阅读说明：本技术 一种替硝唑工艺杂质及其合成方法 (Tinidazole process impurity and synthesis method thereof ) 是由 孙立杰 石红超 田鹏美 魏赛丽 张伟丽 延春霞 张雪彤 孙朝振 于 2021-08-27 设计创作，主要内容包括：本发明涉及化学合成技术领域,具体公开一种替硝唑工艺杂质及其合成方法。所述替硝唑工艺杂质的结构如式(Ⅰ)所示,合成方法包括如下步骤：以4-硝基咪唑和羟基乙硫醚为原料,以苯类化合物为溶剂,在浓硫酸的作用下进行缩合反应,得式(Ⅱ)所示的化合物；式(Ⅱ)所示的化合物在可溶性钼酸盐的催化作用下,经双氧水氧化,得式(Ⅰ)所示的替硝唑工艺杂质。本发明通过特定的合成工艺,制备得到了纯度可达99.7％以上的替硝唑工艺杂质,解决了替硝唑工艺杂质对照品来源的问题,有利于进一步完善替硝唑原料药或其制剂的质量标准。(The invention relates to the technical field of chemical synthesis, and particularly discloses a tinidazole process impurity and a synthesis method thereof. The structure of the tinidazole process impurity is shown as a formula (I), and the synthesis method comprises the following steps: taking 4-nitroimidazole and hydroxyethyl sulfide as raw materials, taking benzene compounds as a solvent, and carrying out condensation reaction under the action of concentrated sulfuric acid to obtain a compound shown in a formula (II); oxidizing the compound shown in the formula (II) by hydrogen peroxide under the catalytic action of soluble molybdate to obtain tinidazole process impurities shown in the formula (I). The tinidazole technical impurity with the purity of more than 99.7 percent is prepared by a specific synthesis process, the problem of the source of the tinidazole technical impurity reference substance is solved, and the method is favorable for further synthesisAnd the quality standard of the tinidazole bulk drug or the preparation thereof is improved.)

1. A tinidazole technical impurity is characterized in that the structure is shown in formula (I):

2. the method for synthesizing tinidazole technical impurities according to claim 1, characterized by comprising the following steps:

taking 4-nitroimidazole and hydroxyethyl sulfide as raw materials, taking benzene compounds as a solvent, and carrying out condensation reaction under the action of concentrated sulfuric acid to obtain a compound shown in a formula (II);

oxidizing the compound shown in the formula (II) by hydrogen peroxide under the catalytic action of soluble molybdate to obtain tinidazole process impurities shown in the formula (I);

3. the method for synthesizing tinidazole technical impurities according to claim 2, characterized by comprising the following steps:

step a, dissolving 4-nitroimidazole and hydroxyethyl sulfide in a benzene compound, adding concentrated sulfuric acid at 45-60 ℃, heating to 85-90 ℃, reacting for 5-7 h, cooling, adjusting pH to 6.5-7.5, filtering, washing a filter cake, collecting filtrate, and separating liquid to obtain a reaction liquid containing the compound shown in the formula (II);

and b, adding a molybdate aqueous solution into the reaction liquid containing the compound shown in the formula (II), uniformly stirring, adding hydrogen peroxide at the temperature of 60-70 ℃, reacting for 0.5-1.5 h under heat preservation, cooling, filtering, washing a filter cake, and drying the obtained filter cake to obtain the tinidazole process impurity.

4. The method for synthesizing tinidazole process impurities according to claim 3, wherein in step a, the benzene compound is at least one of toluene, o-xylene, m-xylene or p-xylene.

5. The method for synthesizing tinidazole process impurities according to claim 3, wherein in step a, the molar ratio of 4-nitroimidazole to hydroxyethylsulfide is 1: 0.63-1.10.

6. The method for synthesizing tinidazole process impurities according to claim 3, wherein in step a, the 4-nitroimidazole and H in concentrated sulfuric acid₂SO₄The molar ratio of (A) to (B) is 1: 0.9-1.2.

7. The method for synthesizing tinidazole process impurities according to claim 3, wherein in step b, the mass ratio of the 4-nitroimidazole to the molybdate aqueous solution is 1: 1-1.1.

8. The method for synthesizing tinidazole process impurities according to claim 7, wherein in step b, the mass concentration of the molybdate aqueous solution is 1.0 wt% -1.5 wt%.

