阅读说明：本技术 一种芳香类衍生物单硝酸酯及其制备方法 (Aromatic derivative mononitrate and preparation method thereof ) 是由 张冬冬 于 2020-05-19 设计创作，主要内容包括：本发明涉及一种芳香类衍生物单硝酸酯及其制备方法,其通式如式(Ⅰ)所示<Image he="64" wi="54" file="598353DEST_PATH_IMAGE002.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>,其中Ar基团为苯环、单取代或多取代的苯环、吡啶环或单取代的吡啶环,苯环或吡啶环上的取代基为CH<Sub>3</Sub>、卤素、OH、NO<Sub>2</Sub>或CF<Sub>3</Sub>。Ar基团为吡啶环时,制备方法如下：(1)4-醛基吡啶在冰乙酸中与三氯化钛的盐酸水溶液反应得到邻二醇中间体化合物1；(2)化合物1在浓硝酸或浓硝酸与发烟硝酸的混酸中反应得到单硝酸酯化合物2；制备所用原料成本低廉,合成步骤少,操作简单,提取纯化方便,收率高。该化合物具有硝酸酯的特性,在扩血管、抑制血小板聚集和黏附,抗血栓形成方面有潜在的应用,并且有利于冠状动脉粥样硬化所引起的心绞痛治疗。(The invention relates to an aromatic derivative mononitrate and a preparation method thereof, wherein the general formula of the mononitrate is shown as a formula (I) Wherein Ar group is benzene ring, mono-substituted or poly-substituted benzene ring, pyridine ring or mono-substituted pyridine ring, and the substituent on the benzene ring or the pyridine ring is CH 3 Halogen, OH, NO 2 Or CF 3 . When Ar group is pyridine ring, the preparation method is as follows: (1) 4-aldehyde pyridine reacts with hydrochloric acid aqueous solution of titanium trichloride in glacial acetic acid to obtain an o-diol intermediate compound 1; (2) compound 1 in concentrated nitric acid or concentrated nitric acid and fuming nitric acidReacting in the mixed acid to obtain a mononitrate compound 2; the preparation method has the advantages of low cost of raw materials, few synthesis steps, simple operation, convenient extraction and purification and high yield. The compound has the characteristics of nitrate, has potential application in the aspects of expanding blood vessels, inhibiting platelet aggregation and adhesion and resisting thrombosis, and is beneficial to treating angina caused by coronary atherosclerosis.)

1. The aromatic derivative mononitrate ester is characterized in that the general formula is shown as formula (I), wherein Ar group is benzene ring, mono-substituted or poly-substituted benzene ring, pyridine ring or mono-substituted pyridine ring, and substituent on the benzene ring or the pyridine ring is CH₃Halogen, OH, NO₂Or CF₃，

（Ⅰ）。

2. The aromatic derivative mononitrate of claim 1, wherein the Ar group is benzene ring, mono-or poly-substituted benzene ring, pyridine ring.

3. The method of claim 2, wherein when the Ar group is a pyridine ring, the method comprises the steps of:

step 1): 4-aldehyde pyridine reacts with hydrochloric acid aqueous solution of titanium trichloride in glacial acetic acid to obtain an intermediate of vicinal diol such as a compound 1;

step 2): reacting the compound 1 in concentrated nitric acid or mixed acid of the concentrated nitric acid and fuming nitric acid to obtain mononitrate such as a compound 2;

the synthetic route is as follows:

。

4. the production method according to claim 3, wherein the concentration of titanium trichloride in the aqueous hydrochloric acid solution of titanium trichloride in the step (1) is 15%, and the concentration of HCl is 30%.

5. The method according to claim 3, wherein the step (1) is carried out in a nitrogen atmosphere.

6. The method according to claim 3, wherein the volume ratio of the concentrated nitric acid to the fuming nitric acid in the step (2) is 1: 1.

7. The method according to claim 3, wherein the reaction temperature in the step (2) is 90 ℃ and the reaction time is 3 hours.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to aromatic derivative mononitrate and a preparation method thereof.

Background

Cardiovascular diseases refer to ischemic or hemorrhagic diseases of heart and systemic tissues caused by hyperlipidemia, blood viscosity, atherosclerosis, hypertension, etc. Cardiovascular diseases are common diseases seriously threatening the health of human beings, particularly the middle-aged and old people over 50 years old, have the characteristics of high morbidity, high disability rate and high mortality, and the number of people dying from cardiovascular and cerebrovascular diseases every year in the world is as high as 1500 thousands of people living at the first position of various causes of death. The nitrate medicine has the functions of expanding peripheral blood vessels and changing blood flow, and the medicine expands various blood vessels through the direct action on vascular smooth muscles, expands veins to increase the vein reserve, reduces the amount of return blood, reduces the wall tension of heart chamber and reduces the oxygen consumption of heart machine; the dilated artery is mainly the aorta, and can reduce left ventricular afterload and left ventricular work. Myocardial oxygen consumption is reduced by reducing the load of the heart. The nitrate medicine also has the effect of changing the distribution of myocardial blood and being beneficial to blood supply of an ischemic area. By improving myocardial compliance, reducing sub-endocardial vascular pressure, increasing the sub-endocardial blood supply area; selectively dilating the epicardial large delivery vessel; open collateral circulation; increasing blood supply to the ischemic area.

