CN115650925A

CN115650925A - Triazole alcohol derivative and preparation method and application thereof

Info

Publication number: CN115650925A
Application number: CN202211089784.0A
Authority: CN
Inventors: 谢斐; 郝雨濛; 张大志; 暴军合; 阎澜; 姜远英; 倪廷峻弘; 丁子超; 刘昱; 王瑞娜; 刘佳存
Original assignee: Second Military Medical University SMMU
Current assignee: Second Military Medical University SMMU; Shanghai Pharmaceuticals Holding Co Ltd
Priority date: 2022-09-07
Filing date: 2022-09-07
Publication date: 2023-01-31

Abstract

The invention relates to a triazole alcohol derivative and a preparation method and application thereof. The chemical structure of the triadimenol derivative is shown as a formula I, wherein R is ₁ Represents a benzene ring or a substituted benzene ring, and the substituent of the substituted benzene ring can be positioned at each position of the benzene ring, can be mono-substituted or multi-substituted and can be selected from: a) Halogen, wherein the halogen is F, cl, br or I; b) An electron withdrawing group which is a cyano group, a nitro group or a trifluoromethyl group; c) Lower alkyl of 1 to 4 carbon atoms, aryl or lower alkyl substituted by halogen; d) Lower alkoxy of 1 to 4 carbon atoms or lower alkoxy substituted by halogen. The compound has the advantages of strong antifungal activity, low toxicity, wide antibacterial spectrum and the like, and can be used for preparing antifungal medicaments.

Description

Triazole alcohol derivative and preparation method and application thereof

Technical Field

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

Background

Fungal infections are becoming more serious, and are mainly Superficial Fungal Infections (SFIs) and deep Invasive Fungal Infections (IFIs) which threaten life, wherein the morbidity and mortality of the IFIs in patient groups such as immunodeficiency, cancer, organ transplantation and the like are increased year by year, and the treatment burden of patients and medical industries is increased.

Antifungal drugs used clinically at present are very limited in types compared with antitumor drugs and antibacterial drugs, and mainly include five types: 1. polyenes, represented by amphotericin B, act on ergosterol on fungal cell membranes to destroy fungal cell membrane structures; 2. allylamines, represented by terbinafine, act on fungal squalene epoxidase to inhibit synthesis of fungal cell membranes; 3. pyrimidines, represented by 5-fluorouracil, which interfere with the synthesis of fungal DNA; 4. echinocandins, represented by caspofungin, act on fungal cell wall β - (1, 3) -glucan synthase to inhibit cell wall β - (1, 3) -glucan synthesis; 5. azole, represented by fluconazole, acts on fungal lanosterol 14 alpha-demethylase to inhibit the synthesis of fungal cell membranes. The azole drugs are first-line drugs widely used in clinic, but the drugs have the problems of low drug effect, narrow antibacterial spectrum, easy drug interaction caused by combined administration and the like. In addition, the fungi gradually generate drug resistance, which is also one of the reasons for poor therapeutic effect of the drugs. Therefore, there is a need to develop a new generation of azole compounds having novel structure and remarkable antifungal effect to cope with the above problems. No reports on 3- ((1-substituted-1H-1, 2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-alcohol compounds and antifungal activity thereof are found so far.

The previous patent CN104817508A of the present applicant discloses a triazole alcohol derivative, a preparation method and an application thereof, wherein the chemical structure of the triazole alcohol derivative is shown as the following formula:

R ₁ the group represents a heterocyclic ring or a benzene ring, the heterocyclic ring is selected from a pyridine ring or a pyrimidine ring, the benzene ring is selected from phenyl, substituted phenyl, benzyl or substituted benzyl, and the substituent is selected from a), b), c) or d): a) halogen, wherein the halogen is F, cl, br or I, b) an electron-withdrawing group, wherein the electron-withdrawing group is cyano, nitro, trifluoromethyl, acetyl or methylsulfonyl, c) lower alkyl of 1-4 carbon atoms or lower alkyl substituted by halogen, d) lower alkoxy of 1-4 carbon atoms or lower alkoxy substituted by halogen; r ₂ 、R ₃ Or R ₄ Represents a halogen or hydrogen atom.

Another previous patent CN106336383A of the present applicant also discloses a triazoium derivative, its preparation method and application, the chemical structure of the said triazoium derivative is shown as the following formula:

wherein R is ₁ And R ₂ Represents halogen or hydrogen, R ₃ Represents an alkyne or isoxazole ring, R ₅ Represents hydrogen or methyl, R ₄ The group represents a heterocyclic ring or a substituted heterocyclic ring, saidThe heterocyclic ring is selected from pyridine ring, pyrimidine ring, furan ring, thiophene ring, pyrrole ring and thiazole ring, or represents benzene ring or substituted benzene ring; the substituent is selected from a), b), c) or d): a) halogen, wherein the halogen is F, cl, br or I, b) an electron-withdrawing group, wherein the electron-withdrawing group is cyano, nitro or methylsulfonyl, c) lower alkyl with 1-4 carbon atoms or halogen-substituted lower alkyl, d) lower alkoxy with 1-4 carbon atoms or halogen-substituted lower alkoxy.

The triazole alcohol compounds have remarkable fungus inhibition activity, are stronger than fluconazole, and have the advantages of low toxicity, wide antibacterial spectrum and the like. However, it is still highly desirable to develop more antifungal compounds.

At present, no reports related to the triazole derivatives and the activity of inhibiting fungi are found.

Disclosure of Invention

The first purpose of the present invention is to provide a triazole alcohol derivative, and a preparation method and applications thereof, aiming at the defects in the prior art.

It is still another object of the present invention to provide pharmacologically acceptable salts of the above-mentioned triazole alcohols.

It is another object of the present invention to provide a pharmacologically acceptable salt for use in the manufacture of an antifungal medicament.

The fourth purpose of the invention is to provide a preparation method of the triazole alcohol compound.

The fifth purpose of the invention is to provide the application of the triazole alcohol compound or the pharmacologically allowable salt thereof.

