Preparation method for important intermediates of butoconazole nitrate

A volume ratio, chlorobenzyl chloride technology, applied in the direction of magnesium organic compounds, organic chemistry, etc., can solve the problems that are not suitable for industrialization, and achieve the effects of easy control of the reaction, reduction of side reactions, and safe operating environment

Inactive Publication Date: 2012-08-29
SICHUAN DIHON MEDICAL DEV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

It is corrosive to many metals, especially in the presence of humid air, so method 1 is not suitable for industrialization

Method used

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  • Preparation method for important intermediates of butoconazole nitrate
  • Preparation method for important intermediates of butoconazole nitrate
  • Preparation method for important intermediates of butoconazole nitrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] The preparation method of embodiment 1 4-chlorobenzylmagnesium chloride (formula I compound)

[0026] Add 5g of magnesium powder, 30ml of ether, and 1 grain of iodine into a 500ml three-necked bottle, and heat up to 30°C. Add 33g of p-chlorobenzyl chloride, 20ml of diethyl ether, and 200ml of methyl tert-butyl ether into the dropping funnel, drop about 10ml into the reaction bottle to initiate the reaction, then control the temperature of 30-40°C to slowly add all the materials dropwise, and then Warm reaction for 2 hours to obtain a mixed solution of bright green Grignard reagent 4-chlorobenzylmagnesium chloride (compound of formula I), diethyl ether and methyl tert-butyl ether. Measure the concentration of 4-chlorobenzylmagnesium chloride to be 0.843mol / l, volume 247ml, yield: 93.8% (concentration determination method: take about 0.5g of sample (sealed and weighed), place in a conical flask, add water 10-15ml, add Quantitatively dilute hydrochloric acid, add indicato...

Embodiment 2

[0027] The preparation method of embodiment 2 4-chlorobenzylmagnesium chloride (formula I compound)

[0028] Add 5g of magnesium powder, 40ml of ether, and 1 grain of iodine into a 500ml three-necked flask, and heat up to 30°C. Add 33g of p-chlorobenzyl chloride, 20ml of diethyl ether, and 180ml of methyl tert-butyl ether into the dropping funnel, drop about 10ml into the reaction bottle to initiate the reaction, then control the temperature of 30-40°C to slowly add all the materials dropwise, and then Warm reaction for 2 hours to obtain a mixed solution of bright green Grignard reagent 4-chlorobenzylmagnesium chloride (compound of formula I), diethyl ether and methyl tert-butyl ether. Measure 4-chlorobenzylmagnesium chloride concentration and be 0.827mol / l, volume 235ml, yield: 93.3% (concentration determination method is the same as above)

Embodiment 3

[0029] Example 3 The preparation method of 1-[2-chloro-4-(4-chlorophenyl)-n-butyl]imidazole (compound of formula III)

[0030] Add 1-[4-(4-chlorophenyl)-2-hydroxy-n-butyl]imidazole (compound 2) 18g (0.072mol), dichloromethane 100ml, thionyl chloride 9.42g into a 250ml three-necked flask (0.079mol), heated and refluxed for 1 hour, lowered to room temperature, added 10ml of water, adjusted pH=8 with saturated aqueous sodium carbonate solution, separated the water layer, concentrated the organic layer to dryness, and obtained brown oil 1-[2-chloro-4 -(4-Chlorophenyl)-n-butyl]imidazole (compound of formula III) 17.3 g (purity measured by HPLC: 98.6%), yield 94.8%.

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Abstract

The invention discloses a preparation method for novel Grignard reagents, namely 4-chlorobenzylmagnesium chloride and 1-(2-chlorine-4-(4-chlorophenyl)-normal-butyl) imidazole. The method comprises the steps as follows: the 4-chlorobenzylmagnesium chloride is prepared from a mixed solvent of ethyl ether and MTBE (Methyl Tertiary Butyl Ether) by taking p-chlorobenzyl chloride as a raw material; and the 1-(2-chlorine-4-(4-chlorophenyl)-normal-butyl) imidazole is prepared from a methylene chloride solvent by taking 1- (4-(4-chlorophenyl)-2-hydroxy-normal-butyl) imidazole as a raw material. The 4-chlorobenzylmagnesium chloride and the 1-(2-chlorine-4-(4-chlorophenyl)-normal-butyl) imidazole are important intermediates for preparing butoconazole nitrate.

Description

technical field [0001] The present invention is the preparation method of Grignard reagent 4-chlorobenzylmagnesium chloride and 1-[2-chloro-4-(4-chlorophenyl)-n-butyl]imidazole, and these two compounds can be used to prepare antifungal drug nitric acid Butoconazole. Background technique [0002] Butoconazole nitrate, chemical name (±)-1-[4-(4-chlorophenyl)-2-(2,6-dichlorophenylthio)]butyl-1H-imidazole nitrate, manufactured by Sytnex USA The company developed and launched in the United States in 1986. This product is a new type of imidazole antifungal drug. Its effect on Candida albicans in the body is superior to other similar drugs that have been marketed, and as the first choice drug for the treatment of vulvovaginal Candida, a large number of foreign clinical studies have shown that it has significant curative effect. Low, good tolerance, low incidence of adverse reactions and other characteristics. Butoconazole nitrate has the characteristics of better curative effect...

Claims

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Application Information

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IPC IPC(8): C07F3/02C07D233/56
Inventor 李蕾蕾陈秀权
Owner SICHUAN DIHON MEDICAL DEV
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