CN110845486B - Triazole alcohol derivative and preparation method and application thereof - Google Patents
Triazole alcohol derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a triazole alcohol derivative and a preparation method and application thereof. The chemical structure of the triazole alcohol 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, which is F, cl; b) The electron-withdrawing group is cyano or trifluoromethyl; c) Lower alkyl of 1 to 4 carbon atoms 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
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
In recent years, with the extensive application of broad-spectrum antibiotics, anti-tumor drugs and immunosuppressive agents, the wide implementation of radiotherapy and organ transplantation, the widespread development of catheters and cannulas, and the rapid increase of patients with immunodeficiency, especially AIDS patients, the fungal infection, especially deep fungal infection, has become a major cause of death of serious diseases such as AIDS, tumors and the like. However, the current antifungal drugs applied clinically have the problems of large side effect, narrow antibacterial spectrum, easy generation of drug resistance and the like, and effective antifungal drugs, particularly deep antifungal drugs, are very lack and far fail to meet the treatment requirements. The existing antifungal drugs mainly comprise allylamine acting on squalene epoxidase, azole acting on lanosterol 14 alpha demethylase, lipopeptide acting on cell wall beta- (1,3) -glucan synthetase and the like.
The patent CN104817508A before the applicant discloses a triazole alcohol derivative, and a preparation method and 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, the substituent of the substituted phenyl or substituted benzyl can be positioned at each position of the benzene ring and can be 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, 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 The radicals represent halogen or hydrogen atoms.
Another previous patent CN106336383A of the present applicant also discloses a triazole derivative, and its preparation method and application, wherein the chemical structure of the triazole 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, the heterocyclic ring is selected from a pyridine ring, a pyrimidine ring, a furan ring, a thiophene ring, a pyrrole ring and a thiazole ring, or represents a benzene ring or a substituted benzene ring; said substituentCan be positioned at each position of a benzene ring or a heterocyclic ring and can be 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, wherein the electron-withdrawing group is cyano, nitro or methylsulfonyl, c) lower alkyl with 1-4 carbon atoms or lower alkyl substituted by halogen, d) lower alkoxy with 1-4 carbon atoms or lower alkoxy substituted by halogen.
The triazole alcohol compounds have remarkable antifungal activity, are stronger than fluconazole, and have the advantages of low toxicity, wide antifungal spectrum and the like. However, it is still necessary to develop more antifungal compounds.
Disclosure of Invention
The invention aims to provide a novel antifungal triazole alcohol compound aiming at the defects in the prior art.
It is still another object of the present invention to provide pharmacologically acceptable salts of the triazole alcohols.
It is another object of the present invention to provide a pharmaceutical composition.
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 use of the triazole alcohol compound or the pharmacologically allowable salt thereof.
In order to achieve 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) A halogen of F, cl,
b) An electron-withdrawing group which is a cyano group or a trifluoromethyl group,
c) Lower alkyl of 1 to 4 carbon atoms or lower alkyl substituted by halogen,
d) Lower alkoxy of 1 to 4 carbon atoms or lower alkoxy substituted by halogen.
As a preferred embodiment of the present invention, R 1 Represents a substituted benzene ring, the substituent of the substituted benzene ring is mono-substituted, and the substituent is selected from F, cl or methyl.
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- ((3- (4-chlorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2-chlorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (3-chlorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (4-fluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2-fluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (3-fluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (4-methylphenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2-methylphenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (3-methylphenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (4-trifluoromethylphenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (4-cyanophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (4-trifluoromethoxyphenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2-fluoro-4-chlorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2-chloro-4-fluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (3-fluoro-4-chlorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (3-chloro-4-fluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2,3-difluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2,4-difluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2,5-difluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2,6-difluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (3,4-difluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (3,5-difluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2,3,6-trifluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2,3,4,5-tetrafluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2,3,4,5,6-pentafluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3-phenylisoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol.
