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Method for industrial production of miconazole nitrate

A technology of miconazole nitrate and imidazole, applied in the directions of organic chemistry, antifungal agent, etc., can solve the problems of difficult N-alkylation reaction of imidazole, affecting reaction yield, reducing chemical activity, etc., so as to avoid the influence of side reactions, The effect of utilizing the reactivity and improving the yield

Inactive Publication Date: 2009-07-22
TAIZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This process has two disadvantages: first, there are many side reactions in the reduction reaction step, which affects the reaction yield.
Secondly, the α-carbonyl chloride in 2,4-dichloro-α-chloroacetophenone itself has very high chemical reactivity. If the carbonyl is reduced to alcohol first, the chemical activity of α-chlorine will be greatly reduced. Not easy to carry out N-alkylation reaction with imidazole

Method used

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  • Method for industrial production of miconazole nitrate

Examples

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Effect test

Embodiment 1

[0026] Put 8g of imidazole, 18mL of triethylamine, and 150ml of benzene in a 500mL three-neck flask, heat to 70°C and stir for 20min, and slowly add the benzene solution of 2,4-dichloro-α-chloroacetophenone dropwise after the raw materials are completely dissolved (Containing 22.35g of 2,4-dichloro-α-chloroacetophenone), react at 70°C for 1.5h. After the reaction is completed, filter through a filter cloth to remove triethylamine hydrochloride, pour the reaction solution into 1% hydrochloric acid water with a concentration three times its volume for full washing, and fully remove triethylamine hydrochloride and unreacted imidazole. Use a separatory funnel to separate the water layer, dry the organic layer by adding anhydrous calcium chloride, add the dried reaction solution into a three-necked reaction flask, add 2.1 g of phase transfer catalyst PEG600, 3.8 g of potassium borohydride, and 2.3 g of lithium carbonate. Reduction at 70°C for 5h. After the reaction was completed, ...

Embodiment 2

[0028]Put 8g of imidazole, 18mL of triethylamine, and 150ml of benzene in a 500mL three-neck flask, heat to 40°C and stir for 20min, and slowly add the benzene solution of 2,4-dichloro-α-chloroacetophenone dropwise after the raw materials are completely dissolved (containing 22.35 g of 2,4-dichloro-α-chloroacetophenone), reacted at 40° C. for 3.0 h, poured the reaction solution into water containing 1.5% hydrochloric acid three times its volume, and washed fully three times. Use a separatory funnel to separate the water layer, add anhydrous calcium chloride to the organic layer to dry, add the dried reaction solution into a three-necked reaction flask, add 2.1 g of phase transfer catalyst PEG400, 3.8 g of potassium borohydride, and 2.0 g of lithium chloride. Reduction at 40°C for 10h. After the reaction was completed, it was cooled to 28°C, 15g NaOH and 4ml of water were directly added to the reaction liquid, and then 16.3g of 2,4-dichlorobenzyl chloride was added dropwise, an...

Embodiment 3

[0030] Put 8g of imidazole, 18mL of triethylamine, and 150ml of toluene in a 500mL three-neck flask, heat to 60°C and stir for 30min, and slowly add the benzene solution of 2,4-dichloro-α-chloroacetophenone dropwise after the raw materials are completely dissolved (Containing 22.35g of 2,4-dichloro-α-chloroacetophenone), react at 60°C for 2.0h. After the reaction is completed, filter through filter paper, pour the reaction solution into water containing 1% hydrochloric acid with a concentration three times its volume, and wash it three times, use a separatory funnel to separate the water layer, add anhydrous calcium chloride to the organic layer, and dry it. The reaction solution was put into a three-necked reaction flask, and 2.1 g of phase transfer catalyst triethylphenylbenzyl ammonium chloride, 3.8 g of potassium borohydride, and 2.3 g of lithium carbonate were added. Reduction at 60°C for 6h. After the reaction was completed, it was cooled to 28°C, 10 g of KOH was direct...

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Abstract

The invention provides an industrialized production method of miconazole nitrate, pertaining to the technical field of medicine synthesis. The method solves such problems as complex technology, comparatively low yield and purity, and the like in the existing industrialized production method of the miconazole nitrate. The industrialized production method of the miconazole nitrate includes the following steps: a. N-alkylation reaction; b. reducing reaction; c. O-alkylation reaction. The industrialized production method has the advantages of simple technology, no requirement for extracting any intermediate product, high yield and purity, etc.

Description

technical field [0001] The invention relates to a method for producing an antifungal drug, in particular to a method for industrially producing the antifungal drug miconazole nitrate; it belongs to the technical field of drug synthesis. Background technique [0002] Miconazole nitrate is widely used in current antifungal drugs. For example, in the domestically familiar drugs such as Daconazole and Pikang Cream, the main ingredient is miconazole nitrate. The antibacterial spectrum and antibacterial activity of miconazole are basically the same as that of clotrimazole. It has a good antibacterial effect on many clinical pathogenic fungi, such as Candida albicans, Aspergillus, Cryptococcus neoformans, Blastomyces, Coccidioides, Toroceres and other deep fungi, some epidermis fungi, and yeasts. In addition, it also has antibacterial effect on Gram-positive bacteria such as Staphylococcus, Streptococcus and Bacillus anthracis. It is clinically used to treat various ringworm dise...

Claims

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Application Information

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IPC IPC(8): C07D233/64A61P31/10
Inventor 潘富友何斌颜秋梅
Owner TAIZHOU UNIV
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