阅读说明：本技术 一种奥硝唑异构体及其制备方法 (Ornidazole isomer and preparation method thereof ) 是由 张庆华 陈波 仇志军 徐汨 于 2020-06-16 设计创作，主要内容包括：本发明提供了一种奥硝唑异构体及其制备方法,奥硝唑异构体的结构如式VI所示；本发明的奥硝唑异构体丰富了奥硝唑类化合物种类,可以进一步研究奥硝唑的药物作用机理,并可以作为标准物质用于奥硝唑中的杂质分析、检测,进而为奥硝唑的质量研究和深入开发提供支持和保障。本发明的制备方法的合成路线合理,操作简单,反应温和,收率较高,产物纯度高,且环境友好,易于操作,适用于奥硝唑质量研究,具有很好的商业价值,为提高奥硝唑的质量研究提供了支持和保障。<Image he="324" wi="543" file="DDA0002540609570000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention provides an ornidazole isomer and a preparation method thereof, wherein the structure of the ornidazole isomer is shown as a formula VI; the ornidazole isomer enriches the types of ornidazole compounds, can further research the drug action mechanism of ornidazole, can be used as a standard substance for analyzing and detecting impurities in ornidazole, and further provides support and guarantee for the quality research and deep development of ornidazole. The preparation method disclosed by the invention is reasonable in synthesis route, simple to operate, mild in reaction, high in yield, high in product purity, environment-friendly, easy to operate, suitable for ornidazole quality research, high in commercial value and capable of providing support and guarantee for improving ornidazole quality research.)

1. An ornidazole isomer, wherein the structure of the ornidazole isomer is shown as formula VI:

2. the preparation method of the ornidazole isomer comprises the following steps:

(1) reacting 2-amino-3- (benzyloxy) propan-1-ol, glyoxal, and acetaldehyde in the presence of ammonium acetate to give the compound 3- (benzyloxy) -2- (2-methyl-1H-imidazol-1-yl) propan-1-ol of formula VI-3;

(2) halogenating 3- (benzyloxy) -2- (2-methyl-1H-imidazol-1-yl) propan-1-ol, a compound of formula VI-3, to give 1- (1- (benzyloxy) -3-chloropropan-2-yl) -2-methyl-1H-imidazole, a compound of formula VI-2;

(3) debenzylating a compound 1- (1- (benzyloxy) -3-chloropropane-2-yl) -2-methyl-1H-imidazole of formula VI-2 to obtain a compound 3-chloro-2- (2-methyl-1H-imidazol-1-yl) propan-1-ol of formula VI-1;

(4) carrying out nitration reaction on 3-chloro-2- (2-methyl-1H-imidazole-1-yl) propan-1-ol of a VI-1 compound to obtain an ornidazole isomer shown in a formula VI;

3. the preparation method according to claim 2, wherein the molar ratio of 2-amino-3- (benzyloxy) propan-1-ol, glyoxal, acetaldehyde and ammonium acetate in the step (1) is 1:1 to 1.2;

preferably, the glyoxal is added in the form of glyoxal aqueous solution, and the concentration of the glyoxal aqueous solution is preferably 20-40 wt%;

preferably, the acetaldehyde is added in the form of an acetaldehyde aqueous solution, and the concentration of the acetaldehyde aqueous solution is preferably 20-40 wt%.

4. The production method according to claim 2 or 3, wherein the reaction in the step (1) is carried out in a first solvent;

preferably, the first solvent is one or more selected from methanol, ethanol, isopropanol, and n-butanol;

preferably, the volume-to-mass ratio of the first solvent to the 2-amino-3- (benzyloxy) propan-1-ol in the step (1) is 15-25: 1 ml/g;

preferably, the reaction in step (1) is carried out at a temperature of 20 to 30 ℃, for example, room temperature, and the reaction time is preferably 6 to 12 hours, for example, 8 to 12 hours.

5. The production method according to any one of claims 2 to 4, wherein the step (1) further comprises the steps of:

(101) after the reaction is finished, carrying out reduced pressure concentration to obtain a crude product;

(102) and (3) purifying the crude product obtained in the step (101) by adopting a chromatography, wherein a mobile phase is dichloromethane-methanol, and the volume ratio of the mobile phase to the methanol is 100-95: 0-5.

