Meta-diaryl-multi-substituted pyrimidine derivatives and its preparation method and application
A multi-substitution, pyrimidine-based technology, applied in the field of medicine, can solve the problems of easy mutation, spread, and reduction of clinical potency of amino acids
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Embodiment 1
[0045] Example 1: N-(4'-cyanophenyl)-2-(2',6'-dimethyl-4'-cyano-phenoxy)-5-nitropyrimidine (Ia-1) preparation of
[0046] 2,4-dichloro-5-nitropyrimidine (Ⅱ) (0.39g, 2mmol) in tetrahydrofuran (15mL) under ice bath magnetic stirring, slowly drop 4-aminobenzyl acetonitrile (Ⅲ) and triethylamine in tetrahydrofuran solution (15 mL). The reaction was kept at 0°C and stirred for 3 hours, and then turned to room temperature. TLC monitored the reaction process. After the reaction was complete, the solvent was evaporated under reduced pressure, 20 mL of water was added, extracted with dichloromethane for 3 times, the organic phase was dried over anhydrous sodium sulfate, and filtered. Concentrate and purify by flash column chromatography to obtain the key intermediate IV. Yellow solid, yield 65.0%, MS (ESI): m / z 276.2 (M+1), 278.2 (M+3), C 11 h 6 ClN 5 o 2 (275.65).
[0047] Dissolve 0.15g (0.5mmol) of intermediate IV, 0.15g potassium carbonate (1.0mmol) and 0.096g 2,6-dimethyl-4...
Embodiment 2
[0048] Example 2: N-(4'-cyanophenyl)-2-(2',6'-dimethyl-4'-cyano-phenoxy)-5-aminopyrimidine (Ib-1) preparation
[0049] 0.5 g of N-(4'-cyanophenyl)-2-(2',6'-dimethyl-4'-cyano-phenoxy)-5-nitropyrimidine prepared by the above method (Ia-1) (1.2 mmol) and 0.1 g of palladium carbon (10%) were placed in a 100 ml round bottom flask, and 30 mL of ethanol was added thereto. After evacuating the reaction system for 3 times, hydrogen gas was introduced, and the hydrogen gas was kept in excess during the whole reaction process. After 15 hours of reaction, the reaction solution was filtered under reduced pressure and concentrated. The concentrated solution was washed with petroleum ether, filtered again under reduced pressure, and the filter cake was dried in air to obtain the target compound Ib-1. White solid, yield: 70.4%.mp: 218-221℃. 1 H NMR (400MHz, DMSO-d 6 ,ppm)δ:8.93(s,1H,NH),7.72(s,3H,C 6 -pyrimidine-H,Ph-H),7.63(d,2H,J=8.80Hz,2H,Ph'-H),7.56(d,2H,J=8.80Hz,2H,Ph'-H),4.93( s,2...
Embodiment 3
[0050] Example 3: N-(4'-cyanophenyl)-2-(2',6'-dimethyl-4'-cyano-phenoxy)-5-trifluoroacetylpyrimidine (Ic- 1) Preparation
[0051] 0.2g of N-(4'-cyanophenyl)-2-(2',6'-dimethyl-4'-cyano-phenoxy)-5-aminopyrimidine (Ib- 1) (0.5mmol) and triethylamine (1.0mmol) tetrahydrofuran solution (15mL) under ice bath magnetic stirring, slowly drop trifluoroacetic anhydride (0.6mmol), keep the temperature for 5 hours, TLC monitoring after the reaction is complete The solvent was evaporated under reduced pressure, 20 mL of water was added, extracted three times with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash column chromatography to obtain the target product Ic-1. White solid, yield: 56.5%.mp:255-257℃. 1 H NMR (400MHz, DMSO-d 6 ,ppm)δ:9.25(s,1H,C 6 -pyrimidine-H),8.18(d,J=8.44Hz,2H,Ph'-H),7.94(d,J=8.44Hz,2H,Ph'-H),7.67(s,2H,Ph-H) ,2.13(s,6H,2×CH 3 ). 13 C-NMR (100MHz, DMSO-d 6 , ppm) δ: 161.82 (C 2 -pyrimidine...
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