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, methanesulfonic acid, p-toluenesulfonic 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 a 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 ℃, 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
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
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
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 to be in EA, dropwise adding a 10-percent NaOH solution until the solid is dissolved, separating the liquid, washing an organic phase and drying to obtain a compound 11;
h) Preparation of Compound 12
Mixing the compound 11,Cs 2 CO 3 Dissolving in acetonitrile, dripping 3-bromopropyne, controlling the temperature to be 80 ℃, filtering and desalting after complete reaction, rotatably drying the solvent in the filtrate, adding water, and extracting with ethyl acetate to obtain a compound 12;
i) Preparation of Compound 14
Compound 13 is dissolved in methanol and NaHCO is added 3 And NH 2 OH, HCl aqueous solution, reacting at room temperature, adding water until white solid is separated out, filtering, and drying to obtain a compound 14;
j) Preparation of Compound 15
Dissolving the compound 14 in DMF, adding NCS, reacting completely at 35 ℃, extracting with ethyl acetate, washing, and drying to obtain a compound 15;
k) Preparing the triazole alcohol compound
Dissolving the compound 12 and the compound 15 in THF, adding TEA, reacting overnight at 35 ℃, extracting with ethyl acetate, washing and drying to obtain the triazole alcohol compound;
wherein, 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:
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:
the compound 15 has the structural formula:
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.
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, aspergillus fumigatus or Microsporum gypseum.
The invention has the advantages that:
the invention synthesizes a novel triazole alcohol compound which has better inhibitory activity on human pathogenic fungi candida albicans, candida parapsilosis, cryptococcus neoformans, candida glabrata, aspergillus fumigatus or microsporum gypseum, and is stronger than fluconazole, and the compound 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 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. The reagents used in the examples were all commercially available analytical grade.
The synthetic route of the compounds 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 partially 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)
The method comprises the following steps: the synthesis of the compound 3 is carried out,
methyl (R) -2-hydroxypropionate (50 mmol) and sodium methoxide (8 mmol) were dissolved in THF, morpholine (100 mmol) was added dropwise, the temperature was controlled at 10 ℃ and stirring was carried out for 3 hours, after completion of the reaction was monitored by TLC, dichloromethane was extracted twice, the organic phase was washed twice with water, dried over anhydrous sodium sulfate and then spin-dried for the next step. 1 H NMR(CDCl 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 two: the synthesis of the compound 5 is carried out,
dissolving compound 3 (50 mmol) in THF, adding p-toluenesulfonic acid (10 mmol), controlling the temperature to 5 ℃, dropwise adding 3,4-dihydropyran (80 mmol), stirring overnight at room temperature, after TLC monitoring reaction completion, extracting dichloromethane twice, washing the organic phase twice with water, and using anhydrous sulfuric acid to perform anhydrous sulfuric acidSodium was dried and the solvent was spin dried to give compound 5 as a pale yellow oil. 1 H NMR(CDCl 3 ,400MHz)δ4.51-4.69(m,2Η),3.86-3.88(m,1H),3.61-3.73(m,8H),3.47-3.50(m,1H),1.70-1.84(m,3H),1.52-1.56(m,3H),1.41(dd,J＝7.0,18.2Hz,3H).
Step three: the synthesis of the compound 7 is carried out,
dissolving Mg powder (40 mmol) in anhydrous THF, adding 1 iodine particle as initiator, controlling the temperature at 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 at 25 ℃ and keeping for 1h after dropwise adding is finished for about half an hour.
Step four: the synthesis of the compound 8 is carried out,
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(CDCl 3 ,400MHz)δ7.85-7.92(m,1H),6.96(dd,J＝8.6,7.8Hz,1H),6.79-6.90(m,1H),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,1H),1.30-1.90(m,6H),1.42(dd,J＝6.8,1.2Hz,3H).
Step five: the synthesis of the compound 9 was carried out,
trimethyl sulphoxide iodide (50 mmol) was dissolved in DMF and compound 8 (40 mmol) was added and stirred at room temperature for 1h and after completion of the reaction was monitored by TLC, the reaction was used in the next step without work-up.