In order to realize the first purpose, the invention adopts the technical scheme that:

an antifungal triazole alcohol compound, the chemical structure of which is shown in formula I:

in the formula I, R ₁ Represents a benzene ring or a substituted benzene ring, wherein the substituent of the substituted benzene ring can be positioned at each position of the benzene ring and is mono-substituted or multi-substituted, and the substituent is selected from a), b), c) or d):

a) Halogen, wherein the halogen is F, cl, br or I,

b) An electron withdrawing group which is a cyano group, a nitro group or a trifluoromethyl group,

c) Lower alkyl of 1 to 4 carbon atoms, aryl or halogen-substituted lower alkyl,

d) Lower alkoxy of 1 to 4 carbon atoms or lower alkoxy substituted by halogen.

Preferably, said lower alkyl of 1 to 4 carbon atoms, aryl or halogen substituted lower alkyl is selected from methyl, ethyl, tert-butyl, benzyl or trifluoromethyl; the lower alkoxy with 1-4 carbon atoms or the lower alkoxy substituted by halogen is selected from methoxy or trifluoromethoxy.

As another preferable example of the present invention, the triazole alcohol compound is racemate, R-type isomer or S-type isomer.

As another preferred example of the present invention, the triazole alcohol compound is selected from:

(2R, 3R) -3- ((1- (2-fluorophenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (3-fluorophenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (4-fluorophenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (2-chlorphenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (3-chlorphenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (4-chlorphenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (2-methylphenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (3-methylphenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (4-methylphenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (4-bromophenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (4-iodophenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-ol,

(2R, 3R) -3- ((1- (4-trifluoromethylphenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-ol,

(2R, 3R) -3- ((1- (4-trifluoromethoxyphenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-ol,

(2R, 3R) -3- ((1- (4-methoxyphenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butane-2-ol,

(2R, 3R) -3- ((1- (4-cyanophenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (4-nitrophenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (2, 4-dichlorophenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (2-fluoro-4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (2-chloro-4-fluorophenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (3-fluoro-4-chlorophenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (3-chloro-4-fluorophenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (3, 4-dichlorophenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (2, 3-difluorophenyl) -1H-1,2, 3-triazol-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (2, 4-difluorophenyl) -1H-1,2, 3-triazol-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (2, 5-difluorophenyl) -1H-1,2, 3-triazol-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (2, 6-difluorophenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (3, 4-difluorophenyl) -1H-1,2, 3-triazol-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (3, 5-difluorophenyl) -1H-1,2, 3-triazol-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (2, 4, 6-trifluorophenylphenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (2, 3,4, 5-tetrafluorophenylphenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (2, 3,4,5, 6-pentafluorophenyl phenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1-phenyl-1H-1, 2, 3-triazole-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-ol,

(2R, 3R) -3- ((1- (3-ethyl phenyl) -1H-1,2, 3-triazole-4-group) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-group) butane-2-alcohol,

(2R, 3R) -3- ((1- (3-tert-butylphenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (3-trifluoromethylphenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (3-benzyl phenyl) -1H-1,2, 3-triazole-4-group) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-group) butane-2-alcohol,

In order to achieve the second object, the invention adopts the technical scheme that:

the above-mentioned pharmacologically acceptable salts of the triazole alcohol compounds are inorganic acid salts or organic acid salts.

As a preferred example of the present invention, 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, methane sulfonic acid, p-toluene sulfonic acid, salicylic acid or oxalic acid.

In order to achieve the third object, the invention adopts the technical scheme that:

a pharmaceutical composition comprising a triazole alcohol compound as defined in any one of the above, or a pharmacologically acceptable salt thereof, together with a conventional pharmaceutical carrier.

As a preferred example of the invention, the pharmaceutical composition can be tablets, dispersible tablets, buccal tablets, orally disintegrating tablets, sustained release tablets, capsules, soft capsules, dripping pills, granules, injections, powder injections or aerosols and the like.

In order to achieve the fourth object, the invention adopts the technical scheme that:

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

a) Preparation of Compound 3

Dissolving a compound 1 and sodium methoxide in THF, dropwise adding the compound 2, controlling the temperature to be 10 ℃, and reacting to generate a compound 3;

b) Preparation of Compound 5

Dissolving the compound 3 in THF, adding the compound 4, controlling the temperature to be 5 ℃, dropwise adding 3, 4-dihydropyran, and reacting at room temperature to generate a compound 5;

c) Preparation of Compound 7

Dissolving Mg powder in anhydrous THF, adding iodine granules as an initiator, controlling the temperature to be 20 ℃, dropwise adding the compound 6, gradually heating to 40 ℃, bubbling out bubbles on the Mg powder, initiating a reaction, reducing the temperature to 25 ℃, continuously dropwise adding the compound 6, and controlling the temperature to be 25 ℃ after dropwise adding to generate a compound 7;

d) Preparation of Compound 8

Adding the THF solution of the compound 5 dropwise into the THF solution of the compound 7, controlling the temperature to be 25 ℃, and extracting to obtain a compound 8;

e) Preparation of Compound 9

Dissolving Me3SOI in DMF, adding a compound 8, and reacting at room temperature to generate a compound 9;

f) Preparation of Compound 10

Dissolving 1H-1,2, 4-triazole in DMF, adding sodium hydroxide, reacting at 50 ℃ until the solution is dissolved, cooling to room temperature, adding DMF solution of a compound 9, reacting at 70 ℃, and extracting to obtain a compound 10;

g) Preparation of Compound 11

Dissolving the compound 10 in EA, controlling the temperature to be 25 ℃, adding methanesulfonic acid to obtain a light yellow solid, taking the light yellow solid in EA, dropwise adding a 10% sodium hydroxide solution until the solid is dissolved, separating liquid, washing an organic phase and drying to obtain a compound 11;

h) Preparation of Compound 12

Reacting compound 11, cs2CO ₃ Dissolving in acetonitrile, dropwise adding 3-bromopropyne, controlling the temperature to be 80 ℃, filtering and desalting after complete reaction, spin-drying the filtrate, adding water, and extracting with ethyl acetate to obtain a compound 12;

