Preparation method of miconazole nitrate

A technology of miconazole nitrate and imidazole, applied in directions such as organic chemistry, can solve the problems of low yield, harsh conditions, expensive reagents and the like, and achieve the effects of high yield, safe reaction and easy operation

Inactive Publication Date: 2015-05-13
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The yield of route two is low. In addition, the reaction raw material 2,4-dichloro-2'-chloroacetophenone is relatively active, has poor stability and is not easy to be used i

Method used

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  • Preparation method of miconazole nitrate

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Experimental program
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Effect test

Embodiment 1

[0017] In a 500 ml three-necked flask, 22.6 grams (0.1 moles) of 2,4-dichloro-2'-chlorophenylethanol, 8.2 grams (0.12 moles) of imidazole, and 23.5 grams of 2,4-dichlorobenzyl chloride ( 0.12 moles) and 163 grams of 1-methyl-3-butylimidazolium hexafluorophosphate ionic liquid were reacted at 50° C. for 5 hours. After the reaction was finished, the temperature of the reaction solution dropped to room temperature (25° C.), and after the pH value of the reaction body fluid was adjusted to 1 with an aqueous nitric acid solution with a volume concentration of 40%, the layers were left to stand, and the lower layer was taken to reclaim the ionic liquid. Concentrate under pressure until the solid precipitates, take the concentrate and let it cool to room temperature to obtain the crude product of miconazole nitrate salt, and finally recrystallize it with absolute ethanol to obtain 34 grams of pure white solid product with a yield of 71% (with 2,4-dichloro- 2′-Chlorophenethyl alcohol ...

Embodiment 2

[0019] In a 500 ml three-necked flask, 22.6 grams (0.1 mole) of 2,4-dichloro-2'-chlorophenylethanol, 6.8 grams (0.1 mole) of imidazole, and 19.6 grams of 2,4-dichlorobenzyl chloride ( 0.1 mole) and 245 grams of 1-methyl-3-butylimidazolium hexafluorophosphate ionic liquid were reacted at 10° C. for 10 hours. After the reaction is finished, the reaction liquid is lowered to room temperature, and the pH value of the reaction liquid is adjusted to 2 with an aqueous solution of nitric acid with a volume concentration of 50%, and the layers are left to stand, and the lower layer is taken to recover the ionic liquid, and the upper layer is concentrated under reduced pressure until solids are precipitated, and then placed Cool to room temperature to obtain the crude product of miconazole nitrate, and finally recrystallize with absolute ethanol to obtain 33 g of white solid pure product with a yield of 69%. HPLC analysis content is ≥ 99%. The melting point is 179-183°C.

Embodiment 3

[0021] In a 500 ml three-necked flask, 22.6 grams (0.1 moles) of 2,4-dichloro-2'-chlorophenylethanol, 10.2 grams (0.15 moles) of imidazole, and 29.3 grams of 2,4-dichlorobenzyl chloride ( 0.15 moles) and 496 grams of 1-methyl-3-butylimidazolium hexafluorophosphate ionic liquid were reacted at 100° C. for 1 hour. After the reaction, the reaction liquid was lowered to room temperature, and the pH value of the reaction liquid was adjusted to 3 with an aqueous nitric acid solution with a volume concentration of 15%, and the layers were allowed to stand, and the lower layer was taken to recover the ionic liquid, and the upper layer was concentrated under reduced pressure until solids were precipitated, and then placed Cool to room temperature to obtain the crude product of miconazole nitrate, and finally recrystallize with absolute ethanol to obtain 32.6 g of white solid pure product with a yield of 68%. HPLC analysis content is ≥ 99%. The melting point is 179-183°C.

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Abstract

The invention discloses a preparation method of miconazole nitrate. The method comprises steps as follows: 2,4-dichloro-2'-chlorinated phenethyl alcohol, imidazole and 2,4-dichlorobenzyl are used as raw materials, an ionic liquid is used as a reaction medium, a reaction is conducted at the temperature 10-100 DEG C, a reaction liquid is cooled to the room temperature after the reaction is finished, the pH value of the reaction liquid is adjusted to range from 1 to 3 by the aid of a nitrate aqueous solution with the volume concentration of 15-50%, the reaction liquid is left to stand for layering, the lower layer is taken for recovery of the ionic liquid, the upper layer is taken for pressure reduced concentration until a solid is separated out, a concentrate is taken and cooled to the room temperature, then a recrystallization solvent is added to the concentrate for recrystallization, crystals are taken and dried, and the miconazole nitrate is obtained. According to the method, the ionic liquid is used as the reaction medium, and a one-pot reaction technology is combined; the method has the technical characteristics that the operation is simple and convenient, the reactions are safe, the yield is high, the ionic liquid can be reused continuously after a product is separated out, the method is environment-friendly and the like.

Description

(1) Technical field [0001] The invention relates to a method for preparing miconazole nitrate by applying a one-pot reaction technology in an ionic liquid reaction medium. (2) Background technology [0002] Miconazole nitrate, the chemical name is 1-[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]-1H-imidazole nitrate ;Molecular formula is C 18 h l4 C1 4 N 2 O HNO 3 , molecular weight 479.15. Miconazole nitrate is a commonly used nitrogen azole antifungal drug, mainly used for the treatment of various ringworm diseases caused by fungi, such as tinea pedis and tinea corporis. There are two main routes for the synthesis of miconazole nitrate. Route one is to reduce the carbonyl group of 2,4-dichloroacetophenone, then alkylate it with the nitrogen atom of imidazole, and finally carry out oxyalkylation reaction with 2,4-dichlorobenzyl chloride; route two is 2, 4-dichloro-2'-chloroacetophenone is alkylated with imidazole on the nitrogen atom, and then the car...

Claims

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Application Information

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IPC IPC(8): C07D233/60
CPCC07D233/60
Inventor 裴文孙莉王海滨杨振平杨涛
Owner ZHEJIANG UNIV OF TECH
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