9. As claimed in claim 3The method for synthesizing the tinidazole technical impurities is characterized in that in the step b, the 4-nitroimidazole and H in hydrogen peroxide₂O₂The molar ratio of (A) to (B) is 1: 1.8-2.5.

10. The method of synthesizing tinidazole process impurities according to claim 3, wherein the filter cake obtained in step a is used as 4-nitroimidazole raw material.

Technical Field

The invention relates to the technical field of chemical synthesis, in particular to tinidazole process impurities and a synthesis method thereof.

Background

Tinidazole belongs to nitroimidazole antibacterial drugs, is a high-efficiency drug for resisting amoeba and anaerobes, and has the advantages of good drug effect, small side effect and the like compared with the traditional anti-anaerobe drug metronidazole. Tinidazole is often used in combination with other anti-anaerobe drugs to treat diseases such as septicemia, respiratory tract infection, abdominal cavity and pelvic cavity infection caused by various anaerobes, and has few adverse reactions.

2-methyl-5-nitroimidazole is an important raw material for synthesizing tinidazole, but 2-methyl-5-nitroimidazole also contains various impurities, some impurities can participate in the synthesis reaction for synthesizing tinidazole, and if the content of the impurities in the raw material of 2-methyl-5-nitroimidazole is high, the purity and yield of tinidazole products can be directly reduced, so that the quality of tinidazole preparations is reduced, and the safety and effectiveness of the clinical use of the medicament are even affected. In order to ensure and improve the quality of tinidazole products and preparations and ensure the safety and effectiveness of medicaments, detailed research and monitoring on impurities in the tinidazole synthesis process and preparations are needed. Although the existing literature and data report some related impurities of tinidazole, the research on the impurities with novel structures generated in the tinidazole synthesis process is a dynamic development and continuously promoted process, can be applied to impurity analysis of tinidazole, and further improves the quality standard of tinidazole bulk drugs or preparations thereof.

Disclosure of Invention

In view of the above, the invention provides tinidazole process impurities and a synthesis method thereof, and the method has the advantages of short steps, simple operation, mild reaction conditions and high purity.

In order to solve the technical problems, the technical scheme provided by the invention is as follows:

a tinidazole process impurity has a structure shown in formula (I):

the inventor finds a new impurity unexpectedly in the research and development process of synthesizing tinidazole, and finds out that the reason for generating the impurity is caused by the 4-nitroimidazole impurity contained in the 2-methyl-5-nitroimidazole in various ways in order to confirm the structure of the impurity. Through detecting a plurality of batches of 2-methyl-5 nitroimidazole raw materials, the content difference of 4-nitroimidazole impurities is found to be large, and the content is floated within the range of 0.1-0.75%. If the synthesis and refining process of tinidazole cannot effectively remove the derived impurities, the derived impurities can be remained in the final product, and the quality of the tinidazole product is influenced. Because the content of 4-nitroimidazole in the 2-methyl-5-nitroimidazole raw material is up to 0.75 percent, the derived impurities of 4-nitroimidazole in tinidazole need to be detected and controlled.

The inventor determines through multi-aspect analysis that the structure of the 4-nitroimidazole derivative impurity is shown as formula (I), and the impurity is a newly discovered process impurity and is named as 1- (2- (ethylsulfonyl) ethyl) -5-nitro-1H-imidazole. In order to more effectively control the quality of a tinidazole product and detect whether the tinidazole product contains impurities shown in formula (I), the impurity is synthesized, the purity of the synthesized impurity is higher and can reach more than 99.7%, and the impurity can be used as a reference substance for impurity detection to verify whether raw materials from different sources can be produced and combined to obtain a qualified tinidazole product, so that the safety and the effectiveness of the tinidazole product are ensured, and the method has very important significance for quality control of the tinidazole raw materials and subsequent preparation research.