Step six: the synthesis of the compound 10 is carried out,
dissolving 1H-1,2,4-triazole (100 mmol) in DMF, adding sodium hydroxide (100 mmol) to react at 50 ℃ until the solution is dissolved, cooling to room temperature, and adding DMF solution (40 mmol) of compound 9. After 4 hours of reaction at 70 ℃, pouring into ice water, extracting for 3 times by ethyl acetate, washing an organic phase twice by saturated sodium chloride aqueous solution, drying the organic phase by 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 was carried out,
dissolving the crude compound 10 in EA, controlling the temperature at 25 ℃, adding methanesulfonic acid (MSA, 70 mmol), stirring for 2h, separating out a large amount of solid, and filtering to obtain a light yellow solid. Adding the above solid into EA, adding 10% NaOH solution dropwise until the solid is dissolved, separating, washing the organic phase with saturated NaCl twice, and adding anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 11. 1 H NMR(DMSO-d 6 ,400MHz)δ8.92(s,1H),8.09(s,1H),7.25-7.19(m,1H),7.18-7.11(m,1H),6.87(td,J＝8.46,2.53Hz,1H),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＝6.31Hz,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 mmol) in acetonitrile, adding 3-bromopropyne (50 mmol) dropwise, stirring overnight at 80 deg.C, monitoring reaction by TLC, filtering to remove salt, spin-drying the filtrate, 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, and performing column chromatography to obtain the compound 12. 1 H NMR(300MHz,DMSO-d 6 )δ8.30(s,1H),7.59(s,1H),7.19(ddd,J＝21.3,17.7,9.2Hz,2H),6.86(td,J＝8.6,2.3Hz,1H),5.77(s,1H),4.82–4.67(m,2H),4.34(ddd,J＝34.2,16.3,2.2Hz,2H),4.20(q,J＝5.7Hz,1H),3.53(s,1H),0.85(d,J＝6.2Hz,3H).
Example 2:
the method comprises the following steps: 4-Chlorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) water solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, drying to obtain the compound 4-chlorobenzaldehyde oxime.
Step two: compound 4-chlorobenzaldehyde oxime (1 mmol) was dissolved in 10mL DMF and NCS (1.1 mmol) was added and stirred at 35 ℃ for 3h. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 4-chlorobenzaldehyde oxime chloride.
Step three: the compounds 4-chlorobenzaldehyde oxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise, stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and column chromatography to obtain the compound 16a.
Example 3:
the method comprises the following steps: 2-Chlorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) water solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, and drying to obtain the compound 2-chlorobenzaldehyde oxime.
Step two: compound 2-chlorobenzaldehyde oxime (1 mmol) was dissolved in 10mL DMF and NCS (1.1 mmol) was added and stirred at 35 ℃ for 3h. After the completion of the reaction was monitored by TLC,extracting with ethyl acetate three times, mixing organic phases, washing with saturated NaCl twice, and extracting with anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 2-chlorobenzaldehyde oxime chloride.
Step three: the compounds 2-chlorobenzaldehyde oxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and column chromatography to obtain compound 16b.
Example 4:
the method comprises the following steps: 3-Chlorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) water solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, and drying to obtain the compound 3-chlorobenzaldehyde oxime.
Step two: compound 3-chlorobenzaldehyde oxime (1 mmol) was dissolved in 10mL DMF and NCS (1.1 mmol) was added and stirred at 35 ℃ for 3h. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 3-chlorobenzaldehyde oxime chloride.
Step three: the compounds 3-chlorobenzaldehyde oxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and column chromatography to obtain compound 16c.
Example 5:
the method comprises the following steps: 4-fluorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) water solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, and drying to obtain the compound 4-fluorobenzaldehyde oxime.
Step two: compound 4-fluorobenzaldoxime (1 mmol) was dissolved in 10mL DMF, NCS (1.1 mmol) was added, and stirring was carried out at 35 ℃ for 3h. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 4-fluorobenzaldehyde oxime chloride.
Step three: the compounds 4-fluorobenzaldoxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and column chromatography to obtain compound 16d.
Example 6:
the method comprises the following steps: 2-fluorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) water solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, and drying to obtain the compound 2-fluorobenzaldehyde oxime.
