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Preparation method of anticoccidial drug diclazuril

A technology of diclazuril and anticoccidiostats, applied in the field of drug synthesis, to achieve the effect of increasing yield

Active Publication Date: 2021-03-16
CHANGZHOU YABANG QH PHARMACHEM +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The object of the present invention is to provide a preparation method of the anticoccidial drug diclazuril, the method is simple in process, easy to operate, solves the odor generation of decarboxylation reaction in the production process, is beneficial to environmental protection, and is suitable for industrial production

Method used

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  • Preparation method of anticoccidial drug diclazuril

Examples

Experimental program
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Effect test

preparation example Construction

[0021] Preparation of 3,4,5-trichloronitrobenzene

[0022] Put 62.5mL of concentrated sulfuric acid into a 250mL four-necked flask, and add 11.5g of sodium nitrite under stirring. Heat up to 70°C and stir for 10 minutes, then cool down to 55°C, slowly add 31.2 g of 2,6-dichloro-4-nitroaniline, keep warm for 20 minutes, then cool down to 5°C. Add 40 mL of acetic acid dropwise and keep warm for 30 min to prepare a diazo solution.

[0023] In another 250 mL four-necked flask, 125 mL of 36.5% hydrochloric acid and 15 g of cuprous chloride were added, and after stirring for 15 min, the above diazo solution was slowly added dropwise. During the dropping process, the temperature is controlled below 25°C. After the dropwise addition was completed, the temperature was raised to 70° C. and kept for 1 hour. After the heat preservation is over, cool down to normal temperature and filter, and wash with 1% lye. The brown crystal obtained by filtration was recrystallized with ethanol, th...

Embodiment 1

[0025] Preparation of 2,6-dichloro-α-(4-chlorophenyl)-4-nitrophenylacetonitrile

[0026] 170 mL of 2-butanone, 55 g of 3,4,5-trichloronitrobenzene, and 40.5 g of p-chlorophenylacetonitrile were put into a 500 mL four-necked flask, and the temperature was raised to 50°C. Add 50% sodium hydroxide solution dropwise, and keep the reaction for 2 hours after dropping. After the heat preservation was completed, the temperature was lowered to 25° C. and hydrochloric acid was added dropwise to adjust the pH=2. After adding 70mL of water, the temperature was raised to 50°C and the layers were separated. The water layer was removed, and the organic layer was distilled under reduced pressure to collect 2-butanone for recycling. Add methanol and cool down to 20° C., and filter to obtain 74.7 g of light yellow powder of the condensate with a yield of 90% and a content of 99.59% (HPLC).

[0027] Preparation of 2,6-dichloro-α-(4-chlorophenyl)-4-aminophenylacetonitrile

[0028] Into a 500 ...

Embodiment 2

[0032] Preparation of 2,6-dichloro-α-(4-chlorophenyl)-4-nitrophenylacetonitrile

[0033] 200 mL of 2-butanone, 55 g of 3,4,5-trichloronitrobenzene, and 42.4 g of p-chlorophenylacetonitrile were put into a 500 mL four-necked flask, and the temperature was raised to 50°C. Add 30% sodium hydroxide solution dropwise, and keep the reaction for 3 hours after dropping. After the heat preservation was completed, the temperature was lowered to 30° C. and hydrochloric acid was added dropwise to adjust the pH to 1. After adding 55mL of water, the temperature was raised to 55°C and the layers were separated. The water layer was removed, and the organic layer was distilled under reduced pressure to collect 2-butanone for recycling. Add methanol and cool down to 20° C., and filter to obtain 73.04 g of light yellow powder of the condensate with a yield of 88% and a content of 99.3% (HPLC).

[0034] Preparation of 2,6-dichloro-α-(4-chlorophenyl)-4-aminophenylacetonitrile

[0035] Into a 5...

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Abstract

The invention discloses a preparation method of an anticoccidial drug Diclazuril. The method takes 3,4,5-trichloronitrobenzene as a raw material and the 3,4,5-trichloronitrobenzene and 4-chlorobenzylcyanide are subjected to condensation reaction to generate 2,6-dichloro-alpha-(4-chlorobenzyl)-4-nitrophenylacetonitrile; enabling a condensate and hydrazine hydrate to be subjected to reduction to generate 2,6-dichloro-alpha-(4-chlorobenzyl)-4-aminophenylacetonitrile, enabling a reduzate and malonyl ethyl dicarbamate to be subjected to diazo, coupling, cyclization, hydrolysis and decarboxylationone-pot reaction to generate the Diclazuril. The method disclosed by the invention has a simple technology and is easy to operate; the environment protection problem caused by the fact that the odor of thioglycolic acid is great in a decarboxylation process of the Diclazuril is solved; meanwhile, the yield is improved and the total yield of the Diclazuril synthesized by taking 2,6-dichloro p-nitroaniline as the raw material is 43.8 percent, so that the preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of anticoccidial drug diclazuril, which belongs to the technical field of drug synthesis. Background technique [0002] Diclazuril, also known as chlorazine benzylnitrile, chemical name: 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dichloro Substitute-1,2,4-triazin-2(3H)-yl)phenylacetonitrile, white or off-white powder, slightly soluble in DMF and tetrahydrofuran, insoluble in water or ethanol. Diclazuril is a non-ionic anticoccidial drug, which was first developed and put into the market by the Belgian Janssen Company in 1992. It is a safe, efficient, broad-spectrum, and residue-free new anticoccidial drug. Its structural formula is as follows: [0003] [0004] At present, there are few domestic reports on the synthesis methods of diclazuril. According to reports, diclazuril was prepared from 2,6-dichloro-p-nitroaniline through diazotization, condensation, reduction, and ethyl cyanoacetamide re...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D253/075
CPCC07D253/075
Inventor 张建峰郑爱华朱云兵刘永林潘如龙谢琪
Owner CHANGZHOU YABANG QH PHARMACHEM
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