i) Preparation of Compound 14

Dissolving the compound 13 in DMF, dropwise adding tert-butyl nitrite in ice bath, reacting for 30 minutes, adding trimethylsilyl azide, and reacting for 2 hours at room temperature to produce a compound 14;

j) Preparing the triazole alcohol compound

Dissolving the compound 12 and the compound 14 in DMF and water, adding copper sulfate and sodium ascorbate, and reacting at 60 ℃ overnight to generate a target compound, namely the triazole alcohol compound;

wherein the content of the first and second substances,

the compound 1 has a structural formula:

the structural formula of the compound 2 is as follows:

the structural formula of the compound 3 is as follows:

the structural formula of the compound 4 is as follows:

the compound 5 has a structural formula:

the structural formula of the compound 6 is as follows:

the structural formula of the compound 7 is as follows:

the structural formula of the compound 8 is as follows:

the compound 9 has a structural formula as follows:

the compound 10 has the structural formula:

the compound 11 has the structural formula:

the compound 12 has the structural formula:

the compound 13 has a structural formula:

the compound 14 has the structural formula: r ₁ -N ₃ 14

The synthesis of the pharmacologically acceptable salt is based on the above reaction and further: dissolving the target compound of triazole alcohol in isopropyl acetate, adding inorganic acid or organic acid, stirring to separate out solid, and filtering to obtain the final product.

In order to achieve the fifth object, the invention adopts the technical scheme that:

use of a triazole alcohol compound as defined in any one of the above, or a pharmacologically acceptable salt thereof, in the manufacture of an antifungal medicament.

As a preferred example of the present invention, the fungus is Candida albicans, candida parapsilosis, cryptococcus neoformans, candida glabrata, candida tropicalis or Candida auriculata.

The invention has the advantages that:

the invention synthesizes a novel triazole alcohol compound which has better inhibitory activity to human pathogenic fungi candida albicans, candida parapsilosis, cryptococcus neoformans, candida glabrata, candida tropicalis or candida auriculata and is stronger than fluconazole, and the compound also has the advantages of low toxicity, wide antifungal spectrum and the like, thereby being used for preparing antifungal medicaments.

Detailed Description

The following provides a detailed description of specific embodiments of the present invention. The reagents and starting materials used in the present invention are either commercially available or can be prepared according to literature procedures. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. All reagents used in the examples were commercially available analytical grade.

The synthetic route of the compound of the invention is as follows:

the structural formulae and nuclear magnetic data of the preferred compounds are shown in Table 1 below.

Table 1 chemical Structure and Nuclear magnetic data for some preferred Compounds

Example 1 Synthesis of (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (Compound 12).

Step one, synthesizing a compound 3,

methyl (R) -2-hydroxypropionate (50 mmol) and sodium methoxide (8 mmol 1) were dissolved in THF, morpholine (100 mmol) was added dropwise, the mixture was stirred at 10 ℃ for 3 hours, and after completion of the reaction by TLC, the organic phase was extracted twice with dichloromethane, washed twice with water, dried over anhydrous sodium sulfate, and then spin-dried for the next step. ¹ H NMR(CDC1 ₃ ,400MHz)：δ4.43-4.48(m,1H)，3.61-3.83(m,7H)，3.42-3.44(m,2H)，1.33(d,3H,J＝6.8Hz)；

Step twoThe synthesis of the compound 5 is carried out,

compound 3 (50 mmo 1) was dissolved in THF, p-toluic acid (10 mmol) was added thereto, 3, 4-dihydrobenzpyrane (80 mmo 1) was added dropwise while controlling the temperature at 5 ℃ and stirred overnight at room temperature, after completion of the reaction monitored by TLC, dichloromethane was extracted twice, the organic phase was washed twice with water, dried over anhydrous sodium sulfate, and the solvent was dried by spin-drying to give compound 5 as a pale yellow oil. ¹ H NMR(CDC1 ₃ ,400MHz)：δ4.51-4.69(m,2H)，3.86-3.88(m,1H)，3.61-3.73(m,8H)，3.47-3.50(m,IH)，1.70-1.84(m,3H)，1.52-1.56(m,3H)，1.41(dd,J＝7.0,18.2Hz,3H)；

Step three, synthesizing a compound 7,

dissolving Mg powder (40 mmol) in anhydrous THF, adding 1 iodine particle as initiator, controlling the temperature to be 20 ℃, dropwise adding compound 6 (5 mmol), gradually heating to 40 ℃, bubbling on the Mg powder, initiating the reaction, reducing the temperature to 25 ℃, continuously dropwise adding compound 6 (5 mmol), controlling the temperature to be 25 ℃ and keeping for 1h after dropwise adding is finished for about half an hour;

step four, synthesizing a compound 8, namely,

and (3) adding the THF solution of the compound 5 into the THF solution of the compound 7 in the third step dropwise, controlling the temperature to be 25 ℃, almost not releasing heat in the adding process, continuously stirring for 30min after 15min is finished, slowly adding a 10% hydrochloric acid solution to quench the reaction, extracting for 3 times by ethyl acetate, washing an organic phase twice by using a saturated sodium chloride aqueous solution, drying by anhydrous sodium sulfate, and then spin-drying to obtain a light yellow oily compound 8. ¹ H NMR(CDC1 ₃ ,400MHz)：δ7.85-7.92(m,IH)，6.96(dd,J＝8.6,7.8Hz,1H)，6.79-6.90(m,IH)，4.86(qd,J＝6.8,1.2Hz,1H)，4.65(t,J＝3.6Hz,1H)，3.66-3.75(m,1H)，3.28-3.36(m,IH)，1.30-1.90(m,6H)，1.42(dd,J＝6.8.1.2Hz 3H)；

