WO2016141747A1 - Triazole alcohol derivative and preparation method and use thereof - Google Patents

Abstract

The present invention relates to a triazole alcohol derivative and a preparation method and use thereof. The triazole alcohol derivative is a 2-(2,4-difluorophenyl )-3-(1-substituted-1H-1,2,3-triazol-4-yl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol compound. The present invention also provides salts, pharmaceutical compositions, the preparation method and the use of the compound. The compound of the present invention has an antifungal activity, and has a low toxicity, a broad antibacterial spectrum, and the like, and can be used for preparing antifungal drugs.

Description

Triazole alcohol derivative and preparation method and application thereof Technical field

The invention relates to the technical field of pharmaceutical compounds, in particular to a novel triazole alcohol derivative and a preparation method and application thereof.

Background technique

In recent years, with the widespread use of broad-spectrum antibiotics, anti-tumor drugs, immunosuppressive agents, radiation therapy and organ transplantation, the widespread development of catheters and intubation, and the rapid increase in immunodeficiency patients, especially AIDS patients, Fungal infections, especially deep fungal infections, have risen dramatically, and deep fungal infections have now become the leading cause of death from major diseases such as AIDS and cancer. However, in the current clinical application of antifungal drugs, there are problems of large side effects, narrow antibacterial spectrum, and easy to produce drug resistance. Effective antifungal drugs, especially anti-deep fungal drugs, are very scarce and far from meeting the therapeutic needs. The existing antifungal drugs are mainly allylamines acting on squalene epoxidase, azoles acting on lanosterol 14a demethylase and b-(1,3)-glucan on cell wall. A lipopeptide of a sugar synthase or the like. However, no related to 2-(2,4-difluorophenyl)-3-(1-substituted-1H-1,2,3-triazol-4-yl)-1-(1H-1,2) , 4-triazol-1-yl)butyl-2-ol compounds and their antifungal activity reports.

Summary of the invention

The object of the present invention is to provide an antifungal triazole alcohol compound in view of the deficiencies in the prior art.

It is still another object of the present invention to provide a pharmacologically acceptable salt of the triazol alcohol compound.

Another object of the invention is to provide a pharmaceutical composition.

A fourth object of the present invention is to provide a process for producing the above-described triazol alcohol compound.

A fifth object of the present invention is to provide the use of the triazole alcohol compound or a pharmacologically acceptable salt thereof.

In order to achieve the above first object, the technical solution adopted by the present invention is:

An antifungal triazole alcohol compound, the chemical structure of the triazole alcohol compound is as shown in formula I:

In formula I, the R ₁ group represents a heterocyclic ring or a benzene ring, the heterocyclic ring is selected from a pyridine ring or a pyrimidine ring, and the benzene ring is selected from a phenyl group, a substituted phenyl group, a benzyl group or a substituted benzyl group. The substituted phenyl or substituted benzyl group substituent may be located at various positions of the benzene ring, and may be mono- or poly-substituted, and the substituent is selected from a), b), c) or d):

a) halogen, said halogen being F, Cl, Br or I,

b) an electron withdrawing group, said electron withdrawing group being a cyano group, a nitro group, a trifluoromethyl group, an acetyl group or a methylsulfonyl group,

c) a lower alkyl group of 1 to 4 carbon atoms or a halogen-substituted lower alkyl group,

d) a lower alkoxy group of 1 to 4 carbon atoms or a halogen-substituted lower alkoxy group;

The R ₂ , R ₃ or R ₄ group represents a halogen or a hydrogen atom.

Preferably, the lower alkyl or halogen-substituted lower alkyl group of 1 to 4 carbon atoms is selected from methyl or trifluoromethyl; the lower alkoxy group or halogen substituted with 1 to 4 carbon atoms The lower alkoxy group is selected from the group consisting of methoxy, trifluoromethoxy or difluoromethoxy.

Preferably, the triazole alcohol compound is a racemate, an R isomer or an S isomer.

More preferably, the triazole alcohol compound is selected from the group consisting of:

(2R*,3S*)-3-(1-(3-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) -1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) -1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) -1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluoro Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) -1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(4-Trifluoromethylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluoro Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) )-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(4-cyanophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) )-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluoro Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(2,6-difluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluoro Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(phenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1- (1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(4-difluoromethoxyphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(4-methanesulfonylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorobenzene -1(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(4-acetylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) )-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(pyridin-3-yl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) -1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(pyrimidin-5-yl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) -1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,5-di Fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(3-ethylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,5-difluorophenyl) )-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,5-di Fluorobenzene -1(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(4-Trifluoromethylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,5-difluoro Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H -1,2,4-triazol-1-yl)butyl-2-ol,

(2R*,3S*)-3-(1-(2,4-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluoro Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol, or

(2R,3S)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorobenzene Base)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol.

The chemical structures of the above preferred triazol alcohol compounds are shown in Table 1.

Table 1 Chemical structure of some preferred compounds

In order to achieve the above second object, the technical solution adopted by the present invention is:

A pharmacologically acceptable salt of the triazol alcohol compound, wherein the pharmacologically acceptable salt is a mineral acid salt or an organic acid salt.

Preferably, the inorganic acid is hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid or nitric acid; the organic acid is acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, lactic acid, methanesulfonic acid , p-toluenesulfonic acid, salicylic acid or oxalic acid.

In order to achieve the above third object, the technical solution adopted by the present invention is:

A pharmaceutical composition comprising a triazolol compound as described above, or a pharmacologically acceptable salt as described above, and comprising a conventional pharmaceutical carrier.

The pharmaceutical composition may be a tablet, a dispersible tablet, a lozenge, an orally disintegrating tablet, a sustained release tablet, a capsule, a soft capsule, a dropping pill, a granule, an injection, a powder injection or an aerosol.

In order to achieve the above fourth object, the technical solution adopted by the present invention is:

The preparation method of the triazole alcohol compound comprises the following steps:

a) Preparation of compound 3

Compound 2 was dissolved in DCM, TEA and MsCl were added dropwise at -78 °C, and reacted for 1 hour to form Compound 3;

b) Preparation of compound 4

Pd(CH ₃ CN) ₂ Cl _{2 is} dissolved in anhydrous THF, PPh _{3 is} added, and reacted at room temperature for 10 minutes, compound 1 and compound 3 are added, and ZnEt2 is added dropwise under ice-soluble conditions, and reacted at room temperature for 1 hour to form compound 4;

c) Preparation of compound 5

Dissolving 1,2,4-triazole and NaOH in DMSO, adding compound 4, reacting at 70 degrees for 4 hours to form compound 5;

d) Preparation of compound 6

The compound 8 is dissolved in aqueous hydrochloric acid, sodium nitrite and sodium azide are added, and the reaction is carried out in an ice bath to form a compound 6;

Or the compound 7 is dissolved in DMF, sodium azide is added, and the compound 6 is formed under heating;

e) Preparation of the target compound triazolol compound (compound 9)

Compound 5 and Compound 6 were dissolved in DMF and water, and copper sulfate and sodium ascorbate were added to react at 60 degrees. In hours, the target compound triazol alcohol compound is formed; the synthesis reaction scheme is as follows:

The synthesis of the pharmacologically acceptable salt is based on the above reaction. Further, the target compound triazole alcohol compound is dissolved in isopropyl acetate, a mineral acid or an organic acid is added, and the solid is stirred and precipitated. The pharmacologically acceptable salt (Compound 10) is filtered, and the reaction formula is as follows:

Among them, HX represents a mineral acid or an organic acid, preferably hydrochloric acid, hydrobromic acid or methanesulfonic acid.

In order to achieve the above fifth object, the technical solution adopted by the present invention is:

The use of a triazole alcohol compound as described above, or a pharmacologically acceptable salt as described above, for the preparation of an antifungal drug.

