阅读说明：本技术 一种甲硝唑的制备方法 (Preparation method of metronidazole ) 是由 李志会 尹焕新 朱树杰 高超 张维金 韩悦 张占元 于 2020-05-15 设计创作，主要内容包括：本发明涉及医药化工技术领域,具体公开一种甲硝唑的制备方法。所述甲硝唑的制备方法,包括以下步骤：a、羟化反应：将2-甲基-5-硝基咪唑加入由甲酸和浓硫酸组成的混酸中,升温溶解,以加入量递减的方式连续同时加入环氧乙烷和硫酸；b、去除甲酸：去除羟化反应液中的甲酸,加水进行水解；c、中和：向水解后的反应液中加入液碱进行中和,分离出甲硝唑。本发明工艺操作简单、甲酸回收利用率高、成本低,产品收率高、质量稳定性好、不易引入杂质。(The invention relates to the technical field of pharmaceutical chemicals, and particularly discloses a preparation method of metronidazole. The preparation method of the metronidazole comprises the following steps: a. hydroxylation reaction: adding 2-methyl-5-nitroimidazole into mixed acid consisting of formic acid and concentrated sulfuric acid, heating to dissolve, and continuously and simultaneously adding ethylene oxide and sulfuric acid in a decreasing adding amount mode; b. removing formic acid: removing formic acid in hydroxylation reaction liquid, and adding water for hydrolysis; c. neutralizing: adding liquid alkali into the reaction liquid after hydrolysis for neutralization, and separating out metronidazole. The method has the advantages of simple process operation, high recovery and utilization rate of formic acid, low cost, high product yield, good quality stability and difficult introduction of impurities.)

1. A preparation method of metronidazole is characterized by comprising the following steps: the method comprises the following steps:

a. hydroxylation reaction: adding 2-methyl-5-nitroimidazole into mixed acid consisting of formic acid and concentrated sulfuric acid, heating to dissolve, and continuously and simultaneously adding ethylene oxide and sulfuric acid in a decreasing adding amount mode;

the continuous adding time of the ethylene oxide and the sulfuric acid is 4-10h, the continuous adding time is averagely divided into at least 8 sections, the difference of the adding amount of the ethylene oxide in two adjacent sections is 1-2% of the total amount of the added ethylene oxide, and the difference of the adding amount of the sulfuric acid in two adjacent sections is 1-2% of the total amount of the added sulfuric acid;

b. removing formic acid: removing formic acid in hydroxylation reaction liquid, and adding water for hydrolysis;

c. neutralizing: adding liquid alkali into the reaction liquid after hydrolysis for neutralization, and separating out metronidazole.

2. The method for preparing metronidazole as claimed in claim 1, characterised in that: in the step a, the mixed acid is prepared by mixing 80-90% by mass of formic acid and 70-90% by mass of sulfuric acid according to the weight ratio of 0.5-2.0: 0.3-1.0 by mass ratio;

the mass ratio of the 2-methyl-5-nitroimidazole to the formic acid in the mixed acid is 1: 0.5-2.0.

3. The method for preparing metronidazole as claimed in claim 1, characterised in that: in the step a, the mass ratio of the addition amount of the ethylene oxide to the 2-methyl-5-nitroimidazole is 0.5-0.8: 1;

the mass concentration of the continuously added sulfuric acid is 70-90%, and the mass ratio of the added amount to the 2-methyl-5-nitroimidazole is 0.1-0.2: 1.

4. the method for preparing metronidazole as claimed in claim 1, characterised in that: in the step a, the temperature of the hydroxylation reaction is 70-95 ℃.

5. The method for preparing metronidazole as claimed in claim 1, characterised in that: in step a, the continuous addition time is divided into 10 segments on average.

6. The method for preparing metronidazole as claimed in claim 5, characterised in that: the addition amount of the ethylene oxide of each section respectively accounts for 15%, 14%, 13%, 12%, 11%, 10%, 8%, 7%, 6% and 4% of the total mass of the ethylene oxide;

the addition amount of the sulfuric acid in each section respectively accounts for 15%, 14%, 13%, 12%, 11%, 10%, 8%, 7%, 6% and 4% of the total mass of the sulfuric acid.