Nitrate drugs are converted to nitrothiols and nitrous oxide by binding with the sulfhydryl group of a specific nitrate receptor on vascular smooth muscle, thereby dilating blood vessels. Nitrate drugs also have different affinities for different blood vessels, stronger affinity for veins than arteries, and stronger affinity for large arteries than small arteries. Therefore, the nitrate ester medicine is widely applied to acute, dangerous and severe cardiovascular diseases such as myocardial ischemia syndrome, congestive heart failure, hypertension and the like and chronic stages of the diseases at present, and is one of the first-line medicines with the most extensive application and the most reliable curative effect in the treatment of the cardiovascular diseases.

The alcoholic hydroxyl function is a very useful chemical function, and can perform a plurality of reactions, such as halogenation, esterification and the like, so that the possibility of synthesizing medical molecules and chemical materials with special properties is provided.

The aromatic derivative mononitrate synthesized by the method belongs to nitrate compounds, has the general property of nitrate and has potential application in the aspect of cardiovascular diseases; in addition, the naked alcoholic hydroxyl group in the molecule can synthesize a plurality of novel chemical molecules, and then the specific application in the aspects of medicines and materials is shown.

Disclosure of Invention

In order to solve the problems of the prior art, the invention aims to provide an aromatic derivative mononitrate and a preparation method thereof.

In order to achieve the purpose, the invention provides the following technical scheme:

the general formula of the aromatic derivative mononitrate ester is shown as the formula (I), wherein Ar group is benzene ring, mono-substituted or poly-substituted benzene ring, pyridine ring or mono-substituted pyridine ring, and substituent on the benzene ring or the pyridine ring is CH₃Halogen, OH, NO₂Or CF₃，

（Ⅰ）。

Preferably, the Ar group is a pyridine ring.

Further, when Ar group is pyridine ring, the preparation method of the aromatic derivative mononitrate comprises the following steps:

step 1): 4-aldehyde pyridine reacts with hydrochloric acid aqueous solution of titanium trichloride in glacial acetic acid to obtain an intermediate of vicinal diol such as a compound 1;

step 2): reacting the compound 1 in concentrated nitric acid or mixed acid of the concentrated nitric acid and fuming nitric acid to obtain mononitrate such as a compound 2;

the synthetic route is as follows:

。

preferably, in the step (1), the concentration of titanium trichloride in the hydrochloric acid aqueous solution of titanium trichloride is 15%, and the concentration of HCl is 30%.

Preferably, the step (1) is carried out in a nitrogen atmosphere.

Preferably, the volume ratio of the concentrated nitric acid to the fuming nitric acid in the step (2) is 1: 1.

Preferably, the reaction temperature of the step (2) is 90 ℃, and the reaction time is 3 h.

Has the advantages that: the invention provides aromatic derivative mononitrate and a preparation method thereof, the raw materials adopted in the preparation of the aromatic derivative mononitrate are low in cost, and the synthesis process of the aromatic derivative mononitrate is taken as an example, so that the synthesis steps are few, the operation is simple, the extraction and purification are convenient, the yield of the final aromatic derivative mononitrate is high, and the yield of each step is over 80 percent. The invention also provides a novel method for preparing the aromatic derivative mononitrate, and the obtained product has great potential application in the aspect of treating cardiovascular diseases. The molecule retains an alcoholic hydroxyl functional group, is used as an organic intermediate, can generate halogenation reaction and esterification reaction, can synthesize a plurality of organic molecules with specific functions, can provide convenience for subsequent modification of the molecule, and has a plurality of applications in the aspects of medicine and materials.

The aromatic derivative mononitrate has the characteristics of nitrate, has potential application in the aspects of expanding blood vessels, inhibiting platelet aggregation and adhesion and resisting thrombosis, and is beneficial to treating angina caused by coronary atherosclerosis.

Drawings

FIG. 1 is a NMR spectrum of Compound 1.

FIG. 2 is a NMR spectrum of Compound 2.

Detailed Description

The present invention is further described below with reference to specific examples, which are only exemplary and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.