As an embodiment of the present invention, the fungus is Candida albicans, Candida parapsilosis, Cryptococcus neoformans or Candida tropicalis.

The invention has the advantages that: the invention synthesizes a novel triazole alcohol compound, which has good inhibition on the human pathogenic fungus Candida albicans, Candida parapsilosis, Cryptococcus neoformans, Candida tropicalis, etc. The activity is stronger than that of fluconazole, and the compound of the present invention has the advantages of low toxicity, wide antifungal spectrum and the like, and thus can be used for preparing an antifungal drug.

detailed description

The specific embodiments provided by the present invention are described in detail below. The reagents and starting materials used in the present invention are either commercially available or can be prepared by literature methods. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. The reagents used in the examples were all commercially available analytical grades.

Example 1: (2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)- Synthesis of 4-pentyn-2-ol

Step 1: Synthesis of 3-butyn-2-ol mesylate

3-butyn-2-ol (25 g) was dissolved in dichloromethane, triethylamine (99 mL) was added, and methanesulfonyl chloride (41 mL) was added dropwise at -78 ° C. After the reaction was completed, 200 mL of hydrogen carbonate was poured. The sodium aqueous solution was extracted twice with dichloromethane, and the organic phase was washed twice with water, dried over anhydrous sodium sulfate and then evaporated to the next.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 5.29 (q, 1H), 3.13 (s, 3H), 2.71 (s, 1H), 1.66 (d, 3H).

Step 2: Synthesis of (2R*,3S*)-1-chloro-2-(2,4-difluorophenyl)-3-methyl-4-pentyn-2-ol

Pd(CH ₃ CN) ₂ Cl _{2 was} dissolved in tetrahydrofuran, triphenylphosphine was added, and after 10 minutes, 2-chloro-2',4'-difluoroacetophenone and 3-butyn-2-ol were added. The mesylate was then slowly added dropwise with a solution of diethylzinc in toluene. After reacting for 1 hour at room temperature, it was poured into a hydrochloric acid solution, extracted with ethyl acetate three times, and the organic phase was washed twice with a saturated aqueous solution of sodium chloride. The aqueous sodium sulfate was dried and then dried to give (2R*,3S*)-1-chloro-2-(2,4-difluorophenyl)-3-methyl-4-pentyne-2-ol. Used directly in the next step.

Step 3: (2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4 Synthesis of -pentyn-2-ol

Dissolve 1H-1,2,4-triazole in DMSO, add sodium hydroxide and obtain (2R*,3S*)-1-chloro-2-(2,4-difluorophenyl)-3 -Methyl-4-pentyn-2-ol. After 70 hours of reaction at 70 degrees, pour into ice water, extract with ethyl acetate 3 times, organic The phase is washed twice with a saturated aqueous solution of sodium chloride, and the organic phase is dried over anhydrous sodium sulfate, and then dried to give (2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl Base-1-(1H-1,2,4-triazol-1-yl)-4-pentyn-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.3 (s, 1H), 7.6 (s, 1H), 6.9-7.2 (m, 3H), 5.97 (s, 1H), 4.6 (s, 2H) , 3.18-3.30 (m, 2H), 0.93 (d, 3H).

Example 2: (2R*,3S*)-2-(2,4-dichlorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)- Synthesis of 4-pentyn-2-ol

Step 1: Synthesis of (2R*,3S*)-1-chloro-2-(2,4-dichlorophenyl)-3-methyl-4-pentyne 2-ol

Pd(CH ₃ CN) ₂ Cl _{2 was} dissolved in tetrahydrofuran, triphenylphosphine was added, and after 10 minutes, 2-chloro-2',4'-dichloroacetophenone and 3-butyn-2-ol were added. The mesylate was then slowly added dropwise with a solution of diethylzinc in toluene. After reacting for 1 hour at room temperature, it was poured into a hydrochloric acid solution, extracted with ethyl acetate three times, and the organic phase was washed twice with a saturated aqueous solution of sodium chloride. The aqueous sodium sulfate was dried and then dried to give (2R*,3S*)-1-chloro-2-(2,4-dichlorophenyl)-3-methyl-4-pentyne-2-ol. Used directly in the next step.

Step 2: (2R*,3S*)-2-(2,4-dichlorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4 Synthesis of -pentyn-2-ol

Dissolve 1H-1,2,4-triazole in DMSO, add sodium hydroxide and obtain (2R*,3S*)-1-chloro-2-(2,4-difluorophenyl)-3 -Methyl-4-pentyn-2-ol. After reacting for 4 hours at 70 °C, it was poured into ice water, extracted with ethyl acetate three times, and the organic phase was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and then dried and then purified by column chromatography (2R*, 3S) *)-2-(2,4-Dichlorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyn-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 7.79 (s, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H) ), 7.13 (dd, J = 8.6, 2.1 Hz, 1H), 5.47 (d, J = 14.4 Hz, 1H), 4.88 (d, J = 14.4 Hz, 1H), 4.66 (s, 1H), 3.74 (qd) , J = 7.0, 2.4 Hz, 1H), 2.34 (d, J = 2.4 Hz, 1H), 0.99 (d, J = 7.0 Hz, 3H).

Example 3: (2R*,3S*)-2-(2,5-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)- Synthesis of 4-pentyn-2-ol

Step 1: Synthesis of (2R*,3S*)-1-chloro-2-(2,5-difluorophenyl)-3-methyl-4-pentyne 2-ol

Pd(CH ₃ CN) ₂ Cl _{2 was} dissolved in tetrahydrofuran, triphenylphosphine was added, and after 10 minutes, 2-chloro-2',5'-difluoroacetophenone and 3-butyn-2-ol were added. The mesylate was then slowly added dropwise with a solution of diethylzinc in toluene. After reacting for 1 hour at room temperature, it was poured into a hydrochloric acid solution, extracted with ethyl acetate three times, and the organic phase was washed twice with a saturated aqueous solution of sodium chloride. The aqueous sodium sulfate was dried and then dried to give (2R*,3S*)-1-chloro-2-(2,5-difluorophenyl)-3-methyl-4-pentyne-2-ol. Used directly in the next step.

Step 2: (2R*,3S*)-2-(2,5-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4 Synthesis of -pentyn-2-ol

Dissolve 1H-1,2,4-triazole in DMSO, add sodium hydroxide and obtain (2R*,3S*)-1-chloro-2-(2,5-di Fluorophenyl)-3-methyl-4-pentyne 2-ol. After reacting for 4 hours at 70 °C, it was poured into ice water, extracted with ethyl acetate three times, and the organic phase was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and then dried and then purified by column chromatography (2R*, 3S) *)-2-(2,5-Difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyn-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.83 (d, J = 15.0 Hz, 2H), 7.17 (ddd, J = 9.4, 6.2, 3.1 Hz, 1H), 7.02 - 6.82 (m, 2H) , 4.96 (d, J = 14.3 Hz, 1H), 4.88 (d, J = 14.2 Hz, 1H), 4.60 (d, J = 13.3 Hz, 1H), 3.23 (qd, J = 7.0, 2.4 Hz, 1H) , 2.32 (d, J = 2.4 Hz, 1H), 1.05 (d, J = 7.0 Hz, 3H).

Example 4: (2R*,3S*)-3-(1-(3-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Synthesis of fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 3-fluorophenyl azide

3-Fluoroaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added under ice-cooling, and the reaction was stirred for ten minutes, then sodium azide (1.5 eq) was added and the reaction was continued for 30 minutes. After the reaction was completed, it was extracted with ethyl acetate, dried and then evaporated to the next.

