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EXAMPLE 3 4,6-Dihydroxy-2-trifluoromethylpyrimidine, Compound VI, starting material for Step 2 Sodium hydride (900 g, 57.5% dispersion in mineral oil; 518 g active NaH; 22.5M) was stirred with 7.5 L toluene in a 22 L round-bottomed flask. Butanol was added over 5 hr. so that the pot temperature was maintained at 40. The mixture was stirred an additional 16 hr. Malonamide (765 g; 7.5 M) was added, followed by ethyl trifluoroacetate (1065 g; 7.5 M). The ensuing reaction was exothermic; the mixture was then heated on a steam-bath for 3.5 hrs. It was then stirred at 23-25 for an additional 16 hrs. The mixture was extracted with water (1*4 L and 1*2 L). The combined aqueous extracts were treated with activated charcoal and filtered. The filtrate was maintained at 10-15 as it was acidified to pH 1-2 with 37% hydrochloric acid. The mixture was chilled to 5. The solid was isolated by filtration and dried at 50 in vacuo to give 600 g (44.4% yield) VI m.p. 255-256 (Lit. 265).
To a suspension of 60% NaH in oil (11.7 g) in toluene (98 mL) was added BuOH (21. 8 g). The mixture was stirred at ambient temperature for 16 hr. To the mixture were added malonamide (10.0 g) and trifluoro-acetic acid ethyl ester (13.9 g). The mixture was stirred at 100C for 3.5 hr and ambient temperature for 16 hr. The organic layer was extracted with water (two times) and the aqueous layer was filtrated through activated carbon. To the aqueous layer was added conc. HCI (pH 1) and the suspension was stirred at 4C for 2 hr. The precipitate was collected by filtration and dried at 80C under reduced pressure to give 2-trifluoromethyl-pyrimidine-4, 6-diol (3.25 g). ESI MS m/e 178, M-H+ ;'H NMR (300 MHz, CDC13) 8 6.00 (s, 1 H), 12.48 (brs, 2 H).
-(Trifluoromethyl)pyrimidine-4,6-diol (15) Sodium hydride (57 g of a 60% dispersion in mineral oil, 1430 mmol) was stirred in toluene under nitrogen and cooled with a wet ice bath. Butanol (130 mL, 1430 mmol) was added drop-wise and mixture was stirred for 30 min.Malonamide (50 g, 480 mmol) was added in one portion followed by the drop-wise addition of methyl trifluoroacetate (14) (67.5 g, 475 mmol), which led to an immediate exotherm. When the addition was complete, the reaction mixture was stirred at 40 C overnight and then cooled to RT. The reaction was diluted with 1 N HCI (300 mL) and then concentrated HCI was added until pH = 2. The layers were separated and the aqueous layer was extracted with ethyl acetate (3X), dried over magnesium sulfate, and concentrated. The resulting orange solid was triturated with 2:1 heptane: DCM (2 x 100 mL), collected by filtration, and dried under vacuum overnight to provide 28.1 g of 15 as a light orange solid. LCMS m/z 181.1 (M+1 ). H NMR (400 MHz, CD3OD) δ 5.90 (s, 1 H).
To the reaction flask was added 500 mL methanol, cooled to 0 ~ 5 C, 118.6 g sodium methoxide was added,Stirring until substantially clear, adding 102.1g malonamide, stirring, warmed to 35 ,153.7 g of methyl trifluoroacetate was added, and after completion of the addition, the mixture was stirred for 30 minutes,The temperature was raised to 65 to 70 C and refluxed for 15 hours. After the reaction, cooling to 25 ~ 35 ,100 mL methyl tertiary ether was added dropwise and the temperature dropped to 5 ~ 10 C. After stirring, the filter cake was rinsed with ruthenium ether. After filtration, the solid was transferred to a single-necked flask and concentrated under reduced pressure. Add water, stir until clear, add concentrated hydrochloric acid to adjust pH = 1 ~ 2, filter to obtain filter cake 95g. The filter cake was added with 250 mL of ethyl acetate, heated to reflux, stirred, filtered and concentrated under reduced pressure to constant weight to give 118.4 g of an off-white solid in a yield of 65.8% and HPLC of 94.3%.
2-(6-trifluoromethyl-pyridin-2-yl)-1H-pyrimidine-4,6-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium; In ethanol; for 1h;Reflux;
Step 1: Preparation of 2-(6-Trifluoromethyl-pyridin-2-yl)-1H-pyrimidine-4, 6-dione To a solution of sodium (32 g, 0.16 mol) in ethanol (500 mL) was added 6-trifluoro- methylpyridine-2-carboxylic acid methyl ester (6.15 g, 3 mmol) and malonamide (1.02 g, 1 mmol). The mixture was heated to reflux for 1 hour, then concentrated to give a residue which was poured to water (100 mL). Saturated NaHCO3 solution was added to adjust to pH 7, the mixture was filtered, and then added iN HC1 solution to adjust pH to 3. DCM (20 mL) was added, and the precipitated solid was collected by filtration and dried to give 2-(6-trifluoromethyl-pyridin-2-yl)- 1 H-pyrimidine-4,6-dione. LCMS: [M+ 1] = 257.9
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