Step two: compound 2-fluorobenzaldoxime (1 mmol) was dissolved in 10mL of DMF, NCS (1.1 mmol) was added, and the mixture was stirred at 35 ℃ for 3 hours. After TLC monitoring reaction was complete, extraction was performed three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 2-fluorobenzaldehyde oxime chloride.
Step three: the compounds 2-fluorobenzaldehyde oxime chloride (1 mmoL) and (2R, 3R) -2- (2,4-difluorophenyl) -3- (prop-2-yne-1-yloxy) -1- (1H-1,2,4-triazole-1-yl) -one-substituted benzeneButane-2-ol (1 mmoL) was dissolved in THF (10 mL), evacuated under nitrogen and TEA (1 mmoL) was slowly added dropwise and stirred at 35 ℃ for 12h. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and column chromatography to obtain the compound 16e.
Example 7:
the method comprises the following steps: 3-fluorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) water solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, and drying to obtain the compound 3-fluorobenzaldehyde oxime.
Step two: compound 3-fluorobenzaldoxime (1 mmol) was dissolved in 10mL DMF, NCS (1.1 mmol) was added, and stirring was carried out at 35 ℃ for 3h. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 3-fluorobenzaldehyde oxime chloride.
Step three: the compounds 3-fluorobenzaldoxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred at 35 ℃ for 12H. After TLC monitoring reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed once with saturated NaCl and anhydrous Na 2 SO 4 Drying, spin drying, and performing column chromatography to obtain compound 16f.
Example 8:
the method comprises the following steps: 4-methylbenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) aqueous solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, and drying to obtain the compound 4-methyl benzaldehyde oxime.
Step two: will be transformed intoCompound 4-methylbenzaldoxime (1 mmol) was dissolved in 10mL DMF, NCS (1.1 mmol) was added, and stirring was carried out at 35 ℃ for 3h. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 4-methyl benzaldehyde oxime chloride.
Step three: the compounds 4-methylbenzaldehyde oxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise, stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and column chromatography to obtain 16g of compound.
Example 9:
the method comprises the following steps: 2-methylbenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) aqueous solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, and drying to obtain the compound 2-methyl benzaldehyde oxime.
Step two: compound 2-methylbenzaldehyde oxime (1 mmol) was dissolved in 10mL of DMF, NCS (1.1 mmol) was added, and the mixture was stirred at 35 ℃ for 3 hours. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 2-methyl benzaldehyde oxime chloride.
Step three: the compounds 2-methylbenzaldoxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying, and performing column chromatography to obtain compound 16h.
Example 10:
the method comprises the following steps: 3-methylbenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) aqueous solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, and drying to obtain the compound 3-methyl benzaldehyde oxime.
Step two: compound 3-methylbenzaldehyde oxime (1 mmol) was dissolved in 10mL of DMF, NCS (1.1 mmol) was added, and stirring was carried out at 35 ℃ for 3 hours. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 3-methyl benzaldehyde oxime chloride.
Step three: the compounds 3-methylbenzaldehyde oxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise, stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and column chromatography to obtain the compound 16i.
Example 11:
the method comprises the following steps: 4-Trifluoromethylbenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) aqueous solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, and drying to obtain the compound 4-trifluoromethyl benzaldehyde oxime.
Step two: compound 4-trifluoromethylbenzaldoxime (1 mmol) was dissolved in 10mL DMF and NCS (1.1 mmol) was added and stirred at 35 ℃ for 3h. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 4-trifluoromethyl benzaldehyde oxime chlorideAnd (4) substitution.
Step three: the compound 4-trifluoromethylbenzaldoxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise, stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin drying, and performing column chromatography to obtain a compound 16j.
Example 12:
the method comprises the following steps: 4-Cyanobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) aqueous solution (10 mL), stirring at room temperature for 2h, adding water until white solid is precipitated, filtering, and drying to obtain the compound 4-cyanobenzaldehyde oxime.
Step two: compound 4-cyanobenzaldoxime (1 mmol) was dissolved in 10mL of DMF, NCS (1.1 mmol) was added, and the mixture was stirred at 35 ℃ for 3 hours. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 4-cyanobenzaldehyde oxime chloride.