Step 2: (2R*,3S*)-3-(1-(3-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluoro Synthesis of Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyne- 2-Alcohol (1mmol) and 3-fluorophenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate were added. The reaction was carried out at 60 °C for 8 hours. After the reaction was completed, it was poured into water, acetic acid. The ethyl ester was extracted three times, the organic phase was washed twice with a saturated aqueous solution of sodium chloride, and the organic phase was dried over anhydrous sodium sulfate, and then evaporated to dryness to give (2R*,3S*)-3-(1-(3-fluoro) Phenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1 -yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.05 (s, 1H), 7.64 - 7.40 (m, 4H), 7.17 (t, J = 8.1 Hz, 2H), 6.80 (s, 2H), 5.12 (s, 2H), 4.20 (s, 1H), 3.88 (d, J = 5.6 Hz, 1H), 1.13 (d, J = 6.3 Hz, 3H).

Example 5: (2R*,3S*)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2 Synthesis of 4-(difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 4-chloro-2-fluorophenyl azide

4-Chloro-2-fluoroaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added under ice-cooling, and the reaction was stirred for ten minutes and then sodium azide (1.5 eq) was added. The reaction was carried out for 30 minutes, and the reaction was completed, extracted with ethyl acetate, dried and then evaporated to the next.

Step 2: (2R*,3S*)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2, Synthesis of 4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 4-chloro-2-fluorophenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate were added. The reaction was carried out at 60 °C for 8 hours. The reaction was complete. After pouring into water, ethyl acetate was extracted three times, and the organic phase was washed twice with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, and then dried and then purified by column chromatography (2R*, 3S*)-3- 1-(4-Chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1 , 2,4-triazol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.11 (d, J = 3.0 Hz, 1H), 8.03 - 7.93 (m, 2H), 7.73 (s, 1H), 7.54 - 7.42 (m, 1H) , 7.42–7.33 (m, 2H), 6.85–6.73 (m, 2H), 5.17 (s, 1H), 4.99 (d, J = 14.4 Hz, 1H), 4.18 (d, J = 14.2 Hz, 1H), 3.90 (q, J = 7.2 Hz, 1H), 1.15 (d, J = 7.2 Hz, 3H).

Example 6: (2R*,3S*)-3-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Synthesis of fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 4-fluorophenyl azide

4-Fluoroaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added under ice-cooling, and the reaction was stirred for ten minutes, then sodium azide (1.5 eq) was added and the reaction was continued for 30 minutes. After the reaction was completed, it was extracted with ethyl acetate, dried and then evaporated to the next.

Step 2: (2R*,3S*)-3-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluoro Synthesis of Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 4-fluorophenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate was added. The reaction was carried out at 60 °C for 8 hours. After the reaction was completed, it was poured into water. The organic phase is washed twice with a saturated aqueous solution of sodium chloride, and the organic phase is dried over anhydrous sodium sulfate, and then dried and then purified by column chromatography (2R*,3S*)-3-(1-(4) -fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole -1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.01 (s, 1H), 7.91 (s, 1H), 7.84 - 7.69 (m, 3H), 7.56 - 7.41 (m, 1H), 7.31 - 7.19 ( m, 2H), 6.91 - 6.73 (m, 2H), 5.20 (s, 1H), 4.98 (d, J = 14.3 Hz, 1H), 4.15 (d, J = 14.2 Hz, 1H), 3.88 (q, J) =7.2 Hz, 1H), 1.14 (d, J = 7.2 Hz, 3H).

Example 7: (2R*,3S*)-3-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Synthesis of fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 2-fluorophenyl azide

2-Fluoroaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added under ice-cooling, and the reaction was stirred for ten minutes, then sodium azide (1.5 eq) was added and the reaction was continued for 30 minutes. After the reaction was completed, it was extracted with ethyl acetate, dried and then evaporated to the next.

Step 2: (2R*,3S*)-3-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluoro Synthesis of Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 2-fluorophenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate was added. The reaction was carried out at 60 °C for 8 hours. After the reaction was completed, it was poured into water. The organic phase is washed twice with a saturated aqueous solution of sodium chloride, and the organic phase is dried over anhydrous sodium sulfate, and then dried and then purified by column chromatography (2R*,3S*)-3-(1-(2) -fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole -1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.14 (d, J = 2.9 Hz, 1H), 8.00 (t, J = 9 Hz, 1H), 7.90 (s, 1H), 7.72 (s, 1H) , 7.57–7.42 (m, 2H), 7.41–7.28 (m, 2H), 6.88–6.72 (m, 2H), 5.20 (s, 1H), 4.99 (d, J = 14.3 Hz, 1H), 4.17 (d) , J = 14.2 Hz, 1H), 3.90 (q, J = 7.2 Hz, 1H), 1.17 (d, J = 7.2 Hz, 3H).

Example 8: (2R*,3S*)-3-(1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2, Synthesis of 4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 3,4-difluorophenyl azide

3,4-difluoroaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added under ice-cooling, and the reaction was stirred for ten minutes, then sodium azide (1.5 eq) was added to continue the reaction. After 30 minutes, the reaction was completed and extracted with ethyl acetate.

Step 2: (2R*,3S*)-3-(1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4 Synthesis of -difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 3,4-difluorophenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate was added. The reaction was carried out at 60 °C for 8 hours. Pour into water, extract with ethyl acetate three times, wash the organic phase twice with saturated aqueous sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, spin dry and then chromatograph (2R*,3S*)-3-(1) -(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2 , 4-triazol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.89 (s, 1H), 7.79 - 7.65 (m, 2H), 7.63 - 7.30 (m, 3H), 6.89 - 6.70 ( m, 2H), 5.17 (s, 1H), 4.99 (d, J = 14.2 Hz, 1H), 4.13 (d, J = 14.1 Hz, 1H), 3.88 (q, J = 7.2 Hz, 1H), 1.13 ( d, J = 7.2 Hz, 3H).

Example 9: (2R*,3S*)-3-(1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2 Synthesis of 4-(difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 4-chloro-3-fluorophenyl azide

4-Chloro-3-fluoroaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL) and sodium nitrite was added under ice bath (1.1 eq), after stirring for 10 minutes, sodium azide (1.5 eq) was added and the reaction was continued for 30 minutes. After completion of the reaction, the mixture was extracted with ethyl acetate.

Step 2: (2R*,3S*)-3-(1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2, Synthesis of 4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 4-chloro-3-fluorophenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate was added. The reaction was carried out at 60 °C for 8 hours. After pouring into water, ethyl acetate was extracted three times, and the organic phase was washed twice with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, and then dried and then purified by column chromatography (2R*, 3S*)-3- 1-(4-Chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1 , 2,4-triazol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.05 (s, 1H), 7.74 (s, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.65 - 7.40 (m, 3H), 6.78 (d, J = 8.0 Hz, 2H), 5.14 (s, 1H), 5.02 (d, J = 13.0 Hz, 1H), 4.14 (d, J = 13.3 Hz, 1H), 3.88 (q, J = 6.9 Hz) , 1H), 1.13 (d, J = 7.0 Hz, 3H).

Example 10: (2R*,3S*)-3-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Synthesis of fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 4-chlorophenyl azide

4-Chloroaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added and the mixture was stirred for ten minutes, then sodium azide (1.5 eq) was added and the reaction was continued for 30 minutes. After the reaction was completed, it was extracted with ethyl acetate, dried and then evaporated to the next.

Step 2: (2R*,3S*)-3-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluoro Synthesis of Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 4-chlorophenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate was added. The reaction was carried out at 60 °C for 8 hours. After the reaction was completed, it was poured into water. The organic phase is washed twice with a saturated aqueous solution of sodium chloride, and the organic phase is dried over anhydrous sodium sulfate, and then dried and then purified by column chromatography (2R*,3S*)-3-(1-(4) -chlorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole -1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.48 (d, J) =7.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 2H), 5.16 (s, 1H), 5.06 (s, 1H), 4.17 (d, J = 11.7 Hz, 1H), 3.88 (d, J) =7.0 Hz, 1H), 1.13 (d, J = 6.9 Hz, 3H).

