阅读说明：本技术 一类四氢苯并呋喃Mannich碱类化合物，制备方法及其应用 (Tetrahydrobenzofuran Mannich alkali compounds, and preparation method and application thereof ) 是由 黄年玉 金蕾 刘明国 姚辉 邓张双 郭志勇 汪鋆植 张雪晴 于 2019-11-11 设计创作，主要内容包括：本发明提供一种四氢苯并呋喃Mannich碱类化合物,该类化合物的结构式为<Image he="348" wi="414" file="DDA0002268130610000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>所述的R为氢或甲基；R<Sup>2</Sup>和R<Sup>3</Sup>包括甲基、乙基、正丙基、异丙基、正丁基、羟乙基、C4或C5的亚甲基链、含N原子的C4或C5的亚甲基链中的任意一种。其制备方法是以碘化亚铜为催化剂,二甲亚砜作溶剂,以甲醛水溶液(优选为30％的甲醛水溶液)、仲胺和呋喃并环己酮肟醚类为原料,用“一锅法”反应制备了系列长链四氢苯并呋喃并环己酮Mannich碱,该反应产物单一,无副反应发生,具有良好的官能团耐受性,含有羟基及杂原子的仲胺对反应均无影响。本发明将所制备得到的产品应用于抗胃癌药物中,并取得了显著的效果。(The invention provides a tetrahydrobenzofuran Mannich alkali compound, which has a structural formula R is hydrogen or methyl; r 2 And R 3 Including any one of methyl, ethyl, N-propyl, isopropyl, N-butyl, hydroxyethyl, a methylene chain of C4 or C5, a methylene chain of C4 or C5 containing N atom. The preparation method takes cuprous iodide as a catalyst, dimethyl sulfoxide as a solvent, and a formaldehyde aqueous solution (preferably a 30% formaldehyde aqueous solution), secondary amine and furo-cyclohexanone oxime ether as raw materials to prepare the series of long-chain tetrahydrobenzofuran-cyclohexanone Mannich bases by a one-pot reaction, wherein the reaction product is single and has no side reactionThe method has the advantages that the method has good functional group tolerance, and secondary amine containing hydroxyl and hetero atoms has no influence on the reaction. The invention applies the prepared product to the anti-gastric cancer medicine and obtains obvious effect.)

1. A tetrahydrobenzofuran Mannich alkali compound is characterized in that the structural formula of the compound is shown in the specification

2. The tetrahydrobenzofuran Mannich base compound of claim 1, wherein said compound formula comprises

3. A heterocyclic Mannich base compound comprising the tetrahydrobenzofuran mother nucleus structure as described in claim 1 or 2, and characterized by having a structural formula

4. Heterocyclic Mannich base compounds according to claim 3,

the structural formula of the compound is

5. The process for the preparation of tetrahydrobenzofuran Mannich base compounds according to claim 1 or 2, characterized by comprising the following steps:

mixing a compound 3, secondary amine and formaldehyde aqueous solution, adding DMSO (dimethyl sulfoxide) for dissolving, heating to 70-90 ℃, uniformly stirring at constant temperature, adding a catalyst CuI, stirring, monitoring by TLC (thin-layer chromatography) until the reaction is complete, pouring the reaction solution into cold water, extracting with ethyl acetate, drying, removing the solvent by organic phase vacuum distillation, and purifying the obtained crude product by column chromatography to obtain a compound 4, namely a long-chain tetrahydrobenzofuran Mannich alkali compound; the reaction formula is as follows:

6. The method for preparing tetrahydrobenzofuran Mannich base compounds according to claim 5, wherein the mass fraction of the aqueous formaldehyde solution is 25-35%; wherein the mol ratio of the compound 3, the secondary amine, the formaldehyde aqueous solution and the CuI is 1: 1.2-1.8: 3-5: 0.05-0.1.

7. The process for the preparation of heterocyclic Mannich base compounds according to claim 3 or 4, characterized in that it comprises the following steps:

putting the compound 3, substituted aniline and formaldehyde aqueous solution into a container, adding glycol for dissolution and a catalyst of glacial acetic acid, heating to 75-95 ℃, stirring at a constant temperature, monitoring by TLC (thin-layer chromatography) until the reaction is complete, pouring the reaction solution into cold water, extracting with ethyl acetate, drying, removing the solvent by organic phase vacuum distillation, and purifying the obtained crude product by column chromatography to obtain heterocyclic Mannich alkali 5, namely the heterocyclic Mannich alkali compound, wherein the reaction formula is as follows:

8. Use of the tetrahydrobenzofuran Mannich base compound according to any one of claims 1 to 4 in the preparation of an anti-gastric cancer medicament.

Technical Field

The invention relates to a tetrahydrobenzofuran Mannich base compound and application thereof in preparing a medicament for treating gastric cancer.