Step five Compound9, synthesizing the mixture by the chemical reaction of the raw materials,

dissolving trimethyl sulfoxide iodide (50 mmol) in DMF, adding compound 8 (40 mmol), stirring at room temperature for 1h, monitoring by TLC to obtain a reaction solution, and directly using the reaction solution in the next step without treatment;

step six, the synthesis of the compound 10,

dissolving 1H-1,2, 4-triazole (100 mmo 1) in DMF, adding sodium hydroxide (100 mmol) to react at 50 ℃ until the sodium hydroxide is dissolved, cooling to room temperature, adding DMF (40 mmol) of a compound 9, reacting at 70 ℃ for 4 hours, pouring into ice water, extracting with ethyl acetate for 3 times, washing an organic phase twice with saturated sodium chloride aqueous solution, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain a crude compound 10 which is directly used in the next step;

step seven, the synthesis of the compound 11,

dissolving crude compound 10 in EA, controlling temperature at 25 deg.C, adding methanesulfonic acid (MSA, 70 mmol), stirring for 2 hr to precipitate a large amount of solid, filtering to obtain light yellow solid, adding the above solid in EA, dropwise adding 10% Na0H solution to the solid until the solid is dissolved, separating, washing organic phase with saturated NaC1 twice, and removing anhydrous NaSO ₄ Drying and spin-drying to obtain the compound 11. ¹ H NMR(CDC1 ₃ ,400MHz)：δ8.92(s,IH),8.09(s,1H),7.25-7.19(m,1H)，7.18-7.11(m,1H),6.87(td,J＝8.46,2.53Hz,1I)，4.80(d,J＝14.40Hz,1H)，4.72(d,J＝14.40Hz,1H)，4.19(qd,J＝6.31,2.78Hz,1H)，2.40(s,3H)，0.80(d,J＝6.311z,3H)；

Step eight: synthesis of compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (compound 12),

compound 11 (20 mmol), cs ₂ CO ₃ Dissolving (100 mmo 1) in acetonitrile, adding 3-bromopropyne (50 mmo 1) dropwise, stirring overnight at 80 deg.C, monitoring reaction by TLC, filtering to remove salt, spin-drying the filtrate to remove solvent, adding water, extracting with ethyl acetate for three times, mixing organic phases, washing with saturated NaCl twice, and adding anhydrous Na ₂ SO ₄ And (5) drying. Spin drying, column chromatography to obtain compound 12. ¹ HNMR(300MHz,DMSO-d ₆ )：δ8.30(s,1H)，7.60(s,1H)，7.32-7.06(m,2H)，6.86(td,J＝8.4,2.5Hz,1H)，5.77(s,1H)，4.75(s,2H)，4.40(dd,J＝16.3,2.4Hz,1H)，4.35-4.14(m,2H)，3.54(t,J＝2.4Hz,1H)，0.85(d,J＝6.2Hz,3H)。

Example 2: compound 15-1

The method comprises the following steps: dissolving aniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, monitoring by TLC for complete reaction, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, monitoring by TLC for complete reaction to obtain a crude product, namely phenyl azide, and directly carrying out the next reaction;

step two: the crude compound phenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butane-2-ol (1 mmol) are dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) are added, vacuum is applied under nitrogen protection, the mixture is placed in a 60-DEG oil bath pot for reaction for 18h, and the reaction is monitored by TLC to be complete. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ Drying, spin-drying and performing column chromatography (EA: PE = 2.

Example 3: compound 15-2

The method comprises the following steps: dissolving a compound 2-fluoroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in an ice bath, reacting for 30 minutes, monitoring by TLC to react completely, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, monitoring by TLC to react completely to obtain a crude compound 2-fluorophenyl azide, and directly carrying out the next reaction;

step two: the crude compound 2-fluorophenylazide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and the reaction was monitored by TLC for completion. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 4: compound 15-3

The method comprises the following steps: dissolving a compound 3-fluoroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in an ice bath, reacting for 30 minutes, monitoring by TLC to react completely, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, monitoring by TLC to react completely to obtain a crude compound 3-fluorophenyl azide, and directly carrying out the next reaction;

step two: the crude compound 3-fluorophenylazide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and the reaction was monitored by TLC for completion. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 5: compound 15-4

The method comprises the following steps: dissolving a compound 4-fluoroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in an ice bath, reacting for 30 minutes, monitoring by TLC to react completely, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, monitoring by TLC to react completely to obtain a crude compound 4-fluorophenyl azide, and directly carrying out the next reaction;

step two: the crude compound 4-fluorophenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) are dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) are added, vacuum is applied under nitrogen protection, the mixture is placed in a 60-DEG oil bath for reaction for 18h, and the reaction is monitored by TLC to be complete. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 6: compound 15-5

The method comprises the following steps: dissolving a compound 2-chloroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, monitoring by TLC (thin layer chromatography) for complete reaction, adding trimethylsilyl azide (2 mmol), reacting at room temperature for 2 hours, monitoring by TLC for complete reaction to obtain a crude compound 2-chlorophenyl azide, and directly carrying out the next reaction;

step two: the crude compound 2-chlorophenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, the mixture was placed in a 60 ℃ oil bath for reaction 18h and reaction completion was monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. After spin-drying and column chromatography (EA: PE = 2)Obtaining the white triazole alcohol compound 15-5.

Example 7: compound 15-6

The method comprises the following steps: dissolving a compound 3-chloroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, after TLC monitoring reaction is completed, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, and TLC monitoring reaction is completed to obtain a crude compound 3-chlorophenyl azide, and directly entering the next reaction;

step two: the crude compound 3-chlorophenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and the reaction was monitored by TLC for completion. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (4) spin-drying and performing column chromatography (EA: PE = 2.