The invention also provides a method for synthesizing tinidazole process impurities, which comprises the following steps:

taking 4-nitroimidazole and hydroxyethyl sulfide as raw materials, taking benzene compounds as a solvent, and carrying out condensation reaction under the action of concentrated sulfuric acid to obtain a compound shown in a formula (II);

oxidizing the compound shown in the formula (II) by hydrogen peroxide under the catalytic action of soluble molybdate to obtain tinidazole process impurities shown in the formula (I);

the tinidazole technical impurity with the purity of over 99.7 percent and the yield of more than 40 percent, which is shown in the formula (I), is prepared by a specific synthesis process, can be used as a related substance reference substance, solves the problem of the source of the tinidazole technical impurity reference substance, and increases the control type detection of the tinidazole impurity. The synthesis method of the tinidazole impurity provided by the invention can stably prepare and supply the impurity, and ensures that the impurity is very conveniently applied to qualitative and quantitative analysis of the impurity in the tinidazole production, so that the quality standard of the tinidazole raw material can be improved, and an important guiding significance is provided for safe medication of tinidazole.

Preferably, the method for synthesizing the tinidazole process impurities specifically comprises the following steps:

step a, dissolving 4-nitroimidazole and hydroxyethyl sulfide in a benzene compound, adding concentrated sulfuric acid at 45-60 ℃, heating to 85-90 ℃, reacting for 5-7 h, cooling, adjusting pH to 6.5-7.5, filtering, washing a filter cake, collecting filtrate, and separating liquid to obtain a reaction liquid containing the compound shown in the formula (II);

and b, adding a molybdate aqueous solution into the reaction liquid containing the compound shown in the formula (II), uniformly stirring, adding hydrogen peroxide at the temperature of 60-70 ℃, reacting for 0.5-1.5 h under heat preservation, cooling, filtering, washing a filter cake, and drying the obtained filter cake to obtain the tinidazole process impurity.

The synthesis method of the tinidazole impurity provided by the invention is simple to operate, the prepared impurity is good in yield and high in purity, the tinidazole impurity can be used as an impurity reference substance, the method is suitable for mass preparation, and a qualified, cheap and easily-obtained reference substance is provided for quality control of tinidazole bulk drug and preparations thereof.

The concentrated sulfuric acid is 98.3% by mass, and the mass percentage of the hydrogen peroxide is 30%.

Preferably, in step a, the benzene compound is at least one of toluene, o-xylene, m-xylene or p-xylene.

The preferential reaction solvent is favorable for promoting the full dissolution of reaction raw materials, improving the reaction rate and reducing the occurrence of side reactions.

Preferably, in the step a, the molar ratio of the 4-nitroimidazole to the hydroxyethylsulfide is 1: 0.63-1.10.

Further preferably, in the step a, the molar ratio of the 4-nitroimidazole to the hydroxyethylsulfide is 1:1.

Preferably, in step a, the 4-nitroimidazole is reacted with H in concentrated sulfuric acid₂SO₄The molar ratio of (A) to (B) is 1: 0.9-1.2.

Further preferably, in step a, the 4-nitroimidazole is reacted with H in concentrated sulfuric acid₂SO₄Is 1:1.

The preferred ratio of the reaction substances can ensure that the forward reaction is promoted under the condition of small usage amount, and the yield and the purity of the target product are improved.

Optionally, in step a, after adjusting the pH to 6.5-7.5, before filtering, the concentration of the system is diluted with toluene in the reaction system to improve the filtration efficiency.

Preferably, in the step b, the mass ratio of the 4-nitroimidazole to the molybdate aqueous solution is 1: 1-1.1.

Preferably, in the step b, the mass concentration of the molybdate aqueous solution is 1.0 wt% to 1.5 wt%.

Preferably, in step b, the molybdate is at least one of ammonium molybdate, sodium molybdate or potassium molybdate.

Further preferably, in step b, the molybdate is ammonium molybdate.

The optimized catalyst, namely the dosage of the catalyst, can not only accelerate the reaction rate and shorten the reaction time, but also improve the selectivity of the reaction and reduce the occurrence of side reactions, thereby improving the purity and the yield of the target compound.

Preferably, in step b, the 4-nitroimidazole is mixed with H in hydrogen peroxide₂O₂The molar ratio of (A) to (B) is 1: 1.8-2.5.

Further preferably, in step b, the 4-nitroimidazole is reacted with H in hydrogen peroxide₂O₂Is 1: 2.0.

The optimized dosage of the hydrogen peroxide is beneficial to fully oxidizing the compound shown in the formula (II) and improving the purity and yield of the target compound.

Preferably, the filter cake obtained in step a is recycled for use as 4-nitroimidazole feedstock.

The unreacted 4-nitroimidazole is recycled, so that not only can the generation of hazardous wastes be reduced, but also the raw material cost is reduced, and higher economic benefit and environmental benefit are achieved.

