阅读说明：本技术 一种三唑并苯并噻唑衍生物的制备方法 (Preparation method of triazolobenzothiazole derivative ) 是由 李艾 李海花 于 2018-01-19 设计创作，主要内容包括：本发明公开了一种三唑并苯并噻唑衍生物的制备方法,该方法是以2-氨基苯并噻唑衍生物和芳酰肼类化合物为起始原料,2-氨基苯并噻唑衍生物1、水合肼在盐酸作用下,在乙二醇溶剂中回流反应得到化合物2；该化合物2进一步与对氯甲基苯甲酰氯在三氯氧磷作用下反应得到化合物4,芳香酰肼和适量KOH溶于乙醇中,常温下和CS<Sub>2</Sub>反应得到化合物6,该化合物6在浓硫酸作用下反应得到化合物7,化合物4和化合物7在碳酸钾催化作用下,在乙腈溶剂中反应得到目标产物<Image he="21" wi="9" file="100004_DEST_PATH_IMAGE001.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>。本发明所采用的方法简单、操作容易、易于规模化生产,制备的化合物I经过实验验证,其具有较强的抑菌活性,可以在抑菌药物制剂中广泛应用。(The invention discloses a preparation method of triazolobenzothiazole derivatives, which takes 2-aminobenzothiazole derivatives and aroyl hydrazine compounds as starting materials, and 2-aminobenzothiazole derivatives 1 and hydrazine hydrate are subjected to reflux reaction in an ethylene glycol solvent under the action of hydrochloric acid to obtain compounds 2; the compound 2 further reacts with p-chloromethyl benzoyl chloride under the action of phosphorus oxychloride to obtain a compound 4, and the aromatic hydrazide and a proper amount of KOH are dissolved in ethanol and react with CS at normal temperature 2 Reacting to obtain a compound 6, reacting the compound 6 under the action of concentrated sulfuric acid to obtain a compound 7, and reacting the compound 4 and the compound 7 in an acetonitrile solvent under the catalytic action of potassium carbonate to obtain a target product)

1. A process for the preparation of a triazolobenzothiazole derivative, which comprises the steps of:

(a) taking 2-aminobenzothiazole derivative 1 and hydrazine hydrate as raw materials, and carrying out reflux reaction in an ethylene glycol solvent under the action of hydrochloric acid to obtain an intermediate compound 2-hydrazinobenzothiazole derivative 2; the molar ratio of the 2-aminobenzothiazole derivative to the hydrazine hydrate is 1: 4;

(b) reacting the 2-hydrazinobenzothiazole derivative 2 with p-chloromethyl benzoyl chloride in phosphorus oxychloride, pouring a reaction solution into ice water after the reaction is finished, separating out solids, filtering, drying, and separating by column chromatography to obtain an intermediate 4, wherein the molar ratio of the 2-hydrazinobenzothiazole derivative 2 to the p-chloromethyl benzoyl chloride is 1: 1.1;

(c) dissolving aromatic hydrazide derivative 5 and appropriate amount of KOH in ethanol, and dropwise adding CS at normal temperature₂Precipitating light yellow solid, filtering and drying to obtain an intermediate 6, wherein the aromatic hydrazide derivative 5, KOH and CS are₂In a molar ratio of 1:1.5: 1.5;

(d) putting the intermediate 6 into concentrated sulfuric acid, reacting at 0-5 ℃, pouring the reaction solution into crushed ice water after the reaction is finished, separating out yellow solid, filtering, washing the solution, putting the filtered solution into NaOH solution, filtering out insoluble impurities, adjusting the pH value of the solution to 5 by using hydrochloric acid to generate precipitate, filtering, and recrystallizing by using ethanol to obtain a 2-mercaptothiadiazole derivative 7;

(e) intermediate 4 and 2-mercaptothiadiazole derivative 7 are reacted at K₂CO₃The triazole benzothiazole derivative I is obtained by reaction in acetonitrile under catalysis, and the molar ratio of the intermediate 4 to the 2-mercaptothiadiazole derivative 7 is 1: 1.1;

the R is₁Is hydrogen, chlorine, bromine, fluorine or methyl; r₂Hydrogen, chlorine, bromine or fluorine.

2. The process for producing a triazolobenzothiazole derivative according to claim 1, wherein R is₁Is hydrogen, 4-chloro, 4-methyl.

3. The process for producing a triazolobenzothiazole derivative according to claim 1, wherein R is₂Is hydrogen, 2-chloro.

Technical Field

The invention relates to a preparation method of antibacterial drugs, in particular to a preparation method and application of triazolobenzothiazole derivatives.

Background

At present, people find that more and more bacteria generate serious drug resistance to the existing antibacterial drugs in anti-infection clinical treatment, even "super bacteria" with drug resistance to almost all antibacterial drugs appears, and in order to deal with the increasingly serious problem of bacterial drug resistance, the development of novel and more effective antibacterial drugs is urgently needed.

The nitrogen heterocyclic compound has wide biological activity, a plurality of medicine structures contain the structure, and the compound containing thiadiazole has excellent insecticidal and bactericidal medicinal activity; the triazole compound has the advantages of good biological activity, small toxicity to human cells and the like, and is widely used as various medicaments for resisting virus, bacteria and infection, and the like, and the study on a sterilization mechanism shows that the triazole compound can be combined with iron of enzyme system cytochrome P-450 of ergosterol in pathogenic bacteria through an azole ring nitrogen atom to interfere the activity of the enzyme system and block 14 alpha-demethylation reaction of ergosterol precursor lanosterol, so that the synthesis of ergosterol is inhibited, the irreparable damage of cell membranes is triggered, and the growth or death of the pathogenic bacteria is inhibited.