Example 8: compound 15-7

The method comprises the following steps: dissolving a compound 4-chloroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, after TLC monitoring reaction is completed, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, and TLC monitoring reaction is completed to obtain a crude compound 4-chlorophenyl azide, and directly entering the next reaction;

step two: the crude compound 4-chlorophenylazide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and the completion of the reaction was monitored by TLC. By usingExtracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, and extracting with anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 9: compound 15-8

The method comprises the following steps: dissolving a compound 2-methylaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, after TLC monitoring reaction is completed, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, and TLC monitoring reaction is completed to obtain a crude compound 2-methylphenyl azide, and directly entering the next reaction;

step two: the crude compound 2-methylphenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) are dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) are added, vacuum is applied under nitrogen protection, the mixture is placed in a 60-DEG oil bath pot for reaction for 18h, and the completion of the reaction is monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 10: compound 15-9

The method comprises the following steps: dissolving a compound 3-methylaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, after TLC monitoring reaction is completed, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, and TLC monitoring reaction is completed to obtain a crude compound 3-methylphenyl azide, and directly entering the next reaction;

step two: dissolving the crude compound of 3-methylphenyl azide (1 mmol) and the compound of (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yne-1-yloxy) -1- (1H-1, 2, 4-triazole-1-yl) -butane-2-ol (1 mmol)To 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and completion of the reaction was monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 11: compound 15-10

The method comprises the following steps: dissolving a compound 4-methylaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, after TLC monitoring reaction is completed, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, and TLC monitoring reaction is completed to obtain a crude compound 4-methylphenyl azide, and directly entering the next reaction;

step two: the crude compound 4-methylphenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, the mixture was placed in a 60 ℃ oil bath for reaction for 18h and reaction completion was monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing with saturated NaCl solution twice, and extracting with anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 12: compound 15-11

The method comprises the following steps: dissolving a compound 4-bromoaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, monitoring by TLC to react completely, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, monitoring by TLC to react completely to obtain a crude compound 4-bromophenyl azide, and directly carrying out the next reaction;

step two: the crude compound 4-bromophenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was pulled under nitrogen protection, placed in a 60 ℃ oil bath for reaction 18h, and the reaction was monitored by TLC for completion. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (4) spin-drying and performing column chromatography (EA: PE = 2.

Example 13: compound 15-12

The method comprises the following steps: dissolving a compound 4-iodoaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, monitoring by TLC (thin layer chromatography) for complete reaction, adding trimethylsilyl azide (2 mmol), reacting at room temperature for 2 hours, monitoring by TLC for complete reaction, obtaining a crude compound 4-iodophenyl azide, and directly carrying out the next reaction;

step two: the crude compound 4-iodophenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, the mixture was placed in a 60 ℃ oil bath for reaction 18h and reaction completion was monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 14: compounds 15 to 13

The method comprises the following steps: dissolving a compound 4-trifluoromethylaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, monitoring by TLC (thin layer chromatography) for complete reaction, adding trimethylsilyl azide (2 mmol), reacting at room temperature for 2 hours, monitoring by TLC for complete reaction, obtaining a crude compound 4-trifluoromethylphenyl azide, and directly carrying out the next reaction;

step two: the crude compound 4-trifluoromethylphenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, placed in a 60 ℃ oil bath for reaction for 18h, and the completion of the reaction was monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 15: compounds 15 to 14

The method comprises the following steps: dissolving a compound 4-trifluoromethoxybenzene (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, monitoring by TLC (thin layer chromatography) for complete reaction, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, monitoring by TLC for complete reaction to obtain a crude compound 4-trifluoromethoxyphenyl azide, and directly carrying out the next reaction;

step two: the crude compound 4-trifluoromethoxyphenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and the completion of the reaction was monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (4) spin-drying and performing column chromatography (EA: PE = 2.

Example 16: compounds 15 to 15

The method comprises the following steps: dissolving a compound 4-methoxyaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, monitoring by TLC (thin layer chromatography) for complete reaction, adding trimethylsilyl azide (2 mmol), reacting at room temperature for 2 hours, monitoring by TLC for complete reaction to obtain a crude compound 4-methoxyphenyl azide, and directly carrying out the next reaction;

step two: the crude compound 4-methoxyphenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and the reaction was monitored by TLC for completion. Extracting with ethyl acetate for three times, mixing organic phases, washing with saturated NaCl solution twice, and extracting with anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 17: compounds 15 to 16

The method comprises the following steps: dissolving a compound 4-cyanoaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, monitoring by TLC to react completely, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, monitoring by TLC to react completely to obtain a crude compound 4-cyanophenyl azide, and directly carrying out the next reaction;

step two: the crude compound 4-cyanophenylazide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, the mixture was placed in a 60 ℃ oil bath for reaction for 18h and reaction completion was monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. Spin-drying and column chromatography (EA: PE =215-16.

Example 18: compounds 15 to 17

The method comprises the following steps: dissolving a compound 4-nitroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, after TLC monitoring reaction is completed, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, and TLC monitoring reaction is completed to obtain a crude compound 4-nitrophenyl azide, and directly entering the next reaction;

step two: the crude compound 4-nitrophenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and the completion of the reaction was monitored by TLC. Extracted three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl solution and dried over anhydrous Na2SO 4. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 19: compounds 15 to 18

The method comprises the following steps: dissolving a compound 2, 4-dichloroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, after TLC monitoring reaction is completed, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, and TLC monitoring reaction is completed to obtain a crude compound 2, 4-dichlorophenyl azide, and directly entering the next reaction;

step two: the crude compound 2, 4-dichlorophenyl azide (1 mmol) and compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, placed in a 60 ℃ oil bath for reaction for 18h, and the completion of the reaction was monitored by TLC. Extracting with ethyl acetateTaking three times, combining organic phases, washing twice with saturated NaCl solution and anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 20: compounds 15 to 19

The method comprises the following steps: dissolving a compound 2-fluoro-4-chloroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in a DMF under ice bath, reacting for 30 minutes, after the TLC monitors that the reaction is complete, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, and monitoring that the reaction is complete by TLC to obtain a crude compound 2-fluoro-4-chlorophenyl azide, and directly entering the next reaction;

step two: the crude compound 2-fluoro-4-chlorophenylazide (1 mmol) and compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, placed in a 60 ℃ oil bath for reaction for 18h, and the reaction was monitored by TLC for completion. Extracting with ethyl acetate for three times, mixing organic phases, washing with saturated NaCl solution twice, and extracting with anhydrous Na ₂ SO ₄ And (5) drying. And (3) spin-drying and performing column chromatography (EA: PE = 2.