7. The method for preparing metronidazole as claimed in claim 1, characterised in that: in the step b, removing formic acid in the hydroxylation reaction liquid in a vacuum rectification mode; and/or

In the step b, the adding amount of the water is 1-2 times of the mass of the 2-methyl-5-nitroimidazole, the hydrolysis temperature is 60-90 ℃, and the hydrolysis time is 0.5-3 h.

8. The method for preparing metronidazole as claimed in claim 1, characterised in that: in the step c, the neutralization comprises primary neutralization and secondary neutralization; the end point pH value of the primary neutralization is 1.5-3.0, and unreacted 2-methyl-5-nitroimidazole is separated after the primary neutralization; the pH value of the end point of the secondary neutralization is 9.0-11.0.

9. The method for preparing metronidazole as claimed in claim 1, characterised in that: further comprises refining metronidazole separated in the neutralization process; the refining method comprises the following steps: dissolving metronidazole with water, decolorizing and crystallizing to obtain refined metronidazole product.

10. The method for preparing metronidazole as claimed in claim 9, characterised in that: the water consumption in the refining process is 5-8 times of the mass of the metronidazole; and/or

Decoloring by adopting a carbon fiber film; and/or

The crystallization method combines ultrasonic wave and austenite curing; the specific crystallization method comprises the following steps: crystallizing for 0.5-3h under the condition that the ultrasonic crystallization frequency is 20KHz-60 KHz; heating to 92-95 deg.C at a rate of 0.1-0.3 deg.C/min, maintaining for 1-2 hr, cooling to 85-88 deg.C at a rate of 0.1-0.3 deg.C/min, and repeatedly heating and cooling for 3-5 times; finally, cooling to 15-25 ℃, and carrying out vacuum filtration to obtain a refined metronidazole product.

Technical Field

The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of metronidazole.

Background

Metronidazole (molecular formula: C)₆H₉N₃O₃CAS number: 443-48-1), chinese name: 1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole. Metronidazole is nitroimidazole antiprotozoal and anaerobe medicine, has strong killing effect on trichomonas in urogenital system, amoeba protozoa and giardia in intestinal tract and tissue, and can be used for treating diseases caused by trichomoniasis, amoebic dysentery and amoeba liver abscess. Metronidazole has effect in killing anaerobic microorganism, and can be used for treating and preventing diseases caused by anaerobic bacteria, and is used in growth phase of protozoa or anaerobic bacteria, and the protozoa and anaerobic bacteria are killed by destroying DNA chain or inhibiting DNA synthesis. Metronidazole was chosen by the world health organization as the primary drug against anaerobic infections in 1978.

The preparation process of metronidazole usually uses 2-methyl-5-nitroimidazole and ethylene oxide as raw materials, and makes them produce hydroxylation reaction under the acidic condition (in the presence of formic acid) to produce metronidazole, in which the ethylene oxide is generally introduced by stage, and in the intermediate process the sulfuric acid is added by stage. Because ethylene oxide is hydrolyzed to generate ethylene glycol in the reaction process, the ethylene glycol is easy to generate esterification reaction with formic acid to consume the formic acid, the solubility of 2-methyl-5-nitroimidazole is reduced along with the reduction of the acidity, and the contact effect with the ethylene oxide is influenced after the 2-methyl-5-nitroimidazole is separated out, so that the hydroxylation reaction is influenced, the acidity of the system is maintained by supplementing sulfuric acid along with the reaction, and the solubility of the 2-methyl-5-nitroimidazole is ensured. Although the situation can be relieved by adopting the mode of introducing ethylene oxide in sections and adding sulfuric acid in a plurality of times, the phenomenon that the 2-methyl-5-nitroimidazole is separated out before the sulfuric acid is supplemented every time, and the acid value in the system fluctuates greatly when the sulfuric acid is supplemented, so that the synthesized metronidazole is decomposed, and the yield and the quality are influenced.

Disclosure of Invention

Aiming at the problems that the yield and purity of metronidazole prepared by the existing metronidazole preparation method are low and pollutants are easily introduced into the product, the invention provides a metronidazole preparation method.