Background

Malignant tumors, one of the global public health problems, have become the first killer of 21 st century to harm human health. The 2008 statistics of the World Health Organization (WHO) show that Gastric Cancer (Gastric Cancer) is one of common digestive tract malignant tumors, the incidence rate of Gastric Cancer accounts for the second place in male malignant tumors and the fourth place in female malignant tumors, 100 ten thousand new Gastric cancers occur every year in the world, and about 80 ten thousand deaths occur. The incidence of gastric cancer in China accounts for more than 30% of the total incidence of digestive tract tumors in the world, and is one of the countries with high incidence and mortality of gastric cancer. Therefore, the development of high-efficiency anti-gastric cancer drugs has important social significance and economic value. The Mannich reaction is also called amine methylation reaction, which refers to an asymmetric condensation reaction of a compound containing active hydrogen atoms, formaldehyde (or other aldehydes) and amine, and the obtained product is called Mannich alkali. The Mannich alkali compounds can be used as plant protective agents, coatings, chemical polymers and the like, and are also important drug molecules, such as Tramadol, Osnervan, pyrrolocyclohexanone Mannich alkali Modan and the like. Cyclopentanone Mannich base compounds reported by Chenhaitao and the like have anticancer and anti-inflammatory activities, and Qinhua and the like also find that the compounds can selectively inhibit the synthesis of prostaglandin at an inflammation part without affecting the synthesis of prostaglandin in gastric mucosa, show the action characteristics of a selective COX-2 inhibitor and possibly be further developed as an anti-gastric cancer medicament with multiple effects. Benzofuran compounds have wide biological activity, a series of compounds containing benzofuran structures are reported in Atta and the like in 2010, and most of compounds are found to have good cytotoxic activity (5.56 mu g/mL)<IC₅₀<20.8. mu.g/mL), and anti-tumorTumor drug adriamycin (IC)₅₀2.97 μ g/mL) was equivalent. However, the application of the tetrahydrobenzofuran compounds in anti-gastric cancer drugs is reported in a few documents, and the Mannich base skeleton and the tetrahydrobenzofuranone parent nucleus are spliced in the claims so as to provide reference for the research and development of anti-gastric cancer drugs.

The Mannich reaction is widely applied to alkaloid and medical chemical pharmacy since the 20 th century, chemists pay increasing attention to Mannich reaction catalyst and selectivity, and are continuously working on seeking a Mannich reaction catalyst which is light in environmental pollution, low in corrosivity and high in efficiency and a new catalytic method. The traditional Mannich reaction mostly adopts protonic acid or Lewis acid catalyst, but the acid catalyst has corrosivity and volatility in post-treatment, and is easy to cause environmental pollution.

Disclosure of Invention

The method takes cuprous iodide as a catalyst, dimethyl sulfoxide as a solvent, and a formaldehyde aqueous solution (preferably a 30% formaldehyde aqueous solution), secondary amine and furo-cyclohexanone oxime ether as raw materials, and prepares a series of long-chain tetrahydrobenzofuran-cyclohexanone Mannich bases by a one-pot reaction. The method takes glycol dissolution and catalytic amount of glacial acetic acid as catalysts, efficiently prepares series heterocyclic Mannich alkali, has simple post-treatment and small environmental pollution, and avoids the generation of a large amount of organic solvent and strong acid waste liquid.

The structural formula of the tetrahydrobenzofuran Mannich alkali compounds is shown in the specification

R is hydrogen or methyl; r²And R³Including any one of methyl, ethyl, N-propyl, isopropyl, N-butyl, hydroxyethyl, a methylene chain of C4 or C5, a methylene chain of C4 or C5 containing N atom.

Preferred compounds include those having the following structural formula:

any one of them.

According to the structural formula, the invention also provides a heterocyclic Mannich alkali compound which comprises the compound with the tetrahydrobenzofuran parent nucleus structure and has the structural formula

R is hydrogen or methyl; r⁴Including any one of ortho-, meta-, and para-methyl, halogen atom, methoxy group, or nitro group.

Preferably, the compound has a structural formula

Any one of them.

The preparation method of the tetrahydrobenzofuran Mannich alkali compound comprises the following steps:

mixing the compound 3, secondary amine and formaldehyde aqueous solution, adding DMSO (dimethyl sulfoxide) for dissolving, heating to 70-90 ℃ (preferably 80 ℃) for reaction, stirring uniformly at constant temperature, adding a catalyst CuI, stirring, monitoring by TLC (thin layer chromatography) until the reaction is complete, pouring the reaction solution into cold water, extracting by ethyl acetate, drying, distilling by organic phase under reduced pressure to remove the solvent, and purifying the obtained crude product by column chromatography to obtain a compound 4, namely a long-chain tetrahydrobenzofuran Mannich alkali compound; the reaction formula is as follows:

r is hydrogen or methyl; r²And R³Comprising a methylene chain of methyl, ethyl, N-propyl, isopropyl, N-butyl, hydroxyethyl, C4 or C5, containing N atomsAny one of methylene chains of C4 or C5.

The mass fraction of the formaldehyde aqueous solution is 25-35%; wherein the mol ratio of the compound 3, the secondary amine, the formaldehyde aqueous solution and the CuI is 1: 1.2-1.8: 3-5: 0.05-0.1.

The preparation method of the heterocyclic Mannich alkali compound comprises the following steps:

putting the compound 3, substituted aniline and formaldehyde aqueous solution into a container, adding glycol for dissolution and a catalyst of glacial acetic acid, heating to 75-95 ℃, stirring at a constant temperature, monitoring by TLC (thin-layer chromatography) until the reaction is complete, pouring the reaction solution into cold water, extracting with ethyl acetate, drying, removing the solvent by organic phase vacuum distillation, and purifying the obtained crude product by column chromatography to obtain heterocyclic Mannich alkali 5, namely the heterocyclic Mannich alkali compound, wherein the reaction formula is as follows:

r is hydrogen or methyl; r⁴Including any one of ortho-, meta-, and para-methyl, halogen atom, methoxy group, or nitro group.

In another technical scheme of the invention, the tetrahydrobenzofuran Mannich base compound is applied to preparation of anti-gastric cancer drugs, and a remarkable effect is achieved.

Detailed Description