Example 21: compounds 15 to 20

The method comprises the following steps: dissolving a compound 2-chloro-4-fluoroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in DMF under ice bath, reacting for 30 minutes, after TLC monitoring reaction is completed, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, and TLC monitoring reaction is completed to obtain a crude compound 2-chloro-4-fluorophenylazide, and directly entering the next reaction;

step two: mixing crude compound 2-chloro-4-fluorophenyl azide (1 mmol) and compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yne-1-yloxy) -1- (1H-1, 2, 4-triazole-1-yl) -butane-2-ol(1 mmol) was dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and the completion of the reaction was monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing with saturated NaCl solution twice, and extracting with anhydrous Na ₂ SO ₄ And (5) drying. And (3) spin-drying and performing column chromatography (EA: PE = 2.

Example 22: compounds 15 to 21

The method comprises the following steps: dissolving a compound 3-fluoro-4-chloroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in DMF under ice bath, reacting for 30 minutes, adding trimethylsilyl azide (2 mmol) after TLC monitoring reaction is completed, reacting for 2 hours at room temperature, and TLC monitoring reaction is completed to obtain a crude compound 3-fluoro-4-chlorophenyl azide, and directly entering the next reaction;

step two: the crude compound 3-fluoro-4-chlorophenylazide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and the completion of the reaction was monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) spin-drying and performing column chromatography (EA: PE = 2.

Example 23: compounds 15 to 22

The method comprises the following steps: dissolving a compound 3-chloro-4-fluoroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in DMF under ice bath, reacting for 30 minutes, monitoring by TLC for complete reaction, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, monitoring by TLC for complete reaction, obtaining a crude compound 3-chloro-4-fluorophenylazide, and directly entering the next reaction;

step two: the crude compound 3-chloro-4-fluorophenylazide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, placed in a 60 ℃ oil bath for reaction for 18h, and the reaction was monitored by TLC for completion. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 24: compounds 15 to 23

The method comprises the following steps: dissolving a compound 3, 4-dichloroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, after TLC monitoring reaction is completed, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, and after TLC monitoring reaction is completed, obtaining a crude compound 3, 4-dichlorophenyl azide, and directly entering the next reaction;

step two: the crude compound 3, 4-dichlorophenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) are dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) are added, vacuum is applied under nitrogen protection, the mixture is placed in a 60 ℃ oil bath pot for reaction for 18h, and the completion of the reaction is monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 25: compounds 15 to 24

The method comprises the following steps: dissolving 2, 3-difluoroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, monitoring by TLC to react completely, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, monitoring by TLC to react completely to obtain a crude product compound 2, 3-difluorophenyl azide, and directly carrying out the next reaction;

step two: the crude compound 2, 3-difluorophenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and the reaction was monitored by TLC for completion. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 26: compounds 15 to 25

The method comprises the following steps: dissolving a compound 2, 4-difluoroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in the DMF under ice bath, reacting for 30 minutes, monitoring by TLC (thin layer chromatography) for complete reaction, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, monitoring by TLC for complete reaction, obtaining a crude compound 2, 4-difluorophenyl azide, and directly entering the next reaction;

step two: the crude compound 2, 4-difluorophenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and the reaction was monitored by TLC for completion. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 27: compounds 15 to 26

The method comprises the following steps: dissolving 2, 5-difluoroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, monitoring by TLC to react completely, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, monitoring by TLC to react completely to obtain a crude product compound 2, 5-difluorophenyl azide, and directly carrying out the next reaction;

step two: the crude compound 2, 5-difluorophenyl azide (1 mmol) and compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen, placed in a 60 ℃ oil bath for reaction for 18h, and the completion of the reaction was monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 28: compounds 15 to 27

The method comprises the following steps: dissolving a compound 2, 6-difluoroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in the DMF under ice bath, reacting for 30 minutes, monitoring by TLC (thin layer chromatography) for complete reaction, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, monitoring by TLC for complete reaction, obtaining a crude compound 2, 6-difluorophenyl azide, and directly entering the next reaction;

step two: the crude compound 2, 6-difluorophenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and the reaction was monitored by TLC for completion. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. Spin-drying, and performing column chromatography (EA: PE = 2)15-27 parts of white triazole alcohol compound.

Example 29: compounds 15 to 28

The method comprises the following steps: dissolving a compound 3, 4-difluoroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in DMF under ice bath, reacting for 30 minutes, monitoring by TLC (thin layer chromatography) for complete reaction, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, monitoring by TLC for complete reaction to obtain a crude compound 3, 4-difluorophenyl azide, and directly carrying out the next reaction;

step two: the crude compound 3, 4-difluorophenyl azide (1 mmol) and compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen, placed in a 60 ℃ oil bath for reaction for 18h, and the completion of the reaction was monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 30: compounds 15 to 29

The method comprises the following steps: dissolving a compound 3, 5-difluoroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in DMF under ice bath, reacting for 30 minutes, monitoring by TLC (thin layer chromatography) for complete reaction, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, monitoring by TLC for complete reaction to obtain a crude compound 3, 5-difluorophenyl azide, and directly carrying out the next reaction;

step two: dissolving crude compound 3, 5-difluorophenyl azide (1 mmol) and compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazole-1-yl) -butane-2-ol (1 mmol) in 10ml of DMF and water (2 drops), adding copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol), vacuumizing under the protection of nitrogen, and reacting in a 60-degree oil bath kettle18h, tlc monitored the reaction completion. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 31: compounds 15 to 30

The method comprises the following steps: dissolving a compound 2,4, 6-trifluorophenylamine (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in DMF under ice bath, reacting for 30 minutes, after TLC monitoring reaction is completed, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, and TLC monitoring reaction is completed to obtain a crude compound 2,4, 6-trifluorophenylazide, and directly entering the next reaction;

step two: the crude compound 2,4, 6-trifluorophenylazide (1 mmol) and compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, placed in a 60 ℃ oil bath for reaction for 18h, and the reaction was monitored by TLC for completion. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) spin-drying and performing column chromatography (EA: PE = 2.

