CN111217795A - Antibacterial medicine and preparation method thereof - Google Patents
Antibacterial medicine and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an antibacterial drug which is 2- (2, 4-difluorophenyl) -1- (1H-1,2, 4-triazole-1-yl) -3- (1H-1,2,3, 4-tetrazole-1-yl) -2-propanol, the compound is modified and reformed on the basis of fluconazole, and a tetrazole ring is introduced. The invention also discloses a preparation method of the antibacterial drug, which obtains 2- (2, 4-difluorophenyl) -1- (1H-1,2, 4-triazol-1-yl) -3- (1H-1,2,3, 4-tetrazol-1-yl) -2-propanol by introducing a tetrazole ring on the basis of keeping the structure that most of fluconazole has drug efficacy.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to an antibacterial drug and a preparation method thereof.
Background
Fluconazole (FCZ) is used as antifungal triazole drugs for systemic fungal infection and has the advantages of low toxicity, easy absorption, high bioavailability, wide action range and the like. However, due to abuse of fluconazole, the drug resistance of fungi to the fluconazole is more serious, so that the method is very important in the aspect of deep modification of the fluconazole.
The tetrazole ring is used as an electron-rich five-membered plane conjugated system and has the dual characteristics of electron donors and acceptors. The characteristic enables the tetrazole compound to form various secondary bonds, such as hydrogen bonds, metal coordination, pi-pi accumulation and electrostatic interaction, so that more different performances can be shown, and the tetrazole compound can be widely applied to a plurality of fields. Some tetrazolium compounds themselves exhibit a wide range of biological activities including antibacterial and antifungal properties in medicine, and excellent clinical data have been obtained [ see Muszalska I, j.pharm.sci.,2014,103(1):2-28 ]; meanwhile, in the process of drug design and development, the tetrazole ring can be used for improving the biological activity of a known drug, and the introduction of the tetrazole ring can enhance the efficacy of the drug and prolong the action time of the drug [ see V.A. Ostrovskii, Russian Chemical Bulletin,2012,61(4):768-780 ]. In addition, there is generally no increase in concomitant acute toxicity [ see v.a. ostrovskii, comp.heterocyclic. chem.iii,2008,6:257 ]. The tetrazole ring is an important structural fragment in modern drug molecule design, can be combined with action targets such as various enzymes or receptors in organisms through various interactions, and shows excellent biological activity.
Based on the background, modification and modification of fluconazole are planned on the basis of keeping most of structures of fluconazole with medicinal effect.
Disclosure of Invention
The object of the present invention is to provide an antibacterial agent having a broader spectrum of antimicrobial activity (compared to fluconazole) by introducing a tetrazole ring, and a method for preparing the same.
In order to achieve the purpose, the technical scheme of the invention is as follows:
an antibacterial agent, wherein the antibacterial agent is 2- (2, 4-difluorophenyl) -1- (1H-1,2, 4-triazol-1-yl) -3- (1H-1,2,3, 4-tetrazol-1-yl) -2-propanol, and the chemical structural formula of the antibacterial agent is as follows:
after the technical scheme is adopted, the antibacterial drug has the following beneficial effects: the compound is modified and modified on the basis of fluconazole, and a tetrazole ring is introduced, so that compared with fluconazole, the compound disclosed by the invention has broader-spectrum antimicrobial activity.
The preparation method of the antibacterial drug comprises the following steps:
(1) using chloroacetyl chloride and m-difluorobenzene as raw materials, using aluminum chloride as a catalyst, reacting at room temperature, adding a hydrochloric acid aqueous solution under ice bath, separating out a solid, dissolving the solid obtained after filtration by using a solvent, and removing the solvent by rotary evaporation to obtain 2-chloro-2 ',4' -difluoroacetophenone;
(2) dissolving 1,2, 4-1H-triazole and 2-chloro-2 ',4' -difluoroacetophenone obtained in the step (1) in ethyl acetate, dropwise adding triethylamine, reacting for 6-8 hours, filtering, and separating the filtrate by using ethyl acetate and petroleum ether in a set ratio as an eluent through a chromatographic column to obtain α - (1H-1,2, 4-triazole-1-yl) -2, 4-difluoroacetophenone;
(3) dissolving α - (1H-1,2, 4-triazole-1-yl) -2, 4-difluoroacetophenone in the step (2) in a solvent, adding trimethyl sulfoxide iodide and trimethyl hexadecyl ammonium bromide, reacting at 40-80 ℃, dropwise adding a sodium hydroxide aqueous solution with the mass concentration of 20%, reacting for 1-5 hours, extracting, washing with water, performing rotary evaporation to remove the solvent, diluting the residual liquid with ethyl acetate, dropwise adding an ethyl acetate solution of methane sulfonic acid under an ice bath condition, separating out a solid, dissolving the obtained solid with hot ethanol, separating out the solid after complete dissolution, and filtering to obtain 1- [ α - (2, 4-difluorophenyl) ] -2, 3-epoxypropyl-1H-1, 2, 4-triazole;
(4) dissolving 1H-tetrazole and 1- [ α - (2, 4-difluorophenyl) ] -2, 3-epoxypropyl-1H-1, 2, 4-triazole obtained in the step (3) in ethanol, dropwise adding triethylamine, raising the reaction temperature to a set temperature, reacting for 9-12 hours, and separating by using ethyl acetate and petroleum ether in a set ratio as eluents through a chromatographic column to obtain 2- (2, 4-difluorophenyl) -1- (1H-1,2, 4-triazol-1-yl) -3- (1H-1,2,3, 4-tetrazol-1-yl) -2-propanol.
