阅读说明：本技术 一种替硝唑的合成方法 (Synthesis method of tinidazole ) 是由 陶舟 何全斌 李亚军 于 2019-10-16 设计创作，主要内容包括：本发明属于化学制药合成领域,具体涉及一种替硝唑的合成方法。一种替硝唑的合成方法,以β-羟基乙硫醚和2-甲基-5-硝基咪唑为原料,用甲苯作溶剂,在三氯化铝的作用下进行缩合反应,经过淬灭过滤后得到缩合物,再将该缩合物在钼酸钠催化下滴加双氧水氧化,得到替硝唑粗品。本发明使用甲苯作溶剂,三氯化铝作脱水剂,钼酸钠作氧化催化剂,溶剂便宜可回收节约成本,减少三废。(The invention belongs to the field of chemical pharmaceutical synthesis, and particularly relates to a method for synthesizing tinidazole. A method for synthesizing tinidazole comprises the steps of taking beta-hydroxyethyl sulfide and 2-methyl-5-nitroimidazole as raw materials, taking methylbenzene as a solvent, carrying out condensation reaction under the action of aluminum trichloride, carrying out quenching and filtering to obtain a condensation compound, and dropwise adding hydrogen peroxide to oxidize the condensation compound under the catalysis of sodium molybdate to obtain a tinidazole crude product. The invention uses toluene as solvent, aluminum trichloride as dehydrating agent and sodium molybdate as oxidation catalyst, the solvent is cheap and can be recovered, thereby saving cost and reducing three wastes.)

1. A method for synthesizing tinidazole takes beta-hydroxyethyl sulfide and 2-methyl-5-nitroimidazole as raw materials, and is characterized in that: toluene is used as a solvent, condensation reaction is carried out under the action of aluminum trichloride, a condensation compound is obtained after quenching and filtering, and then hydrogen peroxide is dropwise added into the condensation compound under the catalysis of sodium molybdate for oxidation, so as to obtain a tinidazole crude product.

2. The method for synthesizing tinidazole according to claim 1, characterized in that: the mass ratio of the 2-methyl-5-nitroimidazole to the beta-hydroxyethyl sulfide is 1.3-1.5: 1, the mass ratio of the 2-methyl-5-nitroimidazole to the aluminum trichloride is 10-14: 1.

3. the method for synthesizing tinidazole according to claim 1, characterized in that: the mass ratio of the hydrogen peroxide to the beta-hydroxyethyl sulfide is 0.5-1: 1.

4. the method for synthesizing tinidazole according to claim 1, characterized in that: the condensation reaction temperature is 95 +/-2 ℃, and the reaction time is 2-3 hours.

5. The method for synthesizing tinidazole according to claim 1, characterized in that: the temperature of the oxidation process is 45-50 ℃.

6. The method for synthesizing tinidazole according to claim 1, characterized in that: the usage amount of the sodium molybdate oxidation catalyst is 0.5-5% of the mass of the substrate.

7. The method for synthesizing tinidazole according to claim 1, characterized in that: refining the obtained tinidazole crude product by using 70% ethanol water and activated carbon, and drying to obtain tinidazole refined product.

8. The method for synthesizing tinidazole according to claim 7, characterized in that: the dosage of the ethanol water is 2 times of the weight of the tinidazole crude product.

9. The method for synthesizing tinidazole according to claim 7, characterized in that: the dosage of the active carbon is 1-2% of the weight of the tinidazole crude product.

Technical Field

The invention belongs to the field of chemical pharmaceutical synthesis, and particularly relates to a method for synthesizing tinidazole.

Background

Tinidazole is a high-efficiency anti-amoebic and anti-anaerobic drug, and compared with the traditional anti-anaerobic drug metronidazole, the tinidazole has the advantages of good drug effect, small side effect and the like.

Regarding the preparation method of tinidazole, the current literature reports that hydroxy ethyl sulfide and 2-methyl-5-nitroimidazole are generally used as raw materials, methyl isobutyl ketone is used as a solvent, condensation reaction is carried out under the catalysis of Lewis acid to obtain a condensate 1- (ethyl thioethyl) -2-methyl-5-nitroimidazole, and then oxidation is carried out by about 30% of hydrogen peroxide under the acidic condition to obtain the required product, tinidazole. The reaction steps of the process need four steps, and the process mainly has the defects of numerous required raw materials, large pollution on the operation site, complex process, low yield (the total yield is about 40 percent), long production period, poor product quality and the like.

