Tetrazole alcohol compound as well as preparation method and application thereof

Abstract

The invention provides a tetrazole alcohol compound as well as a preparation method and application thereof, and belongs to the field of medicines. The tetrazole alcohol compound provided by the invention has the characteristics that the structural formula is as shown in the formula I: # imgabs0 #, in the formula I, R1 represents H or F, R2 represents H or F, R3 is independently selected from any one of C1-C4 alkyl, C1-C4 alkoxy, halogen, halogenated alkane, halogenated alkoxy, cyano, a benzene ring and a substituted benzene ring, R4 represents H or CH3, X represents CH or N, and Y represents CH or N. The azaconazole compound has remarkable in-vitro and in-vivo antifungal activity on human pathogenic fungi such as candida albicans, cryptococcus neoformans and aspergillus fumigatus, and the in-vitro and in-vivo antifungal activity is higher than that of a traditional antifungal drug fluconazole, and meanwhile, the azaconazole compound has a low inhibition effect on human CYP450 enzyme, especially on human liver drug enzyme CYP3A4, and has a good application prospect. Therefore, the compound can be used for preparing antifungal drugs.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and specifically relates to a tetrazolol compound, a preparation method and application thereof. Background Art

[0002] In recent years, with the extensive application of broad-spectrum antibiotics, anti-tumor drugs, and immunosuppressants, the widespread implementation of radiotherapy and organ transplantation, the widespread use of catheters and intubation, and the rapid increase in immunodeficient patients, especially AIDS patients, fungal infections, especially deep fungal infections, have increased significantly. Deep fungal infections have now become the main cause of death from major diseases such as AIDS and tumors. Existing antifungal drugs mainly include allylamines that act on squalene epoxidase, nitrogen azoles that act on lanosterol 14a demethylase, and lipopeptides that act on cell wall b-(1,3)-glucan synthase. However, as far as the antifungal drugs currently used in clinical practice are concerned, there are problems such as large side effects, narrow antibacterial spectrum, and easy to develop drug resistance. Effective antifungal drugs, especially anti-deep fungal drugs, are in short supply and far from meeting the treatment needs. Therefore, it is very necessary to develop more efficient antifungal drugs. Summary of the invention

[0003] The present invention is made to solve the above problems, and aims to provide a tetrazolium alcohol compound, a preparation method and an application thereof.

[0004] The present invention provides a tetrazolium alcohol compound having the following characteristics, and the structural formula is as shown in Formula I:

[0005]

[0006] Wherein, in formula I, R1 represents H or F, R2 represents H or F, R3 is independently selected from any one of C1-C4 alkyl, C1-C4 alkoxy, halogen, halogenated alkyl, halogenated alkoxy, cyano, benzene ring and substituted benzene ring, R4 represents H or CH3, X represents CH or N, and Y represents CH or N.

[0007] The tetrazolyl alcohol compounds provided by the present invention may also have the following characteristics: wherein the halogen includes F, Cl, Br and I, the halogenated alkyl groups include CF3 and CF2H, and the halogenated alkoxy groups include OCF3, OCF2H and OCF2CF3.

[0008] The present invention provides a method for preparing a tetrazolium alcohol compound, which has the following characteristics:

[0009]

[0010] The method for preparing the tetrazolium alcohol compound provided by the present invention may also have the following characteristics, comprising the following steps:

[0011] Step 1, dissolve trimethyl sulfoxide iodide in dry DMF, add sodium tert-butoxide in batches under ice bath, stir and react for 10 minutes, add DMF solution of compound 1, continue to react for 1 hour under ice bath, after LCMS detection, completely convert into epoxide intermediate 2, add potassium carbonate and 1H-tetrazole, heat the mixture to 85°C and continue to react for 12 hours, pour into ice water after the reaction, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride aqueous solution twice, dry the organic phase with anhydrous sodium sulfate, concentrate by rotary evaporator and separate by column chromatography to obtain compound 3;

[0012] Step 2, dissolving compound 3 in ethyl acetate, adding methanesulfonic acid, stirring and reacting for 12 hours, after the reaction is complete, washing the organic phase twice with sodium bicarbonate aqueous solution, drying the organic phase over anhydrous sodium sulfate and concentrating it on a rotary evaporator to obtain compound 4;

[0013] Step 3, compound 4 was dissolved in THF, triethylamine was added, and methylsulfonyl chloride was added dropwise under ice bath. After the addition was completed, stirring was continued for 1 hour. After the reaction was complete, sodium hydroxide aqueous solution was added, and the reaction was vigorously stirred for 1 hour. Then, it was extracted twice with ethyl acetate, and the organic phase was washed twice with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and separated by column chromatography to obtain compound 5.