Example 11: (2R*,3S*)-3-(1-(4-trifluoromethylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2, Synthesis of 4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 4-trifluoromethylphenyl azide

4-Trifluoromethylaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added under ice-cooling, and the reaction was stirred for ten minutes, then sodium azide (1.5 eq) was added to continue the reaction. After 30 minutes, the reaction was completed and extracted with ethyl acetate.

Step 2: (2R*,3S*)-3-(1-(4-Trifluoromethylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4 Synthesis of -difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1 mmol) and 4-trifluoromethylphenyl azide (1 mmol) were dissolved in aqueous DMF solution, a catalytic amount of copper sulfate and sodium ascorbate were added, and the reaction was carried out at 60 °C for 8 hours. Pour into water, extract with ethyl acetate three times, wash the organic phase twice with saturated aqueous sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, spin dry and then chromatograph (2R*,3S*)-3-(1) -(4-trifluoromethylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2 , 4-triazol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.13 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.88 - 7.72 (m, 3H), 7.47 (dd, J = 15.4, 8.7 Hz, 1H), 6.87 - 6.72 (m, 2H), 5.18 (s, 1H), 5.02 (d, J = 14.1 Hz, 1H), 4.18 (d, J = 13.9 Hz, 1H), 3.91 (q, J = 7.3 Hz, 1H), 1.15 (d, J = 7.1 Hz, 3H).

Example 12: (2R*,3S*)-3-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4- Synthesis of difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 4-nitrophenyl azide

4-Nitroaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added and the mixture was stirred for ten minutes, then sodium azide (1.5 eq) was added and the reaction was continued for 30 minutes. After the reaction was completed, it was extracted with ethyl acetate, dried and then evaporated to the next.

Step 2: (2R*,3S*)-3-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Synthesis of fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 4-nitrophenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate were added. The reaction was carried out at 60 °C for 8 hours. In water, ethyl acetate was extracted three times, the organic phase was washed twice with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, and then dried and then purified to afford (2R*,3S*)-3-(1-( 4-nitrophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-tri Azol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.45 (d, J = 8.8 Hz, 2H), 8.19 (s, 1H), 8.05 (d, J = 8.9 Hz, 2H), 7.78 (s, 1H) ), 7.53 - 7.40 (m, 1H), 6.80 (t, J = 10.0 Hz, 2H), 5.15 (s, 1H), 5.02 (d, J = 14.0 Hz, 1H), 4.14 (d, J = 14.0 Hz) , 1H), 3.92 (q, J = 6.9 Hz, 1H), 1.15 (d, J = 7.1 Hz, 3H).

Example 13: (2R*,3S*)-3-(1-(4-cyanophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4- Synthesis of difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 4-cyanophenyl azide

4-cyanoaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added and the mixture was stirred for ten minutes, then sodium azide (1.5 eq) was added and the reaction was continued for 30 minutes. After the reaction was completed, it was extracted with ethyl acetate, dried and then evaporated to the next.

Step 2: (2R*,3S*)-3-(1-(4-cyanophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Synthesis of fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol.

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 4-cyanophenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate were added. The reaction was carried out at 60 °C for 8 hours. In water, ethyl acetate was extracted three times, the organic phase was washed twice with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, and then dried and then purified to afford (2R*,3S*)-3-(1-( 4-cyanophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-tri Azol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.15 (s, 1H), 7.99 (d, J = 8.6 Hz, 2H), 7.87 (d, J = 8.5 Hz, 2H), 7.81 (s, 1H) ), 7.46 (dd, J = 15.5, 8.9 Hz, 1H), 6.80 (dd, J = 13.0, 7.7 Hz, 2H), 5.15 (s, 1H), 5.02 (d, J = 13.7 Hz, 1H), 4.15 (d, J = 14.0 Hz, 1H), 3.91 (q, J = 7.0 Hz, 1H), 1.14 (d, J = 7.1 Hz, 3H).

Example 14: (2R*,3S*)-3-(1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2, Synthesis of 4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 2,4-difluorophenyl azide

2,4-difluoroaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added under ice-cooling, and the reaction was stirred for ten minutes, then sodium azide (1.5 eq) was added to continue the reaction. After 30 minutes, the reaction was completed and extracted with ethyl acetate.

Step 2: (2R*,3S*)-3-(1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4 Synthesis of -difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 2,4-difluorophenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate was added. The reaction was carried out at 60 °C for 8 hours. Pour into water, extract with ethyl acetate three times, wash the organic phase twice with saturated aqueous sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, spin dry and then chromatograph (2R*,3S*)-3-(1) -(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2 , 4-triazol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.08 (d, J = 2.9 Hz, 1H), 8.03 - 7.88 (m, 2H), 7.73 (s, 1H), 7.48 (dd, J = 15.8, 9.1 Hz, 1H), 7.17 - 7.03 (m, 2H), 6.89 - 6.72 (m, 2H), 5.17 (s, 1H), 4.99 (d, J = 14.3 Hz, 1H), 4.16 (d, J = 13.9) Hz, 1H), 3.89 (q, J = 7.2 Hz, 1H), 1.15 (d, J = 7.2 Hz, 3H).

Example 15: (2R*,3S*)-3-(1-(2,6-difluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2, Synthesis of 4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 2,6-difluorophenyl azide

2,6-Difluoroaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added under ice-cooling, and the reaction was stirred for ten minutes, then sodium azide (1.5 eq) was added to continue the reaction. After 30 minutes, the reaction was completed and extracted with ethyl acetate.

Step 2: (2R*,3S*)-3-(1-(2,6-difluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4 Synthesis of -difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 2,6-difluorophenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate were added. The reaction was carried out at 60 °C for 8 hours. Pour into water, extract with ethyl acetate three times, wash the organic phase twice with saturated aqueous sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, spin dry and then chromatograph (2R*,3S*)-3-(1) -(2,6-difluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2 , 4-triazol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.88 (s, 1H), 7.73 (s, 1H), 7.60 - 7.40 (m, 2H), 7.17 (t, J = 8.2 Hz, 2H), 6.89 - 6.68 (m, 2H), 5.20 (s, 1H), 5.00 (d, J = 14.3 Hz, 1H), 4.15 (d, J = 14.2 Hz, 1H), 3.89 (q, J = 7.2 Hz, 1H), 1.18 (d, J = 7.2 Hz, 3H).

Example 16: (2R*,3S*)-3-(1-(phenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) Synthesis of 1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of Phenyl Azide

The aniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added under ice-cooling, and the reaction was stirred for ten minutes, then sodium azide (1.5 eq) was added and the reaction was continued for 30 minutes. Extract with ethyl acetate, dry and spin dry for use in the next step.

Step 2: (2R*,3S*)-3-(1-(phenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) Synthesis of 1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and phenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate was added. The reaction was carried out at 60 °C for 8 hours. After the reaction was completed, it was poured into water. The ester was extracted three times, the organic phase was washed twice with a saturated aqueous solution of sodium chloride, and the organic phase was dried over anhydrous sodium sulfate, and then evaporated to dryness to give (2R*,3S*)-3-(1-(phenyl)- 1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl) Keto-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.86 (s, 1H), 7.80 (d, J = 7.7 Hz, 2H), 7.71 (s, 1H), 7.52 (ddd , J = 15.8, 12.4, 7.4 Hz, 4H), 6.86 - 6.74 (m, 2H), 5.22 (s, 1H), 4.98 (d, J = 14.4 Hz, 1H), 4.16 (d, J = 14.3 Hz, 1H), 3.89 (q, J = 7.2 Hz, 1H), 1.15 (d, J = 7.2 Hz, 3H).

