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2-trifluoromethyl-4-aminoquinazoline compound and application thereof

A technology of aminoquinazoline and trifluoromethyl, which is applied in the field of quinazoline compounds to achieve the effects of improving druggability, increasing biological activity, and increasing the probability of interaction

Pending Publication Date: 2022-05-06
THE KEY LAB OF CHEM FOR NATURAL PROD OF GUIZHOU PROVINCE & CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are very few public reports and applications of 2-trifluoromethyl-4-aminoquinazoline compound types and anti-tumor aspects.

Method used

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  • 2-trifluoromethyl-4-aminoquinazoline compound and application thereof
  • 2-trifluoromethyl-4-aminoquinazoline compound and application thereof
  • 2-trifluoromethyl-4-aminoquinazoline compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1: the synthesis of intermediate M3:

[0031]

[0032] Take 12g (14.7mmol) of anthranilamide S (14.7mmol) and 2.44g (17.6mmol) of potassium carbonate in a reaction flask, add 15mL of anhydrous dichloromethane, and slowly drop in 2.17mL (15.4mmol) of trifluoroacetic anhydride under stirring in an ice-water bath , continue to stir until the reaction is complete, add 15 mL each of dichloromethane and water, extract, dry the organic phase with anhydrous magnesium sulfate, and evaporate to dryness under reduced pressure. The resulting crude product is purified by silica gel column chromatography to obtain 2.98 g of white solid M1, and the yield is 87.4%. 1 H NMR (600MHz, DMSO-d 6)δ13.70(s,1H),8.55(s,1H),8.40(dd,J=8.3,0.7Hz,1H),8.03(s,1H),7.97(dd,J=7.9,1.3Hz,1H ), 7.63 (t, J=7.8Hz, 1H), 7.32 (t, J=7.6Hz, 1H). Take 12g (8.60mmol) of intermediate M and 483mg (8.60mmol) of potassium hydroxide in a reaction flask, add 20mL of acetonitrile, stir at 80°C for 4h unt...

Embodiment 2

[0033] Embodiment 2: the synthesis of compound A1:

[0034]

[0035] Take 120mg (1.29mmol) of aniline and 330mg (1.42mmol) of intermediate M3 in a reaction flask, add 4mL of isopropanol and 218μL (2.58mmol) of concentrated hydrochloric acid, stir at 80°C for 6h until the reaction is complete, and solids precipitate out after the reaction solution is cooled , suction filtration, the filter cake was washed with petroleum ether, and dried to obtain 351 mg of white solid M4, with a yield of 94.1%. 1 H NMR (600MHz, DMSO-d 6 )δ10.41(s,1H),8.80(d,J=8.2Hz,1H),7.98(t,J=7.5Hz,1H),7.95–7.89(m,3H),7.79(t,J=7.5 Hz, 1H), 7.43 (t, J = 7.9Hz, 2H), 7.19 (t, J = 7.4Hz, 1H). Take 180 mg (622 μmol) of intermediate M4 in a reaction flask, add 5 mL of anhydrous DMF, add 30 mg (1.24 mmol) of sodium hydrogen in an ice-water bath with stirring, stir until no bubbles are generated, then inject 77 μL (1.24 mmol) of methyl iodide, and slowly rise to Stir at room temperature overnight until the reac...

Embodiment 3

[0036] Example 3: Synthesis of Compound A2: Referring to the preparation of A1 in Example 2, 4-difluoromethoxyaniline was used instead of aniline to obtain a white solid with a yield of 85.3%. 1 H NMR (600MHz, DMSO-d 6 )δ7.91(d,J=8.3Hz,1H),7.78(ddd,J=8.3,7.0,1.2Hz,1H),7.50–7.44(m,2H),7.44–7.17(m,4H),6.97 (d,J=8.0Hz,1H),3.60(s,3H). 13 C NMR (151MHz, DMSO-d 6 )δ162.14,151.19(q,J=34.7Hz),150.93,150.11(t,J=3.3Hz),144.18,133.85,129.23,128.38,127.59,126.34,120.81,120.42(q,J=275.6Hz),118.40 ,116.69,116.20,114.98. 19 F NMR (565MHz, DMSO-d 6 )δ-69.40,-82.46.

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PUM

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Abstract

The invention discloses a 2-trifluoromethyl-4-aminoquinazoline compound and application thereof, and the compound has a structural formula as shown in the following general formula I. According to the invention, trifluoromethyl is introduced to a 2-site of a 4-aminoquinazoline compound, and 4-amino is modified, so that the 2-trifluoromethyl-4-aminoquinazoline compound is obtained. A series of 2-trifluoromethyl-4-aminoquinazoline derivatives with novel structures are designed and synthesized by taking 2-trifluoromethyl-4-aminoquinazoline as a raw material, the probability of interaction between the compound and a target is increased, the biological activity and chemical stability of the compound are improved, and the druggability of the compound is improved, so that the 2-trifluoromethyl-4-aminoquinazoline compound has efficient and broad-spectrum anti-tumor activity.

Description

technical field [0001] The invention relates to a quinazoline compound, especially a 2-trifluoromethyl-4-aminoquinazoline compound and application thereof. Background technique [0002] Tumor is one of the factors that seriously endanger human health and is the second leading cause of human death. The current treatment of tumors is mainly based on surgery, radiotherapy, chemotherapy and immunotherapy, and chemotherapy is one of the most effective ways to treat malignant tumors. , specificity and some toxic side effects, multi-drug resistance and other problems, resulting in the current anti-tumor drugs are far from meeting the clinical needs. [0003] Quinazoline alkaloids are a class of benzopyrimidine nitrogen-containing heterocyclic compounds that widely exist in nature and have various pharmacological and biological activities. As an advantageous structure for drug development, quinazoline skeletons have been widely used in the field of antineoplastic drug research, an...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07D405/12C07D403/12C07D401/12C07D409/12C07D239/93C07D239/90C07D403/04A61K31/517A61K31/5377A61P35/00A61P35/02
CPCC07D239/94C07D405/12C07D403/12C07D401/12C07D409/12C07D239/93C07D239/90C07D403/04A61P35/00A61P35/02
Inventor 徐必学骆衡余刚余佳孟雪玲曾晓萍吴辉韦娇梅
Owner THE KEY LAB OF CHEM FOR NATURAL PROD OF GUIZHOU PROVINCE & CHINESE ACADEMY OF SCI
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