Further, in the step (1), the molar ratio of m-difluorobenzene to chloroacetyl chloride is 1: 1-1.2; the mol ratio of the m-difluorobenzene to the aluminum chloride is 1: 1-1.2.
Further, in the step (1), the volume ratio of hydrochloric acid to water in the hydrochloric acid aqueous solution is 1:1-1:5, and the ratio of aluminum chloride: hydrochloric acid: the mass ratio of the water is 1:1:1-1:3: 15.
Further, in the step (2), the molar ratio of 2-chloro-2 ',4' -difluoroacetophenone to 1,2, 4-1H-triazole is 1: 1-1.2; the molar ratio of the 2-chloro-2 ',4' -difluoroacetophenone to the triethylamine is 1: 1-1.2.
Further, in the step (2), the volume ratio of the ethyl acetate to the petroleum ether is 5:1-5: 5.
Further, in the step (3), the solvent used is toluene, benzene or cyclohexane.
further, in the step (3), the molar ratio of α - (1H-1,2, 4-triazole-1-yl) -2, 4-difluoroacetophenone to trimethyl sulfoxide iodide is 1:1, and the molar ratio of α - (1H-1,2, 4-triazole-1-yl) -2, 4-difluoroacetophenone to sodium hydroxide is 1: 3-1: 9.
Further, in the step (4), the volume ratio of the ethyl acetate to the petroleum ether is 5:1-5: 5.
further, in the step (4), the molar ratio of 1- [ α - (2, 4-difluorophenyl) ] -2, 3-epoxypropyl-1H-1, 2, 4-triazole to 1H-tetrazole is 1: 1-1.2, and the molar ratio of 1- [ α - (2, 4-difluorophenyl) ] -2, 3-epoxypropyl-1H-1, 2, 4-triazole to triethylamine is 1: 1-1.2.
After the technical scheme is adopted, the preparation method of the antibacterial drug has the following beneficial effects: the method obtains the 2- (2, 4-difluorophenyl) -1- (1H-1,2, 4-triazol-1-yl) -3- (1H-1,2,3, 4-tetrazol-1-yl) -2-propanol by introducing a tetrazole ring on the basis of keeping the structure that most of fluconazole has medicinal effect.
Drawings
FIG. 1 is a Fourier transform infrared spectrum of 2- (2, 4-difluorophenyl) -1- (1H-1,2, 4-triazol-1-yl) -3- (1H-1,2,3, 4-tetrazol-1-yl) -2-propanol of the present invention.
FIG. 2 is a NMR spectrum of 2- (2, 4-difluorophenyl) -1- (1H-1,2, 4-triazol-1-yl) -3- (1H-1,2,3, 4-tetrazol-1-yl) -2-propanol of the present invention.
FIG. 3 is a NMR carbon spectrum of 2- (2, 4-difluorophenyl) -1- (1H-1,2, 4-triazol-1-yl) -3- (1H-1,2,3, 4-tetrazol-1-yl) -2-propanol of the present invention.
Detailed Description
In order to further explain the technical solution of the present invention, the present invention is explained in detail by the following specific examples.
