3-(5-Aminopyrimidin-4-yl)benzoic acid synthesis

Yield:856905-14-1 94%

Reaction Conditions:

Stage #1: 3-pyrimidin-4-yl-benzoic acid methyl esterwith sodium methylate in ethanol; for 0.5 h;Heating / reflux;
Stage #2: with hydrogenchloride in water; pH=~ 2;

Steps:

21

Methyl 3-bromobenzoate (110 g, 0.51 mol), dry acetonitrile (500 mL), ethynyl(trimethyl)silane (60.0 g, 0.61 mol), diisopropylamine (62.0 g, 0.61 mol) and tetra(triphenylphosphine)palladium (23.6 g, 0.02 mol) were placed under an atmosphere of argon in a three-necked round-bottomed 1 liter flask, equipped with a magnetic stirrer and a thermometer. The mixture was stirred for 30 minutes and then cooled to 10 ⁰C. Copper iodide (9.7 g, 0.06 mol) was added, and the obtained suspension was stirred for a further 2.5 hours at 20 ⁰C and finally for 3 hours at 60 ⁰C. Then the mixture was left to stand at room temperature overnight and filtered. The precipitate of hydrobromide was washed with ether, and the combined filtrate was washed with saturated aqueous solutions of NH₄CI and NaCI, dried over Na₂SO₄ and evaporated. The crude product was purified by chromatography (hexane) on a silica gel column to give methyl 3-(2- (trimethylsilyl)ethynyl)benzoate in 95% (112.8 g) yield.A suspension of methyl 3-(2-(trimethylsilyl)ethynyl)benzoate (112.8 g, 0.48 mol), mercury(2+) diacetate (16.2 g, 0.005 mol) in THF (350 mL) and concentrated H₂SO₄ (40 mL) was stirred at 60 ⁰C for 3 hours. Then the mixture was cooled, diluted with ether (500 mL), filtered to remove precipitated mercury salts and washed to obtained neutral medium. Then the solution was dried over Na₂SO₄ and evaporated. The residue was purified by chromatography (hexane/ethyl acetate 4:1) on a silica gel column to give methyl 3-acetylbenzoate in 75% (65.2 g) yield.(Dimethoxymethyl)dimethylamine (90 mL) was added to a suspension of methyl 3-acetylbenzoate (65.2 g, 0.27 mol) in toluene (90 mL). The mixture was refluxed for 9 hours, during which time forming methanol was distilled off. The solution was then concentrated in vacuo, and the residue was purified from ether by crystallization to give methyl 3-(3-(dimethylamino)acryloyl)benzoate as yellow prismatic crystals in 80% (68.1 g) yield. ' . lmidoformamide acetate (20.3 g, 0.19 mol) was added to a suspension of methyl 3-(3- (dimethylamino)acryloyl)benzoate (30.3 g, 0.13 mol) in toluene (300 mL). The reaction mixture was refluxed for 20 hours, during which time toluene and dimethylamine acetate were distilled off_* Then imidoformamide acetate (6.7 g) and toluene (175 mL) were added again, and after 8 hours the mixture was evaporated in vacuo. The residue was purified by chromatography (ethylacetate/hexane 3:1) on a silica gel column to afford methyl 3-(pyrimidin-4-yl)benzoate in 70% (19.5 g) yield.A suspension of methyl 3-(pyrimidin-4-yl)benzoate (19.5 g, 0.091 mol), sodium methylate (7.6 g, 0.14 mol) in ethanol (250 mL) was refluxed for 30 minutes. Then the reaction mixture was cooled, and the formed-precipitate was separated by filtration was dissolved in water. The obtained solution was acidified with concentrated HCI to pH about 2 that caused precipitation. The precipitate was separated by filtration, washed with water and dried to give the title compound as crystals in 94% (17.2 g) yield.

References:

WO2008/65508,2008,A1 Location in patent:Page/Page column 37-38