Example 32: compounds 15 to 31

The method comprises the following steps: dissolving a compound 2,3,4, 5-tetrafluoroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, adding trimethylsilyl azide (2 mmol) after TLC monitoring reaction is completed, reacting for 2 hours at room temperature, and TLC monitoring reaction is completed to obtain a crude compound 2,3,4, 5-tetrafluorophenyl azide, and directly entering the next reaction;

step two: crude compound 2,3,4, 5-tetrafluorophenyl azide (1 mmol) and compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (propylone-2-alkyne-1-yloxy) -1- (1H-1, 2, 4-triazole-1-yl) -butane-2-alcohol (1 mmol) is dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) are added, vacuum pumping is carried out under the protection of nitrogen, the mixture is placed in a 60-DEG oil bath pot for reaction for 18h, and the completion of the reaction is monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 33: compounds 15 to 32

The method comprises the following steps: dissolving a compound 2,3,4,5, 6-pentafluoroaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, adding trimethylsilyl azide (2 mmol) after TLC monitoring reaction is completed, reacting for 2 hours at room temperature, and monitoring reaction by TLC to obtain a crude compound 2,3,4,5, 6-pentafluorophenylazide, and directly entering the next reaction;

step two: the crude compound 2,3,4,5, 6-pentafluorophenylazide (1 mmol) and compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, placed in a 60 ℃ oil bath for reaction for 18h, and TLC monitored for reaction completion. Extracting with ethyl acetate for three times, mixing organic phases, washing with saturated NaCl solution twice, and extracting with anhydrous Na ₂ SO ₄ And (5) drying. And (4) spin-drying and performing column chromatography (EA: PE = 2.

Example 34: compounds 15 to 33

The method comprises the following steps: dissolving a compound 3-ethylaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, after TLC monitoring reaction is completed, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, and TLC monitoring reaction is completed to obtain a crude compound 3-ethylphenyl azide, and directly entering the next reaction;

step two: the crude compound 3-ethylphenylazide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and the completion of the reaction was monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) performing spin-dry column chromatography (EA: PE = 2).

Example 35: compounds 15 to 34

The method comprises the following steps: dissolving a compound 3-tert-butyl aniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, monitoring by TLC (thin layer chromatography) for complete reaction, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, monitoring by TLC for complete reaction to obtain a crude compound 3-tert-butylphenyl azide, and directly carrying out the next reaction;

step two: the crude compound 3-tert-butylphenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml of DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and the completion of the reaction was monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 36: compounds 15 to 35

The method comprises the following steps: dissolving a compound 3-trifluoromethylaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, monitoring by TLC (thin layer chromatography) for complete reaction, adding trimethylsilyl azide (2 mmol), reacting at room temperature for 2 hours, monitoring by TLC for complete reaction, obtaining a crude compound 3-trifluoromethylphenyl azide, and directly carrying out the next reaction;

step two: the crude compound 3-trifluoromethylphenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and the completion of the reaction was monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing twice with saturated NaCl solution, anhydrous Na ₂ SO ₄ And (5) drying. And (3) carrying out spin drying and column chromatography (EA: PE = 2).

Example 37: compounds 15 to 36

The method comprises the following steps: dissolving a compound 3-benzylaniline (1 mmol) in DMF, dropwise adding tert-butyl nitrite (2 mmol) in ice bath, reacting for 30 minutes, monitoring by TLC to react completely, adding trimethylsilyl azide (2 mmol), reacting for 2 hours at room temperature, monitoring by TLC to react completely to obtain a crude compound 3-benzylphenyl azide, and directly carrying out the next reaction;

step two: the crude compound 3-benzylphenyl azide (1 mmol) and the compound (2R, 3R) -2- (2, 4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1, 2, 4-triazol-1-yl) -butan-2-ol (1 mmol) were dissolved in 10ml DMF and water (2 drops), copper sulfate (0.05 mmol) and sodium ascorbate (0.1 mmol) were added, vacuum was applied under nitrogen protection, the mixture was placed in a 60 ℃ oil bath for reaction for 18h, and the completion of the reaction was monitored by TLC. Extracting with ethyl acetate for three times, mixing organic phases, washing with saturated NaCl solution twice, and extracting with anhydrous Na ₂ SO ₄ And (5) drying. And (4) spin-drying and performing column chromatography (EA: PE = 2.

Example 38 in vitro bacteriostatic experiments with Compounds of the invention

(I) Experimental method

Conventional in vitro antibacterial assays were used (see: antimicrob Agents Chemother 1995,39 (5): 1169).

1. Materials and methods

(1) Experimental strains

The experiment selects the following 6 common human body pathogenic standard fungus strains as screening objects, wherein the fungus strains are provided by fungus rooms of Shanghai Yangzhong hospitals (or purchased from pharmaceutical institute of Chinese academy of sciences). Respectively as follows: candida albicans (C Candida albicans, ATCC 10231), cryptococcus neoformans (ATCC 32609), candida parapsilosis (ATCC 22019), candida glabrata (C Candida glabrata, ATCC 537), candida tropicalis (ATCC 8915), and Candida auris (ATCC 891).

(2) Test method

Preparing a bacterial suspension: culturing the above fungi in YEPD liquid culture medium at 35 deg.C for 16 hr, activating twice, counting with blood cell counting plate, and adjusting the concentration of the fungi to 1 × 10 in RPM1640 liquid culture medium ⁴ ～1*10 ⁵ one/mL.

Preparing a liquid medicine: the compound to be tested is dissolved in dimethyl sulfoxide to prepare 64mg/mL medicament stock solution, and the medicament stock solution is diluted to 6.4 mu g/mL by RPM1640 before an experiment.

Inoculation: adding RPM1640100 mu L to No. 1 well of a 96-well plate as blank control; the bacterial suspension 100 mu L in each of the No. 3-12 holes, the bacterial suspension 200 mu L in the No. 2 hole and the liquid medicine 2uL, the medicine concentration in the No. 2-11 hole is diluted by 10 times, and the liquid medicine is not added in the No. 12 hole and is used as a positive control. The drug control is fluconazole.

