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A kind of preparation method of econazole nitrate

A technology of econazole nitrate and dilute nitric acid, applied in the direction of organic chemistry, can solve the problems of difficult solid-liquid separation, high reaction temperature, low yield, etc., to avoid the formation of by-products, speed up the reaction rate, and low price Effect

Active Publication Date: 2021-05-14
XUZHOU COLLEGE OF INDAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0005] Liao Yongwei et al. used imidazole ethanol and p-chlorobenzyl as raw materials, TEBA as catalyst, and toluene as solvent, reacted in NaOH solution at 80 °C for 4 h, acidified with concentrated nitric acid, and recrystallized with 95% ethanol to obtain econazole nitrate , yield 79%, acidification in toluene, high viscosity, difficult to achieve solid-liquid separation
[0006] Shao Lucheng et al used imidazole ethanol and p-chlorobenzyl as raw materials, TEBA as catalyst and toluene as solvent in 50% NaOH solution at 100 °C for 2 h, and acidified with nitric acid to obtain econazole nitrate with a yield of 66.19%. High temperature, low yield

Method used

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  • A kind of preparation method of econazole nitrate

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Experimental program
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Effect test

Embodiment 1

[0025] Add 51.4 g imidazole ethanol, 35 g anhydrous potassium carbonate, 105 g isopropanol Ⅰ, 1.5 g TBAB, 3.5 g [bmim] BF into a 500 mL four-necked reaction flask with mechanical stirring and reflux condenser 4 , heated to reflux for 1 h, cooled to 75 ° C, added 34 g p-chlorobenzyl chloride, reacted at 72 ± 1 ° C for 4.0 h, filtered, recovered isopropanol by vacuum distillation, added 160 g toluene, 20 % NaOH solution, stirred, washed with water To neutrality, the supernatant liquid is distilled under reduced pressure to obtain free alkali oil, add 140 g isopropanol II for dissolving, use 18 g mass fraction as 68% concentrated nitric acid and 23 g water to be mixed with 30% dilute nitric acid for acidification, After the precipitation stopped, filter, wash with water, and dry to obtain the crude product of econazole nitrate.

[0026] Add the obtained econazole nitrate crude product and 230 g 95% ethanol in a 500 mL four-necked reaction flask with mechanical stirring and reflux...

Embodiment 2

[0028] Add 51.4 g imidazole ethanol, 30 g anhydrous potassium carbonate, 115 g isopropanol Ⅰ, 2.5 g TBAB, 2.0 g [bmim] BF 4 , heated to reflux for 1 h, cooled to 75 ° C, added 34.5 g p-chlorobenzyl chloride, reacted at 73 ± 1 ° C for 4.5 h, filtered, recovered isopropanol by vacuum distillation, added 170 g toluene, 20 % NaOH solution, stirred, Wash with water until neutral, distill the supernatant under reduced pressure to obtain free alkali oil, add 130 g of isopropanol II to dissolve, and use 22 g of concentrated nitric acid with a mass fraction of 68% and 28 g of water to prepare dilute nitric acid with a mass fraction of 30% for acidification , until the precipitation stopped, filtered, washed with water, and dried to obtain the crude product of econazole nitrate.

[0029] Add the obtained econazole nitrate crude product and 206 g95% ethanol in the 250 mL four-necked reaction flask with mechanical stirring and reflux condenser, stir, and be heated to the complete dissolut...

Embodiment 3

[0031] Add 51.4 g imidazole ethanol, 40 g anhydrous potassium carbonate, 125 g isopropanol Ⅰ, 2.0 g TBAB, 2.5 g [bmim] BF into a 250 mL four-necked reaction flask with mechanical stirring and reflux condenser 4 , heated to reflux for 1h, cooled to 75°C, added 35g p-chlorobenzyl chloride, reacted at 74±1°C for 4.0h, filtered, recovered isopropanol by vacuum distillation, added 175g toluene, 20%NaOH solution, stirred, washed with water until Neutral, the supernatant liquid is distilled under reduced pressure to obtain free alkali oil, add 135 g of isopropanol II for dissolution, and use 20.5 g of mass fraction as 68% concentrated nitric acid and 26 g of water to prepare dilute nitric acid with a mass fraction of 30% for acidification until After the precipitation stopped, filter, wash with water, and dry to obtain the crude product of econazole nitrate.

[0032] Add the obtained econazole nitrate crude product and 220 g95% ethanol in the 250 mL four-necked reaction flask with me...

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Abstract

The invention discloses a preparation method of econazole nitrate, comprising the following steps: using 1-(2,4-dichlorophenyl)-2-(1-imidazolyl)ethanol (imidazole ethanol for short) and p-chlorochloro Benzyl as raw material, ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF 4 ) as a solvent and an in-phase reaction catalyst, tetrabutylammonium bromide (TBAB) as a phase transfer catalyst, isopropanol as a solvent, and anhydrous potassium carbonate as a basic catalyst through O-alkylation reaction, acidification, and recrystallization to obtain Econazole nitrate. The preparation method of the invention is simple and convenient to operate, has mild reaction conditions and high yield, and the purity of the obtained econazole nitrate is higher than 99.9%, which has great industrial application value.

Description

technical field [0001] The invention relates to a preparation method of econazole nitrate, in particular to a preparation method of econazole nitrate. Background technique [0002] Econazole nitrate, the chemical name is 1-[2,4-dichloro-β(4-chlorobenzyloxy) phenethyl] imidazole nitrate, is a broad-spectrum antifungal drug, effective against dermatophytes It is the drug of choice for the clinical treatment of tinea cruris, tinea manus, tinea versicolor, candidal dermatitis and other superficial fungal infections. [0003] It has been reported in the literature that there are many ways to synthesize econazole nitrate. The production process commonly used in industry is as follows: O-alkylation of imidazole ethanol with p-chlorobenzyl chloride to obtain econazole, and finally salt formation with nitric acid to obtain econazole nitrate. [0004] Xu Jian et al. used sodium methoxide as the base, DMF as the solvent, imidazole ethanol and p-chlorobenzyl chloride at 45-50 ℃ for 2 h...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D233/60
CPCC07D233/60
Inventor 李敢孙婷婷王德堂
Owner XUZHOU COLLEGE OF INDAL TECH
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