Preparation method of flubendazole

A technology of fluorobenzimidazole and p-fluorobenzoyl chloride, applied in the field of preparation of fluorobenzimidazole, can solve the problems of increased difficulty in industrialization, harsh reaction conditions, and high impurity content, achieves strong development space and competitiveness, and low difficulty in industrialization , the effect of shortening the reaction process

Pending Publication Date: 2022-01-28
SHANDONG GUOBANG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] At present, industrial production mainly uses p-chlorobenzoic acid as raw material to obtain flubendazole after a series of steps of nitration, Friedel-Crafts, ammoniation, reduction, and condensation. Although some patented technologies have made some improvements to the existing production process, but There are still more or less problems, for example: in the patent CN201410354529.3, it is mentioned that platinum carbon is used as a catalyst, hydrogen is used as a reducing agent for reduction, instead of the traditional sodium sulfide reduction, but because it uses hydrogen for reduction, there is defluorination Problems such as carbonyl reduction and other problems lead to high impurity content in the product, and the need to increase the oxidation step, which makes industrialization more difficult and dangerous; patent CN201711123626.1 mentions that ammonia water is used instead of liquid ammonia for substitutional amination reactions, etc. Although the use of liquid ammonia is avoided, there are problems such as a large amount of solvent used, harsh reaction conditions, and long reaction time.

Method used

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  • Preparation method of flubendazole
  • Preparation method of flubendazole
  • Preparation method of flubendazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Take 7.66g (0.0562mol) of zinc chloride and 4.05g (0.2249mol) of water, stir and dissolve; take 40g (0.1874mol) of 4-fluoro-trichloromethylbenzene into a four-necked flask, raise the temperature to 70°C, and control the stirring speed to 300rpm , slowly add zinc chloride aqueous solution dropwise, the dropping time is controlled at about 1h, and the temperature is kept at 70°C during the period, and the temperature is kept for 1h after the dropwise addition; after the reaction is completed, vacuum distillation at -0.09mpa and 40°C 28.00 g (0.1766 mol) of p-fluorobenzoyl chloride was obtained, the gas phase purity was 100%, and the molar yield was 94.23%.

[0029] Take 35.45g (0.1854mol) carbendazim and dissolve it in 80g acetic acid, then put it into a flask together with 28.25g (0.2119mol) anhydrous aluminum chloride, control the stirring speed at 300rpm, cool down to 15°C, add p-fluorobenzene Formyl chloride solution, the dropwise addition time is controlled at about ...

Embodiment 2

[0031] Take 5.11g (0.0375mol) of zinc chloride and 4.05g (0.2249mol) of water, stir and dissolve; take 40g (0.1874mol) of 4-fluoro-trichloromethylbenzene into a four-necked flask, heat up to 70°C, and control the stirring speed to 300rpm , Slowly add zinc chloride aqueous solution dropwise, the dropwise addition time is controlled at about 1h, during which the temperature is kept at 70°C, and the temperature is kept for 1h after the dropwise addition. After the reaction was completed, 23.72g (0.1496mol) of p-fluorobenzoyl chloride was obtained by distillation under reduced pressure at a vacuum degree of -0.09mpa and a temperature of 25°C. The gas phase purity was 100%, and the molar yield was 79.85%.

[0032] Take 30.04g (0.1571mol) carbendazim and dissolve it in 80g acetic acid, then put it into a flask together with 23.94g (0.1795mol) anhydrous aluminum chloride, control the stirring speed at 300rpm, cool down to 15°C, add p-fluorobenzene For the formyl chloride solution, th...

Embodiment 3

[0034] Take 10.22g (0.0750mol) of zinc chloride and 4.05g (0.2249mol) of water, stir and dissolve; take 40g (0.1874mol) of 4-fluoro-trichloromethylbenzene into a four-necked flask, raise the temperature to 70°C, and control the stirring speed to 200rpm , Slowly add zinc chloride aqueous solution dropwise, the dropwise addition time is controlled at about 1h, during which the temperature is kept at 70°C, and the temperature is kept for 1h after the dropwise addition. After the reaction was completed, 28.13 g (0.1774 mol) of p-fluorobenzoyl chloride was obtained by distillation under reduced pressure at a vacuum degree of -0.095 mpa and a temperature of 30° C., with a gas phase purity of 100% and a molar yield of 94.67%.

[0035] Take 35.61g (0.1863mol) carbendazim and dissolve it in 80g acetic acid, then put it into a flask together with 28.38g (0.2129mol) anhydrous aluminum chloride, control the stirring speed at 200rpm, cool down to 15°C, add p-fluorobenzene For the formyl ch...

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Abstract

The invention discloses a preparation method of fluorobendazole, wherein the preparation method comprises the steps: carrying out catalytic hydrolysis on 4-fluoro-trichlorotoluene serving as a raw material through zinc chloride or ferric chloride to obtain p-fluorobenzoyl chloride; and carrying out Friedel-Crafts reaction on the p-fluorobenzoyl chloride, carbendazim (N-(2-benzimidazolyl)-methyl carbamate) dissolved in formic acid or acetic acid and anhydrous aluminum chloride to obtain the flubendazole. Compared with the prior art, the process has the advantages that the reaction process can be remarkably shortened, intermediate loss is reduced, high-pressure hydrogenation and ammoniation are not needed, the reaction conditions are relatively mild, the industrialization difficulty is low, and the process has strong development space and competitive capacity.

Description

technical field [0001] The invention belongs to the technical field of organic chemical industry and also belongs to the technical field of drug synthesis, in particular to a preparation method of flubendazole. Background technique [0002] Flubendazole (flubendazole) chemical name 5-(4-fluorobenzoyl)-benzimidazole-2-oxymethyl formate, is a new broad-spectrum anti-insect drug synthesized in my country in 1983. Inhibits aggregation of microtubules in nematode uptake cells. It has an excellent deworming effect on most nematodes and tapeworms in the gastrointestinal tract of pigs and most nematodes in the gastrointestinal tract of chickens. [0003] At present, industrial production mainly uses p-chlorobenzoic acid as raw material to obtain flubendazole after a series of steps of nitration, Friedel-Crafts, ammoniation, reduction, and condensation. Although some patented technologies have made some improvements to the existing production process, but There are still more or les...

Claims

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Application Information

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Patent Type & AuthorityApplications(China)
IPC IPC(8): C07D235/32
CPCC07D235/32
Inventor刘聪李芳陈士刚刘嘉俊吴青华
OwnerSHANDONG GUOBANG PHARMA