阅读说明：本技术 一种含甲硝唑的药物单体及其制备方法 (Metronidazole-containing drug monomer and preparation method thereof ) 是由 王玮 陈思 于 2019-09-10 设计创作，主要内容包括：本发明公开了一种含甲硝唑的药物单体及其制备方法。具体地说,是以甲硝唑和丙烯酰胺为原料,在一定的条件下反应生成2-(2-甲基-5-硝基-1H-咪唑-1-基)乙基丙烯酸酯,并对产物进行核磁表征。2-(2-甲基-5-硝基-1H-咪唑-1-基)乙基丙烯酸酯同时具有硝基咪唑基团和丙烯酸酯基团。硝基咪唑基团具有低氧响应性,丙烯酸酯基团可以进行自由基聚合或者与巯基、氨基等进行迈克尔加成反应,因此该单体可对聚合物进行修饰,使其带有硝基咪唑基团,从而获得具有低氧响应性的聚合物,在生物工程领域有着潜在的应用价值。(The invention discloses a metronidazole-containing drug monomer and a preparation method thereof. Specifically, metronidazole and acrylamide are used as raw materials, 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate is generated through reaction under a certain condition, and nuclear magnetism characterization is carried out on a product. 2- (2-methyl-5-nitro-1H-imidazol-1-yl) ethyl acrylate has both a nitroimidazole group and an acrylate group. The nitroimidazole group has low oxygen responsiveness, and the acrylate group can be subjected to free radical polymerization or Michael addition reaction with sulfydryl, amino and the like, so that the monomer can modify the polymer to enable the polymer to have the nitroimidazole group, thereby obtaining the polymer with low oxygen responsiveness, and having potential application value in the field of bioengineering.)

1. A metronidazole-containing drug monomer is characterized in that: having a molecular structure shown below

2. A preparation method of a metronidazole-containing drug monomer is characterized by comprising the following steps: the method comprises the following steps: uniformly dispersing metronidazole and triethylamine in an organic solvent, and then uniformly dispersing acryloyl chloride in the organic solvent, wherein the mass ratio of the metronidazole to the triethylamine to the acryloyl chloride is 4: (2-3): (4-5), dropwise adding the acryloyl chloride solution into the metronidazole and acid-binding agent solution in an ice bath to react, so that hydroxyl of the metronidazole and chloride ions of the acryloyl chloride react to generate 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate.

3. The method for preparing the metronidazole-containing pharmaceutical monomer as claimed in claim 2, wherein: the organic solvent is dichloromethane, diethyl ether, petroleum ether, chloroform, tetrahydrofuran or toluene.

4. The method for preparing the metronidazole-containing pharmaceutical monomer as claimed in claim 2, wherein: and dropwise adding the acryloyl chloride solution into the metronidazole and acid-binding agent solution in an ice bath at the temperature of-5-0 ℃, stirring and reacting for 11-13h in the ice bath at the temperature of-5-0 ℃, then heating to room temperature, and continuously stirring and reacting for 11-13 h.

5. The method for preparing the metronidazole-containing pharmaceutical monomer as claimed in claim 2, wherein: filtering after the reaction is finished, carrying out rotary evaporation on the filtrate, diluting the filtrate with an organic solvent and ultrapure water to obtain a concentrated solution, washing the concentrated solution with ultrapure water, adding a drying agent into an organic phase after liquid separation, carrying out overnight drying, filtering again, and carrying out rotary evaporation on the filtrate.

Technical Field

The invention relates to a pharmaceutical monomer containing metronidazole and a preparation method thereof, in particular to a method for preparing 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate by utilizing the reaction of metronidazole and acryloyl chloride under certain conditions and performing nuclear magnetism representation on the product.

Background

Metronidazole, mainly used for treating or preventing the above anaerobic bacteria induced systemic or local infection, such as anaerobic bacteria infection of abdominal cavity, digestive tract, female reproductive system, lower respiratory tract, skin and soft tissue, bone and joint, etc., and also effective on septicemia, endocarditis, meningeal infection and colitis induced by antibiotic; treatment of tetanus is often combined with Tetanus Antitoxin (TAT); can also be used for oral cavity anaerobe infection.

The hydrophobic nitroimidazole group of metronidazole can be reduced into hydrophilic aminoimidazole by a reducing agent under the low-oxygen environment.

The double bond is connected to the metronidazole, so that the dopamine can participate in polymerization reaction, and various biological materials are functionalized to have low-oxygen responsiveness.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a metronidazole-containing drug monomer and a preparation method thereof.

The technical purpose of the invention is realized by the following technical scheme.

The invention relates to a metronidazole-containing drug monomer and a preparation method thereof, which are carried out according to the following steps:

uniformly dispersing metronidazole and triethylamine in an organic solvent, and then uniformly dispersing acryloyl chloride in the organic solvent, wherein the mass ratio of the metronidazole to the triethylamine to the acryloyl chloride is 4: (2-3): (4-5), dropwise adding the acryloyl chloride solution into the metronidazole and acid-binding agent solution in an ice bath to react, so that hydroxyl of the metronidazole and chloride ions of the acryloyl chloride react to generate 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate.