Example 1
First, preparation method
The antibacterial drug is 2- (2, 4-difluorophenyl) -1- (1H-1,2, 4-triazole-1-yl) -3- (1H-1,2,3, 4-tetrazole-1-yl) -2-propanol (TFCZ), and the chemical structural formula of the antibacterial drug is as follows:
the invention relates to a preparation method of the antibacterial drug, which comprises the following synthetic route:
the invention relates to a preparation method of the antibacterial drug, which comprises the following steps:
(1) preparation of 2-chloro-2 ',4' -difluoroacetophenone: to a dried 100ml three-necked flask were added 6.68g of anhydrous aluminum chloride and 5.71g of m-difluorobenzene in this order at room temperature. Under magnetic stirring for 5min, 5.65g of chloroacetyl chloride is slowly dropped into the three-necked flask by using a constant-pressure dropping funnel, and the reaction is finished after 3 h. Adding a hydrochloric acid aqueous solution (the volume ratio of hydrochloric acid to water is 1:2) into a three-neck bottle under ice bath, separating out a large amount of solid, and filtering and drying to obtain a crude product; the crude product was dissolved in 10ml of dichloromethane, filtered to remove insoluble impurities, and the filtrate was passed through a rotary evaporator to remove the solvent (i.e., dichloromethane) to give pure 2-chloro-2 ',4' -difluoroacetophenone 8.66g in 91% yield.
The synthetic route of the 2-chloro-2 ',4' -difluoroacetophenone is as follows:
(2) the preparation of alpha- (1H-1,2, 4-triazole-1-yl) -2, 4-difluoroacetophenone is that 1.91g of 2-chloro-2 ',4' -difluoroacetophenone and 0.69g of 1,2, 4-1H-triazole are sequentially added into a 100ml three-neck flask with a condenser tube, ethyl acetate is added for dissolution, after the dissolution is completed, 1.01g of triethylamine is slowly dropped by a constant pressure funnel under magnetic stirring, the temperature is raised to 60 ℃, the reaction is carried out for 6 to 8 hours, preferably after 8 hours, the reaction is completed, the filtrate is filtered and concentrated, then eluent with the volume ratio of ethyl acetate to petroleum ether being 5:2(V/V) is used for separation by a chromatographic column, and the separated substances are detected by infrared and nuclear magnetism, and finally the separated product is the final product, so that α - (1H-1,2, 4-triazole-1-yl) -2, 4-difluoroacetophenone 0.74g with the yield of 33%.
wherein, the synthetic route of α - (1H-1,2, 4-triazole-1-yl) -2, 4-difluoroacetophenone is as follows:
(3)1- [ α - (2, 4-difluorophenyl) ] -2, 3-epoxypropyl-1H-1, 2, 4-triazole is prepared by adding 2.23g of α - (1H-1,2, 4-triazol-1-yl) -2, 4-difluoroacetophenone and 10ml of benzene to a dried 100ml three-necked flask, adding 2.20g of trimethyl sulfoxide iodide and 0.1g of phase transfer catalyst trimethyl hexadecylammonium bromide after dissolution, raising the temperature to 40-80 ℃, preferably 60 ℃, slowly adding 20% (mass concentration) NaOH aqueous solution (NaOH 1.2g) by using a constant pressure dropping funnel under magnetic stirring, monitoring the reaction progress by TLC, reacting for 1-5 hours, preferably, after 3 hours of reaction, separating out a toluene layer, extracting the aqueous layer with toluene for 3 times, combining the toluene layers, washing with water to neutrality, removing most of toluene by rotary evaporation, diluting the residual liquid with ethyl acetate, adding an ethyl acetate solution of methane sulfonic acid (1 g) in an ice bath, separating out a solid, filtering the solid by using 1-2H-1H filtration, and drying to obtain a white solid (2-4H-difluorophenyl).
wherein, the synthetic route of the 1- [ α - (2, 4-difluorophenyl) ] -2, 3-epoxypropyl-1H-1, 2, 4-triazole is as follows:
(4)2- (2, 4-difluorophenyl) -1- (1H-1,2, 4-triazol-1-yl) -3- (1H-1,2,3, 4-tetrazol-1-yl) -2-propanol was prepared by adding 0.50g of 1- [ α - (2, 4-difluorophenyl) ] -2, 3-epoxypropyl-1H-1, 2, 4-triazole and 0.11g of 1H-tetrazole in sequence to a 100ml three-necked flask with a condenser tube to dissolve, adding 10ml of ethanol to dissolve, adding 1ml of triethylamine, heating to 60 ℃ for reflux, monitoring the progress of the reaction by TLC for 9 to 12 hours, preferably after 9 hours, separating the separated material by a chromatographic column using an eluent of ethyl acetate: petroleum ether ═ 2:1(V/V), and detecting the separated material by infrared (results are shown in FIG. 1) and nuclear magnetism (results are shown in FIGS. 2 and 3), and finally separating the separated product is a final product, which is 2- (2, 4-triazol-1H) -3- (1H-1, 1-tetrazol-1-yl) -2-propanol with a yield of 29.1, 2, 4-triazol-1H-1, 3-propanol, and 13 g.
