阅读说明：本技术 一种脱氢枞酸苯并咪唑-2-苯甲酰胺衍生物及其制备方法和应用 (Dehydroabietic acid benzimidazole-2-benzamide derivative and preparation method and application thereof ) 是由 谷文 李阿良 杨亚群 王文燕 刘青松 孙月 王石发 于 2019-11-04 设计创作，主要内容包括：本发明公开了一种脱氢枞酸苯并咪唑-2-苯甲酰胺衍生物及其制备方法和应用,属于有机合成和药物化学技术领域。该衍生物的结构通式如式(I)所示：<Image he="430" wi="700" file="DDA0002259644790000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>式中,R分别为：-H,-F,-Cl,-Br,-CH<Sub>3</Sub>,-OCH<Sub>3</Sub>,-NO<Sub>2</Sub>,-CN。本发明所涉及的一种脱氢枞酸苯并咪唑-2-苯甲酰胺衍生物,具有良好的抗肿瘤生物活性,药理学实验表明,这类化合物对乳腺癌细胞MCF-7有明显的抑制效果。(The invention discloses a dehydroabietic acid benzimidazole-2-benzamide derivative, and a preparation method and application thereof, and belongs to the technical field of organic synthesis and pharmaceutical chemistry. The structural general formula of the derivative is shown as the formula (I): wherein R is respectively: -H, -F, -Cl, -Br, -CH 3 ，‑OCH 3 ，‑NO 2 -CN. The dehydroabietic acid benzimidazole-2-benzamide derivative has good anti-tumor biological activity, and pharmacological experiments show that the compound can treat breast cancerThe MCF-7 cell has obvious inhibiting effect.)

1. A dehydroabietic acid benzimidazole-2-benzamide derivative is characterized in that the structural general formula is shown as formula (I):

wherein R is respectively: -H, -F, -Cl, -Br, -CH₃，-OCH₃，-NO₂，-CN。

2. The process for producing a dehydroabietic acid benzimidazole-2-benzamide derivative according to claim 1, wherein the dehydroabietic acid 2-aminobenzimidazole derivative IV is subjected to a condensation reaction with benzoyl chlorides having different substituents, and after the reaction is completed, a dehydroabietic acid-2-benzamide derivative I having a corresponding substituent is obtained by post-treatment; the benzoyl chloride with different substituents is any one of benzoyl chloride, 4-bromobenzoyl chloride, 4-fluorobenzoyl chloride, p-chlorobenzaldehyde, p-methylbenzoyl chloride, p-methoxybenzoyl chloride, p-nitrobenzoyl chloride or p-cyanobenzoyl chloride; the condensation reaction temperature is 90-110 ℃, and the reaction time is 7-9 h; the mole ratio of the dehydroabietic acid 2-aminobenzimidazole derivative to benzoyl chloride with different substituents is 1: 2.5-1: 3.

3. The method for producing a dehydroabietic acid benzimidazole-2-benzamide derivative according to claim 2, wherein the benzoyl chloride having different substituents is any one of benzoyl chloride, 4-bromobenzoyl chloride, p-nitrobenzoyl chloride and p-cyanobenzoyl chloride.

4. The method for producing a dehydroabietic acid benzimidazole-2-benzamide derivative according to claim 2, wherein the molar ratio of the dehydroabietic acid 2-aminobenzimidazole derivative to benzoyl chlorides having different substituents is 1: 3.

5. The method for producing a dehydroabietic acid benzimidazole-2-benzamide derivative according to claim 2, wherein the condensation reaction temperature is 100 ℃ and the reaction time is 8 hours.

6. The method for producing a dehydroabietic acid benzimidazole-2-benzamide derivative according to claim 2, wherein the post-treatment comprises: and after the reaction is finished, adding distilled water, extracting for 2-3 times by using ethyl acetate, washing for 2-3 times by using the distilled water, washing for 1 time by using saturated sodium bicarbonate, washing for 1 time by using saturated salt solution, finally drying by using anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, and carrying out silica gel chromatography on petroleum ether and acetone in a ratio of 100: 1-20: 1 to obtain the powdery solid dehydroabietic acid-2-benzamide derivative I.

7. The method for producing a dehydroabietic acid benzimidazole-2-benzamide derivative according to claim 2, wherein the method for producing the dehydroabietic acid 2-aminobenzimidazole derivative IV comprises the steps of:

(1) carrying out methyl esterification, bromination and double nitration on dehydroabietic acid to obtain 12-bromo-13, 14-dinitro de-isopropyl dehydromethyl ester II:

(2) reducing the 12-bromo-13, 14-dinitro isopropyl dehydromethyl ester II by Fe/HCl to prepare 12-bromo-13, 14-diamino isopropyl dehydroabietic acid methyl ester III:

(3) reacting 12-bromo-13, 14-diamino de-isopropyl dehydroabietic acid methyl ester III with BrCN to obtain dehydroabietic acid 2-aminobenzimidazole derivative IV:

8. the method for producing a dehydroabietic acid benzimidazole-2-benzamide derivative according to claim 2, which comprises the steps of:

(1) carrying out methyl esterification, bromination and double nitration on dehydroabietic acid to obtain 12-bromo-13, 14-dinitro de-isopropyl dehydromethyl ester II:

(2) reducing the 12-bromo-13, 14-dinitro isopropyl dehydromethyl ester II by Fe/HCl to prepare 12-bromo-13, 14-diamino isopropyl dehydroabietic acid methyl ester III:

(3) reacting 12-bromo-13, 14-diamino de-isopropyl dehydroabietic acid methyl ester III with BrCN to obtain dehydroabietic acid 2-aminobenzimidazole derivative IV:

(4) reacting dehydroabietic acid 2-aminobenzimidazole derivative IV with benzoyl chloride with different substituents, adding distilled water after the reaction is finished, extracting with ethyl acetate for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, and preparing a powdery solid dehydroabietic acid-2-benzamide derivative I by using a silica gel chromatographic column, wherein petroleum ether and acetone are 100: 1-20: 1:

wherein R is respectively: -H, -F, -Cl, -Br, -CH₃，-OCH₃，-NO₂-CN; the benzoyl chloride with different substituents is any one of benzoyl chloride, 4-bromobenzoyl chloride, paranitrobenzoyl chloride or paracyanobenzoyl chloride; the mole ratio of the dehydroabietic acid 2-aminobenzimidazole derivative to benzoyl chloride with different substituents is 1: 3; the reaction temperature is 100 ℃, and the reaction time is 8 h.

9. Use of the dehydroabietic acid-2-arylamido benzimidazole derivative of claim 1 for the preparation of an anti-cancer medicament.

10. Use of a dehydroabietic acid-2-arylamido benzimidazole derivative, according to claim 9, in the manufacture of an anti-cancer medicament, wherein the cancer is breast cancer.

Technical Field

The invention belongs to the technical field of organic synthesis and pharmaceutical chemistry, and particularly relates to a dehydroabietic acid benzimidazole-2-benzamide derivative, and a preparation method and application thereof.

Background

Tumor is a disease seriously harming human health, is more and more concerned all over the world, becomes a big problem in medical field, and cannot be treated fundamentally up to now. Chemotherapy is one of the main means for treating tumor diseases, and anticancer drugs are a major focus and hot spot in the research and development of the existing drugs. These drugs usually act on a certain target of cancer cells to prevent the division and proliferation of cells, but at the same time, these preparations can also kill normal cells with faster proliferation, and cause symptoms such as infection, hemorrhage, etc. Therefore, the development of tumor-inhibiting drugs with good selectivity, good safety and high curative effect is an important direction for the research of modern tumor diseases.

Dehydroabietic acid is a resin acid with a tricyclic diterpene structure, is a main component of natural forestry resource disproportionated rosin, and can introduce nitrogen-containing groups such as indole, benzimidazole and the like through modification of the dehydroabietic acid structure. The dehydroabietic acid nitrogen heterocyclic derivative has good effects on biological activities such as bacteriostasis, anti-inflammation, anti-tumor and the like, has huge development prospects in the fields of agriculture and medicine, and receives more and more attention.

Benzimidazoles are a class of heterocyclic compounds containing two nitrogen atoms, and the structures of many drugs contain a benzimidazole heterocycle. Many documents show that benzimidazole compounds have significant biological activities, including anti-tumor, anti-cancer, anti-viral, anti-inflammatory, and the like. Therefore, a benzimidazole unit structure is introduced into a dehydroabietic acid molecule, a drug precursor with excellent antitumor activity is searched, and the method has good theoretical and practical significance for researching and developing novel antitumor drugs and deeply utilizing rosin resources in China.

Disclosure of Invention

The invention aims to solve the technical problem of providing a dehydroabietic acid benzimidazole-2-benzamide derivative which has good anti-tumor bioactivity. The invention aims to solve another technical problem of providing a preparation method of the dehydroabietic acid benzimidazole-2-benzamide derivative, which is used for preparing an anti-cancer drug dehydroabietic acid benzimidazole-2-benzamide derivative by using rosin resources. The invention also provides an application of the dehydroabietic acid benzimidazole-2-benzamide derivative in preparing an anti-cancer medicament, wherein the derivative has very good biological activity in resisting breast cancer cells.

In order to solve the problems, the technical scheme adopted by the invention is as follows:

a dehydroabietic acid benzimidazole-2-benzamide derivative has a structural general formula shown as a formula (I):

wherein R is respectively: -H, -F, -Cl, -Br, -CH₃，-OCH₃，-NO₂，-CN。

The preparation method of the dehydroabietic acid benzimidazole-2-benzamide derivative comprises the steps of carrying out condensation reaction on a dehydroabietic acid 2-aminobenzimidazole derivative IV and benzoyl chloride with different substituents, and carrying out post-treatment after the reaction is finished to obtain a dehydroabietic acid-2-benzamide derivative I with the corresponding substituents; the benzoyl chloride with different substituents is any one of benzoyl chloride, 4-bromobenzoyl chloride, 4-fluorobenzoyl chloride, p-chlorobenzaldehyde, p-methylbenzoyl chloride, p-methoxybenzoyl chloride, p-nitrobenzoyl chloride or p-cyanobenzoyl chloride; the condensation reaction temperature is 90-110 ℃, and the reaction time is 7-9 h; the mole ratio of the dehydroabietic acid 2-aminobenzimidazole derivative to benzoyl chloride with different substituents is 1: 2.5-1: 3.

