2-(3,4-dimethoxy)benzoyl-5-(4-substituted phenylethynyl)thiophene and its preparation method and application

A benzoyl and dimethoxy technology, applied in the direction of pharmaceutical formulations, medical preparations containing active ingredients, organic active ingredients, etc., can solve the problem of cardiotoxicity, inappropriate treatment, and inaccurate treatment duration Sexuality and other issues, to achieve the effect of significantly inhibiting proliferation and low cost

Active Publication Date: 2015-12-30
SOUTHERN MEDICAL UNIVERSITY
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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 and its preparation method and application
  • 2-(3,4-dimethoxy)benzoyl-5-(4-substituted phenylethynyl)thiophene and its preparation method and application
  • 2-(3,4-dimethoxy)benzoyl-5-(4-substituted phenylethynyl)thiophene and its preparation method and application

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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 1mmol of 2-bromothiophene in 5ml of dry dichloromethane, add 1.5mmol of anhydrous aluminum trichloride, add dropwise 1mmol of 3,4-dimethoxybenzoyl chloride (dissolved in 3ml of dichloromethane) at 0oC solution. 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 hours. 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 1mm...

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%; mp102-103°C; 1HNMR (400MHz, CDCl3) δ7.63 (d, J=4.0Hz, 1H), 7.57 (m, 2H), 7.39 (m, 3H), 7.30 (d, J=4.0Hz, 1H), 7.25(d, J=8.0Hz, 1H), 7.18(d, J=8.0Hz, 1H), 7.16(s, 1H), 3.96(s, 3H), 3.94(s, [ M+H]+).

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

[0057] Productive rate: 75%; mp104-105 ℃; 1HNMR (400MHz, CDCl3) δ7.58 (d, J=3.6Hz, 1H), 7.40 (d, J=8.0Hz, 2H), 7.25 (d, J=8.0Hz, 2H) 8.0Hz, 1H), 7.24(d, J=3.6Hz, 1H), 7.18(d, J=8.0Hz, 1H), 7.14(d, J=8.0Hz, 2H), 7.12(s, 1H), 3.92...

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Abstract

The invention discloses 2-(3,4-dimethoxy)benzoyl-5-(4-substituted phenylethynyl)thiophene, whose structural formula is as follows: ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ; Its preparation method comprises steps: 1) In the presence of a catalyst, react 2-bromothiophene and 3,4-dimethoxybenzoyl chloride in a solvent, and subsequently purify and separate to obtain 2-(3,4-dimethoxy Methoxy) benzoyl-5-bromothiophene; 2) In the presence of tetrakis (triphenylphosphine) palladium, CuI, acid binding agent, 2-(3,4-dimethoxy) benzoyl- 5-bromothiophene and 4-substituted phenylacetylene are reacted in a solvent, followed by subsequent purification and separation. The application of the compound in the preparation of anti-mammary cancer targeted therapy drugs. The application of the compound in the preparation of an anti-breast cancer drug resistance reversal agent. The compound of the present invention has obvious anti-proliferation effect on human breast cancer cells and drug-resistant strains of breast cancer cells, and can be used to prepare anti-breast cancer targeted therapy drugs and anti-breast cancer drug resistance reversal agents. Moreover, the compound of the present invention has the potential for large-scale industrial production, and the cost is relatively low.

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 Patents(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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