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Water soluble triazole compound and synthesis method thereof

A compound and triazole technology, applied in the field of water-soluble triazole compounds and the preparation of the compound, can solve problems such as safety risks

Active Publication Date: 2012-01-11
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the water solubility of this type of drug, it is either made into a large-capacity infusion solution, or a cosolvent is added to make a suitable clinical preparation, but it also brings safety risks

Method used

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  • Water soluble triazole compound and synthesis method thereof
  • Water soluble triazole compound and synthesis method thereof
  • Water soluble triazole compound and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] (1) 4-[2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propoxy]-butanoic acid Synthesis of Ethyl Ester

[0084]

[0085] Add 30.6g (0.1mol) of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propanol into the three-necked flask (fluconazole), 27.2g (1.3mol) of ethyl 4-bromobutyrate, 2.5g of n-Bu4Br, 5mL of triethylamine, and 100ml of ethanol. Under stirring, the temperature was raised to reflux for 5 hours, the temperature was lowered, 100 mL of water was added to the reaction mixture, stirred, extracted with 150 mL of ethyl acetate x 2. Concentrate to dryness under reduced pressure, and separate by column chromatography. 17.6 g of yellow oil was obtained, yield: 42.0%.

[0086] (2) 4-[2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propoxy]-butanoic acid Sodium synthesis

[0087]

[0088] Add 17.6 g (0.042 mol) of the above-mentioned oily substance, 1.8 g (0.045 mol) of sodium hydroxide, 75 ml of water, and 50 ml of ethanol into the t...

Embodiment 2

[0090] (1) 2-[2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propoxyl]-ethyl acetate Synthesis of esters

[0091]

[0092] Add 30.6g (0.1mol) of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propanol into the three-necked flask (fluconazole), 15.9g (1.3mol) of ethyl 4-chloroacetate, 2.2g of n-Bu4Br, 5mL of triethylamine, and 100ml of ethanol. Under stirring, the temperature was raised to reflux for 5 hours, the temperature was lowered, 100 mL of water was added to the reaction mixture, stirred, extracted with 150 mL of ethyl acetate x 2. Concentrate to dryness under reduced pressure, and separate by column chromatography. 19.6 g of yellow oil was obtained, yield: 50.1%.

[0093] (2) 4-[2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propoxy]-sodium acetate Synthesis

[0094]

[0095] Add 19.6 g (0.05 mol) of the above-mentioned oily substance, 2.1 g (0.053 mol) of sodium hydroxide, 80 ml of water, and 55 ml of ethanol into the three-necked...

Embodiment 3

[0097] (1) 4-[(2R, 3S)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[4-( Synthesis of 4-cyanophenyl)-3-thiazolyl]-2-butoxy]-butyric acid ethyl ester

[0098]

[0099] Add 43.7g (0.1mol) of (2R,3S)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3 -[4-(4-cyanophenyl)-3-thiazolyl]-2-butanol, 23.3g (0.12mol) of ethyl 4-bromobutyrate, n-Bu 4 Br 2.2g, triethylamine 5mL, ethanol 120ml. Under stirring, the temperature was raised to reflux for 3 hours, the temperature was lowered, 100 mL of water was added to the reaction mixture, stirred, and extracted with 150 mL×2 ethyl acetate. Concentrate to dryness under reduced pressure, and separate by column chromatography. 23.7 g of yellow oil was obtained, yield: 43.1%.

[0100] (2) 4-[(2R, 3S)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-[4-( Synthesis of 4-cyanophenyl)-3-thiazolyl]-2-butoxy]-sodium butyrate

[0101]

[0102] Take 23.7g (0.043mol) of the product from the previous step, 2.0g (0.05mol) of sodium hydr...

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Abstract

The invention discloses a water soluble triazole compound and a synthesis method thereof. The water soluble triazole compound has a structure as shown in Formula Ia, Formula Ib, Formula Ic or Formula Id, wherein R1 is a group in Formula II. The compound of the invention is formed by adding a new group on the structural basis of a broad-spectrum, high-efficiency antifungal compound discovered in the present clinical application and new drug development process to increase the water solubility and reduce the toxicity, is a derivate of the triazole antifungal drug, and has the characteristics ofbroad antifungal spectrum, high antifungal activity, good safety and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a water-soluble triazole compound and a preparation method of the compound. Background technique [0002] Triazole antifungal drugs are currently the most widely used drugs for the treatment of mycoses, especially deep mycoses. It is a five-membered heterocyclic ring in which a carbon atom in the imidazole ring is replaced by nitrogen. As a pharmacophore, triazole has lower toxicity than imidazole, and it is widely used in many types of medicines and pesticides. So far, there have been many Triazoles are used clinically and in agriculture. As an important functional group, triazole has a strong ability to complex metal ions and form hydrogen bonds, so it is favored in the chemical field. Its mechanism of action is that N-4 on the triazole ring coordinates with the iron atom of the iron porphyrin center in the fungal cytochrome P-450 to inhibit the demethylation re...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D249/08C07D417/06C07D403/06C07F9/6558A61K31/4196A61K31/427A61K31/506A61K31/675A61P31/10
Inventor 张孝清宋丰发蒋玉伟
Owner NANJING HUAWE MEDICINE TECH DEV
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