The organic solvent is dichloromethane, diethyl ether, petroleum ether, chloroform, tetrahydrofuran or toluene.

And dropwise adding the acryloyl chloride solution into the metronidazole and acid-binding agent solution in an ice bath at the temperature of-5-0 ℃, stirring and reacting for 11-13h in the ice bath at the temperature of-5-0 ℃, then heating to room temperature, and continuously stirring and reacting for 11-13 h.

Filtering after the reaction is finished, carrying out rotary evaporation on the filtrate, diluting the filtrate with an organic solvent and ultrapure water to obtain a concentrated solution, washing the concentrated solution with ultrapure water, adding a drying agent into an organic phase after liquid separation, carrying out overnight drying, filtering again, and carrying out rotary evaporation on the filtrate.

It is worth noting that the first rotary evaporation concentration should be stopped before the solid is precipitated.

The chemical reactions involved in the present invention are carried out according to the following chemical reaction formulae.

The invention has the beneficial effects that: the 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate prepared by the invention has both a nitroimidazole group and an acrylate group, the nitroimidazole group has low-oxygen responsiveness, and the acrylate group can be subjected to free radical polymerization or Michael addition reaction with sulfydryl, amino and the like, so that the monomer can modify a polymer to enable the polymer to have the nitroimidazole group, thereby obtaining the polymer with low-oxygen responsiveness, and having potential application value in the field of bioengineering.

Drawings

FIG. 1 is a drawing showing 2- (2-methyl-5-nitro-1H-imidazol-1-yl) ethyl acrylate prepared by an example of the present invention¹H-NMR spectrum.

Detailed Description

The following is a further description of the invention and is not intended to limit the scope of the invention.

Preparing the instruments needed by the experiment, cleaning the round-bottom flask, the constant-pressure dropping funnel, the beaker and the magnetons used for the reaction, and placing the flask, the constant-pressure dropping funnel, the beaker and the magnetons in an oven for drying.

Firstly, weighing 4g of metronidazole by using a tray balance, placing the metronidazole into a round-bottom flask, adding magnetons, adding 70ml of dichloromethane, adding 3ml of triethylamine into the solution, and uniformly mixing. Adding 10ml of chloroform into a constant pressure dropping funnel, adding 4ml of acryloyl chloride into the constant pressure dropping funnel, uniformly mixing, dropwise adding into the solution after preparation, and starting dropwise adding after gently stirring by a dropper.

Preparing broken ice blocks in advance, putting the broken ice blocks into an aluminum basin, adding a proper amount of water, and carrying out an ice-water bath reaction. And (3) putting the reaction system into an ice water bath for reaction for 12 hours, and then reacting at room temperature for 12 hours.

After the reaction is finished, the round-bottom flask is taken out by wearing a cloth glove, the round-bottom flask is wiped dry by using clean toilet paper, and each bottle mouth is opened to suck out small magnetons by using a magnet. Pouring off ice water for reaction, filtering the reaction solution, carrying out rotary evaporation on the filtrate for concentration, adding 50ml of chloroform for dilution after the filtrate is concentrated to about 15ml, washing with ultrapure water for three times, adding anhydrous calcium chloride particles into an organic phase for overnight drying after liquid separation, and carrying out rotary evaporation on the filtrate after filtration to obtain a light yellow solid product.

Triethylamine, acryloyl chloride and chloroform all have pungent odor, and care should be taken when using.

Attention should be paid to stop rotary evaporation before solid is precipitated when the rotary evaporation is concentrated for the first time.

The organic phase was dried after washing with water overnight to ensure complete removal of water.

By using¹The chemical structure of 2- (2-methyl-5-nitro-1H-imidazol-1-yl) ethyl acrylate obtained in the examples of the present invention was characterized by H NMR, and it is apparent from FIG. 1 that an absorption peak at 8.2ppm for a hydrogen atom on an imidazole group and an absorption peak at 2.3ppm for a methyl group on an imidazole group were observed, the absorption peak of the double bond at 5.9-6.6ppm and the absorption peak of the methylene at 3.8-4.3ppm well characterize the structure of 2- (2-methyl-5-nitro-1H-imidazol-1-yl) ethyl acrylate, from which the successful synthesis of 2- (2-methyl-5-nitro-1H-imidazol-1-yl) ethyl acrylate can be demonstrated.

The preparation of the metronidazole-containing drug monomer can be realized by adjusting the process parameters according to the content of the invention, and the performance of the metronidazole-containing drug monomer is basically consistent with that of the embodiment of the invention.

The invention has been described in an illustrative manner, and it is to be understood that any simple variations, modifications or other equivalent changes which can be made by one skilled in the art without departing from the spirit of the invention fall within the scope of the invention.