6. The production method according to any one of claims 2 to 5, wherein methanesulfonyl chloride, thionyl chloride or phosphorus oxychloride is used as a halogenating agent in the halogenation reaction in the step (2);

preferably, the molar ratio of the halogenated reagent to the 3- (benzyloxy) -2- (2-methyl-1H-imidazol-1-yl) propan-1-ol in the step (2) is 1.05-1.5: 1, preferably 1.1-1.2: 1;

preferably, methanesulfonyl chloride is used as a halogenating reagent in the step (2), triethylamine is used as a catalyst for the halogenating reaction, and the molar ratio of triethylamine to 3- (benzyloxy) -2- (2-methyl-1H-imidazol-1-yl) propan-1-ol is 1.2-2: 1, such as 1.5-1.8: 1;

preferably, the halogenation reaction in the step (2) is carried out in a second solvent; more preferably, the second solvent is one or more selected from the group consisting of dichloromethane, chloroform and carbon tetrachloride; more preferably, the volume-to-mass ratio of the second solvent to the 3- (benzyloxy) -2- (2-methyl-1H-imidazol-1-yl) propan-1-ol is 30-50: 1ml/g, especially 40-50: 1 ml/g;

preferably, the halogenation reaction in the step (2) is performed at a temperature of 20-30 ℃, for example, room temperature, and the reaction time is preferably 1-6 hours, for example, 2-4 hours.

7. The production method according to any one of claims 2 to 6, wherein the step (2) includes the steps of:

(201) dissolving 3- (benzyloxy) -2- (2-methyl-1H-imidazol-1-yl) propan-1-ol represented by formula VI-3 and triethylamine in a second solvent;

(202) adding a halogenating reagent at the temperature of 0-5 ℃, and heating to the temperature of 20-30 ℃ for halogenating reaction to obtain a reaction solution;

(203) adding water into the reaction liquid obtained in the step (202) for quenching, extracting by adopting an organic solvent, and washing the obtained organic phase by using saturated saline water to obtain a saline water washed product;

(204) drying the product obtained in the step (203) after washing with brine, and concentrating under reduced pressure to obtain a crude product;

(205) purifying the crude product obtained in the step (204) by adopting a chromatography, wherein a mobile phase is petroleum ether-ethyl acetate, and the volume ratio of the mobile phase to the ethyl acetate is 95-90: 5-10;

preferably, the step (203) is performed by extraction with one or more organic solvents selected from dichloromethane, chloroform and carbon tetrachloride, such as chloroform;

preferably, the product obtained after the brine washing in the step (203) is dried by using anhydrous sodium sulfate in the step (204).

8. The method according to any one of claims 2 to 7, wherein the step (3) uses a catalyst selected from Pd/C-H₂Removing 1- (1- (benzyloxy) -3-chloropropane-2-yl) -2-methyl-1H-imidazole by using one reaction system of-ethanol, raney nickel-ethanol, ferric trichloride-acetic anhydride and stannic chloride-Dichloromethane (DMC)Benzyl group of (a);

preferably, the step (3) is performed by removing benzyl group of 1- (1- (benzyloxy) -3-chloropropan-2-yl) -2-methyl-1H-imidazole by a method comprising the following steps:

(301) adding 1- (1- (benzyloxy) -3-chloropropane-2-yl) -2-methyl-1H-imidazole and a Pd/C catalyst into ethanol, and reacting at 55-65 ℃, for example, 55-60 ℃ in a hydrogen atmosphere;

preferably, the Pd/C catalyst is used in an amount of 40 to 60 wt% based on the weight of 1- (1- (benzyloxy) -3-chloropropan-2-yl) -2-methyl-1H-imidazole;

preferably, the volume-to-mass ratio of the ethanol to the 1- (1- (benzyloxy) -3-chloropropane-2-yl) -2-methyl-1H-imidazole in the step (301) is 40-60: 1 ml/g.

9. The production method according to claim 8, wherein the step (3) further comprises the steps of:

(302) filtering and concentrating the reaction product obtained in the step (301) to obtain a crude product;

(303) and (3) purifying the crude product obtained in the step (303) by adopting a chromatography, wherein a mobile phase is petroleum ether-ethyl acetate, and the volume ratio of the petroleum ether-ethyl acetate is 60-50: 40-50.

