A kind of triazole-modified 5-fluoro-2,4-pyrimidinediamine compound and its application
A compound and catalyst technology, applied in the field of preparation of anti-tumor drugs, can solve the problems of large adverse reactions and poor curative effect of solid tumors, and achieve good anti-tumor activity
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Embodiment 1
[0100] Embodiment 1: Preparation of N-propargyl-5-fluoro-2-chloropyrimidin-4-amine (IV-1)
[0101]
[0102] Add 5-fluorouracil (3.9g, 0.03mol) and phosphorus oxychloride (27g, 0.18mol) into a 100ml three-necked flask, stir, and after the temperature rises to 90°C, start to add xylidine (7.27g, 0.06mol) dropwise ), after about 0.5h of dripping, continue to heat up to 95°C, and keep the temperature for 15h. After the reaction is completed, slowly add 30ml of ice water dropwise under ice bath conditions, control the temperature of the system not to exceed 30°C, stir for 1h, then extract with dichloromethane, wash the organic layer with water, dry over anhydrous sodium sulfate, and distill under reduced pressure to remove solvent to obtain a yellow liquid, which gradually formed crystals of the compound of formula (VI-1) (2.79 g, yield 56.0%) after refrigerated storage, m.p.38-39°C.
[0103] In a test tube reactor was added 5-fluoro-2,4-dichloropyrimidine (0.166 g, 1 mmol), pr...
Embodiment 2
[0105] Example 2: Preparation of N-propargyl-2-morpholinyl-5-fluoropyrimidin-4-amine (Ⅱ-1)
[0106]
[0107] In a test tube reactor was added N-propargyl-5-fluoro-2-chloropyrimidin-4-amine (IV-1) (0.185 g, 1 mmol), morpholine (0.0871 g, 1 mmol), K 2 CO 3 (0.207g, 1.5mmol) and 2ml DMF, placed in an oil bath at 100°C for 18h. Add 30ml of ethyl acetate to the reaction solution, wash with 30ml of water three times, dry the organic layer with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and use petroleum ether / ethyl acetate (V / V=6 / 1) as eluent The compound of formula (II-1) (0.155 g, yield 66.0%) was obtained as a light yellow solid product by silica gel column chromatography.
[0108] m.p.106-108℃; 1 H NMR (500MHz, CDCl 3 )δ7.78(d,J=3.1Hz,1H),7.28(s,1H),5.11(s,1H),4.24(dd,J=5.5,2.5Hz,2H),3.78–3.72(m,4H ), 3.73–3.66 (m, 4H), 2.26 (t, J=2.5Hz, 1H).
Embodiment 3
[0109] Example 3: Preparation of N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-morpholino-5-fluoropyrimidin-4-amine (Ⅰ -1)
[0110]
[0111] Add N-(propargyl)-2-morpholinyl-5-fluoropyrimidin-4-amine (II-1) (0.235 g, 1 mmol) and phenyl azide (III-1) ( 0.179g, 1.5mmol), copper sulfate pentahydrate (0.050g, 0.2mmol), sodium ascorbate (0.0792g, 0.4mmol) and 2ml solvent (volume ratio DMF:H 2 O=1:1), placed in an oil bath at 70°C for 6 hours. Add 30ml of ethyl acetate to the reaction solution, wash with 30ml of water 3 times, dry the organic layer with anhydrous sodium sulfate, distill off the solvent under reduced pressure, use dichloromethane / methanol (V / V=20 / 1) as eluent The compound of formula (I-1) (0.281 g, yield 79.2%) was obtained as a white solid product by silica gel column chromatography.
[0112] m.p.159-161℃; 1 H NMR (500MHz, CDCl 3 )δ7.93(s,1H),7.78(d,J=3.1Hz,1H),7.73–7.68(m,2H),7.72–7.69(m,2H),7.53(m,2H),5.60(s , 1H), 4.85 (d, J=5.8Hz, 2H), 3.76–3.74 (m, 4H), ...
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