General procedure for the synthesis of methyl 5-bromo-2-fluorobenzoate from methanol and 2-fluoro-5-bromobenzoic acid: 5-bromo-2-fluorobenzoic acid (100 g, 0.457 mol) was added to a methanolic solution of HCl (400 mL; ~11%). The suspension was refluxed for 8 hours and then evaporated under vacuum. The residue was dissolved in benzene (500 mL) and the solution was washed with aqueous K2CO3 (2 x 50 mL) and water (3 x 100 mL), dried with Na2SO4 and vacuum evaporated to give methyl 5-bromo-2-fluorobenzoate as a yellow oil in 88% yield (93.7 g).
Methyl 5-bromo-2-fluorobenzoate (154.2 g, 0.66 mol), anhydrous benzene (450 mL), ethynyl (trimethyl) silane (78.0 g, 0.79 mol), diisopropylamine (100 g, 0.99 mol), and tetrakis(triphenylphosphine) palladium (20.0 g, 0.017 mol) were placed in a three-necked, round-bottomed, 1- liter flask under argon atmosphere. The mixture was stirred for 30 minutes and then cooled to 10°C. Copper iodide (12.5 g, 0.066 mol) was added and the resulting suspension was stirred at 20 °C for 2.5 h, then at 60 °C for 3 h, and finally left at room temperature overnight. Thereafter, the mixture was diluted with ether (200 mL), the precipitate was separated by filtration and washed with ether (2 x 100 mL). The resulting organic solution (800 mL) was washed with saturated aqueous NH4Cl and NaCl, dried with Na2SO4 and evaporated. The crude product was purified by chromatography (hexane/ethyl acetate 10:1) on a silica gel column to afford methyl 2-fluoro-5-(2-trimethylsilyl ethynyl)benzoate containing about 13% methyl 5-bromo-2-fluorobenzoate in about 80% yield (148.1 g).
A suspension of methyl 2-fluoro-5-(2-trimethylsilyl ethynyl)benzoate (171.1 g, 0.684 mol), mercury diacetate (12.0 g, 0.051 mol) in THF (400 mL) and concentrated H2SO4 (74 mL, 1.37 mol) was stirred for 2 hr at 50-60 °C. The mixture was then cooled and THF (350 mL) was evaporated under vacuum. The residue was diluted with ether (700mL) and filtered to remove the mercury salt, which was washed from the acid. The ether solution was then dried with Na2SO4 and concentrated. The crude product (125 g) was purified by silica gel column chromatography, first eluting with a mixture of hexane/ethyl acetate (10:1) to remove methyl 5-bromo-2-fluorobenzoate, and then eluting with hexane/ethyl acetate (1:1) to give methyl 5-acetyl-2-fluorobenzoate in 75% (90.0 g) yield.
(Dimethoxymethyl)dimethylamine (92 mL, 0.69 mol) was added to a solution of methyl 5-acetyl-2-fluorobenzoate (90.0 g, 0.46 mol) in toluene (90 mL). The mixture was refluxed for 7 hours. During this time the methanol formed was distilled out. The solution was then concentrated in vacuum and the residue (115.2 g) was purified by crystallization to give methyl 5-(3-(dimethylamino)acryloyl)-2-fluorobenzoate as yellow prismatic crystals in 80% yield (93.9 g).
A solution of methyl 5-(3-(dimethylamino)acryloyl)-2-fluorobenzoate (50 g, 0.2 mol), hydrazine hydrate (11.0 g, 0.22 mol) in methanol (500 mL) was allowed to stand for 48 hours at 20°C. The solvent was then evaporated and the residue was purified by chromatography (ethyl acetate/hexane 1:2) on a silica gel column to give 22.0 g of methyl 2-fluoro-5-(1H-pyrazol-3-yl)benzoate, which contained impurities. It was purified by crystallization from ethanol. Methyl 2-fluoro-5-(1H-pyrazol-3-yl)benzoate was obtained as yellow prismatic crystals in 45% yield (19.9 g).
Methyl 2-fluoro-5-(1H-pyrazol-3-yl)benzoate (25.2 g, 0.115 mol) was refluxed in concentrated HCl (150 ml) for 2 hours. The reaction mixture was then cooled and filtered. The isolated precipitate was washed with ethanol, dried, and then refluxed in water (200 mL) for 30 min to remove traces of methyl ester and HCl. cooled and filtered. The isolated precipitate was washed with water and dried to give the title compound in 90.7% yield (21.4 g).