Example 17: (2R*,3S*)-3-(1-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-4-yl)-2-(2 Synthesis of 4-(difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 4-trifluoromethoxyphenyl azide

4-Trifluoromethoxyaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added and the mixture was stirred for ten minutes, then sodium azide (1.5 eq) was added to continue The reaction was carried out for 30 minutes, and the reaction was completed, extracted with ethyl acetate, dried and then evaporated to the next.

Step 2: (2R*,3S*)-3-(1-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-4-yl)-2-(2, Synthesis of 4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 4-trifluoromethoxyphenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate was added. The reaction was carried out at 60 °C for 8 hours. The reaction was complete. After pouring into water, ethyl acetate was extracted three times, and the organic phase was washed twice with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, and then dried and then purified by column chromatography (2R*, 3S*)-3- 1-(4-Trifluoromethoxyphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1 , 2,4-triazol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.85 (d, J = 9.0 Hz, 2H), 7.74 (s, 1H), 7.54 - 7.35 (m, 3H), 6.88 – 6.70 (m, 2H), 5.18 (s, 1H), 4.99 (d, J = 14.1 Hz, 1H), 4.13 (dd, J = 14.4, 7.3 Hz, 1H), 3.89 (q, J = 7.1 Hz, 1H), 1.14 (d, J = 7.2 Hz, 3H).

Example 18: (2R*,3S*)-3-(1-(4-difluoromethoxyphenyl)-1H-1,2,3-triazol-4-yl)-2-(2 Synthesis of 4-(difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 4-difluoromethoxyphenyl azide

4-Difluoromethoxyaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added under ice-cooling, and the reaction was stirred for ten minutes, then sodium azide (1.5 eq) was added. The reaction was carried out for 30 minutes, and the reaction was completed, extracted with ethyl acetate, dried and then evaporated to the next.

Step 2: (2R*,3S*)-3-(1-(4-difluoromethoxyphenyl)-1H-1,2,3-triazol-4-yl)-2-(2, Synthesis of 4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 4-difluoromethoxyphenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate were added. The reaction was carried out at 60 °C for 8 hours. The reaction was complete. After pouring into water, ethyl acetate was extracted 3 times, and the organic phase was saturated. Wash twice with aqueous sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, spin dry and then chromatograph to give (2R*,3S*)-3-(1-(4-difluoromethoxyphenyl)-1H -1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl -2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.88 (s, 1H), 7.81 (d, J = 9.0 Hz, 2H), 7.73 (s, 1H), 7.54 - 7.42 (m, 1H), 7.31 (t, J = 7.9 Hz, 2H), 6.85 - 6.74 (m, 2H), 5.20 (s, 1H), 4.98 (d, J = 14.5 Hz, 1H), 4.20 - 4.08 ( m, 1H), 3.89 (q, J = 7.2 Hz, 1H), 1.14 (d, J = 7.2 Hz, 3H).

Example 19: (2R*,3S*)-3-(1-(4-methanesulfonylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4 Synthesis of -difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 4-methanesulfonylphenyl azide

4-Methanesulfonylaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added under ice-cooling, and the reaction was stirred for ten minutes, then sodium azide (1.5 eq) was added to continue the reaction. After a minute, the reaction was completed and extracted with ethyl acetate.

Step 2: (2R*,3S*)-3-(1-(4-methanesulfonylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4- Synthesis of difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 4-methanesulfonylphenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate was added. The reaction was carried out at 60 °C for 8 hours. Into the water, ethyl acetate was extracted three times, the organic phase was washed twice with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, then dried and then purified by column chromatography (2R*,3S*)-3-(1- (4-methanesulfonylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4 -Triazol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.31 - 7.97 (m, 5H), 7.90 (s, 1H), 7.76 (s, 1H), 7.48 (d, J = 6.1 Hz, 1H), 6.80 (s, 2H), 5.16 (s, 1H), 5.01 (d, J = 13.8 Hz, 1H), 4.15 (d, J = 13.2 Hz, 1H), 3.92 (d, J = 6.4 Hz, 1H), 3.13 (s, 3H), 1.15 (d, J = 6.3 Hz, 3H).

Example 20: (2R*,3S*)-3-(1-(4-acetylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4- Synthesis of difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 4-acetylphenyl azide

4-Acetylaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added and the mixture was stirred for ten minutes, then sodium azide (1.5 eq) was added and the reaction was continued for 30 minutes. After the reaction was completed, it was extracted with ethyl acetate, dried and then evaporated to the next.

Step 2: (2R*,3S*)-3-(1-(4-acetylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Synthesis of fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) And 4-acetylphenyl azide (1mmol) dissolved in aqueous DMF solution, adding a catalytic amount of copper sulfate and sodium ascorbate, reacting at 60 degrees for 8 hours, the reaction was completed, poured into water, and extracted with ethyl acetate three times. The organic phase was washed twice with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. 1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl) Keto-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.16 (d, J = 8.1 Hz, 3H), 7.94 (d, J = 8.5 Hz, 2H), 7.78 (s, 1H), 7.48 (d, J) =7.0 Hz, 1H), 6.80 (t, J = 10.0 Hz, 2H), 5.17 (s, 1H), 5.02 (d, J = 13.3 Hz, 1H), 4.13 (dd, J = 16.5, 9.6 Hz, 1H) ), 3.90 (d, J = 6.7 Hz, 1H), 2.68 (s, 3H), 1.15 (d, J = 7.1 Hz, 3H).

Example 21: (2R*,3S*)-3-(1-(pyridin-3-yl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Synthesis of fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 3-azidopyridine

3-Aminopyridine (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added and the mixture was stirred for ten minutes, then sodium azide (1.5 eq) was added and the reaction was continued for 30 minutes. After the reaction was completed, it was extracted with ethyl acetate, dried and then evaporated to the next.

Step 2: (2R*,3S*)-3-(1-(pyridin-3-yl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluoro Synthesis of Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1 mmol) and 3-azidopyridine (1 mmol) were dissolved in aqueous DMF solution, a catalytic amount of copper sulfate and sodium ascorbate were added, and the reaction was carried out at 60 °C for 8 hours. After the reaction was completed, it was poured into water. The mixture was extracted three times with ethyl acetate. The organic phase was washed twice with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. 3-yl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole- 1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.12 (s, 1H), 8.76 (s, 1H), 8.20 (d, J = 8.1 Hz, 1H), 8.12 (s, 1H), 7.76 (t) , J=44.0 Hz, 2H), 7.62–7.35 (m, 2H), 6.79 (t, J = 10.2 Hz, 2H), 5.17 (s, 1H), 5.01 (d, J = 14.2 Hz, 1H), 4.15 (d, J = 14.1 Hz, 1H), 3.91 (q, J = 7.1 Hz, 1H), 1.15 (d, J = 7.1 Hz, 3H).

Example 22: (2R*,3S*)-3-(1-(pyrimidin-5-yl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Synthesis of fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 5-azidopyrimidine

5-Aminopyrimidine (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added under ice-cooling, and the reaction was stirred for ten minutes, then sodium azide (1.5 eq) was added and the reaction was continued for 30 minutes. After the reaction was completed, it was extracted with ethyl acetate, dried and then evaporated to the next.