Disclosure of Invention

The invention aims to provide a preparation method of a triazolobenzothiazole-containing derivative, and simultaneously provides an application of the derivative in preparing an antibacterial preparation, so as to provide more medication options for clinically treating bacterial infection.

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

a process for the preparation of a triazolobenzothiazole derivative, which comprises the steps of:

(a) taking 2-aminobenzothiazole derivative 1 and hydrazine hydrate as raw materials, and carrying out reflux reaction in an ethylene glycol solvent under the action of hydrochloric acid to obtain an intermediate compound 2-hydrazinobenzothiazole derivative 2; the molar ratio of the 2-aminobenzothiazole derivative to the hydrazine hydrate is 1: 4;

(b) reacting the 2-hydrazinobenzothiazole derivative 2 with p-chloromethyl benzoyl chloride in phosphorus oxychloride, pouring a reaction solution into ice water after the reaction is finished, separating out solids, filtering, drying, and separating by column chromatography to obtain an intermediate 4, wherein the molar ratio of the 2-hydrazinobenzothiazole derivative 2 to the p-chloromethyl benzoyl chloride is 1: 1.1;

(c) dissolving aromatic hydrazide derivative 5 and appropriate amount of KOH in ethanol, and dropwise adding CS at normal temperature₂Precipitating light yellow solid, filtering and drying to obtain an intermediate 6, wherein the aromatic hydrazide derivative 5, KOH and CS are₂In a molar ratio of 1:1.5: 1.5;

(d) putting the intermediate 6 into concentrated sulfuric acid, reacting at 0-5 ℃, pouring the reaction solution into crushed ice water after the reaction is finished, separating out yellow solid, filtering, washing the solution, putting the filtered solution into NaOH solution, filtering out insoluble impurities, adjusting the pH value of the solution to 5 by using hydrochloric acid to generate precipitate, filtering, and recrystallizing by using ethanol to obtain a 2-mercaptothiadiazole derivative 7;

(e) intermediate 4 and 2-mercaptothiadiazole derivative 7 are reacted at K₂CO₃The triazole benzothiazole derivative I is obtained by reaction in acetonitrile under catalysis, and the molar ratio of the intermediate 4 to the 2-mercaptothiadiazole derivative 7 is 1: 1.1;

the R is₁Is hydrogen, chlorine, bromine, fluorine or methyl; r₂Hydrogen, chlorine, bromine or fluorine.

Preferably, said R is₁Is hydrogen, 4-chloro, 4-methyl.

Preferably, said R is₂Is hydrogen, 2-chloro.

The compound of the present invention can be uniformly mixed with a pharmacologically acceptable carrier to prepare various forms of pharmaceutical preparations for antibacterial agents according to conventional preparation methods.

If the compound synthesized by the invention is an active ingredient, the compound can be combined with water, cane sugar, sorbitol sugar, fructose and other components to prepare an oral liquid preparation; mixing with excipient (lactose, glucose, sucrose, and mannitol), disintegrating agent (starch), lubricant (stearic acid and pulvis Talci), and binder (gelatin and polyvinyl alcohol), and making into tablet or capsule.

The compound synthesized by the invention can be used as an active ingredient and can also be prepared into injection with normal saline, glucose solution or a mixed carrier consisting of saline and glucose.

The clinical effective dose of the traditional Chinese medicine composition is 10-20 mg/person/day, and the dosage is 2-3 times per day. The physician can also plan the dosage to be taken according to individual differences of patients.

The invention takes aminobenzothiazole derivative and aryl hydrazide compound as initial raw materials, the aminobenzothiazole derivative reacts with hydrazine hydrate to obtain compound 2, the compound 2 further reacts with p-chloromethyl benzoyl chloride under the action of phosphorus oxychloride to obtain compound 4, and the aryl hydrazide compound 5 reacts with CS in ethanol/KOH medium₂The compound 6 is obtained by reaction, the compound 4 and the compound 6 react in acetonitrile solvent under the catalysis of potassium carbonate, and the target product is successfully synthesized. The invention adopts an active group splicing method to introduce a thiadiazole pharmacophore into a triazolobenzothiazole structure to obtain a series of triazolo-thiadiazole derivatives containing thiadiazole substituted by specific groups. Meanwhile, the thiadiazole and the triazolothiadiazole contain a plurality of S, N and other heteroatoms in the structure, and are expected to generate strong hydrogen bond effect when combined with target protein in an organism, so that the compound can exert better biological activity. Test results show that the compounds have good antibacterial activity. The thiadiazole-containing material provided by the inventionThe triazolothiadiazole derivative as the antibacterial agent is reported for the first time in the industry, and the successful research and development of the active ingredient of the antibacterial agent greatly expands the selection range of antibacterial drugs and provides a new thought for the research and development of novel antibacterial drugs.

The preparation method of the triazolothiadiazole derivative containing thiadiazole is simple to operate, easy to operate and easy for large-scale production, and the prepared compound I has strong bacteriostatic activity and can be widely applied to bacteriostatic pharmaceutical preparations through experimental verification.

Detailed Description

The following examples serve to illustrate the invention in further detail, but without restricting it in any way.