10. The production method according to any one of claims 2 to 9, wherein the nitration reaction is carried out in the step (4) by a method comprising:

(401) dissolving 3-chloro-2- (2-methyl-1H-imidazol-1-yl) propan-1-ol in concentrated sulfuric acid, adding concentrated nitric acid with the concentration of 60-70 wt% at the temperature of-20-0 ℃, preferably-10-5 ℃, and then reacting at the temperature of 20-30 ℃, for example, room temperature;

preferably, the step (4) further comprises the steps of:

(402) pouring the nitration reaction product obtained in the step (401) into ice water, separating out solid, filtering and drying to obtain a crude product;

(403) recrystallizing the crude product obtained in the step (402), and drying to obtain a target product;

preferably, the reaction time in the step (401) is 1 to 5 hours, preferably 2 to 4 hours;

preferably, the solvent used for recrystallization in step (403) is ethyl acetate, methanol, ethanol, isopropanol or n-butanol, preferably ethyl acetate.

Technical Field

The invention belongs to the technical field of chemical pharmacy, and particularly relates to an ornidazole isomer and a preparation method thereof.

Background

Ornidazole (Ornidazole) is a third generation nitroimidazole derivative, and its structural formula is as follows:

ornidazole has antimicrobial effect, and is mainly used for treating anaerobe, protozoan and trichomonad infection. The mechanism of the antimicrobial action of ornidazole may be as follows: the nitro group in the molecule is reduced to an amino group in an anaerobic environment or interacts with cellular components through the formation of free radicals, resulting in microbial death.

The type and content of impurities contained in the ornidazole product are important parameters for the quality research of the ornidazole product. Chinese patents CN102539564B and CN105254569B disclose impurities that may be contained in ornidazole, and the structures of these ornidazole impurities are as follows:

among them, chinese patent CN102539564B discloses impurities 1 to IV, and chinese patent CN105254569B synthesizes impurity V.

Disclosure of Invention

In view of the above, the invention provides an ornidazole isomer and a preparation method thereof, the ornidazole isomer enriches the types of ornidazole compounds, can further research the drug action mechanism of ornidazole, can be used as a standard substance for impurity analysis and detection in ornidazole, and further provides support and guarantee for the quality research and deep development of ornidazole.

In one aspect, the invention provides an ornidazole isomer, wherein the structure of the ornidazole isomer is shown in formula VI:

on the other hand, the invention also provides a preparation method of the ornidazole isomer, wherein the preparation method comprises the following steps:

(1) reacting 2-amino-3- (benzyloxy) propan-1-ol, glyoxal, acetaldehyde and ammonium acetate to obtain 3- (benzyloxy) -2- (2-methyl-1H-imidazol-1-yl) propan-1-ol represented by formula VI-3;

(2) carrying out halogenation reaction on 3- (benzyloxy) -2- (2-methyl-1H-imidazole-1-yl) propan-1-ol shown in a formula VI-3 to obtain 1- (1- (benzyloxy) -3-chloropropane-2-yl) -2-methyl-1H-imidazole shown in a formula VI-2;

(3) removing benzyl from 1- (1- (benzyloxy) -3-chloropropane-2-yl) -2-methyl-1H-imidazole shown in a formula VI-2 to obtain 3-chloro-2- (2-methyl-1H-imidazole-1-yl) propane-1-ol shown in the formula VI-1;

(4) carrying out nitration reaction on 3-chloro-2- (2-methyl-1H-imidazole-1-yl) propan-1-ol shown in VI-1 to obtain an ornidazole isomer shown in a formula VI;

the synthetic route of the preparation method of the invention is summarized as follows:

the preparation method disclosed by the invention is reasonable in synthesis route, simple to operate, mild in reaction, high in yield, high in product purity, environment-friendly, easy to operate, suitable for ornidazole quality research, high in commercial value and capable of providing support and guarantee for improving ornidazole quality research.

The preparation method provided by the invention is characterized in that the reaction for generating the 3- (benzyloxy) -2- (2-methyl-1H-imidazole-1-yl) propan-1-ol in the step (1) is a Debus-Radzizzewski imidazole synthesis reaction.

The preparation method provided by the invention is characterized in that the molar ratio of the 2-amino-3- (benzyloxy) propan-1-ol, the glyoxal, the acetaldehyde and the ammonium acetate in the step (1) is 1: 1-1.2. For example, in some embodiments, the molar ratio of 2-amino-3- (benzyloxy) propan-1-ol, glyoxal, acetaldehyde, and ammonium acetate in step (1) is 1:1:1: 1.