[0014] The present invention also provides an application of a tetrazolol compound in the preparation of antifungal drugs.

[0015] In the above application provided by the present invention, it can also have the following characteristics: wherein the antifungal drug is used to treat or prevent fungal infection diseases, comprising: at least one azole compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof.

[0016] In the above-mentioned application provided by the present invention, it can also have the following characteristics: wherein the pharmaceutically acceptable salt is any one of hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, nitrate, maleate, fumarate, tartrate, succinate, lactate, methanesulfonate, p-toluenesulfonate, salicylate or oxalate.

[0017] The above application provided by the present invention may also have the following characteristics, and further include: a pharmaceutically acceptable carrier or excipient.

[0018] In the above application provided by the present invention, it can also have the following characteristics: wherein the pharmaceutically acceptable carrier or excipient is one or more of an auxiliary agent, a wetting agent, an emulsifier, a suspending agent, a preservative, a salt affecting osmotic pressure, a buffer, a sweetener, a flavoring agent or a coloring agent.

[0019] In the above application provided by the present invention, it can also have the following characteristics: wherein the fungus is any one or more of Candida albicans, Candida parapsilosis, Cryptococcus neoformans, Candida glabrata, Candida tropicalis, Candida krusei, Candida auris, Aspergillus fumigatus, Trichophyton rubrum or Microsporum gypseum.

[0020] Functions and Effects of the Invention

[0021] According to the tetrazolin compounds, preparation methods and applications of the present invention, the tetrazolin compounds have significant in vitro and in vivo antifungal activity against human pathogenic fungi Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus, and are stronger than the traditional antifungal drug fluconazole. At the same time, the tetrazolin compounds have low inhibitory effects on human liver drug enzymes, so they can be used to prepare antifungal drugs. DETAILED DESCRIPTION

[0022] In order to make the technical means, creative features, objectives and effects of the present invention easy to understand, the tetrazolium alcohol compounds, preparation methods and applications of the present invention are specifically described below in conjunction with examples.

[0023] The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturers. All reagents used in the examples are commercially available analytically pure.

[0024] <Example 1>

[0025] Example 1 provides a tetrazolol compound and a preparation method thereof.

[0026] The preparation method of tetrazolol compounds comprises:

[0027]

[0028] Step 1, trimethyl sulfoxide iodide (10.5 mmol) was dissolved in dry DMF (20 mL), sodium tert-butoxide (10.5 mmol) was added in batches under ice bath, and the mixture was stirred for reaction for 10 minutes, and a DMF solution of compound 1 (10 mmol) was added, and the reaction was continued for 1 hour under ice bath. After complete conversion into epoxide intermediate 2 by LCMS detection, potassium carbonate (20 mmol) and 1H-tetrazole (20 mmol) were added, and the mixture was heated to 85° C. and continued to react for 12 hours. After the reaction was completed, ice water was poured into the mixture, and the mixture was extracted three times with ethyl acetate. The organic phase was washed twice with a saturated sodium chloride aqueous solution, and the organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure. The residue was separated by column chromatography to obtain compound 3.

[0029]

[0030] Step 2, compound 3 (5 mmol) was dissolved in ethyl acetate (20 mL), methanesulfonic acid (5 mmol) was added, and the mixture was stirred for 12 hours. After the reaction was complete, the organic phase was washed twice with aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain a residue (i.e., compound 4) which was directly used in the next step.

[0031]

[0032] Step 3, compound 4 (5 mmol) was dissolved in THF (20 mL), triethylamine (10 mmol) was added, and methylsulfonyl chloride (6 mmol) was added dropwise under ice bath. After the addition was completed, stirring and reacting for 1 hour was continued. After the reaction was complete, sodium hydroxide aqueous solution (10 mmol) was added, and stirring and reacting vigorously for 1 hour, and then extracted twice with ethyl acetate. The organic phase was washed twice with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and then distilled under reduced pressure. The residue was separated by column chromatography to obtain compound 5.

[0033] The hydrogen spectrum of compound 5 is as follows:

[0034] 1 H NMR (600MHz, DMSO) δ9.25(s,1H),7.25–7.22(m,1H),7.07(dd,J=15.1,8.5Hz,1H),6.97(td,J=8.5,2. 4Hz, 1H), 5.11 (d, J = 15.0Hz, 1H), 4.93 (d, J = 14.9Hz, 1H), 3.29 (q, J = 5.6Hz, 1H), 1.61 (d, J = 5.6Hz, 3H).