Step 2: (2R*,3S*)-3-(1-(pyrimidin-5-yl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluoro Synthesis of Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1 mmol) and 5-azidopyrimidine (1 mmol) were dissolved in aqueous DMF solution, a catalytic amount of copper sulfate and sodium ascorbate were added, and the reaction was carried out at 60 °C for 8 hours. After the reaction was completed, it was poured into water. The organic phase was extracted twice with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. 5-yl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole- 1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.31 (d, J = 21.0 Hz, 3H), 8.17 (s, 1H), 7.84 (s, 1H), 7.47 (d, J = 7.2 Hz, 1H) ), 6.81 (t, J = 10.0 Hz, 1H), 5.15 (s, 1H), 5.05 (d, J = 12.4 Hz, 1H), 4.16 (d, J = 14.1 Hz, 1H), 3.94 (q, J) =6.9 Hz, 1H), 1.15 (d, J = 7.1 Hz, 3H).

Example 23: (2R*,3S*)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2 Synthesis of 5-(difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 4-chloro-2-fluorophenyl azide

4-Chloro-2-fluoroaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added under ice-cooling, and the reaction was stirred for ten minutes and then sodium azide (1.5 eq) was added. The reaction was carried out for 30 minutes, and the reaction was completed, extracted with ethyl acetate, dried and then evaporated to the next.

Step 2: (2R*,3S*)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2, Synthesis of 5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,5-Difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 4-chloro-2-fluorophenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate were added. The reaction was carried out at 60 °C for 8 hours. The reaction was complete. After pouring into water, ethyl acetate was extracted three times, and the organic phase was washed twice with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, and then dried and then purified by column chromatography (2R*, 3S*)-3- 1-(4-Chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,5-difluorophenyl)-1-(1H-1 , 2,4-triazol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.13 (d, J = 2.9 Hz, 1H), 7.98 (t, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.43 - 7.32 (m) , 2H), 7.25 - 7.17 (m, 1H), 7.08 - 6.85 (m, 2H), 5.19 (s, 1H), 5.04 (d, J = 14.2 Hz, 1H), 4.18 (d, J = 14.2 Hz, 1H), 3.92 (q, J = 7.2 Hz, 1H), 1.17 (d, J = 7.2 Hz, 3H).

Example 24: (2R*,3S*)-3-(1-(3-ethylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,5- Synthesis of difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 3-ethylphenyl azide

3-Ethyl aniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL) and sodium nitrite (1. After stirring for 10 minutes, sodium azide (1.5 eq) was added and the reaction was continued for 30 minutes. After completion, the mixture was extracted with ethyl acetate.

Step 2: (2R*,3S*)-3-(1-(3-ethylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,5-di Synthesis of fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,5-Difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 3-ethylphenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate were added. The reaction was carried out at 60 °C for 8 hours. In water, ethyl acetate was extracted three times, the organic phase was washed twice with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, and then dried and then purified to afford (2R*,3S*)-3-(1-( 3-ethylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,5-difluorophenyl)-1-(1H-1,2,4-tri Azol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H-NMR (300 MHz, CDCl ₃ ): δ 8.05 (s, 1H), 7.92 (s, 1H), 7.74 (s, 1H), 7.64 (s, 1H), 7.58 (d, 1H, J = 9.0 Hz), 7.45 (t, 1H, J = 9.0 Hz), 7.31 (d, 1H, J = 9.0 Hz), 7.23 (m, 1H), 6.97 (m, 1H), 6.91 (m, 1H) , 5.26 (br.s, 1H), 5.02 (d, 1H, J = 15.0 Hz), 4.15 (d, 1H, J = 15.0 Hz), 3.91 (q, 1H, J = 9.0 Hz), 2.77 (q, 2H, J = 9.0 Hz), 1.32 (t, 3H, J = 9.0 Hz), 1.15 (d, 3H, J = 9.0 Hz).

Example 25: (2R*,3S*)-3-(1-(4-trifluoromethylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2, Synthesis of 5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 4-chlorophenyl azide

4-Trifluoromethylaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added under ice-cooling, and the reaction was stirred for ten minutes, then sodium azide (1.5 eq) was added to continue the reaction. After 30 minutes, the reaction was completed and extracted with ethyl acetate.

Step 2: (2R*,3S*)-3-(1-(4-trifluoromethylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,5 Synthesis of -difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,5-Difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1 mmol) and 4-trifluoromethylphenyl azide (1 mmol) were dissolved in aqueous DMF solution, a catalytic amount of copper sulfate and sodium ascorbate were added, and the reaction was carried out at 60 °C for 8 hours. Pour into water, extract with ethyl acetate three times, wash the organic phase twice with saturated aqueous sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, spin dry and then chromatograph (2R*,3S*)-3-(1) -(4-trifluoromethylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,5-difluorophenyl)-1-(1H-1,2 , 4-triazol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H-NMR (300 MHz, CDCl ₃ ): δ 8.15 (s, 1H), 7.95 (d, 2H, J = 9.0 Hz), 7.85 (s, 1H), 7.84 (d, 2H, J = 9.0.0 Hz), 7.74 (s, 1H), 7.25 (m, 1H), 7.0 (m, 1H), 6.93 (m, 1H), 5.21 (br.s, 1H), 5.03 (d, 1H, J = 15.0 Hz), 4.13 (d, 1H, J = 15.0 Hz), 3.93 (q, 1H, J = 9.0 Hz), 1.16 (d, 3H, J = 9.0 Hz).

Example 26: (2R*,3S*)-3-(1-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-4-yl)-2-(2 Synthesis of 5-(difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 4-trifluoromethoxyphenyl azide

4-Trifluoromethoxyaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added and the mixture was stirred for ten minutes, then sodium azide (1.5 eq) was added to continue The reaction was carried out for 30 minutes, and the reaction was completed, extracted with ethyl acetate, dried and then evaporated to the next.

Step 2: (2R*,3S*)-3-(1-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-4-yl)-2-(2, Synthesis of 5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,5-Difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 4-trifluoromethoxyphenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate was added. The reaction was carried out at 60 °C for 8 hours. The reaction was complete. After pouring into water, ethyl acetate was extracted three times, and the organic phase was washed twice with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, and then dried and then purified by column chromatography (2R*, 3S*)-3- 1-(4-Trifluoromethoxyphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,5-difluorophenyl)-1-(1H-1 , 2,4-triazol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H-NMR (300 MHz, CDCl ₃ ): δ 8.07 (s, 1H), 7.86 (d, 2H, J = 9.0 Hz), 7.85 (s, 1H), 7.74 (s, 1H), 7.42 (d, 2H, J = 9.0 Hz), 7.25 (m, 1H), 6.98 (m, 1H), 6.93 (m, 1H), 5.21 (br.s, 1H), 5.03 (d, 1H, J = 15.0) Hz), 4.13 (d, 1H, J = 15.0 Hz), 3.92 (q, 1H, J = 9.0 Hz), 1.15 (d, 3H, J = 9.0 Hz).

Example 27: (2R*,3S*)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2 Synthesis of 4-(dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 4-chloro-2-fluorophenyl azide

4-Chloro-2-fluoroaniline (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added under ice-cooling, and the reaction was stirred for ten minutes and then sodium azide (1.5 eq) was added. The reaction was carried out for 30 minutes, and the reaction was completed, extracted with ethyl acetate, dried and then evaporated to the next.

Step 2: (2R*,3S*)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2, Synthesis of 4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-Dichlorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 4-chloro-2-fluorophenyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate were added. The reaction was carried out at 60 °C for 8 hours. The reaction was complete. After pouring into water, ethyl acetate was extracted three times, and the organic phase was washed twice with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, and then dried and then purified by column chromatography (2R*, 3S*)-3- 1-(4-Chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-dichlorophenyl)-1-(1H-1 , 2,4-triazol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.15 (d, J = 2.9 Hz, 1H), 7.99 (t, J = 8.5 Hz, 1H), 7.78 (s, 1H), 7.65 (d, J) = 8.5 Hz, 1H), 7.38 (dd, J = 11.9, 3.1 Hz, 3H), 7.16 (d, J = 7.3 Hz, 1H), 5.59 (d, J = 13.6 Hz, 1H), 5.22 (s, 1H) ), 4.42 (q, J = 7.1 Hz, 1H), 4.10 (d, J = 11.8 Hz, 1H), 1.09 (d, J = 7.1 Hz, 3H).