Wherein, the synthetic route of the 2- (2, 4-difluorophenyl) -1- (1H-1,2, 4-triazole-1-yl) -3- (1H-1,2,3, 4-tetrazole-1-yl) -2-propanol is as follows:
in the step (1), the molar ratio of the m-difluorobenzene to the chloroacetyl chloride is 1: 1-1.2; the mol ratio of the m-difluorobenzene to the aluminum chloride is 1: 1-1.2; the volume ratio of hydrochloric acid to water in the hydrochloric acid aqueous solution is 1:1-1:5, and the ratio of aluminum chloride: hydrochloric acid: the mass ratio of the water is 1:1:1-1:3: 15.
In the step (2), the molar ratio of 2-chloro-2 ',4' -difluoroacetophenone to 1,2, 4-1H-triazole is 1: 1-1.2; the molar ratio of the 2-chloro-2 ',4' -difluoroacetophenone to the triethylamine is 1: 1-1.2.
in the step (3), the solvent can be toluene or cyclohexane besides the benzene, the molar ratio of α - (1H-1,2, 4-triazole-1-yl) -2, 4-difluoroacetophenone to trimethyl sulfoxide iodide is 1:1, and the molar ratio of α - (1H-1,2, 4-triazole-1-yl) -2, 4-difluoroacetophenone to sodium hydroxide (NaOH) is 1: 3-1: 9.
in the step (4), the molar ratio of 1- [ α - (2, 4-difluorophenyl) ] -2, 3-epoxypropyl-1H-1, 2, 4-triazole to 1H-tetrazole is 1: 1-1.2, and the molar ratio of 1- [ α - (2, 4-difluorophenyl) ] -2, 3-epoxypropyl-1H-1, 2, 4-triazole to triethylamine is 1: 1-1.2.
Second, antibacterial property test
All target compounds and reference samples were tested for in vitro antibacterial, antifungal activity using the standardized antibacterial susceptibility test method specified by the American clinical laboratory standards Committee (NCCLS) using a microtitre broth dilution method on 96-well plates and MIC80The antibacterial activity is shown, and the activity data are detailed in table 1. Wherein the selected test fungi are candida albicans (c.albicans), the selected test bacteria include gram positive bacteria staphylococcus aureus (s.aureus) and gram negative bacteria escherichia coli (e.coli), and Fluconazole (FCZ) is selected as the reference.
TABLE 1 MIC of minimum inhibitory concentration for TFCZ and FCZ80
As can be seen from the above table, the product TFCZ of the present invention has antimicrobial activity with broader spectrum of properties relative to FCZ and shows certain biological activity against e. Wherein the MICs 80 of TFCZ and FCZ to C.albicans are 4. mu.g/mL and 0.25. mu.g/mL, respectively. After introduction of the tetrazole ring on FCZ, the antifungal effect of the resulting product TFCZ on c. It is possible that because the tetrazole ring is introduced on FCZ, the synthesized compound is a chiral small molecule, and because chemical drugs, if containing chiral factors, have significant differences in toxicity, pharmacological effects and physiological metabolic processes of the enantiomers in organisms, the enantiomers may be ineffective or harmful in the obtained product, resulting in the synthesized compound not having the expected effect on the antibacterial activity of c. Of these, FCZ showed no inhibitory effect on both e.coli and s.aureus, whereas the MICs 80 of TFCZ were 128 μ g/mL and 16 μ g/mL for e.coli and s.aureus, respectively. After the tetrazole ring is introduced into FCZ, the antibacterial activity of the obtained product TFCZ on tested bacteria is obviously improved compared with fluconazole, and particularly the antibacterial activity on gram-positive bacteria S.