[0035] <Example 2>

[0036] The reaction formula for the synthesis of compound A is as follows:

[0037]

[0038] The specific steps are as follows:

[0039] Steps: Compound 5 (1 mmol) was dissolved in DMF (5 mL), and compound 7 (1.5 mmol) and potassium carbonate (2 mmol) were added. The mixture was heated to 85° C. and the reaction was continued for 12 hours. After the reaction was completed, ice water was poured into the mixture, and the mixture was extracted three times with ethyl acetate. The organic phase was washed twice with a saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and then distilled under reduced pressure. The target product A was obtained after separation by column chromatography.

[0040] The hydrogen spectrum of compound A is as follows:

[0041] 1H NMR(600MHz,DMSO)δ8.99(s,1H),8.37(dd,J=8.9,5.8Hz,1H),7.60(d,J=7.6Hz, 1H),7.54(dd,J=9.7,2.4Hz,1H),7.40–7.32(m,2H),7.21(dd,J=15.7,8.9Hz,1H ),6.97(td,J=8.5,2.2Hz,1H),6.77(d,J=7.6Hz,1H),6.41(s,1H),6.02(q,J=7. 3Hz, 1H), 5.19 (d, J = 14.6Hz, 1H), 4.35 (d, J = 14.5Hz, 1H), 1.13 (d, J = 7.3Hz, 3H).

[0042] <Example 3>

[0043] The reaction formula for the synthesis of compound B is as follows:

[0044]

[0045] The specific steps are as follows:

[0046] Steps: Compound 5 (1 mmol) was dissolved in DMF (5 mL), and compound 8 (1.5 mmol) and potassium carbonate (2 mmol) were added. The mixture was heated to 85 ° C and continued to react for 12 hours. After the reaction, ice water was poured into it, and the mixture was extracted three times with ethyl acetate. The organic phase was washed twice with a saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and then distilled under reduced pressure. After separation by column chromatography, the target product B was obtained.

[0047] The hydrogen spectrum of compound B is as follows:

[0048] 1 H NMR(600MHz,DMSO)δ8.99(s,1H),8.30(d,J=8.6Hz,1H),7.85(d,J=2.1Hz,1H), 7.61(d,J=7.7Hz,1H),7.56(dd,J=8.6,2.1Hz,1H),7.35–7.31(m,1H),7.23–7. 19(m,1H),6.99–6.96(m,1H),6.76(d,J=7.6Hz,1H),6.41(s,1H),6.02(q,J=7. 3Hz, 1H), 5.18 (d, J = 14.6Hz, 1H), 4.36 (d, J = 14.5Hz, 1H), 1.13 (d, J = 7.3Hz, 3H).

[0049] <Example 4>

[0050] The reaction formula for the synthesis of compound C is as follows:

[0051]

[0052] The specific steps are as follows:

[0053] Steps: Compound 5 (1 mmol) was dissolved in DMF (5 mL), and compound 9 (1.5 mmol) and potassium carbonate (2 mmol) were added. The mixture was heated to 85 ° C and continued to react for 12 hours. After the reaction, ice water was poured into it, and the mixture was extracted three times with ethyl acetate. The organic phase was washed twice with a saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and then distilled under reduced pressure. After separation by column chromatography, the target product C was obtained.

[0054] The hydrogen spectrum of compound C is as follows:

[0055] 1 H NMR (300MHz, DMSO) δ9.01(s,1H),8.59(s,1H),8.32(d,J=8.6Hz,1H),8.19(d,J=1.7Hz,1H),7.94(dd,J=8.6,1.8Hz,1H),7.32 –7.21(m,2H),6.93(dd,J=8.3,6.5Hz,1H),5.89(s,2H),5.21(d,J=14.4Hz,1H),4.54(d,J=14.3Hz,1H),1.20(d,J=6.9Hz,3H).

[0056] <Example 5>

[0057] The reaction formula for the synthesis of compound D is as follows:

[0058]

[0059] The specific steps are as follows:

[0060] Steps: Compound 5 (1 mmol) was dissolved in DMF (5 mL), and compound 10 (1.5 mmol) and potassium carbonate (2 mmol) were added. The mixture was heated to 85 ° C and continued to react for 12 hours. After the reaction, ice water was poured into it, and the mixture was extracted three times with ethyl acetate. The organic phase was washed twice with a saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and then distilled under reduced pressure. After separation by column chromatography, the target product D was obtained.

