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Method for preparing triclabendazole serving as medicine for animal distomiasis

A technology for triclabendazole and flukes, which is applied in the field of preparation of new veterinary drugs, can solve the problems of low reaction yield, complicated preparation process, and "three wastes" to achieve high reaction efficiency, high reaction yield, and low process cost. low effect

Inactive Publication Date: 2017-05-10
杭州洪桥中科基因技术有限公司 +1
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  • Abstract
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Problems solved by technology

[0003] At present, the preparation method of triclabendazole in the prior art has diversity, but there are many problems in the preparation method of triclabendazole in the prior art: high risk, high cost, complicated preparation process, etc.
For example, the intermediate improvement method published in the fourth issue of volume 29 of "Guangzhou Chemistry" uses expensive and dangerous metal sodium; "Technology Research", with 1,2,4-trichlorobenzene as the starting route, after nitration and then high-pressure ammoniation, and the reaction temperature is 190°C, and a high pressure of 4MPa is used in the reaction, which is relatively dangerous; Another example is "Synthesis of the anti-hepatic fluke drug triclabendazole" published in the ninth issue of "Chinese Journal of Pharmaceutical Industry" in 2001. It also uses 1,2,4-trichlorobenzene as the starting material, and high-pressure equipment is used in the reaction , unsafe, and the methyl iodide used in the preparation of finished products is expensive, and dimethyl sulfate is more toxic
In addition, in the process of preparing triclabendazole in the prior art, the etherification reaction steps all use potassium hydroxide as an alkaline raw material to react with phenolic compounds to form a phenoxide intermediate, and then carry out etherification reaction, the reaction step It is cumbersome, and the reaction time is long, correspondingly, there are many side reactions, and the reaction yield is low, which is far from meeting the needs of current scientific research and actual production
The nitro reduction step in the prior art is mainly through the iron powder reduction method, the hydrazine hydrate method, and the catalytic hydrogenation method. Due to the large amount of iron powder used in the iron powder reduction method, the production cost is high, and more "three wastes" are produced; hydrazine hydrate The products produced by the reduction method are of good quality, but hydrazine hydrate is expensive, costly, highly toxic, and has high requirements for production equipment
Although the catalytic hydrogenation method has high product purity and simple process, it is easy to cause dehalogenation due to poor control of the reduction conditions, resulting in low product yield. At the same time, the cost of the noble metal catalyst used in catalytic hydrogenation is high

Method used

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  • Method for preparing triclabendazole serving as medicine for animal distomiasis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] (1) Preparation of potassium methoxide

[0020] Add 200mL of petroleum ether (pre-dried) and 46.8g (1.2mol) of potassium metal into a 2L reactor, add about 200mL of anhydrous methanol dropwise under stirring, and the dropping speed depends on the solution temperature and H 2 Depends on the amount released. Reflux for 0.5 h after the addition, and cool to room temperature to obtain a white slurry potassium methoxide solution for later use.

[0021] (2) Preparation of 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline

[0022] Under the microwave radiation condition of 1000W, the potassium methoxide solution prepared in step (1) (1.2mol of potassium methoxide), 2,3-dichlorophenol (1mol), 3,4-dichloro-5-nitroaniline (0.9 mol) and 20ml of DMF solvent into the reactor, 2,3-dichlorophenol, 3,4-dichloro-5-nitroaniline, sodium alkoxide or potassium alkoxide solution were fully stirred and mixed in the reactor, under nitrogen atmosphere , heated to 155°C for full reaction. After...

Embodiment 2

[0030] (1) Preparation of potassium methoxide

[0031] Add 200mL of petroleum ether (pre-dried) and 42.9g (1.1mol) of metal potassium into a 2L reactor, add about 200mL of anhydrous methanol dropwise under stirring, and the dropping speed depends on the solution temperature and H 2 Depends on the amount released. Reflux for 0.5 h after the addition, and cool to room temperature to obtain a white slurry potassium methoxide solution for later use.

[0032] (2) Preparation of 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline

[0033] Under the microwave radiation condition of 1000W, the potassium methoxide solution prepared in step (1) (potassium methoxide 1.1mol), 2,3-dichlorophenol (1mol), 3,4-dichloro-5-nitroaniline (0.9 mol) and 20ml of DMF solvent into the reactor, 2,3-dichlorophenol, 3,4-dichloro-5-nitroaniline, sodium alkoxide or potassium alkoxide solution were fully stirred and mixed in the reactor, under nitrogen atmosphere , heated to 150°C for full reaction. After fu...

Embodiment 3

[0041] The reaction conditions of other step 1 are the same as those of Example 2, only the etherification reaction of step 2 is reacted at a temperature of 160°C, the reaction time is 20min, the reaction raw materials are completely reacted, and the yellow solid 4-chloro- 5-(2,3-dichlorophenoxy)-2-nitroaniline 323.7g, yield 97.5%, HPLC purity 98.9%.

[0042] (3) Preparation of 4-chloro-5-(2,3-dichlorophenoxy)-1,2-phenylenediamine

[0043] Add 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (1 mol), 1 mol of 10% Pd / C catalyst and 1.6 mol of sodium borohydride and 100 ml of anhydrous toluene into the reactor , heated to reflux, fully reacted for 2 hours, cooled to room temperature, filtered, concentrated under reduced pressure to recover the reaction solvent, added petroleum ether, and crystallized to obtain 4-chloro-5-(2,3-dichlorophenoxy)-1 , 284.2g of 2-phenylenediamine, yield 94.1%, purity 99.0%.

[0044] (4) Preparation of 4-chloro-5-(2,3-dichlorophenoxy)-1H-benzimidazol...

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Abstract

The invention relates to a method for preparing triclabendazole serving as a medicine for animal distomiasis. 2,3-dichlorophenol and 3,4-dichloro-5-nitroaniline are used as raw materials and subjected to etherification, reduction reaction, cyclization and methylation to obtain triclabendazole. In the step of etherification, high-alkalinity potassium ethoxide or potassium methoxide is adopted for replacement of potassium hydroxide in the prior art while microwave irradiation heating is performed, and consequently step-by-step preparation of potassium phenoxide is avoided, phase transfer catalysts are not required, 'one-step' etherification is realized, etherification yield is up to 96% or above, product purity reaches 98% or above, and demands of industrial application are met.

Description

technical field [0001] The invention relates to a preparation method of a novel veterinary drug, in particular to a preparation method of triclabendazole, an animal liver fluke drug. Background technique [0002] Triclosendazole, Chinese alias Ganzhijing, chemical name 5-chloro-6-(2,3-dichlorophenoxy)-2-methylthiobenzimidazole, white to off-white powder crystal, melting point 174~178℃. Triclobendazole is a high-efficiency anti-liver fluke drug, which is highly effective against adults and larvae of bovine and sheep liver flukes, and is superior to nitrophenol. It is safe to take orally, has few side effects, and is well tolerated. It is the drug of choice for the treatment of liver fluke, and it can be taken together with thiabendazole, benthiamidazole, and levamisole. [0003] At present, the preparation method of triclabendazole in the prior art has diversity, but there are many problems in the preparation method of triclabendazole in the prior art: high risk, high cost,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/28
CPCC07D235/28
Inventor 舒建洪杨芳金甲张宇王晗周泉丽
Owner 杭州洪桥中科基因技术有限公司
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