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Preparation method of fenbendazole

A technology for the preparation of fenbendazole, which is applied in the field of preparation of fenbendazole, can solve the problems of high production cost and achieve the effects of reduced production cost, sufficient reaction and mild reaction conditions

Active Publication Date: 2019-03-15
JIANGSU BAOZONG & BAODA PHARMACHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the stage of the cyclization reaction, S-methylisothiourea formate or O-methyl isothiourea formate is currently used as the cyclizing agent, and the production cost is relatively high.

Method used

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  • Preparation method of fenbendazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] (1) Preparation of methyl cyanamide formate aqueous solution

[0017] 44.0g of cyanamide aqueous solution is cooled to 0-5°C, and 10.93g of methyl chloroformate and 16.03g of sodium hydroxide solution (30%) are added dropwise under stirring, and the temperature of the dropping process is controlled at 0-5°C. The materials drop off at the same time or the methyl chloroformate drops slightly earlier than the sodium hydroxide solution. After both materials were added dropwise, stir at 0-5°C for 2 hours to obtain 70.91 g of an aqueous solution of methyl cyanamide with a concentration of 14.0%, and store it at a low temperature around 0°C for future use.

[0018] (2) Intermediate 1 (2,4-dibromonitrobenzene)

[0019] Dissolve 24.5g of m-dibromobenzene in 49.0g of concentrated sulfuric acid (98%) at room temperature, cool to 0-5°C, add 9.80g of nitric acid (68%) dropwise, and control the temperature at 0-5°C during the dropping process. After the addition was complete, stir ...

Embodiment 2

[0029] (1) Preparation of methyl cyanamide formate aqueous solution

[0030] 220.0g of cyanamide aqueous solution was cooled to 0-5°C, and 54.65g of methyl chloroformate and 80.15g of sodium hydroxide solution (30%) were added dropwise under stirring, and the temperature of the dropping process was controlled at 0-5°C. The materials drop off at the same time or the methyl chloroformate drops slightly earlier than the sodium hydroxide solution. After the addition of the two materials was completed, stir at 0-5°C for 2 hours to obtain 355.0 g of an aqueous solution of methyl cyanamide with a concentration of 14.0%, and store it at a low temperature of about 0°C for future use.

[0031] (2) Intermediate 1 (2,4-dibromonitrobenzene)

[0032] Dissolve 122.5g m-dibromobenzene in 245.0g concentrated sulfuric acid (98%) at room temperature, cool to 0-5°C, add 49.0g nitric acid (68%) dropwise, control the temperature at 0-5°C during the dropwise addition, After the addition was comple...

Embodiment 3

[0042] (1) Preparation of methyl cyanamide formate aqueous solution

[0043] 440.0g of cyanamide aqueous solution is cooled to 0-5°C, and 109.3g of methyl chloroformate and 160.3g of sodium hydroxide solution (30%) are added dropwise under stirring, and the temperature of the dropping process is controlled at 0-5°C. The materials drop off at the same time or the methyl chloroformate drops slightly earlier than the sodium hydroxide solution. After both materials were added dropwise, stir at 0-5°C for 2 hours to obtain 708.0 g of methyl cyanamide aqueous solution with a concentration of 14.0%, and store it at a low temperature of about 0°C for future use.

[0044] (2) Intermediate 1 (2,4-dibromonitrobenzene)

[0045] Dissolve 245.0g m-dibromobenzene in 490.0g concentrated sulfuric acid (98%) at room temperature, cool to 0-5°C, add 98.0g nitric acid (68%) dropwise, control the temperature at 0-5°C during the dropping process, and drop After the addition was complete, stir at 5-...

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Abstract

The invention discloses a preparation method of fenbendazole. The preparation method of fenbendazole is characterized by (1) taking m-dibromobenzene as a starting material, and nitrating a nitric acid / sulfuric acid system to prepare an intermediate 1(2,4-dibromonitrobenzene); (2) using the intermediate 1 as a raw material, and carrying out an ammoniation reaction with an ammonia methanol solutionto prepare an intermediate 2(5-bromo-2-nitroaniline); (3) taking the intermediate 2 and a sodium thiophenolate solution as raw materials, and carrying out condensation reaction to prepare an intermediate 3(4-phenylthio-2-nitroaniline); (4) carrying out hydrogenation reduction on the intermediate 3 through the catalysis of palladium charcoal to form intermediate 4(4-phenylthio-1,2-phenylenediamine); (5) carrying out cyclization reaction on the intermediate 4 and a methyl cyanamide aqueous solution to form the product, namely fenbendazole. The method is clean and environmentally friendly and lowin production cost, the purity of the product is more than 99.5%, and the yield is not less than 84.0%.

Description

technical field [0001] The invention relates to the preparation of fenbendazole and an intermediate thereof, in particular to a preparation method of fenbendazole. Background technique [0002] Fenbendazole, also known as benzimidazole, chemically named 5-phenylthiobenzimidazole-2-methyl carbamate, is a benzimidazole anthelmintic. It not only has high anthelmintic activity against adults and larvae of gastrointestinal nematodes, but also has good effects on Dictyocaulus, Fasciola and tapeworm, and has a strong effect on killing insect eggs. It has the advantages of maggot spectrum light, low toxicity, good tolerance, wide safety range and good palatability. [0003] At present, m-dichlorobenzene is often used as the starting material when selecting synthetic routes at home and abroad. Liquid ammonia should be selected as the ammoniating reagent when the ammoniation reaction is carried out. The ammoniation step is a high-risk reaction. In the reaction step of producing phe...

Claims

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Application Information

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IPC IPC(8): C07D235/32
CPCC07D235/32Y02P20/584
Inventor 陈荣张智红林楠
Owner JIANGSU BAOZONG & BAODA PHARMACHEM
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