Step three: the compounds 4-cyanobenzaldoxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and column chromatography to obtain the compound 16k.
Example 13:
the method comprises the following steps: 4-trifluoromethoxybenzaldehyde (1 mmol) was dissolved in methanol (10 mL), and NaHC was addedO 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) aqueous solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, and drying to obtain the compound 4-trifluoromethoxy benzaldehyde oxime.
Step two: compound 4-trifluoromethoxybenzaldehyde oxime (1 mmol) was dissolved in 10mL DMF, NCS (1.1 mmol) was added, and the mixture was stirred at 35 ℃ for 3h. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 4-trifluoromethoxy benzaldehyde oxime chloride.
Step three: the compounds 4-trifluoromethoxybenzaldehyde oxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise, stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and column chromatography to obtain 16l of compound.
Example 14:
the method comprises the following steps: 2-fluoro-4-chlorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, aqueous solution (10 mL) of HCl (1.1 mmoL), stirring at room temperature for 2h, adding water until white solid is precipitated, filtering, and drying to obtain the compound 2-fluoro-4-chlorobenzaldehyde oxime.
Step two: the compound 2-fluoro-4-chlorobenzaldehyde oxime (1 mmol) was dissolved in 10mL DMF, NCS (1.1 mmol) was added, and the mixture was stirred at 35 ℃ for 3 hours. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 2-fluoro-4-chlorobenzaldehyde oxime chloride.
Step three: the compounds 2-fluoro-4-chlorobenzaldehyde oxime chloride (1 mmoL) and (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 THF (10 mL) and NVacuumizing under the protection of gas, slowly adding TEA (1 mmoL) dropwise, and stirring at 35 ℃ for 12h. After TLC monitoring reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed once with saturated NaCl and anhydrous Na 2 SO 4 Drying, spin-drying and performing column chromatography to obtain a compound 16m.
Example 15:
the method comprises the following steps: 2-chloro-4-fluorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) water solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, drying to obtain the compound 2-chloro-4-fluorobenzaldehyde oxime.
Step two: compound 2-chloro-4-fluorobenzaldehyde oxime (1 mmol) was dissolved in 10mL of DMF, NCS (1.1 mmol) was added, and stirring was carried out at 35 ℃ for 3 hours. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 2-chloro-4-fluorobenzaldehyde oxime chloride.
Step three: the compounds 2-chloro-4-fluorobenzaldoxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise, stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and carrying out column chromatography to obtain the compound 16n.
Example 16:
the method comprises the following steps: 3-fluoro-4-chlorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) water solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, drying to obtain the compound 3-fluoro-4-chlorobenzaldehyde oxime.
Step two: will combine withThe substance 3-fluoro-4-chlorobenzaldehyde oxime (1 mmol) was dissolved in 10mL of DMF, NCS (1.1 mmol) was added, and the mixture was stirred at 35 ℃ for 3 hours. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 3-fluoro-4-chlorobenzaldehyde oxime chloride.
Step three: the compounds 3-fluoro-4-chlorobenzaldehyde oxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) slowly added dropwise and stirred for 12H at 35 ℃. After TLC monitoring reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed once with saturated NaCl and anhydrous Na 2 SO 4 Drying, spin-drying and column chromatography to obtain the compound 16o.
Example 17:
the method comprises the following steps: 3-chloro-4-fluorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) water solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, drying to obtain the compound 3-chloro-4-fluorobenzaldehyde oxime.
Step two: compound 3-chloro-4-fluorobenzaldehyde oxime (1 mmol) was dissolved in 10mL of DMF, NCS (1.1 mmol) was added, and stirring was carried out at 35 ℃ for 3 hours. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 3-chloro-4-fluorobenzaldehyde oxime chloride.
Step three: the compounds 3-chloro-4-fluorobenzaldoxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and column chromatography to obtain the compound 16p.
Example 18:
the method comprises the following steps: 2,3-difluorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) aqueous solution (10 mL), stirring for 2h at room temperature, adding water until white solid is precipitated, filtering, and drying to obtain the compound 2,3-difluorobenzaldehyde oxime.
