Cinnamic acid derivative and preparation method thereof

文档序号：997762 发布日期：2020-10-23 浏览：21次中文

阅读说明：本技术 一种肉桂酸衍生物及其制备方法 (Cinnamic acid derivative and preparation method thereof ) 是由刘文锋陈勃旭于 2020-05-11 设计创作，主要内容包括：本发明提供一种肉桂酸衍生物及其制备反方法,在氮气保护下将2mmol肉桂酸、D-丙氨酸甲酯盐酸盐、2.4mmol缩合试剂、1-羟基-7-偶氮苯并三氮唑加入50ml溶剂中,缓慢滴加0.2mmol催化剂,室温反应2h,浓缩后用硅胶柱分离,然后在强碱的作用下进行水解,接着加酸进行酸化,调节pH值；然后加入1mmol D-苯丙氨酸甲酯盐酸盐、1.2mmol缩合试剂和1.2mmol HOAT、30ml溶剂,0.1mmol催化剂,室温反应2h,浓缩后用硅胶柱纯化,然后在强碱的作用下进行水解,加酸进行酸化,调节pH值。本发明的化合物具有优良的抑制神经炎症活性,能够应用于制备神经炎症抑制剂和治疗老年痴呆药物中。(The invention provides a cinnamic acid derivative and a preparation method thereof, wherein 2mmol cinnamic acid, D-alanine methyl ester hydrochloride, 2.4mmol condensation reagent and 1-hydroxy-7-azobenzotriazole are added into 50ml solvent under the protection of nitrogen, 0.2mmol catalyst is slowly dripped, the reaction is carried out for 2h at room temperature, the reaction is separated by a silica gel column after concentration, then the hydrolysis is carried out under the action of strong base, then the acidification is carried out by adding acid, and the pH value is adjusted; then adding 1mmol of D-phenylalanine methyl ester hydrochloride, 1.2mmol of condensation reagent, 1.2mmol of HOAT, 30ml of solvent and 0.1mmol of catalyst, reacting for 2h at room temperature, concentrating, purifying by using a silica gel column, hydrolyzing under the action of strong base, adding acid for acidification, and adjusting the pH value. The compound has excellent neuroinflammation inhibiting activity, and can be applied to preparing neuroinflammation inhibitors and medicaments for treating senile dementia.)

1. A cinnamic acid derivative, wherein the cinnamic acid derivative has the following structural formula:

wherein R is₁、R₃And R₄Are respectively H, OCH₃Any one of the above; r₃Is CH₃、OCH₃、F、CF₃Any one of (1) and (b);

the cinnamic acid derivative has aldose reductase inhibiting activity.

2. The cinnamic acid derivative of claim 1, wherein: the cinnamic acid derivative is selected from one or a mixture of more of the following compounds:

(E) - (3- (p-tolyl) acryloyl) -D-alanine methyl ester (2 a);

(E) - (3- (p-methoxyphenyl) acryloyl) -D-alanine methyl ester (2 b);

(E) - (3- (p-fluorophenyl) acryloyl) -D-alanine methyl ester (2 c);

(E) - (3- (p-trifluoromethylphenyl) acryloyl) -D-alanine methyl ester (2D);

(E) - (3- (3,4, 5-trimethoxyphenyl) acryloyl) -D-alanine methyl ester (2E);

(E) - (3- (p-tolyl) acryloyl) -D-alanine (3 a);

(E) - (3- (p-methoxyphenyl) acryloyl) -D-alanine (3 b);

(E) - (3- (p-fluorophenyl) acryloyl) -D-alanine (3 dc);

(E) - (3- (p-trifluoromethylphenyl) acryloyl) -D-alanine (3D);

(E) - (3- (3,4, 5-trimethoxyphenyl) acryloyl) -D-alanine (3E);

(E) -3- (p-tolyl) acryloyl) -D-alanine-D-phenylalanine methyl ester (4 a);

(E) -3- (p-methoxyphenyl) acryloyl) -D-alanine-D-phenylalanine methyl ester (4 b);

(E) -3- (p-fluorophenyl) acryloyl) -D-alanine-D-phenylalanine methyl ester (4 c);

(E) -3- (p-trifluoromethylphenyl) acryloyl) -D-alanine-D-phenylalanine methyl ester (4D);

(E) -3- (3,4, 5-trimethoxyphenyl) acryloyl) -D-alanine-D-phenylalanine methyl ester (4E);

(E) -3- (p-tolyl) acryloyl) -D-alanine-D-phenylalanine (5 a);

(E) -3- (p-methoxyphenyl) acryloyl) -D-alanine-D-phenylalanine (5 b);

(E) -3- (p-fluorophenyl) acryloyl) -D-alanine-D-phenylalanine (5 c);

(E) -3- (p-trifluoromethylphenyl) acryloyl) -D-alanine-D-phenylalanine (5D);

(E) -3- (3,4, 5-trimethoxyphenyl) acryloyl) -D-alanine-D-phenylalanine (5E).