[0061] The hydrogen spectrum of compound D is as follows:

[0062] 1H NMR(300MHz,DMSO)δ8.99(s,1H),8.44(s,1H),8.31(dd,J=8.8,6.3Hz,1H),7.58–7.44(m,2H),7.41–7.33(m,1H),7.24–7.15(m,1H), 6.98(td,J=8.4,2.1Hz,1H),6.62(s,1H),5.89(q,J=7.3Hz,1H),5.10(d,J=14.3Hz,1H),4.45(d,J=14.4Hz,1H),1.22(d,J=7.3Hz,3H)

[0063] <Example 6>

[0064] The reaction formula for the synthesis of compound E is as follows:

[0065]

[0066] The specific steps are as follows:

[0067] Steps: Compound 5 (1 mmol) was dissolved in DMF (5 mL), and compound 11 (1.5 mmol) and potassium carbonate (2 mmol) were added. The mixture was heated to 85 ° C and continued to react for 12 hours. After the reaction, ice water was poured into it, and the mixture was extracted three times with ethyl acetate. The organic phase was washed twice with a saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and then distilled under reduced pressure. After separation by column chromatography, the target product E was obtained.

[0068] The hydrogen spectrum of compound E is as follows:

[0069] 1 H NMR (600MHz, DMSO) δ8.98(s,1H),8.44(s,1H),8.24(d,J=8.5Hz,1H),7.82(d,J= 2.1Hz,1H),7.63(dd,J=8.5,2.1Hz,1H),7.36(ddd,J=11.7,9.0,2.5Hz,1H),7.2 0(dd,J=15.6,8.9Hz,1H),6.98(td,J=8.0,2.1Hz,1H),6.61(s,1H),5.89(q,J=7 .4Hz,1H),5.10(d,J=14.5Hz,1H),4.47(d,J=14.5Hz,1H),1.22(d,J=7.4Hz,3H).

[0070] <Example 7>

[0071] The reaction formula for the synthesis of compound F is as follows:

[0072]

[0073] The specific steps are as follows:

[0074] Steps: Compound 5 (1 mmol) was dissolved in DMF (5 mL), and compound 12 (1.5 mmol) and potassium carbonate (2 mmol) were added. The mixture was heated to 85 ° C and continued to react for 12 hours. After the reaction, ice water was poured into it, and the mixture was extracted three times with ethyl acetate. The organic phase was washed twice with a saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and then distilled under reduced pressure. After separation by column chromatography, the target product F was obtained.

[0075] The hydrogen spectrum of compound F is as follows:

[0076] 1 H NMR (300MHz, DMSO) δ8.97(s,1H),8.51(s,1H),8.44(d,J=8.3Hz,1H),8.09(s,1H),7.90(d,J=8.2Hz,1H),7.42–7.34(m,1H),7.20(dd,J=15. 6,8.8Hz,1H),7.03–6.96(m,1H),6.64(s,1H),5.91(q,J=7.4Hz,1H),5.09(d,J=14.4Hz,1H),4.51(d,J=14.4Hz,1H),1.25(d,J=7.3Hz,3H).

[0077] <Example 8>

[0078] The reaction formula for the synthesis of compound G is as follows:

[0079]

[0080] The specific steps are as follows:

[0081] Steps: Compound 5 (1 mmol) was dissolved in DMF (5 mL), and compound 13 (1.5 mmol) and potassium carbonate (2 mmol) were added. The mixture was heated to 85 ° C and continued to react for 12 hours. After the reaction, ice water was poured into it, and the mixture was extracted three times with ethyl acetate. The organic phase was washed twice with a saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and then distilled under reduced pressure. After separation by column chromatography, the target product G was obtained.

[0082] The hydrogen spectrum of compound G is as follows:

[0083] 1H NMR (300MHz, DMSO) δ8.98(s,1H),8.47(s,1H),8.37(d,J=8.8Hz,1H),7.69(s,1H),7.58(d,J=8.8Hz,1H),7.37(t,J=10.5Hz,1H),7.20(dd,J=15 .7,8.7Hz,1H),6.99(t,J=7.3Hz,1H),6.62(s,1H),5.90(q,J=7.1Hz,1H),5.10(d,J=14.5Hz,1H),4.49(d,J=14.4Hz,1H),1.23(d,J=7.3Hz,3H).

