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Substituted diaryl ester compound, and preparation method and application thereof

A technology of compound and diaryl ether, which is applied in the field of substituted diaryl ether compounds and their preparation, can solve problems such as severe adverse reactions of myocardial infarction, achieve the effect of inhibiting malignant proliferation phenotype and promoting expression

Inactive Publication Date: 2014-11-26
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But sorafenib is often accompanied by a higher incidence of mild and moderate adverse reactions such as rash, diarrhea and oral ulcers, and severe adverse reactions of myocardial infarction (Lin Lin et al., Journal of Clinical Oncology, 2009, 14 (4): 366-368)

Method used

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  • Substituted diaryl ester compound, and preparation method and application thereof
  • Substituted diaryl ester compound, and preparation method and application thereof
  • Substituted diaryl ester compound, and preparation method and application thereof

Examples

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preparation example Construction

[0041] The preparation method of substituted diaryl ether compound of the present invention, its reaction process is as follows:

[0042]

[0043] That is, under the action of a base, the substituted halogenated benzene or substituted aniline shown in the compound (II) is reacted with the substituted ethyl benzoate shown in the compound (III) to generate the compound (IV), and the compound (IV) is hydrolyzed or Condensation reaction with substituted amine after acid chlorination to obtain compound (I), namely the substituted diaryl ether compound of the present invention.

[0044] Concretely include the following steps:

[0045] (1) The synthetic method of intermediate acid:

[0046]

[0047] (2) The synthesis method of the target compound, including two kinds of A and B, wherein A is as follows:

[0048]

[0049] B is as follows:

[0050]

Embodiment 1

[0052] Example 1: Synthesis of 4-(4-fluorophenoxy)benzoic acid (B1)

[0053]

[0054] 1.0mL (8.9moL) of 1-fluoro-4-iodobenzene, 1.85g (13.4moL) of p-hydroxybenzoic acid, 170mg (0.9mmoL) of cuprous iodide, and 276mg (2.7mmoL) of N,N-dimethylglycine Dissolve 5.81g (17.8moL) of cesium carbonate in 25mL of 1,4-dioxane, heat and stir at 90°C for 24 hours under the protection of argon. After the reaction was completed, the solvent was evaporated under reduced pressure, water was added, and ethyl acetate was extracted three times. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed and separated by silica gel column chromatography (ethyl acetate:petroleum ether=1:30) to obtain a yellow liquid. 1.0 g (4.1 moL) of the synthesized ethyl 1-fluoro-4-phenoxybenzoate was dissolved in 8 mL of ethanol and 8 mL of water, 1.82 g (4.5 moL) of sodium hydroxide was added, and heated to reflux for 3 hours. After completion of the r...

Embodiment 2

[0057] Embodiment 2: the synthesis (B2) of 4-phenoxybenzoic acid

[0058]

[0059] The synthesis method of Example 1 above gave B2 white solid, and the two-step yield was 87%.

[0060] 1 H NMR (600MHz, DMSO-d 6 )δ: 7.02(d, J=8.8Hz, 2H), 7.11(d, J=7.7Hz, 2H), 7.23(t, J=7.3Hz, 1H), 7.45(t, J=7.5Hz, 2H) , 7.95 (d, J=8.8Hz, 2H), 12.82 (br s, 1H) ppm;

[0061] 13 C NMR (150MHz, DMSO-d 6 )δ: 117.2, 119.9, 124.7, 125.2, 130.3, 131.7, 155.1, 161.0, 166.8ppm.

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Abstract

The invention discloses a substituted diaryl ether compound. The structural formula of the compound is shown in the specification. In the structural formula, Z is -CH- or -N-; W is -CH-or -N-; Y is -O-, -CH2-, -NH- or -NRy-; R1 is one of hydrogen, halogen, NO2, CN, CF3, ORa, CORa, COORa, SO2Ra, SO2NRaRb, NRaRb, NRaCORb, a non-substituted / substituted C1-C4 alkyl group, a non-substituted / substituted aryl group and a non-substituted / substituted heterocyclic group; R2 is hydrogen, a non-substituted / substituted C1-C4 alkyl group, or halogen; and R is one of a non-substituted / substituted C1-C12 alkyl group, a non-substituted / substituted C3-C12 cycloalkyl group, a non-substituted / substituted C2-C12 alkenyl group, a non-substituted / substituted aryl group, substituted alkylamine, and a non-substituted / substituted heterocyclic group. The substituted diaryl ether compound can obviously inhibit the malignant proliferation phenotype of cancer cells, promotes the expression of cell apoptosis factor proteins, and provides a new potential anticancer drug.

Description

technical field [0001] The invention belongs to the field of chemical medicines, and in particular relates to a substituted diaryl ether compound and its preparation method and application. Background technique [0002] Malignant tumor is a common and frequently-occurring disease that seriously threatens human health. It is a major scientific research topic in the field of medical science in all countries in the world. At present, there are no satisfactory prevention and control measures. About 7 million people die of cancer in the world every year, accounting for about a quarter of the total death toll. Among the three major therapies for malignant tumors (surgery, chemotherapy and radiotherapy), chemotherapy is still an important method for clinical treatment. The selectivity of anticancer drugs to cancer cells and normal human cells is not much different, so the adverse reactions in the application process are extensive and serious. In addition, easy drug resistance is ...

Claims

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Application Information

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IPC IPC(8): C07C235/50C07D295/13C07C235/54C07C235/56C07C255/60C07C231/02C07C253/30A61P35/00
Inventor 李福男李善花王利娟杨少梅侯瑾黄志宁郑满意姜吉利陈秋月
Owner XIAMEN UNIV
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