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

a preparation method of metronidazole comprises the following steps:

a. hydroxylation reaction: adding 2-methyl-5-nitroimidazole into mixed acid consisting of formic acid and concentrated sulfuric acid, heating to dissolve, and continuously and simultaneously adding ethylene oxide and sulfuric acid in a decreasing adding amount mode;

the continuous adding time of the ethylene oxide and the sulfuric acid is 4-10h, the continuous adding time is averagely divided into at least 8 sections, the difference of the adding amount of the ethylene oxide in two adjacent sections is 1-2% of the total amount of the added ethylene oxide, and the difference of the adding amount of the sulfuric acid in two adjacent sections is 1-2% of the total amount of the added sulfuric acid;

b. removing formic acid: removing formic acid in hydroxylation reaction liquid, and adding water for hydrolysis;

c. neutralizing: adding liquid alkali into the reaction liquid after hydrolysis for neutralization, and separating out metronidazole.

Compared with the prior art, the preparation method of metronidazole provided by the invention has the advantages that ethylene oxide and sulfuric acid are continuously and simultaneously added in a mode of decreasing the adding amount in the hydroxylation reaction process, the utilization rate of ethylene oxide is obviously improved, 2-methyl-5-nitroimidazole is ensured to be always in a dissolved state, severe fluctuation of acid value in reaction liquid and decomposition of metronidazole generated by reaction are avoided, side reaction is reduced, the conversion rate and selectivity of the reaction are improved, and the yield and quality of metronidazole are further improved.

After the formic acid removing process, the hydrolysis process is added, and ester impurities generated in the reaction liquid can be hydrolyzed into metronidazole through hydrolysis, so that the yield of the metronidazole is greatly improved.

The preparation method of metronidazole provided by the invention has the advantages of simple process operation, low cost, high product yield and good quality stability, and is suitable for popularization and use.

Preferably, in the step a, the mixed acid is prepared by mixing 80-90% by mass of formic acid and 70-90% by mass of sulfuric acid according to the mass ratio of 0.5-2.0: 0.3-1.0 by mass ratio; the mass ratio of the 2-methyl-5-nitroimidazole to the formic acid in the mixed acid is 1: 0.5-2.0.

Further, in the step a, the mixed acid is prepared by mixing 80-90% by mass of formic acid and 70-90% by mass of sulfuric acid according to the weight ratio of 0.8-1.2: 0.4-0.6 by mass ratio; the mass ratio of the 2-methyl-5-nitroimidazole to the formic acid in the mixed acid is 1: 0.8-1.2. The composition of the mixed acid solution and the proportion of the mixed acid solution to the 2-methyl-5-nitroimidazole can further improve the selectivity of the initial reaction and the product yield.

Preferably, in the step a, the mass ratio of the added amount of the ethylene oxide to the 2-methyl-5-nitroimidazole is 0.5-0.8: 1; the concentration of the continuously added sulfuric acid is 70-90% in a decreasing mode, and the mass ratio of the added amount to the 2-methyl-5-nitroimidazole is 0.1-0.2: 1.

further, in the step a, the mass ratio of the added amount of the ethylene oxide to the 2-methyl-5-nitroimidazole is 0.6-0.7: 1; the concentration of the continuously added sulfuric acid is 70-90% in a decreasing mode, and the mass ratio of the added amount to the 2-methyl-5-nitroimidazole is 0.12-0.16: 1.

preferably, in step a, the temperature of the hydroxylation reaction is 70-95 ℃.

Further, in the step a, the temperature of the hydroxylation reaction is 80-90 ℃; the continuous adding time of the ethylene oxide and the sulfuric acid is 6-8 h.

Preferably, the continuous addition time is divided into 10 segments on average.

Preferably, the addition amount of the ethylene oxide of each segment respectively accounts for 15%, 14%, 13%, 12%, 11%, 10%, 8%, 7%, 6% and 4% of the total mass of the ethylene oxide;

the addition amount of the sulfuric acid in each section respectively accounts for 15%, 14%, 13%, 12%, 11%, 10%, 8%, 7%, 6% and 4% of the total mass of the sulfuric acid. The method of continuously and uninterruptedly adding the ethylene oxide from fast to slow according to the specific aeration rate of the ethylene oxide and the dropping rate of the sulfuric acid adopted in the hydroxylation reaction process further improves the utilization rate of the ethylene oxide and the yield of the reaction.