According to the preparation method of the dehydroabietic acid benzimidazole-2-benzamide derivative, the benzoyl chloride with different substituents is any one of benzoyl chloride, 4-bromobenzoyl chloride, p-nitrobenzoyl chloride or p-cyanobenzoyl chloride.

According to the preparation method of the dehydroabietic acid benzimidazole-2-benzamide derivative, the molar ratio of the dehydroabietic acid 2-aminobenzimidazole derivative to benzoyl chloride with different substituents is 1: 3.

The preparation method of the dehydroabietic acid benzimidazole-2-benzamide derivative has the condensation reaction temperature of 100 ℃ and the reaction time of 8 hours.

The preparation method of the dehydroabietic acid benzimidazole-2-benzamide derivative comprises the following steps: adding distilled water after the reaction is finished, extracting for 2-3 times by using ethyl acetate, washing for 2-3 times by using the distilled water, washing for 1 time by using saturated sodium bicarbonate, washing for 1 time by using saturated salt water, finally drying by using anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, and performing silica gel chromatography column petroleum ether: and (3) preparing the powdery solid dehydroabietic acid-2-benzamide derivative I by acetone of 100: 1-20: 1.

The preparation method of the dehydroabietic acid benzimidazole-2-benzamide derivative, the preparation method of the dehydroabietic acid 2-aminobenzimidazole derivative IV comprises the following steps:

(1) carrying out methyl esterification, bromination and double nitration on dehydroabietic acid to obtain 12-bromo-13, 14-dinitro de-isopropyl dehydromethyl ester II:

(2) reducing the 12-bromo-13, 14-dinitro isopropyl dehydromethyl ester II by Fe/HCl to prepare 12-bromo-13, 14-diamino isopropyl dehydroabietic acid methyl ester III:

(3) reacting 12-bromo-13, 14-diamino de-isopropyl dehydroabietic acid methyl ester III with BrCN to obtain dehydroabietic acid 2-aminobenzimidazole derivative IV:

the preparation method of the dehydroabietic acid benzimidazole-2-benzamide derivative comprises the following steps:

(1) carrying out methyl esterification, bromination and double nitration on dehydroabietic acid to obtain 12-bromo-13, 14-dinitro de-isopropyl dehydromethyl ester II:

(2) reducing the 12-bromo-13, 14-dinitro isopropyl dehydromethyl ester II by Fe/HCl to prepare 12-bromo-13, 14-diamino isopropyl dehydroabietic acid methyl ester III:

(3) reacting 12-bromo-13, 14-diamino de-isopropyl dehydroabietic acid methyl ester III with BrCN to obtain dehydroabietic acid 2-aminobenzimidazole derivative IV:

(4) reacting dehydroabietic acid 2-aminobenzimidazole derivative IV with benzoyl chloride with different substituents, adding distilled water after the reaction is finished, extracting with ethyl acetate for 2-3 times, washing with distilled water for 2-3 times, washing with saturated sodium bicarbonate for 1 time, washing with saturated salt for 1 time, drying with anhydrous sodium sulfate, concentrating and distilling the filtered solution under reduced pressure, and performing silica gel chromatography on petroleum ether: and (3) preparing a powdery solid dehydroabietic acid-2-benzamide derivative I by acetone (100: 1-20: 1):

wherein R is respectively: -H, -F, -Cl, -Br, -CH₃，-OCH₃，-NO₂-CN; the benzoyl chloride with different substituents is any one of benzoyl chloride, 4-bromobenzoyl chloride, paranitrobenzoyl chloride or paracyanobenzoyl chloride; the dehydroabietic acid 2-aminobenzimidazole derivative and the derivative have a structure ofThe molar ratio of the benzoyl chloride with the substituent group is 1: 3; the reaction temperature is 100 ℃, and the reaction time is 8 h.

The dehydroabietic acid-2-arylamido benzimidazole derivative is applied to the preparation of anti-cancer drugs.

The dehydroabietic acid-2-arylamide benzimidazole derivative is applied to preparation of an anti-cancer drug, wherein the cancer is breast cancer.

Has the advantages that: compared with the prior art, the invention has the advantages that:

the nitrogenous heterocyclic compound is a dehydroabietic acid benzimidazole-2-benzamide derivative, has good anti-tumor biological activity, and pharmacological experiments show that the compound has an obvious inhibition effect on breast cancer cell strains MCF-7 and has good development prospects.

Detailed Description

In order to make the aforementioned objects, features and advantages of the present invention comprehensible, embodiments accompanied with examples are described in detail below.