2-[5-(2-hydroxyphenyl]-4H-1,2,4-triazole-3-thioether]-1-acetophenone compound or pharmaceutically acceptable salt and preparation and application thereof

Abstract

The invention provides a 2-[5-(2-hydroxyphenyl]-4H-1,2,4-triazole-3-thioether]-1-acetophenone compound of formula (III) or pharmaceutically acceptable salt and a preparation method and application thereof in antimicrobial. The preparation method comprises the following steps of: reacting substituted gaultherolin with a hydrazine hydrate to generate a substituted salicylyl hydrazine, then reacting the substituted gaultherolin with ammonium thiocyanate and an acid, further reacting the obtained product under alkaline conditions to generate a compound II, and finally carrying out a nucleophilic substitution reaction on the compound II and a substituted halogeno-benzene butanone to generate the 2-[5-(2-hydroxyphenyl]-4H-1,2,4-triazole-3-thioether]-1-acetophenone compound, wherein a general formula is shown as the description. The compound or the pharmaceutically acceptable salt thereof has important application potentials in the aspects of the development of antifungal and anti-gram-negative bacteria medicaments.

Description

technical field

[0001] The present invention relates to a kind of triazole compound and its preparation method and the application in antimicrobial aspect; Particularly relate to a kind of 2-[5-(2-hydroxyphenyl)-4H-1,2,4 of formula (III) -triazole-3-thioether]-1-acetophenone compound or its pharmaceutically acceptable salt and its preparation method and application.

[0002] The 2-[5-(2-hydroxyphenyl)-4H-1,2,4-triazole-3-sulfide]-1-acetophenone compound of formula (III) provided by the invention or its pharmaceutical The salt used has important application prospects in the development of drugs such as antifungal and anti-gram-negative bacteria. Background technique

[0003] In recent years, fungal infection in immunocompromised hosts caused by immunodeficiency or use of anticancer drugs has become a serious problem in inducing mycosis due to fungal infection. Various antifungal agents have been developed to solve this problem. For example, EP.A.333059 discloses a compoun...

Examples

Embodiment 1

[0058] Synthesis of salicylhydrazide:

[0059] In a 100mL three-neck flask, dissolve 0.10mol methyl salicylate and 0.13mol hydrazine hydrate in 40mL of absolute ethanol, stir at room temperature, the solution is colorless and transparent, heat to reflux at 80°C, react at this temperature for about 9 hours, follow the reaction by TLC , the developer is V (ethyl acetate): V (petroleum ether) = 1: 5 (volume ratio), the reaction is stopped after the spots of the raw materials disappear, the solvent is spin-dried after cooling, a white solid is obtained by suction filtration, and a white powder is obtained by ethanol recrystallization , yield: 88.7%, melting range: 147-148°C.

Embodiment 2

[0061] Synthesis and structure identification of 5-(2-hydroxyphenyl)-1,2,4-triazole-3-thione:

[0062] In a 100mL three-necked flask, dissolve 0.01mol salicylic hydrazide in 50mL ethanol, stir and dissolve until clear. Add 0.011mol ammonium thiocyanate and 2mL concentrated hydrochloric acid at room temperature. Under stirring, the temperature was raised to 80°C, the reaction mixture was heated to reflux, and the reaction was tracked by TLC. The developer was a mixed solution of V (ethyl acetate): V (petroleum ether) = 1: 3. After the raw material spots disappeared, the reaction was stopped and evaporated under reduced pressure. Remove the solvent, filter with suction, and dry in vacuo to obtain 1.91 g of white powdery solid, which is directly used in the next reaction. Yield: 90.3%, melting point: 195-197°C. Dissolve the product of the first step in 30mL of 5% NaOH aqueous solution, raise the temperature to 100°C under stirring, heat the reaction mixture to reflux, follow th...

