1-[[2-Fluoro-6-(trifluoromethyl)phenyl]methyl]-6-methyl-2,4(1H,3H)-pyrimidinedione

(2-Fluoro-6-trifluoromethyl-benzyl)-urea (2.568 g, 10.9 mmol) in toluene (125 niL) was heated briefly to reflux under a Dean-Stark trap. T-butyl acetoacetate (5.0 g) was added and the mixture heated to reflux for 4 hrs. p-Toluenesulfonic acid monohydrate (2.82 g, 14.8 mmol) was added and the reflux was continued for one additional hour. Toluene was displaced with i-PrOH and the volume of the solution was reduced to approximately 30 mL. The solution was stirred overnight at room temp. The crystalline product was filtered and washed with a few mL of i-PrOH to provide 2.01 g (63percent yield) of l-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-lH-pyrimidine-2, 4-dione. LCMS (ESI) m/z 303.0 (MH+)2-Fluoro-6-(trifluoromethyl)bromobenzyl (2.0 g), tert-butyl 4-methyl-2, 6-dioxo-2, 3-dihydropyrimidin-1 (6H)-carboxylic acid tert-butyl ester (1.81 g), A 100 mL flask of dimethyl sulfoxide (40 ml), and potassium carbonate (2.34 g) was stirred at 0 C to 10 C for 4 h. Ethyl acetate and a water layer were added to the reaction system, the upper organic layer was left, the organic layer was washed with brine, and the organic layer was concentrated. 30 ml of dichloromethane was added to the concentrate, and the mixture was heated to 30 C to 40 C by adding trifluoroacetic acid (2.0 g). Reaction 4h, systemThe organic layer was extracted with a saturated aqueous solution of sodium bicarbonate, and the aqueous layer was extracted with 20 ml of dichloromethane. The organic layer was washed with brine, and the organic layer was washed with methyl t-butyl ether and dried to give the product 2.23 g. The product content of formula IV is 97.6%, the IV-imp content is 1.0%, and the yield is 95.0%.Operation step: in a reactor, 1.0 g, 1.0 equiv. of (2-fluoro-6-(trifluoromethyl)phenyl)methanol as shown in Formula V, 1.2 equiv. as shown in Formula VI 6-methyluracil was dissolved in 10 mL of THF, and 1.5 equiv. of triphenylphosphine was added sequentially at room temperature. 1.5 equiv. DIAD, followed by reaction at room temperature for 5 h;After the reaction is completed, a mixture of ethyl acetate and 1N aqueous hydrochloric acid is used as a detergent washing reaction mixture, and the organic phase is separated, and then the organic phase is washed with a saturated aqueous solution of sodium hydrogencarbonate and brine.Then dry with sodium sulfate and spin dry the solvent.Finally, by column chromatography, a polysubstituted pyrimidine derivative of the formula I was obtained in a yield of 89%. The detection was performed by high resolution mass spectrometry (ESI+) with a detection value of 303.0758; the high resolution mass spectrum of M+H+ was calculated to be 303.0751, and the product structure was confirmed by comparison.6.13 g of l-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2.4(lH, 3H)-dione, 10.23 g of (R)-2-((tert-butoxycarbonyl)amino)-2-phenylethyl methanesulfonate and 7 g of potassium carbonate were suspended in 72 ml of DMF under the stream of Argon. The mixture was heated to 50-55 C. The mixture was stirred at this temperature for 23 hours. To the reaction mixture 100 ml of water and 100 ml of methyl tert-butyl ether were added. Layers were separated and the aqueous phase was extracted with 2 x 50 ml of methyl tert- butyl ether. The combined organic phases were washed with 70 ml of water and 70 ml 2 M of aqueous NaOH. The organic phase was concentrated to approx. 1/5 of the original volume. To this solution 25 ml of n-heptane was added in the course of 20 minutes. After few minutes the solid started forming. The mixture was stirred for 30 min. 25 ml of heptane was added and the suspension was filtered. The solid was dried under vacuo at room temperature to provide 10.02 g (95% of the theoretical yield) of compound (4) (purity 98.3%. HPLC IN).To a 50 mL round botom flask was added DMF (5 mL), compound V (1 g) and compound VII (1.07 g). The reaction mixture was heated to 140 °C for 0.5 h. After completion of the reaction, H O (15 mL) was added to the reaction mixture at 50~60°C. The resulting suspension was filtered. The cake was washed with EtOH (1 mL) to give the product as a white solid (1.05 g, 67percent yield, 98.6percent purity).

Molecular Weight:302.22
XLogP3:2.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:2
Exact Mass:302.06784021
Monoisotopic Mass:302.06784021
Topological Polar Surface Area:49.4
Heavy Atom Count:21
Complexity:475
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes