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2-(3,4-Dimethoxy)benzoyl-5-(4-substituted phenylethynyl) thiophene as well as preparation method and application thereof

A benzoyl and dimethoxy technology, applied in pharmaceutical formulations, medical preparations containing active ingredients, organic active ingredients, etc., can solve the problem of easily causing cardiotoxicity, inappropriate use of this treatment, and inaccurate treatment duration. It can achieve the effect of low cost and obvious inhibition of proliferation.

Active Publication Date: 2014-07-02
SOUTHERN MEDICAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

However, trastuzumab also has its own defects and limitations. For example, it can only be used for HER2-positive patients, and more than 3 / 4 of the patients do not express HER2 protein, so it is not suitable for this treatment; in addition, the duration of treatment is uncertain. sex; easy to cause cardiotoxicity, etc.

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  • 2-(3,4-Dimethoxy)benzoyl-5-(4-substituted phenylethynyl) thiophene as well as preparation method and application thereof
  • 2-(3,4-Dimethoxy)benzoyl-5-(4-substituted phenylethynyl) thiophene as well as preparation method and application thereof
  • 2-(3,4-Dimethoxy)benzoyl-5-(4-substituted phenylethynyl) thiophene as well as preparation method and application thereof

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preparation example Construction

[0030] The preparation method of 2-(3,4-dimethoxy)benzoyl-5-(4-substituted phenylethynyl)thiophene comprises the following steps:

[0031] 1) In the presence of a catalyst, fully react 2-bromothiophene and 3,4-dimethoxybenzoyl chloride in a solvent, add acid after the reaction, remove the solvent, and extract the residue with an organic extractant The extractant layer is obtained, washed with water, and then the extractant layer is dried with a desiccant to remove the organic extractant in the extractant layer, and the residue is separated and purified to obtain 2-(3,4-dimethoxy)benzoyl-5 - Bromothiophene;

[0032] 2) In the presence of tetrakis(triphenylphosphine)palladium, CuI, and acid-binding agent, 2-(3,4-dimethoxy)benzoyl-5-bromothiophene, 4-substituted phenylacetylene Fully react in an organic solvent, remove the solvent after the reaction is completed, and separate and purify the residue to obtain the product.

[0033] In step 1), the molar ratio of 2-bromothiophene ...

Embodiment 1

[0044] The preparation method of described 2-(3,4-dimethoxy)benzoyl-5-(4-substituted phenylethynyl)thiophene comprises the following steps:

[0045]1) Dissolve 1 mmol of 2-bromothiophene in 5 ml of dry dichloromethane, add 1.5 mmol of anhydrous aluminum trichloride, and drop 1 mmol of 3,4-dimethoxybenzoyl chloride (dissolved in 3 ml of dichloromethane). During the dropwise addition, nitrogen protection was applied, and after the addition was completed, the temperature was raised to room temperature and stirred for 6 h. After the reaction is completed, add 20 wt% dilute hydrochloric acid to decompose aluminum trichloride, remove the solvent under reduced pressure, extract the residue with ethyl acetate, and wash with water. The organic layer was dried with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated and purified by column chromatography to obtain a solid with a yield of 78%;

[0046] 2) Dissolve 1 mmol 2-(3,4-dimetho...

Embodiment 2

[0050] Synthesize the compound of the present invention according to the method for above-mentioned embodiment 1, when the substituting group R in the 4-substituted phenylacetylene is respectively H, CH 3 、CH 3 CH 2 , OCH 3 , Br, the productive rate of product is as follows:

[0051] Table 1:

[0052]

[0053] The following are the NMR data and mass spectrometry data of the five compounds:

[0054] 1. 2-(3,4-dimethoxy)benzoyl-5-(phenylethynyl)thiophene

[0055] Yield: 78 %; mp 102-103 °C; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 4.0 Hz, 1H), 7.57 (m, 2H), 7.39 (m, 3H), 7.30 ( d, J = 4.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 3.96 (s, 3H), 3.94 ( s, 3H). 13C NMR (101 MHz, CDCl3) δ 186.2, 153.0, 143.4, 142.0, 134.1, 132.1, 131.5, 129.1, 128.4, 122.0, 106.7, 96.8, 60.9, 56.3. ESI-MS: m / z 349.3 ([M+H]+).

[0056] 2. 2-(3,4-dimethoxy)benzoyl-5-(4-methylphenylethynyl)thiophene

[0057] Yield: 75 %; mp 104-105 °C; 1H NMR (400 MHz, C...

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Abstract

The invention discloses a 2-(3,4-dimethoxy)benzoyl-5-(4-substituted phenylethynyl) thiophene. The structural formula of the 2-(3,4-dimethoxy)benzoyl-5-(4-Substituted phenylethynyl) thiophene is as shown in the specification. The preparation method of the 2-(3,4-dimethoxy)benzoyl-5-(4-Substituted phenylethynyl) thiophene comprises the following steps: 1) reacting 2-bromothiophene with 3,4-dimethoxybenzoyl in a solvent in the presence of a catalyst and then carrying out purification and separation to obtain 2-(3,4-dimethoxy)benzoyl-5-bromothiophene; 2) reacting the 2-(3,4-dimethoxy)benzoyl-5-bromothiophene with 4-substituted phenylacetylene in a solvent in the presence of tetra(triphenylphosphine) palladium, CuI and an acid-binding agent, and then carrying out subsequent purification and separation. The invention also relates to application of the compound in preparation of anti-breast cancer targeted treatment drugs, and an application of the compound in preparation of anti-breast cancer resistance-reversal agents. The compound has relatively obvious proliferation inhibition effect on human breast cancer cells and breast cancer cell drug-resistant strains, and thus can be applied to preparation of the anti-breast cancer targeted treatment drug and the anti-breast cancer resistance-reversal agent. The compound has the potential of large-scale industrial production and relatively low cost.

Description

technical field [0001] The invention relates to 2-(3,4-dimethoxy)benzoyl-5-(4-substituted phenylethynyl)thiophene and its preparation method and application. Background technique [0002] Breast cancer, called "Ruyan" in ancient Chinese medicine, is one of the most common malignant tumors that seriously affects women's physical and mental health and even threatens their lives. Recently, my country's first large-scale breast cancer epidemic research project initiated by the China Cancer Foundation showed that the age of onset of breast cancer in my country tends to be younger, and the median age of onset of female breast cancer is 48 years old, earlier than in Western countries 10 years. Breast cancer is now one of the greatest threats to women's health. [0003] There are many factors that cause breast cancer. Although genetic factors (breast cancer susceptibility genes BRCA1 and BRCA2) have a certain impact, the incidence of breast cancer is mainly attributed to environmen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/22A61K31/381A61P35/00
CPCC07D333/22
Inventor 吕琳陈之朋吴少瑜杨光饶进军王文雅杨迎暴赵想玲
Owner SOUTHERN MEDICAL UNIVERSITY
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