ethyl acetate=2:1) was performed to isolate methyl 2-fluoro-5-hydroxybenzoate (3f), 833 mg white solid (yield 98%). 1H NMR (600 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.20-7.18 (m, 1H), 7.13-7.09 (m, 1H), 6.99-6.97 (m, 1H), 3.80 (s, 3H); ESI-MS m/z: calculated for 170.04. found 171.25 [M+H]+. refluxed for two hours The reaction solution was concentrated

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

Procedure: In the presence of hydrazine hydrate/glacial acetic acid, phthalic anhydride (3a) with substituent R was transformed into R-substituted phthalhydrazide (3b), which subsequently generated substituted dichlorophthalazine compounds (3c) under the action of phosphorus pentachloride. In another aspect, under the action of hydrobromic acid, 2-fluoro-5-methoxybenzonitrile (3d) was converted to 2-fluoro-5-hydroxybenzoic acid (3e), which was esterificated with methanol to give methyl 2-fluoro-5-hydroxybenzoate (3f). Under the action of sodium hydride, the prepared dichlorophthalazine compounds with substituent R (3c) was reacted with methyl 2-fluoro-5-hydroxybenzoate (3f) to give methyl 5-((4-chloronaphthyridine-1-yl)oxy)-2-fluorobenzoate with substituent R (3g), 3g was transformed into methyl 2-fluoro-5-((4-oxo-3,4-dihydro-phthalazin-1-yl)oxy)benzoate (3h) in the presence of AcOH/NaOAc under the reflux condition, 3h was then hydrolyzed under alkali condition into substituent-contained 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-yl-oxyl)benzoic acid (3i), which finally condensated with R′ substituted nitrogen heterocycles, e.g. piperazine, piperidine, 4-hydroxypiperidine, tetrahydropyridine and 1,4-diazacycloheptane in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), triethylamine and 1-hydroxy-7-azabenzotriazole (HOAt) to generate target compounds, wherein the definition of R and R′ is as described above.

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

Procedure: To a solution of sodium hydride (1.7 g, 44.11 mmol) in tetrahydrofuran (50 mL) was added solution of 2-fluoro-5-hydroxy benzoic acid methyl ester (5 g, 29.41 mmol) in tetrahydrofuran (50 mL) under argon atmosphere and stirred for 15 minutes. A solution of 2-amino-5-bromothiazole (5.2 g, 29.41 mmol) in tetrahydrofuran (47 mL) was added dropwise over a period of 30 min and stirred at room temperature for 4 hrs. Reaction mixture was poured into ice cold water (300 mL) extracted with ethyl acetate (3×200 mL), combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Crude compound was purified by silica gel column chromatography using 40% ethyl acetate in hexane as eluent to afford pure 5-[(2-amino-5H-thiazol-5-yl)oxy]-2-fluoro-benzoic acid methyl ester. (2.5 g). stirred at room temperature for 4 hrs Reaction mixture extracted with ethyl acetate (3×200 mL) were washed with brine dried over anhydrous sodium sulfate filtered concentrated under reduced pressure Crude compound was purified by silica gel column chromatography