Step two: the compound 2,3-difluorobenzaldehyde oxime (1 mmol) was dissolved in 10mL DMF and NCS (1.1 mmol) was added and stirred at 35 ℃ for 3h. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 2,3-difluorobenzaldehyde oxime chloride.
Step three: the compounds 2,3-difluorobenzaldoxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and carrying out column chromatography to obtain a compound 16q.
Example 19:
the method comprises the following steps: 2,4-difluorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and Na was added 2 HCO 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) aqueous solution (10 mL), stirring for 2h at room temperature, adding water until white solid is precipitated, filtering, and drying to obtain the compound 2,4-difluorobenzaldehyde oxime.
Step two: the compound 2,4-difluorobenzaldehyde oxime (1 mmol) was dissolved in 10mL DMF and NCS (1.1 mmol) was added and stirred at 35 ℃ for 3h. After TLC monitoring reaction was complete, extraction was performed three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spinningAnd drying to obtain the compound 2,4-difluorobenzaldehyde oxime chloride.
Step three: the compounds 2,4-difluorobenzaldoxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and column chromatography to obtain the compound 16r.
Example 20:
the method comprises the following steps: 2,5-difluorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) aqueous solution (10 mL), stirring for 2h at room temperature, adding water until white solid is precipitated, filtering, and drying to obtain the compound 2,5-difluorobenzaldehyde oxime.
Step two: the compound 2,5-difluorobenzaldehyde oxime (1 mmol) was dissolved in 10mL DMF and NCS (1.1 mmol) was added and stirred at 35 ℃ for 3h. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 2,5-difluorobenzaldehyde oxime chloride.
Step three: the compounds 2,5-difluorobenzaldoxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin drying, and performing column chromatography to obtain compound 16s.
Example 21:
the method comprises the following steps: the process comprises the steps of mixing the raw materials 2,6-Difluorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) aqueous solution (10 mL), stirring for 2h at room temperature, adding water until white solid is precipitated, filtering, and drying to obtain the compound 2,6-difluorobenzaldehyde oxime.
Step two: the compound 2,6-difluorobenzaldehyde oxime (1 mmol) was dissolved in 10mL DMF and NCS (1.1 mmol) was added and stirred at 35 ℃ for 3h. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 2,6-difluorobenzaldehyde oxime chloride.
Step three: the compound 2,6-difluorobenzaldehyde oxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred for 12H at 35 ℃. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin drying, and performing column chromatography to obtain compound 16t.
Example 22:
the method comprises the following steps: 3,4-difluorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, aqueous solution (10 mL) of HCl (1.1 mmoL), stirring at room temperature for 2h, adding water until white solid is precipitated, filtering, and drying to obtain the compound 3,4-difluorobenzaldehyde oxime.
Step two: the compound 3,4-difluorobenzaldehyde oxime (1 mmol) was dissolved in 10mL DMF and NCS (1.1 mmol) was added and stirred at 35 ℃ for 3h. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 3,4-difluorobenzaldehyde oxime chloride.
Step three: the compounds 3,4-difluorobenzaldoxime chloride (1 mmoL) and (2R, 3R) -2- (2,4-difluorophenyl) -3- (prop-2-yn-1-yloxy) -1- (1H-1,2,4-triazol-1-yl) -butan-eAlkyl-2-ol (1 mmoL) was dissolved in THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred at 35 ℃ for 12h. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying, and performing column chromatography to obtain compound 16u.
Example 23:
the method comprises the following steps: 3,5-difluorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) aqueous solution (10 mL), stirring for 2h at room temperature, adding water until white solid is precipitated, filtering, and drying to obtain the compound 3,5-difluorobenzaldehyde oxime.
Step two: the compound 3,5-difluorobenzaldehyde oxime (1 mmol) was dissolved in 10mL DMF and NCS (1.1 mmol) was added and stirred at 35 ℃ for 3h. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 3,5-difluorobenzaldehyde oxime chloride.
Step three: the compound 3,5-difluorobenzaldehyde oxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred for 12H at 35 ℃. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and column chromatography to obtain the compound 16v.