Preferably, in the step b, formic acid in the hydroxylation reaction liquid is removed by means of vacuum rectification.

The recovered formic acid also needs to be treated after the hydroxylation reaction is finished so as to reduce the consumption of liquid caustic soda for subsequent neutralization. The formic acid recovered by the conventional direct reduced pressure distillation has high water content and cannot be recycled; the method of esterification of the lower alcohol adopted can introduce other substances, can involve the problem of solvent residue of the product, and causes pollution to the final product. The invention adopts the way of vacuum rectification in the process of removing formic acid, can ensure that the water content in the recovered formic acid is less than 15 percent, can be directly and repeatedly used in the hydroxylation reaction process, reduces the preparation cost and does not attract other substances.

Preferably, in the step c, the addition amount of the water is 1-2 times of the mass of the 2-methyl-5-nitroimidazole, the hydrolysis temperature is 60-90 ℃, and the hydrolysis time is 0.5-3 h.

Further, in the step c, the adding amount of the water is 1.2-1.5 times of the mass of the 2-methyl-5-nitroimidazole, the hydrolysis temperature is 70-85 ℃, and the hydrolysis time is 1-2 hours.

The selection of the hydrolysis conditions can further reduce the ester impurities in the reaction liquid, so that the ester impurities generated in the reaction liquid are directionally hydrolyzed to become metronidazole, and the yield of the metronidazole is increased.

Preferably, in step d, the neutralization comprises primary neutralization and secondary neutralization; the pH value of the primary neutralization end point is 1.5-3.0, and unreacted 2-methyl-5-nitroimidazole is separated out after the primary neutralization; the pH value of the end point of the secondary neutralization is 9.0-11.0.

Further, the pH value of the primary neutralization end point is 2.0-2.5; the pH value of the end point of the secondary neutralization is 9.5-10.0.

Preferably, the method also comprises refining metronidazole separated in the neutralization process; the refining method comprises the following steps: dissolving metronidazole with water, decolorizing and crystallizing to obtain refined metronidazole product.

Preferably, the water consumption in the refining process is 5-8 times of the mass of the metronidazole;

furthermore, the water consumption in the refining process is 6-7 times of the mass of the metronidazole.

Preferably, the decolorization is performed using a carbon fiber membrane. The carbon fiber membrane decoloration technology is adopted to replace the traditional activated carbon decoloration, the decoloration effect of the carbon fiber membrane decoloration technology on the reaction liquid is equivalent to that of the activated carbon technology, but the labor intensity is greatly reduced, the operation environment is improved, the generation of dangerous waste of the activated carbon is avoided, and the dangerous waste treatment cost is reduced.

Preferably, the crystallization process uses ultrasound in combination with austenite ripening. The specific crystallization method comprises the following steps: crystallizing for 0.5-3h under the condition that the ultrasonic crystallization frequency is 20KHz-60 KHz; heating to 92-95 deg.C at a rate of 0.1-0.3 deg.C/min, maintaining for 1-2 hr, cooling to 85-88 deg.C at a rate of 0.1-0.3 deg.C/min, and repeatedly heating and cooling for 3-5 times; finally, cooling to 15-25 ℃, and carrying out vacuum filtration to obtain a refined metronidazole product. The crystallization operation is carried out by adopting a mode of combining ultrasonic wave and austenite curing, the crystal form of the product is effectively improved, the product quality is further improved, the precipitation rate of the crystallization product is improved, and the yield of metronidazole is increased.

Further, the specific crystallization method comprises the following steps: crystallizing for 1-2h under the condition that the ultrasonic crystallization frequency is 30KHz-40 KHz; heating to 92-95 deg.C at a rate of 0.1-0.3 deg.C/min, maintaining for 1-2 hr, cooling to 85-88 deg.C at a rate of 0.1-0.3 deg.C/min, and repeating the heating and cooling for 3 times; finally, cooling to 15-25 ℃, and carrying out vacuum filtration to obtain metronidazole.

Drawings

FIG. 1 is a flow chart of the preparation of metronidazole in example 1 of the present invention;

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.