Example 2
The present example differs from example 1 in step (1): in this example, the preparation method of 2-chloro-2 ',4' -difluoroacetophenone was as follows: to a dried 100ml three-necked flask, 8.01g of anhydrous aluminum chloride and 5.71g of m-difluorobenzene were successively added at room temperature. Under magnetic stirring for 5min, 6.78g of chloracetyl chloride is slowly dropped into the three-necked flask by using a constant-pressure dropping funnel, and the reaction is finished after 3 h. Adding 16.02g of hydrochloric acid and 32.04g of water into a three-neck flask in ice bath, separating out a large amount of solid, filtering and drying to obtain a crude product; the crude product was dissolved in 10ml of dichloromethane, insoluble impurities were filtered off, and the solvent was removed from the filtrate by rotary evaporator to give pure 2-chloro-2 ',4' -difluoroacetophenone 8.19g in 86% yield.
Example 3
the difference between this example and example 1 is that in step (2), in this example, α - (1H-1,2, 4-triazol-1-yl) -2, 4-difluoroacetophenone was prepared by sequentially adding 1.91g of 2-chloro-2 ',4' -difluoroacetophenone and 0.83g of 1,2, 4-1H-triazole to a 100ml three-necked flask equipped with a condenser tube, dissolving them in ethyl acetate, slowly adding 1.21g of triethylamine to the flask under magnetic stirring, heating to reflux temperature, after 6 hours, completing the reaction, separating the separated material by a chromatographic column using an eluent of ethyl acetate: 5:2, detecting the separated material by infrared and nuclear magnetic detection, and finding that the finally separated product was the final product, thus obtaining α - (1H-1,2, 4-triazol-1-yl) -2, 4-difluoroacetophenone in 47% yield.
Example 4
this example differs from example 1 in step (3)1- [ α - (2, 4-difluorophenyl) ] -2, 3-epoxypropyl-1H-1, 2, 4-triazole was prepared by adding 2.23g of α - (1H-1,2, 4-triazol-1-yl) -2, 4-difluoroacetophenone and 10ml of toluene to a dried 100ml three-necked flask, after dissolution, 2.20g of trimethyl sulphoxide iodide and 0.1g of trimethyl hexadecylammonium bromide as a phase transfer catalyst, raising the temperature to 60 ℃, slowly dropping 20% aqueous NaOH (NaOH 3.6g) with a constant pressure dropping funnel under magnetic stirring, monitoring the progress of the reaction by TLC, after 5H the reaction is complete, separating out the toluene layer, extracting with toluene 3 times, combining the toluene layers, washing with water to neutrality, spinning off most of toluene by evaporation, diluting the residual liquid with ethyl acetate, dropping an ethyl acetate solution of methanesulfonic acid (1 g) in a bath of methanesulfonic acid (1 g), filtering the aqueous layer, cooling the solid to a white solid, filtering the solid to obtain 1-3H-4 g of difluorophenyl triazole, drying to obtain a pure solid, and drying to obtain 1H-3H-4H-triazole.
Example 5
this example differs from example 1 in step (4) in that in this example, 2- (2, 4-difluorophenyl) -1- (1H-1,2, 4-triazol-1-yl) -3- (1H-1,2,3, 4-tetrazol-1-yl) -2-propanol was prepared by adding 1- [ α - (2, 4-difluorophenyl) ] -2, 3-epoxypropyl-1H-1, 2, 4-triazole 0.50g and 1H-tetrazole 0.13g to a 100ml three-necked flask with a condenser in this order, dissolving in 10ml of absolute ethanol, adding 1ml of triethylamine, heating to reflux, monitoring the progress of the reaction by TLC, after completion of the reaction after 12H, eluting with ethyl acetate, petroleum ether ═ 2:1(V/V), separating by a chromatographic column, subjecting the separated material to infrared and detection, and nuclear magnetic resonance to find that the finally separated product was the final product, which was 2- (2, 4-difluorophenyl) -1- (1H-1,2, 4-triazol-1, 1H-1, 3-tetrazol-1, 1-2, 1-1, 3-tetrazol, 1-2, and 1-2-propanol, with a yield of 50.23 g.
The above examples and drawings are not intended to limit the product and the preparation method of the present invention, and any suitable changes or modifications thereof by those skilled in the art should be considered as not departing from the scope of the present invention.