Example 28: (2R*,3S*)-3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)- Synthesis of 1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of benzyl azide

The benzyl bromide (1 mmol) was dissolved in DMF (5 mL), sodium azide (1.5 eq) was added, and the mixture was reacted at 80 °C for 2 hours. After the reaction was completed, it was extracted with ethyl acetate.

Step 2: (2R*,3S*)-3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1 Synthesis of -(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and benzyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate was added. The reaction was carried out at 60 °C for 8 hours. After the reaction was completed, it was poured into water. The ester was extracted three times, the organic phase was washed twice with a saturated aqueous solution of sodium chloride, and the organic phase was dried over anhydrous sodium sulfate, and then evaporated to dryness to give (2R*,3S*)-3-(1-benzyl-1H- 1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl- 2-alcohol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 7.68 (s, 1H), 7.49 - 7.36 (m, 4H), 7.34 - 7.27 (m, 3H), 6.80 - 6.67 ( m, 2H), 5.55 (q, J = 14.8 Hz, 2H), 5.24 (s, 1H), 4.88 (d, J = 14.3 Hz, 1H), 4.09 (d, J = 14.2 Hz, 1H), 3.75 ( q, J = 7.2 Hz, 1H), 1.05 (d, J = 7.2 Hz, 3H).

Example 29: (2R*,3S*)-3-(1-(2,4-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-2-(2, Synthesis of 4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of 2,4-difluorobenzyl azide

2,4-Difluorobenzyl bromide (1 mmol) was dissolved in 1 M hydrochloric acid (5 mL), sodium nitrite (1.1 eq) was added under ice-cooling, and the reaction was stirred for ten minutes, then sodium azide (1.5 eq) was added to continue. The reaction was carried out for 30 minutes, and the reaction was completed, extracted with ethyl acetate, dried and then evaporated to the next.

Step 2: (2R*,3S*)-3-(1-(2,4-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-2-(2,4 Synthesis of -difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R*,3S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Alkyn-2-ol (1mmol) and 2,4-difluorobenzyl azide (1mmol) were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate were added. The reaction was carried out at 60 °C for 8 hours. Pour into water, extract with ethyl acetate three times, wash the organic phase twice with saturated aqueous sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, spin dry and then chromatograph (2R*,3S*)-3-(1) -(2,4-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2 , 4-triazol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.91 (d, J = 25.2 Hz, 1H), 7.69 (d, J = 6.6 Hz, 1H), 7.56 (s, 1H), 7.50 - 7.28 (m) , 2H), 7.01–6.83 (m, 2H), 6.74 (t, J = 8.2 Hz, 2H), 5.57 (s, 2H), 5.20 (s, 1H), 4.89 (d, J = 14.1 Hz, 1H) , 4.06 (d, J = 14.5 Hz, 1H), 3.76 (q, J = 7.0 Hz, 1H), 1.06 (d, J = 7.2 Hz, 3H).

Example 30: (2R,3S)-3-(1-(4-Chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4 Synthesis of -difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

Step 1: Synthesis of (R)-3-butyn-2-ol mesylate

(R)-3-butyn-2-ol (25 g) was dissolved in dichloromethane, triethylamine (99 mL) was added, and methanesulfonyl chloride (41 mL) was added dropwise at -78. It was poured into 200 mL of an aqueous sodium hydrogencarbonate solution, extracted twice with dichloromethane, and the organic phase was washed twice with water, dried over anhydrous sodium sulfate

Step 2: (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Synthesis of alkyn-2-ol

Pd(CH ₃ CN) ₂ Cl _{2 was} dissolved in tetrahydrofuran, triphenylphosphine was added, and after 12 minutes, 2-chloro-2',4'-difluoroacetophenone and (R)-3-butyne were added. 2-Alkyl mesylate, then slowly adding a solution of diethylzinc in toluene, reacting at room temperature for 1 hour, pouring into a hydrochloric acid solution, extracting with ethyl acetate three times, and washing the organic phase with a saturated aqueous solution of sodium chloride Two times, anhydrous sodium sulfate was dried and then dried to obtain (2R,3S)-1-chloro-2-(2,4-difluorophenyl)-3-methyl-4-pentyn-2-ol crude . Used directly in the next step.

Step 3: (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyl Synthesis of alkyn-2-ol

Dissolve 1H-1,2,4-triazole in DMSO, add sodium hydroxide and obtain (2R,3S)-1-chloro-2-(2,4-difluorophenyl)-3-methyl Ke-4-pentyn-2-ol. After reacting for 4 hours at 70 °C, it was poured into ice water, extracted with ethyl acetate three times, and the organic phase was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then dried and then purified by column chromatography (2R, 3S) 2-(2,4-Difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyn-2-ol.

Step 4: Synthesis of 4-chloro-2-fluorophenyl azide

Dissolve 4-chloro-2-fluoroaniline in 1M hydrochloric acid, add sodium nitrite under ice bath, stir the reaction for ten minutes, add sodium azide, continue the reaction for 30 minutes, complete the reaction, extract with ethyl acetate, and dry. The spin dry is used directly in the next step.

Step 5: (2R,3S)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4- Synthesis of difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol

(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-pentyne- 2-Alcohol and 4-chloro-2-fluorophenyl azide were dissolved in aqueous DMF solution, and a catalytic amount of copper sulfate and sodium ascorbate were added. The reaction was carried out at 60 °C for 8 hours. After the reaction was completed, it was poured into water and extracted with ethyl acetate. 3 times, the organic phase was washed twice with saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate, and then evaporated to dryness to give (2R,3S)-3-(1-(4-chloro-2-fluorobenzene) Base-1H-1,2,3-triazole-4- 2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol.

Nuclear magnetic data: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.11 (d, J = 3.0 Hz, 1H), 8.03 - 7.93 (m, 2H), 7.73 (s, 1H), 7.54 - 7.42 (m, 1H) , 7.42–7.33 (m, 2H), 6.85–6.73 (m, 2H), 5.17 (s, 1H), 4.99 (d, J = 14.4 Hz, 1H), 4.18 (d, J = 14.2 Hz, 1H), 3.90 (q, J = 7.2 Hz, 1H), 1.15 (d, J = 7.2 Hz, 3H).

Example 31: (2R,3S)-3-(1-(4-Chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4 Of -difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol methanesulfonate

Take the compound (2R,3S)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Fluorobenzene

144 (1H-1,2,4-triazol-1-yl)butyl-2-ol 448 mg (1 mmol) was dissolved in 5 mL of isopropyl acetate, and 1 equivalent of methanesulfonic acid was added. Stir at room temperature for 3 hours to precipitate a precipitate, (2R,3S)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2 -(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol methanesulfonate, yield 90.3%.

Example 32: In vitro antibacterial experiment of the compound of the present invention

(I) Experimental method: A conventional in vitro bacteriostatic test method was used (for details: Antimicrob Agents Chemother 1995, 39(5): 1169).

1. Materials and methods

(1) Test strain

In this experiment, the following common human pathogenic standard fungal strains were selected as screening objects. The fungal strains were provided by the fungi laboratory of Shanghai Changzheng Hospital or purchased from the Institute of Traditional Chinese Medicine.

