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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

Active Publication Date: 2021-03-23
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Cytotoxic drugs are still the mainstay of tumor treatment drugs at present, but there are problems such as poor curative effect on solid tumors, large adverse reactions, and easy drug resistance.

Method used

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  • A kind of triazole-modified 5-fluoro-2,4-pyrimidinediamine compound and its application
  • A kind of triazole-modified 5-fluoro-2,4-pyrimidinediamine compound and its application
  • A kind of triazole-modified 5-fluoro-2,4-pyrimidinediamine compound and its application

Examples

Experimental program
Comparison scheme
Effect test

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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Abstract

The invention discloses a triazole modified 5-fluoro-2,4-pyrimidine diamine compound, and applications thereof. According to the invention, the compound represented by a formula (I) has a certain inhibition effect on HepG-2 cell strains, A549 cell strains, HL-60 cell strains and K-562 cell strains, has good anti-tumor activity, and provides a basis for new drug screening. The invention provides apreparation method of the compound represented by the formula (I), wherein the preparation method is simple, and industrial production is facilitated.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a triazole-modified 5-fluoro-2,4-pyrimidinediamine compound, a preparation method thereof, and an application thereof in the preparation of antitumor drugs. Background technique [0002] The treatment of cancer has always been a worldwide problem, and anti-tumor drugs are also in constant progress, mainly including cytotoxic anti-tumor drugs, anti-tumor drugs targeting cell signal transduction molecules, and secondly, angiogenesis Inhibitors, resistance reversal agents, antisense drugs, telomerase inhibitors, etc. Cytotoxic drugs are still the mainstay of tumor treatment drugs at present, but there are problems such as poor curative effect on solid tumors, large adverse reactions, and easy drug resistance. In recent years, with the completion of human genome sequencing and the continuous understanding and elaboration of the molecular biological mechanisms of tumor cell growth, prolifera...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12C07D239/42C07D239/48A61K31/5377A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D239/42C07D239/48C07D403/12
Inventor 周卫张倩张文
Owner ZHEJIANG UNIV OF TECH
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