Claims (10)
1. An antibacterial drug, which is characterized in that: the antibacterial drug is 2- (2, 4-difluorophenyl) -1- (1H-1,2, 4-triazol-1-yl) -3- (1H-1,2,3, 4-tetrazol-1-yl) -2-propanol, and the chemical structural formula of the antibacterial drug is as follows:
2. a method for preparing the antibacterial agent according to claim 1, comprising the steps of:
(1) using chloroacetyl chloride and m-difluorobenzene as raw materials, using aluminum chloride as a catalyst, reacting at room temperature, adding a hydrochloric acid aqueous solution under ice bath, separating out a solid, dissolving the solid obtained after filtration by using a solvent, and removing the solvent by rotary evaporation to obtain 2-chloro-2 ',4' -difluoroacetophenone;
(2) dissolving 1,2, 4-1H-triazole and 2-chloro-2 ',4' -difluoroacetophenone obtained in the step (1) in ethyl acetate, dropwise adding triethylamine, reacting for 6-8 hours, filtering, and separating the filtrate by using ethyl acetate and petroleum ether in a set ratio as an eluent through a chromatographic column to obtain α - (1H-1,2, 4-triazole-1-yl) -2, 4-difluoroacetophenone;
(3) dissolving α - (1H-1,2, 4-triazole-1-yl) -2, 4-difluoroacetophenone in the step (2) in a solvent, adding trimethyl sulfoxide iodide and trimethyl hexadecyl ammonium bromide, reacting at 40-80 ℃, dropwise adding a sodium hydroxide aqueous solution with the mass concentration of 20%, reacting for 1-5 hours, extracting, washing with water, performing rotary evaporation to remove the solvent, diluting the residual liquid with ethyl acetate, dropwise adding an ethyl acetate solution of methane sulfonic acid under an ice bath condition, separating out a solid, dissolving the obtained solid with hot ethanol, separating out the solid after complete dissolution, and filtering to obtain 1- [ α - (2, 4-difluorophenyl) ] -2, 3-epoxypropyl-1H-1, 2, 4-triazole;
(4) dissolving 1H-tetrazole and 1- [ α - (2, 4-difluorophenyl) ] -2, 3-epoxypropyl-1H-1, 2, 4-triazole obtained in the step (3) in ethanol, dropwise adding triethylamine, raising the reaction temperature to a set temperature, reacting for 9-12 hours, and separating by using ethyl acetate and petroleum ether in a set ratio as eluents through a chromatographic column to obtain 2- (2, 4-difluorophenyl) -1- (1H-1,2, 4-triazol-1-yl) -3- (1H-1,2,3, 4-tetrazol-1-yl) -2-propanol.
3. A method for preparing an antibacterial agent according to claim 2, characterized in that: in the step (1), the molar ratio of m-difluorobenzene to chloroacetyl chloride is 1: 1-1.2; the mol ratio of the m-difluorobenzene to the aluminum chloride is 1: 1-1.2.
4. A method for preparing an antibacterial agent according to claim 2, characterized in that: in the step (1), the volume ratio of hydrochloric acid to water in the hydrochloric acid aqueous solution is 1:1-1:5, and the ratio of aluminum chloride: hydrochloric acid: the mass ratio of the water is 1:1:1-1:3: 15.
5. The method for preparing an antibacterial agent according to claim 2, characterized in that: in the step (2), the molar ratio of 2-chloro-2 ',4' -difluoroacetophenone to 1,2, 4-1H-triazole is 1: 1-1.2; the molar ratio of the 2-chloro-2 ',4' -difluoroacetophenone to the triethylamine is 1: 1-1.2.
6. The method for preparing an antibacterial agent according to claim 2, characterized in that: in the step (2), the volume ratio of the ethyl acetate to the petroleum ether is 5:1-5: 5.
7. The method for preparing an antibacterial agent according to claim 2, characterized in that: in the step (3), the solvent is toluene, benzene or cyclohexane.
8. the preparation method of the antibacterial drug according to claim 1, wherein in the step (3), the molar ratio of α - (1H-1,2, 4-triazol-1-yl) -2, 4-difluoroacetophenone to trimethyl sulfoxide iodide is 1:1, and the molar ratio of α - (1H-1,2, 4-triazol-1-yl) -2, 4-difluoroacetophenone to sodium hydroxide is 1: 3-1: 9.
9. The method for preparing an antibacterial agent according to claim 1, characterized in that: in the step (4), the volume ratio of the ethyl acetate to the petroleum ether is 5:1-5: 5.
10. the preparation method of the antibacterial drug according to claim 1, wherein in the step (4), the molar ratio of 1- [ α - (2, 4-difluorophenyl) ] -2, 3-epoxypropyl-1H-1, 2, 4-triazole to 1H-tetrazole is 1: 1-1.2, and the molar ratio of 1- [ α - (2, 4-difluorophenyl) ] -2, 3-epoxypropyl-1H-1, 2, 4-triazole to triethylamine is 1: 1-1.2.
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