3. A production method for producing the cinnamic acid derivative of claim 1 or 2, comprising the steps of:

1) under the protection of nitrogen, adding 2.0mmol of cinnamic acid, 2.0mmol of D-alanine methyl ester hydrochloride, 2.4mmol of condensation reagent and 2.4mmol of 1-hydroxy-7-azobenzotriazole (HOAT) into 50ml of solvent, slowly dropwise adding 0.2mmol of organic base as a catalyst, reacting for 2h at room temperature, concentrating, and separating by using a silica gel column to obtain first-step products 2 a-e;

2) then 1.5mmol of the product of the first step is hydrolyzed under the action of strong alkali, then acid is added for acidification, and the pH value is adjusted to obtain the products 3a-e of the second step;

3) adding 1.0mmol of the second step product, 1.0mmol of D-phenylalanine methyl ester hydrochloride, 1.2mmol of condensation reagent and 1.2mmol of HOAT into 30ml of solvent, adding 0.1mmol of organic base as a catalyst, reacting for 2h at room temperature, concentrating, and purifying by using a silica gel column to obtain a third step product 4 a-e;

4) then 0.5mmol of the product obtained in the fourth step is hydrolyzed under the action of strong alkali, and then acid is added for acidification, and the pH value is adjusted, namely the product cinnamic acid derivatives 5a-e obtained in the fourth step, and the reaction route is shown as follows:

4. the method for preparing a cinnamic acid derivative according to claim 3, wherein: in the step 1) and the step 3), the solvent is dichloromethane or tetrahydrofuran.

5. The method for preparing a cinnamic acid derivative according to claim 3, wherein: in the steps 1) and 3), the condensation reagent is prepared by mixing one of ethyl chloroformate, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl), N-diisopropyl carbodiimide (DIC) and benzotriazole-1-yl-oxy tripyrrolidinyl phosphorus hexafluorophosphate (PyBOP) with 1-hydroxy-7-azo benzotriazole (HOAT) according to the molar ratio of 1: 1.

6. The method for preparing a cinnamic acid derivative according to claim 3, wherein: in the step 1) and the step 3), the organic base is one of diethylamine (EEA), Triethylamine (TEA) and Diisopropylethylamine (DIPEA).

7. The method for preparing a cinnamic acid derivative according to claim 3, wherein: in the step 2) and the step 4), the strong base is one of sodium hydroxide, potassium hydroxide and lithium hydroxide.

8. The method for preparing a cinnamic acid derivative according to claim 3, wherein: step 2) and step 4), the added acid is one of hydrochloric acid or nitric acid solution with the volume concentration of 1-10%, and the adjusted pH value is 1-4.

9. Use of the cinnamic acid derivative according to any one of claims 1 to 8, for the preparation of a neuroinflammation inhibitor.

10. Use of cinnamic acid derivatives according to claim 9, characterized in that: the application of the cinnamic acid derivative in preparing a medicament for treating Alzheimer disease is provided.

Technical Field

The invention relates to the technical field of medicines, in particular to a cinnamic acid derivative and a preparation method thereof.

Background

The inflammatory reaction is closely related to neurodegenerative diseases such as senile dementia and the like. In the case of senile dementia, oligomers and polymers formed by a β activate brain immune cells, microglia and astrocytes, through various receptors, thereby triggering local chronic inflammatory responses. Activated glial cells release pro-inflammatory cytokines or other inflammatory mediators in large amounts. These pro-inflammatory cytokines or other inflammatory mediators can cause damage to neurons to varying degrees or directly induce apoptosis in neurons. Meanwhile, the apoptotic neurons can further activate the non-activated glial cells, and malignant circulation is formed to continuously cause damage to the neurons and abnormal synaptic function. Numerous studies have shown that neuroinflammation caused by excessive activation of microglia is one of the most direct causes of abnormal neuronal synaptic function and decreased cognitive ability.

Many studies have pointed out. The existing clinical medicines only have curative effect on early senile dementia, so the development of effective anti-senile dementia medicines is concerned.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a cinnamic acid derivative and a preparation method thereof.

The technical scheme of the invention is as follows: a cinnamic acid derivative having the formula:

wherein R is₁、R₃And R₄Are respectively H, OCH₃Any one of the above; r₃Is CH₃、OCH₃、F、CF₃Any one of (1) and (b);

the cinnamic acid derivative has aldose reductase inhibitory activity.

Preferably, the cinnamic acid derivative is selected from one or more of the following compounds:

(E) - (3- (p-tolyl) acryloyl) -D-alanine methyl ester (2 a);

(E) - (3- (p-methoxyphenyl) acryloyl) -D-alanine methyl ester (2 b);

1.23.(E) - (3- (p-fluorophenyl) acryloyl) -D-alanine methyl ester (2 c);