Example 24:
the method comprises the following steps: 2,4,6-trifluorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and Na was added 2 HCO 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) water solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, drying to obtain the compound 2,4,6-trifluorobenzaldehyde oxime.
Step two: compound 2,4,6-trifluorobenzaldehyde oxime (1 mmol) was dissolved in 10mL DMF and NCS (1.1 mmol) was added and stirred at 35 ℃ for 3h. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 2,4,6-trifluoro-benzaldehyde oxime chloride.
Step three: the compound 2,4,6-trifluorobenzaldehyde oxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred at 35 ℃ for 12H. After TLC monitoring reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed once with saturated NaCl and anhydrous Na 2 SO 4 Drying, spin-drying and carrying out column chromatography to obtain the compound 16w.
Example 25:
the method comprises the following steps: 2,3,4,5-tetrafluorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) water solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, and drying to obtain the compound 2,3,4,5-tetrafluorobenzaldehyde oxime.
Step two: compound 2,3,4,5-tetrafluorobenzaldoxime (1 mmol) was dissolved in 10mL DMF and NCS (1.1 mmol) was added and stirred at 35 ℃ for 3h. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 2,3,4,5-tetrafluoro benzaldehyde oxime chloride.
Step three: the compound 2,3,4,5-tetrafluorobenzaldehyde oxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and column chromatography to obtain the compound 16x.
Example 26:
the method comprises the following steps: 2,3,4,5,6-Pentafluorobenzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) water solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, drying to obtain the compound 2,3,4,5,6-pentafluorobenzaldehyde oxime.
Step two: compound 2,3,4,5,6-pentafluorobenzaldehyde oxime (1 mmol) was dissolved in 10mL DMF and NCS (1.1 mmol) was added and stirred at 35 ℃ for 3h. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound 2,3,4,5,6-pentafluorobenzaldehyde oxime chloride.
Step three: the compound 2,3,4,5,6-pentafluorobenzaldehyde oxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise and stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and column chromatography to obtain the compound 16y.
Example 27:
the method comprises the following steps: benzaldehyde (1 mmol) was dissolved in methanol (10 mL) and NaHCO was added 3 (1.1 mmol) and NH 2 OH, HCl (1.1 mmoL) aqueous solution (10 mL), stirring for 2h at room temperature, adding water until white solid is separated out, filtering, and drying to obtain the compound benzaldehyde oxime.
Step two: the compound benzaldehyde oxime (1 mmol) was dissolved in 10mL DMF and NCS (1.1 mmol) was added and stirred at 35 ℃ for 3h. TLC after monitoring the reaction was complete, extraction was carried out three times with ethyl acetate, the organic phases were combined, washed twice with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying to obtain the compound benzaldehyde oxime chloride.
Step three: the compounds benzaldoxime chloride (1 mmoL) and (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 THF (10 mL), evacuated under nitrogen, TEA (1 mmoL) was slowly added dropwise, stirred at 35 ℃ for 12H. TLC monitoring reaction, using ethyl acetate extraction three times, combining the organic phase, saturated NaCl each time, anhydrous Na 2 SO 4 Drying, spin-drying and column chromatography to obtain the compound 16z.
Example 28: in vitro bacteriostatic assay for Compounds of the invention
The experimental method comprises the following steps: conventional in vitro antibacterial test method (see: antimicrob Agents Chemothers 1995,39 (5): 1169) is adopted.
1. Materials and methods
(1) Experimental strains
The following 6 common human body pathogenic standard fungal strains are selected as screening objects in the experiment, and the fungal strains are provided by a fungal room (or purchased from a pharmaceutical institute of Chinese academy of sciences) in Shanghai Yangcheng Hospital.
Candida albicans (Candida albicans, standard strain SC 5314),
candida parapsilosis (ATCC 22019),
cryptococcus neoformans (Cryptococcus neoformans, standard strain 32609),
candida glabrata (Candida glabrata, standard strain 537),
aspergillus fumigatus (Aspergillus fumigatus, standard strain 07544),
microsporidia gypseum (Microsporum gypseum, standard strain Cmccfmza).
(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 a drug stock solution of 0.8mg/mL, and the drug stock solution is diluted to 8 mu g/mL by RPM1640 before an experiment.