[0084] <Test Example 1>

[0085] In vitro antibacterial assay

[0086] Experimental strains: This experiment selected a common human pathogenic fungal strain as the screening object. The fungal strain was provided by the Fungi Laboratory of Shanghai Changzheng Hospital (or purchased from the Institute of Materia Medica, Chinese Academy of Sciences).

[0087] Candida albicans SC5314

[0088] Cryptococcus neoformans H99

[0089] Aspergillus fumigatus 7544

[0090] Candida tropicalis 2718

[0091] Candida glabrata 537

[0092] Candida krusei (Candida krusei 4946)

[0093] Candida parapsilosis 22019

[0094] Resistant Candida auris (Candida auris 789, Candida auris 791, Candida auris 887, Candida auris 888, Candida auris D12, Candida auris BS12372)

[0095] The experimental method adopted the conventional in vitro antibacterial experimental method (see: CLSI. Performance standards for antifungal susceptibility testing of yeast, M60, first ed., Clinical and Laboratory Standards Institute, Wayne, PA, 2017).

[0096] Specifically, the steps are as follows:

[0097] Preparation of bacterial suspension: The above fungi were cultured in YPD solid medium at 30°C for a certain period of time, and 5 clones were selected and the bacterial concentration was adjusted to 1×10 4 ~1×10 5 Pieces / mL.

[0098] Preparation of drug solution: Dissolve the compounds prepared in Examples 2-21 in dimethyl sulfoxide to prepare 6.4 mg / mL drug stock solution, and dilute to the required concentration using RPM1640 according to experimental requirements.

[0099] Inoculation: 100 μL of RPM1640 was added to well 1 of the 96-well plate as a blank control; 100 μL of bacterial suspension was added to wells 3-12, 200 μL of bacterial suspension and 2 μL of drug solution were added to well 2, and the drug concentrations in wells 2-11 were diluted 10 times. No drug solution was added to well 12 as a positive control. Fluconazole was used as a drug control.

[0100] The experimental results are shown in Tables 1 and 2.

[0101] Table 1. In vitro antifungal activity of compounds

[0102]

[0103] Abbreviations: MIC, minimum inhibitory concentration of the drug that inhibits fungal cell growth ≥50%; C.alb, Candidaalbicans; C.par, Candida parapsilosis; C.tro, Candida tropicalis; C.gla: Candidaglabrata; C.kru, Candida krusei; C.neo, Cryptococcus neoformans; A.fum, Aspergillusfumigatus.

[0104] Table 2. In vitro activity of compounds against drug-resistant fungi

[0105]

[0106] Abbreviations: MIC, minimum inhibitory concentration of the drug that inhibits fungal cell growth by ≥50%; C. aur, Candida auris.

[0107] <Test Example 2>

[0108] Determination of inhibition IC50 of five major CYP450 enzyme subtypes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human liver microsomes (with midazolam as substrate).

[0109] The human mixed liver microsomes used in this experiment were from Corning Company or other reliable sources.

[0110] 4. Experimental Plan

[0111] The test compounds will be incubated with human liver microsomes and five mixed probe substrates (phenacetin for CYP1A2, diclofenac for CYP2C9, mephenytoin for CYP2C19, dextromethorphan for CYP2D6, midazolam for CYP3A4) (see table below). The reaction will be initiated by the addition of the coenzyme NADPH. The reaction will be terminated by adding glacial acetonitrile containing internal standard to the incubation system. After protein precipitation, the supernatant will be centrifuged. The characteristic metabolites in the supernatant (acetaminophen for CYP1A2, 4-hydroxydiclofenac for CYP2C9, 4-hydroxymephenytoin for CYP2C19, dextrorphan for CYP2D6, 1-hydroxy-midazolam for CYP3A4) will be analyzed by LC-MS / MS method. Finally, the effects of the test compounds on the formation of these characteristic metabolites will be studied based on the obtained data. The selective inhibitor (ketoconazole for CYP3A) will be used as a positive control. All incubations were performed in duplicate.

[0112] The incubation conditions are summarized in the following table:

[0113]

[0114] 5. Data Analysis

[0115] At different test article (or positive control compound) concentration points, the percentage of residual activity is obtained by the ratio of the amount of characteristic metabolites generated to the amount generated in the absence of the test article (or positive control compound). The half inhibitory concentration (IC) was calculated according to Hill's four-parameter formula using the software GraphPadPrism 6.02 (or other available versions). 50 ):

[0116]

[0117] Where y refers to the percentage of residual activity, x refers to the concentration of the test article (or positive control compound), and S refers to the concentration of the test article (or positive control compound) at IC 50 Top and Bottom refer to the theoretical maximum and minimum residual activity percentages, which are set to 100 and 0 respectively during calculation.