(II) results of the experiment

Results of in vitro bacteriostatic experiments are shown in table 2.

TABLE 2 minimum antifungal inhibitory concentration values (MIC) of the target compounds in vitro ₈₀ ,μg/mL)

The experimental results show that the compound has better antifungal activity, the in vitro bacteriostatic activity is obviously stronger than that of fluconazole, and the compound also has the advantages of low toxicity, wide antifungal spectrum and the like, so the compound can be used for preparing antifungal medicaments.

While the preferred embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that the invention is not limited thereto, and that various changes and modifications may be made without departing from the spirit of the invention, and the scope of the appended claims is to be accorded the full scope of the invention.

Claims

1. An antifungal triadimenol compound, which is characterized in that the chemical structure of the triadimenol compound is shown as the formula I:

a) Halogen, wherein the halogen is F, cl, br or I,

c) Lower alkyl of 1 to 4 carbon atoms, aryl or halogen-substituted lower alkyl,

d) Lower alkoxy of 1 to 4 carbon atoms or lower alkoxy substituted by halogen.

2. The triazole alcohol compound of claim 1, wherein the lower alkyl group having 1-4 carbon atoms, aryl group or halogen-substituted lower alkyl group is selected from methyl, ethyl, tert-butyl, benzyl or trifluoromethyl; the lower alkoxy with 1-4 carbon atoms or the lower alkoxy substituted by halogen is selected from methoxy or trifluoromethoxy.

3. The triazole alcohols compound according to claim 1, which is racemic, R-isomer or S-isomer.

4. The triadimenol compound as claimed in claim 1, characterized in that it is:

(2R, 3R) -3- ((1- (3-fluorophenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (2-chlorophenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (2-methylphenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (3-methylphenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (4-iodophenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (4-trifluoromethylphenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (4-trifluoromethoxyphenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (2-chloro-4-fluorophenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-alcohol,

(2R, 3R) -3- ((1- (3, 4-dichlorophenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (3, 4-difluorophenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (3-ethylphenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol,

(2R, 3R) -3- ((1- (3-trifluoromethylphenyl) -1H-1,2, 3-triazole-4-yl) -methoxyl) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazole-1-yl) butane-2-ol,

(2R, 3R) -3- ((1- (3-benzylphenyl) -1H-1,2, 3-triazol-4-yl) -methoxy) -2- (2, 4-difluorophenyl) -1- (1H-1, 2, 4-triazol-1-yl) butan-2-ol.

5. A pharmacologically acceptable salt of a triazole alcohol compound as claimed in claim 1, which is an inorganic acid salt or an organic acid salt.

6. A pharmacologically acceptable salt according to claim 5, wherein said 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, methane sulfonic acid, p-toluenesulfonic acid, salicylic acid or oxalic acid.

7. A pharmaceutical composition comprising the triazole-based compound of claim 1 or 2, or the pharmacologically acceptable salt of claim 5 or 6, and a conventional pharmaceutical carrier.

8. The method of preparing a triazole alcohol compound of claim 1, comprising the steps of:

a) Preparation of Compound 3

Dissolving a compound 1 and sodium methoxide in THF, dropwise adding a compound 2, controlling the temperature to be 10 ℃, and reacting to generate a compound 3;

b) Preparation of Compound 5

c) Preparation of Compound 7

Dissolving Mg powder in anhydrous THF, adding iodine granules as an initiator, controlling the temperature to be 20 ℃, dropwise adding the compound 6, gradually heating to 40 ℃, discharging bubbles on the Mg powder, initiating a reaction, reducing the temperature to 25 ℃, continuously dropwise adding the compound 6, and controlling the temperature to be 25 ℃ after dropwise adding to generate a compound 7;

d) Preparation of Compound 8

e) Preparation of Compound 9

Mixing Me with water ₃ Dissolving SOI in DMF, adding a compound 8, and reacting at room temperature to generate a compound 9;

f) Preparation of Compound 10

Dissolving 1H-1,2, 4-triazole in DMF, adding sodium hydroxide, reacting at 50 ℃ until the mixture is dissolved, cooling to room temperature, adding DMF solution of a compound 9, reacting at 70 ℃, and extracting to obtain a compound 10;

g) Preparation of Compound 11

h) Preparation of Compound 12

Mixing the compound 11,Cs ₂ CO ₃ Dissolving in acetonitrile, dropwise adding 3-bromopropyne, controlling the temperature to be 80 ℃, filtering and desalting after complete reaction, spin-drying the filtrate, adding water, and extracting with ethyl acetate to obtain a compound 12;

i) Preparation of Compound 14

Dissolving the compound 13 in DMF, dropwise adding trimethylsilyl azide in ice bath, reacting for 30 minutes, adding tert-butyl nitrite, and reacting for 2 hours at room temperature to produce a compound 14;

j) Preparing the triazole alcohol compound

Dissolving the compound 12 and the compound 14 in DMF and water, adding copper sulfate and sodium ascorbate, and reacting at 60 ℃ for 5 hours to generate a target compound, namely a triazole alcohol compound;

wherein the content of the first and second substances,

the compound 1 has a structural formula:

the compound 2 has a structural formula as follows:

the structural formula of the compound 3 is as follows:

the structural formula of the compound 4 is as follows:

the compound 5 has a structural formula:

the structural formula of the compound 6 is as follows:

the compound 7 has a structural formula:

the compound 8 has a structural formula:

the compound 9 has a structural formula as follows:

the compound 10 has the structural formula:

the compound 11 has the structural formula:

the compound 12 has the structural formula:

the compound 13 has the structural formula:

the compound 14 has the structural formula: r ₁ -N ₃ 14。

9. Use of a triazole alcohol compound as claimed in claim 1 or 2, or a pharmacologically acceptable salt as claimed in claim 5 or 6, for the manufacture of a medicament against fungi.

10. The use according to claim 9, wherein the fungus is candida albicans, candida parapsilosis, cryptococcus neoformans, candida glabrata, candida tropicalis or candida auriculata.