Inoculation: adding RPM1640 100 mu L into No. 1 hole of a 96-well plate as a blank control; the bacterial suspension 100 mu L and the bacterial suspension 200 mu L in the No. 3-12 hole, the No. 2 Kong Jiajun suspension and the liquid medicine 2 mu L, the medicine concentration in the No. 2-11 hole are diluted by 10 times, and the liquid medicine is not added in the No. 12 hole to be 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 (8)
1. An antifungal triazole alcohol compound, which is characterized in that the chemical structure of the triazole alcohol compound is shown as formula I:
in the formula I, R 1 Represents a substituted benzene ring, 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) and c):
a) A halogen of F, cl,
c) A lower alkyl group of 1 to 4 carbon atoms,
the triazole alcohol compound is R-type isomer.
2. The triazole alcohols compound according to claim 1, selected from the group consisting of:
(2R, 3R) -3- ((3- (4-chlorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2-chlorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (3-chlorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (4-fluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2-fluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (3-fluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (4-methylphenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol, (2R, 3R) -3- ((3- (2-methylphenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol, (2R, 3R) -3- ((3- (3-methylphenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol, (2R, 3R) -3- ((3- (2-fluoro-4-chlorophenyl) isoxazol-5-yl) methoxy) -2- (1H-1,2,4-triazol-1-yl) butan-2-ol, (2R, 3R, 3- ((3- (2-fluoro-4-chlorophenyl) isoxazol-5-yl) -methoxy) -2- (1H-5725-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2-chloro-4-fluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (3-fluoro-4-chlorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (3-chloro-4-fluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2,3-difluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2,4-difluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2,5-difluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2,6-difluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (3,4-difluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (3,5-difluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2,3,6-trifluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2,3,4,5-tetrafluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol,
(2R, 3R) -3- ((3- (2,3,4,5,6-pentafluorophenyl) isoxazol-5-yl) -methoxy) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol.
3. A pharmacologically acceptable salt of a triazole alcohol compound as claimed in claim 1, wherein said pharmacologically acceptable salt is an inorganic acid salt or an organic acid salt.
4. A pharmacologically acceptable salt according to claim 3, characterized in that 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-toluene sulfonic acid, salicylic acid or oxalic acid.
5. A pharmaceutical composition comprising the triazole alcohol compound of claim 1 or the pharmacologically acceptable salt of claim 4, and a conventional pharmaceutical carrier.
6. 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
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 ℃, 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
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
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
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 to be in EA, dropwise adding a 10-percent NaOH solution until the solid is dissolved, separating the liquid, washing an organic phase and drying to obtain a compound 11;
h) Preparation of Compound 12
Mixing the compound 11,Cs 2 CO 3 Dissolving in acetonitrile, dripping 3-bromopropyne, controlling the temperature to be 80 ℃, filtering and desalting after complete reaction, rotatably drying the solvent in the filtrate, adding water, and extracting with ethyl acetate to obtain a compound 12;
i) Preparation of Compound 14
Compound 13 is dissolved in methanol and NaHCO is added 3 And NH 2 OH, HCl aqueous solution, reacting at room temperature, adding water until white solid is separated out, filtering, and drying to obtain a compound 14;
j) Preparation of Compound 15
Dissolving the compound 14 in DMF, adding NCS, reacting completely at 35 ℃, extracting with ethyl acetate, washing, and drying to obtain a compound 15;
k) Preparing the triazole alcohol compound
Dissolving the compound 12 and the compound 15 in THF, adding TEA, reacting overnight at 35 ℃, extracting with ethyl acetate, washing and drying to obtain the triazole alcohol compound;
wherein, 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 structure of the compound 4The formula 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:
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:
the compound 15 has the structural formula:
7. use of the triazole alcohols of claim 1, or the pharmacologically acceptable salts of claim 4 in the preparation of antifungal agents.
8. The use according to claim 7, wherein the fungus is Candida albicans, candida parapsilosis, cryptococcus neoformans, candida glabrata, aspergillus fumigatus or Microsporum gypseum.
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