The tinidazole impurity with high purity shown in the formula (I) is prepared by taking 4-nitroimidazole and hydroxy ethyl sulfide as raw materials under the conditions of a specific reaction solvent and a catalyst, and the tinidazole impurity is simple to operate, mild in reaction conditions and good in application prospect. The purity of the tinidazole impurity prepared by the method can reach more than 99.7 percent, the purity of the impurity reference substance and the accuracy of analysis work are effectively ensured, and the quality standard of the tinidazole raw material medicine or the preparation thereof is further improved.

Drawings

FIG. 1 is a high performance liquid chromatogram of a tinidazole process impurity and tinidazole mixed solution shown in formula (I) prepared by the 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.

In order to better illustrate the invention, the following examples are given by way of further illustration.

In the following examples and comparative examples, the concentrated sulfuric acid used is 98.3% by mass, and the hydrogen peroxide is 30% by mass.

Example 1

A method for synthesizing tinidazole process impurities comprises the following steps:

adding 30mL of toluene, 30.2g (0.27mol,1.0eq) of 4-nitroimidazole and 28.2g (0.27mol,1.0eq) of hydroxyethylsulfide into a reaction bottle, dropwise adding 26.6g (0.27mol,1.0eq) of concentrated sulfuric acid at 50 ℃, then heating to 88 ℃ for reaction for 6 hours, cooling to 35 ℃, adjusting the pH of the reaction solution to 7.0 by using ammonia water, then adding 50mL of toluene into the reaction solution, filtering, washing a filter cake by using 30mL of toluene, collecting filtrate, separating liquid, and collecting a toluene phase;

adding the toluene phase into a reaction bottle, adding an ammonium molybdate aqueous solution (0.30 g of ammonium molybdate is added into 30mL of water) under the stirring condition, dropwise adding 60.3g of hydrogen peroxide (0.54mol and 2.0eq) at 65 ℃, keeping the temperature for reaction for 1.0h, cooling to 20-30 ℃, filtering, washing the filter cake with 50mL of water, collecting the filter cake, and drying the filter cake at 45 ℃ for 7h in vacuum to obtain 30.9g of tinidazole process impurities shown in the formula (I), wherein the yield is 49.9% and the HPLC purity is 99.7%.

¹H NMR(CDCl₃，500MHz)：8.040(s,1H),7.807(s,1H),4.855～4.880(t,2H),3.506～3.531(t,2H),2.964～3.009(m,2H),1.384～1.414(t,3H)。

¹³C NMR(500MHz,CDCl₃)：142.71,134.20,50.94,48.80,40.99,6.38。

MS：[M+H]⁺The measurement value was 234.2.

Example 2

A method for synthesizing tinidazole process impurities comprises the following steps:

adding 30mL of toluene, 30.2g (0.27mol,1.0eq) of 4-nitroimidazole and 17.8g (0.17mol,0.63eq) of hydroxyethylsulfide into a reaction bottle, dropwise adding 32g (0.32mol,1.2eq) of concentrated sulfuric acid at 60 ℃, heating to 85 ℃ for reaction for 7 hours, cooling to 30 ℃, adjusting the pH of the reaction solution to 6.5 by using ammonia water, adding 50mL of toluene into the reaction solution, filtering, washing a filter cake by using 30mL of toluene, collecting filtrate, separating liquid, and collecting a toluene phase;

adding the toluene phase into a reaction bottle, adding an ammonium molybdate aqueous solution (0.40 g of ammonium molybdate is added into 30mL of water) under the stirring condition, dropwise adding 54.5g of hydrogen peroxide (0.48mol, 1.8eq) at 60 ℃, keeping the temperature for reaction for 1.5h, cooling to 20-30 ℃, filtering, washing the filter cake with 50mL of water, collecting the filter cake, and vacuum-drying the filter cake at 45 ℃ for 6h to obtain 27.3g of tinidazole process impurities shown in the formula (I), wherein the yield is 44.1% and the HPLC purity is 99.8%.

¹H NMR(CDCl₃，500MHz)：8.040(s,1H),7.807(s,1H),4.855～4.880(t,2H),3.506～3.531(t,2H),2.964～3.009(m,2H),1.384～1.414(t,3H)。

¹³C NMR(500MHz,CDCl₃)：142.71,134.20,50.94,48.80,40.99,6.38。

MS：[M+H]⁺The measurement value was 234.2.