Embodiment 3

[0064] Synthesis of bromoacetophenone:

[0065] Add 0.2mol of acetophenone and 100mL of anhydrous diethyl ether to a 250mL four-necked reaction flask equipped with a stirrer, a condenser tube (the condenser tube is connected to a calcium chloride drying tube and a hydrogen chloride absorption device) thermometer and a 50mL constant pressure dropping funnel. , cooled with an ice-salt bath to below 0°C, stirred and added dropwise 0.2mol liquid bromine, first added dropwise, and then continued to drop after the color faded, controlling the rate of addition, and the drop was completed in about 2 hours. Maintain the reaction temperature and continue to stir for about 30 minutes until the color fades to stop the reaction. The reaction solution was poured into a 500 mL separatory funnel, washed with ice water to separate the water layer, washed repeatedly with water until the organic phase became neutral, and dried overnight with anhydrous magnesium sulfate. Magnesium sulfate was fi...

technical field

[0001] The present invention relates to a kind of triazole compound and its preparation method and the application in antimicrobial aspect; Particularly relate to a kind of 2-[5-(2-hydroxyphenyl)-4H-1,2,4 of formula (III) -triazole-3-thioether]-1-acetophenone compound or its pharmaceutically acceptable salt and its preparation method and application.

[0002] The 2-[5-(2-hydroxyphenyl)-4H-1,2,4-triazole-3-sulfide]-1-acetophenone compound of formula (III) provided by the invention or its pharmaceutical The salt used has important application prospects in the development of drugs such as antifungal and anti-gram-negative bacteria. Background technique

[0003] In recent years, fungal infection in immunocompromised hosts caused by immunodeficiency or use of anticancer drugs has become a serious problem in inducing mycosis due to fungal infection. Various antifungal agents have been developed to solve this problem. For example, EP.A.333059 discloses a compoun...

Examples

Embodiment 1

[0058] Synthesis of salicylhydrazide:

[0059] In a 100mL three-neck flask, dissolve 0.10mol methyl salicylate and 0.13mol hydrazine hydrate in 40mL of absolute ethanol, stir at room temperature, the solution is colorless and transparent, heat to reflux at 80°C, react at this temperature for about 9 hours, follow the reaction by TLC , the developer is V (ethyl acetate): V (petroleum ether) = 1: 5 (volume ratio), the reaction is stopped after the spots of the raw materials disappear, the solvent is spin-dried after cooling, a white solid is obtained by suction filtration, and a white powder is obtained by ethanol recrystallization , yield: 88.7%, melting range: 147-148°C.

Embodiment 2

[0061] Synthesis and structure identification of 5-(2-hydroxyphenyl)-1,2,4-triazole-3-thione:

[0062] In a 100mL three-necked flask, dissolve 0.01mol salicylic hydrazide in 50mL ethanol, stir and dissolve until clear. Add 0.011mol ammonium thiocyanate and 2mL concentrated hydrochloric acid at room temperature. Under stirring, the temperature was raised to 80°C, the reaction mixture was heated to reflux, and the reaction was tracked by TLC. The developer was a mixed solution of V (ethyl acetate): V (petroleum ether) = 1: 3. After the raw material spots disappeared, the reaction was stopped and evaporated under reduced pressure. Remove the solvent, filter with suction, and dry in vacuo to obtain 1.91 g of white powdery solid, which is directly used in the next reaction. Yield: 90.3%, melting point: 195-197°C. Dissolve the product of the first step in 30mL of 5% NaOH aqueous solution, raise the temperature to 100°C under stirring, heat the reaction mixture to reflux, follow th...

Embodiment 3

[0064] Synthesis of bromoacetophenone:

[0065] Add 0.2mol of acetophenone and 100mL of anhydrous diethyl ether to a 250mL four-necked reaction flask equipped with a stirrer, a condenser tube (the condenser tube is connected to a calcium chloride drying tube and a hydrogen chloride absorption device) thermometer and a 50mL constant pressure dropping funnel. , cooled with an ice-salt bath to below 0°C, stirred and added dropwise 0.2mol liquid bromine, first added dropwise, and then continued to drop after the color faded, controlling the rate of addition, and the drop was completed in about 2 hours. Maintain the reaction temperature and continue to stir for about 30 minutes until the color fades to stop the reaction. The reaction solution was poured into a 500 mL separatory funnel, washed with ice water to separate the water layer, washed repeatedly with water until the organic phase became neutral, and dried overnight with anhydrous magnesium sulfate. Magnesium sulfate was fi...

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