According to the preparation method provided by the invention, in the step (1), the glyoxal is added in the form of glyoxal water solution. In the invention, the concentration of the glyoxal water solution can be 20-40 wt%.

According to the production method provided by the present invention, in the step (1), acetaldehyde is added in the form of an aqueous acetaldehyde solution. In the present invention, the concentration of the aqueous acetaldehyde solution may be 20 to 40 wt%.

According to the preparation method provided by the invention, the reaction in the step (1) is carried out in a first solvent. Examples of suitable first solvents include, but are not limited to: methanol, ethanol, isopropanol, and n-butanol. In some embodiments, the first solvent is methanol.

The preparation method provided by the invention is characterized in that the volume-to-mass ratio of the first solvent to the 2-amino-3- (benzyloxy) propan-1-ol in the step (1) is 15-25: 1 ml/g.

According to the preparation method provided by the invention, the reaction in the step (1) is carried out at a temperature of 20-30 ℃, for example, room temperature, and the reaction time is preferably 6-12 hours, and more preferably 8-12 hours.

The preparation method provided by the invention, wherein the step (1) further comprises the following steps:

(101) after the reaction is finished, carrying out reduced pressure concentration to obtain a crude product;

(102) and (3) purifying the crude product obtained in the step (101) by adopting a chromatography, wherein a mobile phase is dichloromethane-methanol, and the volume ratio of the mobile phase to the methanol is 100-95: 0-5.

According to the preparation method provided by the invention, methanesulfonyl chloride, thionyl chloride or phosphorus oxychloride is adopted as a halogenating reagent in the halogenating reaction in the step (2). In some embodiments, the halogenating agent is methanesulfonyl chloride.

According to the preparation method provided by the invention, the molar ratio of the halogenated reagent to the 3- (benzyloxy) -2- (2-methyl-1H-imidazole-1-yl) propan-1-ol in the step (2) is 1.05-1.5: 1, and preferably 1.1-1.2: 1.

According to the preparation method provided by the invention, a catalyst may or may not be used in the halogenation reaction in the step (2). In some embodiments, in step (2), methanesulfonyl chloride is used as a halogenating reagent, triethylamine is used as a catalyst for the halogenation reaction, and the molar ratio of triethylamine to 3- (benzyloxy) -2- (2-methyl-1H-imidazol-1-yl) propan-1-ol is 1.2 to 2:1, such as 1.5 to 1.8: 1.

According to the preparation method provided by the invention, in the step (2), the halogenation reaction is carried out in a second solvent. Examples of suitable second solvents include, but are not limited to: dichloromethane, chloroform and carbon tetrachloride. In some embodiments, the second solvent is chloroform.

The preparation method provided by the invention is characterized in that the volume-to-mass ratio of the second solvent to the 3- (benzyloxy) -2- (2-methyl-1H-imidazole-1-yl) propan-1-ol in the step (2) is 30-50: 1ml/g, especially 40-50: 1 ml/g.

According to the preparation method provided by the invention, the halogenation reaction in the step (2) is carried out at a temperature of 20-30 ℃, for example, room temperature, and the reaction time is preferably 1-6 hours, for example, 2-4 hours.

According to the preparation method provided by the invention, the step (2) comprises the following steps:

(201) dissolving 3- (benzyloxy) -2- (2-methyl-1H-imidazol-1-yl) propan-1-ol represented by formula VI-3 and triethylamine in a second solvent;

(202) adding a halogenating reagent at the temperature of 0-5 ℃, and heating to the temperature of 20-30 ℃ for halogenating reaction to obtain a reaction solution;

(203) adding water into the reaction liquid obtained in the step (202) for quenching, extracting by adopting an organic solvent, and washing the obtained organic phase by using saturated saline water to obtain a saline water washed product;

(204) drying the product obtained in the step (203) after washing with brine, and concentrating under reduced pressure to obtain a crude product;

(205) and (3) purifying the crude product obtained in the step (204) by adopting a chromatography, wherein a mobile phase is petroleum ether-ethyl acetate, and the volume ratio of the petroleum ether-ethyl acetate is 95-90: 5-10.

According to the preparation method provided by the invention, in the step (203), one or more organic solvents selected from dichloromethane, chloroform and carbon tetrachloride, such as chloroform, are used for extraction.

According to the preparation method provided by the invention, in the step (204), the product obtained after the brine washing in the step (203) is dried by using anhydrous sodium sulfate.