Also, as the method for preparing tinidazole in chinese patent CN1706832A, a p-xylene system is used as a solvent, and after condensation reaction under an acidic condition, the solvent is quenched, neutralized, extracted and washed, and then oxidized under the direct catalysis of hydrogen peroxide and ammonium molybdate which is an oxidation catalyst, so as to prepare a crude product of nitrozole. But the method has the problems that the unit price of p-xylene is higher, the p-xylene is difficult to recover, a large amount of organic waste liquid is generated, and the manufacturing cost and the cost of three wastes are increased; meanwhile, the oxidation catalyst ammonium molybdate is used in a large amount, the catalytic efficiency is not high, and the yield is low.

Disclosure of Invention

In order to solve the technical problems, the invention provides a method for synthesizing tinidazole.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

a method for synthesizing tinidazole takes beta-hydroxyethyl sulfide and 2-methyl-5-nitroimidazole as raw materials, and is characterized in that: toluene is used as a solvent, condensation reaction is carried out under the action of aluminum trichloride, a condensation compound is obtained after quenching and filtering, and then hydrogen peroxide is dropwise added into the condensation compound under the catalysis of sodium molybdate for oxidation, so as to obtain a tinidazole crude product.

Further, the mass ratio of the 2-methyl-5-nitroimidazole to the beta-hydroxyethyl sulfide is 1.3-1.5: 1, the mass ratio of the 2-methyl-5-nitroimidazole to the aluminum trichloride is 10-14: 1.

further, the mass ratio of the hydrogen peroxide to the beta-hydroxyethyl sulfide is 0.5-1: 1.

further, the temperature of the condensation reaction is 95 +/-2 ℃, and the reaction time is 2-3 hours.

Further, the temperature of the oxidation process is 45-50 ℃.

Further, the usage amount of the sodium molybdate oxidation catalyst is 0.5-5% of the mass of the substrate.

And further, refining the obtained tinidazole crude product by using 70% ethanol water and activated carbon, and drying to obtain a tinidazole refined product.

Furthermore, the dosage of the ethanol water is 2 times of the weight of the tinidazole crude product.

Furthermore, the dosage of the active carbon is 1-2% of the weight of the tinidazole crude product.

The invention has the beneficial effects that:

1. a one-pot method is adopted to synthesize a tinidazole crude product, so that the reaction steps are simplified; the three wastes are reduced; meanwhile, the content of the tinidazole refined product reaches more than 99.90 percent.

2. Compared with the prior art, the method has the advantages that aluminum trichloride is adopted to replace Lewis acid (concentrated sulfuric acid), can be directly and simply separated from condensation reaction liquid by a physical method, and can be recycled, so that the yield of tinidazole is effectively improved; and secondly, the separation time and the separation cost of the catalyst and the condensation reaction liquid after the condensation reaction process are reduced.

3. Sodium molybdate is used as an oxidation catalyst, so that complete catalytic oxidation of condensation reaction liquid can be ensured in the oxidation reaction process, and the yield of the tinidazole crude product is improved; the oxidation reaction has no heat accumulation, and the production safety is improved.

4. In the purification process of the tinidazole crude product, ethanol in the prior art is replaced by 70% ethanol water in an amount which is 2 times that of the tinidazole crude product, the tinidazole crude product is dissolved by the 70% ethanol water, and the active carbon is directly filtered to absorb impurity components in the tinidazole crude product, no new impurity is introduced, no tinidazole by-product is generated, and the content of the tinidazole refined product is effectively improved; and the ethanol water and the active carbon can be recycled, so that the tinidazole refining cost is reduced.

Detailed Description

In order to better understand the present invention, the following embodiments are further described.

A method for synthesizing tinidazole comprises the steps of taking beta-hydroxyethyl sulfide and 2-methyl-5-nitroimidazole as raw materials, taking methylbenzene as a solvent, carrying out condensation reaction under the action of aluminum trichloride, carrying out quenching and filtering to obtain a condensation compound, and dropwise adding hydrogen peroxide to oxidize the condensation compound under the catalysis of sodium molybdate to obtain a tinidazole crude product.

The mass ratio of the 2-methyl-5-nitroimidazole to the beta-hydroxyethyl sulfide is 1.3-1.5: 1, the mass ratio of the 2-methyl-5-nitroimidazole to the aluminum trichloride is 10-14: 1. the mass ratio of the hydrogen peroxide to the beta-hydroxyethyl sulfide is 0.5-1: 1.

the condensation reaction temperature is 95 +/-2 ℃, and the reaction time is 2-3 hours.

The temperature of the oxidation process is 45-50 ℃.

The usage amount of the sodium molybdate oxidation catalyst is 0.5-5% of the mass of the beta-hydroxyethylsulfide.

And refining the obtained tinidazole crude product by using 70% of ethanol water and activated carbon, and drying to obtain a tinidazole refined product, wherein the dosage of the ethanol water is 2 times of the weight of the tinidazole crude product, and the dosage of the activated carbon is 1-2% of the weight of the tinidazole crude product.