Example 3

A method for synthesizing tinidazole process impurities comprises the following steps:

adding 30mL of toluene, 30.2g (0.27mol,1.0eq) of 4-nitroimidazole and 22.3g (0.21mol,0.79eq) of hydroxyethylsulfide into a reaction bottle, dropwise adding 24.1g (0.24mol,0.9eq) of concentrated sulfuric acid at 45 ℃, then heating to 90 ℃ for reaction for 5 hours, cooling to 45 ℃, adjusting the pH of the reaction solution to 7.5 by using ammonia water, then adding 50mL of toluene into the reaction solution, filtering, washing a filter cake by using 30mL of toluene, collecting filtrate, separating liquid, and collecting a toluene phase;

adding the toluene phase into a reaction bottle, adding an ammonium molybdate aqueous solution (0.45 g of ammonium molybdate is added into 30mL of water) under the stirring condition, dropwise adding 75.6g of hydrogen peroxide (0.67mol and 2.5eq) at 70 ℃, keeping the temperature for reaction for 0.5h, cooling to 20-30 ℃, filtering, washing the filter cake with 50mL of water, collecting the filter cake, and vacuum-drying the filter cake at 45 ℃ for 8h to obtain 25.6g of tinidazole process impurities shown in the formula (I), wherein the yield is 41.3 percent and the HPLC purity is 99.7 percent.

¹H NMR(CDCl₃，500MHz)：8.040(s,1H),7.807(s,1H),4.855～4.880(t,2H),3.506～3.531(t,2H),2.964～3.009(m,2H),1.384～1.414(t,3H)。

¹³C NMR(500MHz,CDCl₃)：142.71,134.20,50.94,48.80,40.99,6.38。

MS：[M+H]⁺The measurement value was 234.2.

The technical effects substantially equivalent to those of examples 1 to 3 can be achieved by replacing the ester of examples 1 to 3 with another benzene-based solvent or a combination of benzene-based solvents within the scope of the present invention, and by replacing the molybdate of examples 1 to 3 with another molybdate or a combination of molybdates within the scope of the present invention.

Comparative example 1

The comparison example provides a method for synthesizing tinidazole process impurities, which is completely the same as the example 1, and is different from the method in the step a in that the temperature of the concentrated sulfuric acid added in the step a is replaced by 70 ℃. 23.9g of tinidazole technical impurity is finally prepared, the yield is 38.6%, and the HPLC purity is 98.5%.

The HPLC method for detecting the impurity purity of the tinidazole process shown in formula (I) in examples 1 to 3 and comparative example 1 is as follows:

a chromatographic column: agilent ZORBAX SB-C84.6mm X250 mm, 5 μm;

mobile phase: acetonitrile-methanol-water in a volume ratio of 10:20: 70;

detection wavelength: 320 nm.

Sample introduction amount: 20 μ L.

The reason why the tinidazole process impurity shown in the formula (I) is not detected in the tinidazole raw material is probably because the process for synthesizing the tinidazole can effectively remove the impurity and also probably because the impurity is extremely similar to the structure of the tinidazole, so that chromatographic peaks are superposed. In order to verify whether the tinidazole process impurities prepared by the method can be effectively detected in tinidazole raw materials, the following experiment is carried out.

Weighing a proper amount of tinidazole technical impurity shown in formula (I), precisely weighing, adding a proper amount of methanol for dissolving, and quantitatively diluting with a mobile phase to prepare a solution containing 20 mu g of tinidazole technical impurity mother liquor per 1 mL. Taking 10mg of a test sample (tinidazole raw material), precisely weighing, placing in a 100mL measuring flask, adding a proper amount of methanol for dissolving, adding 1.5mL of the tinidazole process impurity mother liquor, diluting with a mobile phase, and fixing the volume to a scale to obtain a test sample solution. The results of the sample injection detection according to the HPLC method for detecting tinidazole process impurities are shown in figure 1. Wherein the peak time of the tinidazole is 7.118min, and the peak time of the tinidazole process shown in the formula (I) is 5.937 min. Therefore, the tinidazole process impurities prepared by the method can be used as a reference substance, the accuracy of analysis work is ensured, and the quality standard of the tinidazole raw material medicine or the preparation thereof is further improved.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.