The preparation method provided by the invention is characterized in that the Pd/C-H is adopted in the step (3)₂-ethanol, raney nickel-ethanol, ferric chloride-acetic anhydride and stannic chloride-Dichloromethane (DMC) to remove benzyl groups of 1- (1- (benzyloxy) -3-chloropropan-2-yl) -2-methyl-1H-imidazole.

In some embodiments, the step (3) is performed by removing benzyl groups from 1- (1- (benzyloxy) -3-chloropropan-2-yl) -2-methyl-1H-imidazole using a process comprising:

(301) adding 1- (1- (benzyloxy) -3-chloropropane-2-yl) -2-methyl-1H-imidazole and a Pd/C catalyst into ethanol, and reacting at 55-65 ℃, for example, 55-60 ℃ in a hydrogen atmosphere.

In some embodiments, the Pd/C catalyst is used in an amount of 40 to 60 wt%, based on the weight of 1- (1- (benzyloxy) -3-chloropropan-2-yl) -2-methyl-1H-imidazole; and in some embodiments, the volume-to-mass ratio of ethanol to 1- (1- (benzyloxy) -3-chloropropan-2-yl) -2-methyl-1H-imidazole in step (301) is 40-60: 1 ml/g.

According to the preparation method provided by the invention, the step (3) further comprises the following steps:

(302) filtering and concentrating the reaction product obtained in the step (301) to obtain a crude product;

(303) and (3) purifying the crude product obtained in the step (303) by adopting a chromatography, wherein a mobile phase is petroleum ether-ethyl acetate, and the volume ratio of the petroleum ether-ethyl acetate is 60-50: 40-50.

According to the preparation method provided by the invention, in the step (4), the nitration reaction is carried out by a method comprising the following steps:

(401) dissolving 3-chloro-2- (2-methyl-1H-imidazol-1-yl) propan-1-ol in concentrated sulfuric acid, adding concentrated nitric acid with a concentration of 60-70 wt% at a temperature of-20 ℃ to 0 ℃, preferably-10 ℃ to-5 ℃, and then reacting at a temperature of 20-30 ℃, for example, room temperature.

According to the preparation method provided by the invention, the reaction time in the step (401) is 1-5 hours, preferably 2-4 hours.

The preparation method provided by the invention, wherein the step (4) further comprises the following steps:

(402) pouring the nitration reaction product obtained in the step (401) into ice water, separating out solid, filtering and drying to obtain a crude product;

(403) and (4) recrystallizing the crude product obtained in the step (402), and drying to obtain a target product.

According to the preparation method provided by the invention, the solvent used for recrystallization in the step (403) is ethyl acetate, methanol, ethanol, isopropanol or n-butanol, preferably ethyl acetate.

According to the preparation method provided by the invention, the drying in the step (402) and the drying in the step (403) are respectively and independently carried out at the temperature of 50-60 ℃.

The invention has the following advantages:

(1) the ornidazole isomer, namely 3-chloro-2- (2-methyl-5-nitro-1H-imidazole-1-yl) propan-1-ol, enriches the types of ornidazole compounds, can be used for further researching the drug action mechanism of ornidazole, can be used as a standard substance for analyzing and detecting impurities in ornidazole, and further provides support and guarantee for ornidazole quality research and deep development.

In particular, ornidazole is usually prepared starting from 2-methyl-5-nitroimidazole and 1, 2-epichlorohydrin. Without wishing to be bound by theory, it is believed that the bond at the 1 carbon to oxygen linkage is broken to open the ring to produce ornidazole and the 2 carbon to oxygen linkage is broken to produce the ornidazole isomers of the present invention. However, the ornidazole was prepared by methods known in the art, and no ornidazole isomer of the present invention was detected. Therefore, the ornidazole isomer provided by the invention can be used for further research on preparation, action mechanism and the like of ornidazole raw material medicines, and the product quality is ensured.

(2) The preparation method disclosed by the invention is reasonable in synthesis route, simple to operate, mild in reaction, high in yield, high in product purity, environment-friendly, easy to operate, suitable for ornidazole quality research, high in commercial value and capable of providing support and guarantee for improving ornidazole quality research.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of an ornidazole isomer of the present invention;

FIG. 2 is a nuclear magnetic resonance carbon spectrum of an ornidazole isomer according to the present invention;

fig. 3 is a mass spectrum of the ornidazole isomer of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.