[0118] The experimental results are shown in Table 3.

[0119] Table 3. Inhibitory activity of compounds on human CYP450 enzyme activity

[0120]

[0121] Abbreviations: CYP3A4-M, midazolam as substrate.

[0122] Functions and Effects of the Embodiments

[0123] According to the tetrazolyl compounds, preparation methods and applications of the present invention, the tetrazolyl compounds have significant in vitro and in vivo antifungal activity against human pathogenic fungi Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus, and are stronger than the traditional antifungal drug fluconazole. At the same time, the tetrazolyl compounds have low inhibitory effects on human CYP450 enzymes, especially on human liver drug enzyme CYP3A4, so they can be used to prepare antifungal drugs.

[0124] The above-mentioned embodiments are preferred examples of the present invention and are not intended to limit the protection scope of the present invention.

Claims

1. A tetrazolol compound, characterized in that: The structural formula is shown in Formula I: Wherein, in formula I, R1 represents H or F, R2 represents H or F, R3 is independently selected from any one of C1-C4 alkyl, C1-C4 alkoxy, halogen, halogenated alkyl, halogenated alkoxy, cyano, benzene ring and substituted benzene ring, R4 represents H or CH3, X represents CH or N, and Y represents CH or N.

2. The tetrazolium alcohol compound according to claim 1, characterized in that: in, The halogen includes F, Cl, Br and I, The halogenated alkyl groups include CF3 and CF2H, The haloalkoxy group includes OCF3, OCF2H and OCF2CF3.

3. A method for preparing a tetrazolium alcohol compound as claimed in claim 1 or 2, characterized in that: The general reaction formula is as follows:

4. The method for preparing a tetrazolium alcohol compound according to claim 3, characterized in that: The steps include: Step 1, dissolve trimethyl sulfoxide iodide in dry DMF, add sodium tert-butoxide in batches under ice bath, stir and react for 10 minutes, add DMF solution of compound 1, continue to react for 1 hour under ice bath, after LCMS detection, completely convert into epoxide intermediate 2, add potassium carbonate and 1H-tetrazole, heat the mixture to 85°C and continue to react for 12 hours, pour into ice water after the reaction, extract three times with ethyl acetate, wash the organic phase with saturated sodium chloride aqueous solution twice, dry the organic phase with anhydrous sodium sulfate, concentrate by rotary evaporator and separate by column chromatography to obtain compound 3; Step 2, dissolving the compound 3 in ethyl acetate, adding methanesulfonic acid, stirring and reacting for 12 hours, after the reaction is complete, washing the organic phase twice with a sodium bicarbonate aqueous solution, drying the organic phase over anhydrous sodium sulfate, and concentrating it on a rotary evaporator to obtain compound 4; Step 3, the compound 4 was dissolved in THF, triethylamine was added, and methylsulfonyl chloride was added dropwise under ice bath. After the addition was completed, stirring was continued for 1 hour. After the reaction was complete, sodium hydroxide aqueous solution was added, and the reaction was vigorously stirred for 1 hour. Then, it was extracted twice with ethyl acetate, and the organic phase was washed twice with saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and separated by column chromatography to obtain compound 5.

5. Use of the tetrazolol compound according to claim 1 or 2 in the preparation of antifungal drugs.

6. The use according to claim 5, characterized in that: in, The antifungal drug is used for treating or preventing fungal infections, and comprises: at least one azole compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

7. The use according to claim 6, characterized in that: in, The pharmaceutically acceptable salt is any one of hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, nitrate, maleate, fumarate, tartrate, succinate, lactate, methanesulfonate, p-toluenesulfonate, salicylate or oxalate.

8. The antifungal drug according to claim 5, characterized in that Also includes: Pharmaceutically acceptable carrier or excipient.

9. The use according to claim 8, characterized in that: in, The pharmaceutically acceptable carrier or excipient is one or more of an auxiliary agent, a wetting agent, an emulsifier, a suspending agent, a preservative, a salt affecting osmotic pressure, a buffer, a sweetener, a flavoring agent or a coloring agent.

10. The use according to claim 8, characterized in that: in, The fungus is any one or more of Candida albicans, Candida parapsilosis, Cryptococcus neoformans, Candida glabrata, Candida tropicalis, Candida krusei, Candida auris, Aspergillus fumigatus, Trichophyton rubrum or Microsporum gypseum.

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