Candida albicans (standard strain SC5314),

Candida albicans (standard strain Y0109),

Candida parapsilosis (ATCC 22019),

Cryptococcus neoformans (standard strain 32609),

Candida glabrata (standard strain 537),

Aspergillus fumigatus (standard strain 07544),

Trichophyton rubrum (standard strain Cmccftla),

Microsporum gypseum (standard strain Cmccfmza).

(2) Test method

Preparation of bacterial suspension: The above fungus was cultured in YEPD liquid medium at 35 ° C for 16 hours, activated twice, counted by a blood cell counting plate, and adjusted to a concentration of 1*10 ⁴ to 1*10 ⁵ /mL with RPM1640 liquid medium.

Preparation of the drug solution: The compound to be tested of the present invention is dissolved in dimethyl sulfoxide to prepare a drug storage solution of 0.8 mg/mL, and diluted to 8 μg/mL with RPM1640 before the experiment.

Inoculation: 96-well plate No. 1 well plus RPM1640100 μL as blank control; 3-12 wells each add 100 μL of suspension, 200 μL of bacterial suspension 200 μL and 2 μL of drug solution, and the drug concentration of 2-11 holes is 10 The ratio of the drug concentration in each well was 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125 μg/mL. No holes were added to the 12th hole as a positive control. Fluconazole (FCZ) was used as a drug control.

(2) Experimental results

The results of in vitro bacteriostatic experiments are shown in Table 2.

Table 2 In vitro antifungal minimum inhibitory concentration value of target compound (MIC ₈₀ , μg/mL)

The inhibitory effects of other target compounds not listed on the above fungi were also significantly stronger than fluconazole. The above results indicate that the compound of the present invention has good antifungal activity, and the antibacterial activity in vitro is significantly stronger than that of fluconazole, and the compound of the present invention has the advantages of low toxicity, wide antifungal spectrum and the like, and thus can be used for preparing antifungal drugs. .

The preferred embodiments of the present invention have been specifically described above, but the present invention is not limited to the embodiments, and those skilled in the art can make various equivalents without departing from the inventive spirit of the present invention. Variations or substitutions are intended to be included within the scope of the invention as defined by the appended claims.

Claims (10)

1. An antifungal triazole alcohol compound characterized in that the chemical structure of the triazole alcohol compound is as shown in formula I:

   

   In formula I, the R ₁ group represents a heterocyclic ring or a benzene ring, the heterocyclic ring is selected from a pyridine ring or a pyrimidine ring, and the benzene ring is selected from a phenyl group, a substituted phenyl group, a benzyl group or a substituted benzyl group. The substituted phenyl or substituted benzyl group substituent may be located at various positions of the benzene ring, and may be mono- or poly-substituted, and the substituent is selected from a), b), c) or d):

   a) halogen, said halogen being F, Cl, Br or I,

   b) an electron withdrawing group, said electron withdrawing group being a cyano group, a nitro group, a trifluoromethyl group, an acetyl group or a methylsulfonyl group,

   c) a lower alkyl group of 1 to 4 carbon atoms or a halogen-substituted lower alkyl group,

   d) a lower alkoxy group of 1 to 4 carbon atoms or a halogen-substituted lower alkoxy group;

   The R ₂ , R ₃ or R ₄ group represents a halogen or a hydrogen atom.
2. The triazole alcohol compound according to claim 1, wherein the lower alkyl group of 1 to 4 carbon atoms or the halogen-substituted lower alkyl group is selected from a methyl group or a trifluoromethyl group; The lower alkoxy group of 1-4 carbon atoms or the halogen substituted lower alkoxy group is selected from a methoxy group, a trifluoromethoxy group or a difluoromethoxy group.
3. The triazole alcohol compound according to claim 1, wherein the triazole alcohol compound is a racemate, an R form isomer or an S type isomer.
4. The triazole alcohol compound according to claim 1, wherein the triazole alcohol compound is selected from the group consisting of:

   (2R*,3S*)-3-(1-(3-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) -1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) -1-(1H-1,2,4-triazole Zin-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) -1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluoro Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(4-chloro-3-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) -1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(4-Trifluoromethylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluoro Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) )-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(4-cyanophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) )-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluoro Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(2,6-difluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluoro Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(phenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1- (1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(4-difluoromethoxyphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(4-methanesulfonylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorobenzene -1(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(4-acetylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) )-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(pyridin-3-yl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) -1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(pyrimidin-5-yl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl) -1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,5-di Fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(3-ethylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,5-difluorophenyl) )-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(4-trifluoromethoxyphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,5-di Fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(4-Trifluoromethylphenyl)-1H-1,2,3-triazol-4-yl)-2-(2,5-difluoro Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-di Chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorophenyl)-1-(1H -1,2,4-triazol-1-yl)butyl-2-ol,

   (2R*,3S*)-3-(1-(2,4-difluorobenzyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluoro Phenyl)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol, or

   (2R,3S)-3-(1-(4-chloro-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)-2-(2,4-difluorobenzene Base)-1-(1H-1,2,4-triazol-1-yl)butyl-2-ol.
5. The pharmacologically acceptable salt of a triazole alcohol compound according to claim 1, wherein the pharmacologically acceptable salt is a mineral acid salt or an organic acid salt.
6. The pharmacologically acceptable salt according to claim 5, wherein the inorganic acid is hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid or nitric acid; and the organic acid is acetic acid or maleic acid. , fumaric acid, tartaric acid, succinic acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid or oxalic acid.
7. A pharmaceutical composition comprising the triazolol compound according to claim 1 or 2, or the pharmacologically acceptable salt according to claim 5 or 6, and comprising a conventional pharmaceutically acceptable carrier.
8. The method for producing a triazole alcohol compound according to claim 1, comprising the steps of:

   a) Preparation of compound 3

   Compound 2 was dissolved in DCM, TEA and MsCl were added dropwise at -78 °C, and reacted for 1 hour to form Compound 3;

   b) Preparation of compound 4

   Pd(CH ₃ CN) ₂ Cl _{2 is} dissolved in anhydrous THF, PPh _{3 is} added, and reacted at room temperature for 10 minutes, compound 1 and compound 3 are added, and ZnEt2 is added dropwise under ice-soluble conditions, and reacted at room temperature for 1 hour to form compound 4;

   c) Preparation of compound 5

   Dissolving 1,2,4-triazole and NaOH in DMSO, adding compound 4, reacting at 70 degrees for 4 hours to form compound 5;

   d) Preparation of compound 6

   The compound 8 is dissolved in aqueous hydrochloric acid, sodium nitrite and sodium azide are added, and the reaction is carried out in an ice bath to form a compound 6;

   Or the compound 7 is dissolved in DMF, sodium azide is added, and the compound 6 is formed under heating;

   e) preparation of the target compound triazolol compound

   Compound 5 and compound 6 are dissolved in DMF and water, copper sulfate and sodium ascorbate are added, and reacted at 60 degrees for 5 hours to form a target compound triazole alcohol compound;

   among them:

   The chemical structural formula of the compound 1 is:

   

   The chemical structural formula of the compound 2 is:

   

   The chemical structural formula of the compound 3 is:

   

   The chemical structural formula of the compound 4 is:

   

   The chemical structural formula of the compound 5 is:

   

   The chemical structural formula of the compound 6 is: R ₁ -N ₃ 6,

   The chemical structural formula of the compound 7 is:

   

   The chemical structural formula of the compound 8 is:

   
9. Use of the triazole alcohol compound according to claim 1 or 2, or the pharmacologically acceptable salt according to claim 5 or 6, for the preparation of an antifungal drug.
10. The use according to claim 9, wherein the fungus is Candida albicans, Candida parapsilosis, Cryptococcus neoformans or Candida tropicalis.