Method for preparing isoconazole nitrate

A technology of isoconazole nitrate and aluminum isopropoxide, applied in the field of medicine and chemical industry, can solve the problems of harsh conditions, danger, high price, etc., and achieve the effects of mild reaction conditions, improved operability, and reduced product cost

Inactive Publication Date: 2012-04-04
YANGTZE RIVER PHARM GRP NANJING HAILING PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the reaction process, bromine needs to be brominated with liquid bromine, which is highly toxic and pollutes more seriously; using sodium borohydride as a reducing agent is relatively expensive; using anhydrous benzene and dimethylformamide as a mixed solvent , the cost is high, the toxicity is very high, and using sodium hydride as a strong base is dangerous, industrially difficult to operate, and the relative cost is relatively high; the entire preparation route is cumbersome to operate, the conditions are relatively harsh, and the yield is only 15%, which is difficult Industrial production

Method used

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  • Method for preparing isoconazole nitrate
  • Method for preparing isoconazole nitrate
  • Method for preparing isoconazole nitrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] In a 2000mL three-necked reaction flask with mechanical stirring and reflux condenser, add 200g (0.89mol) of trichloroacetophenone, 1200mL of isopropanol and 80g (0.39mol) of aluminum isopropoxide, stir, and heat to 75°C for reaction 7 Hour. Stop the reaction, and concentrate the reaction liquid in the reaction flask to oil under reduced pressure to obtain 1-(2,4-dichlorophenyl)-2-chloro-ethanol.

[0032] Put 1-(2,4-dichlorophenyl)-2-chloro-ethanol, water 200mL, sodium hydroxide 315g, toluene 1000mL, imidazole 106g (1.56mol) and triethylbenzyl ammonium chloride 32g into In the reaction bottle, after 7 hours of heat preservation at 60°C, stop the reaction, separate the reacted mixture, wash the organic phase with water, then cool to 0°C, precipitate crystals, then filter, and recrystallize the filter cake with 95% ethanol. 1-[2-(2,4-Dichlorophenyl)-2-hydroxyethyl]imidazole is obtained.

[0033] Mix 1-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]imidazole, water 360 mL, sodiu...

Embodiment 2

[0036] In a 2000mL reactor, add 200g (0.89mol) of trichloroacetophenone, 1000mL of methanol and 20g (10%wt) of Raney nickel, pressurize to 1MPa, react at 25°C for 4 hours, and stop the reaction. The reaction solution was concentrated to oil under reduced pressure to obtain 1-(2,4-dichlorophenyl)-2-chloro-ethanol.

[0037] Put 1-(2,4-dichlorophenyl)-2-chloro-ethanol, water 200mL, sodium hydroxide 295g, toluene 900mL, imidazole 98g (1.44mol) and triethylbenzyl ammonium chloride 30g into In the reaction flask, keep warm at 60°C for 7 hours, stop the reaction, separate the reacted mixture, wash the organic phase with water, then cool to -5°C, crystallize, then filter, and recrystallize the filter cake with 95% ethanol , to give 1-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]imidazole.

[0038] Mix 1-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]imidazole, water 330 mL, sodium hydroxide 257 g, toluene 1000 mL, triethylbenzyl ammonium chloride 14.2 g (0.06 mol) and 114.5 g (0.59 mol) of 2,6-di...

Embodiment example 3

[0041] In a 2000mL three-necked reaction flask with mechanical stirring and reflux condenser, add 200g (0.89mol) of trichloroacetophenone, 1200mL of isopropanol and 80g (0.39mol) of aluminum isopropoxide, stir, and heat to 75°C for reaction 7 Hour. Stop the reaction, and concentrate the reaction liquid in the reaction flask to oil under reduced pressure to obtain 1-(2,4-dichlorophenyl)-2-chloro-ethanol.

[0042] Put 1-(2,4-dichlorophenyl)-2-chloro-ethanol, water 500mL, sodium carbonate 835g, toluene 1000mL, imidazole 106g (1.56mol) and tetrabutylammonium bromide 45.3g into the reaction bottle in sequence , after 7 hours of heat preservation at 60°C, stop the reaction, separate the reacted mixture, wash the organic phase with water, then cool to -10°C, crystallize, then filter, and recrystallize the filter cake with 95% ethanol to obtain 1-[2-(2,4-Dichlorophenyl)-2-hydroxyethyl]imidazole.

[0043] Mix 1-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]imidazole, water 450mL and sodium ca...

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Abstract

The invention discloses a method for preparing isoconazole nitrate, and relates to the field of pharmaceutical chemicals. The method comprises the following steps of: catalyzing a raw material of trichloroacetophenon by using a reduction catalyst to obtain 1-(2,4-dichlorophenyl)-2-chloro-ethanol, performing N-alkylation reaction on the 1-(2,4-dichlorophenyl)-2-chloro-ethanol and imidazole to obtain an intermediate of 1-[2-(2,4-dichlorophenyl)-2-hydroxyethyl]imidazole, etherifying the intermediate and 2,6-dichlorobenzyl chloride, acidizing by using nitric acid for salt formation to obtain crude isoconazole nitrate, and recrystallizing and purifying to obtain the isoconazole nitrate. The catalyst different from the traditional catalyst is used, so that the method is easy to implement, low in cost and high in yield.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a preparation method of isoconazole nitrate. Background technique [0002] Isoconazole nitrate (structural formula 1, Isoconazole Nitrate, chemical name 1-[2-(2,4-dichlorophenyl)-2-[(2,6-dichlorophenyl)methoxy]ethyl] -1H-imidazole nitrate is a broad-spectrum antifungal drug. [0003] [0004] Formula 1 [0005] Isoconazole nitrate, like other imidazole derivatives, mainly inhibits or kills fungi by competitively inhibiting the 14α-demethylase of cytochrome P450 enzymes, which promotes the transformation of lanosterol into ergosterol Alcohol, which is necessary for fungal cell wall synthesis, leads to changes in fungal membrane permeability and the activity of various enzymes on the membrane. [0006] Isoconazole nitrate can kill or inhibit Candida albicans (Candida albicans), Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton flocculus, Microsporu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/60
Inventor 季世春李琴张明明
Owner YANGTZE RIVER PHARM GRP NANJING HAILING PHARM CO LTD
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