A method for preparing 2-[phenyl]-1,2,4-triazine-3,5(2h,4h)-dione compounds

A technology of compounds and diketones, which is applied in the field of veterinary medicine, can solve the problems of high unit consumption of raw materials, low product purity, and low yield, and achieve the effects of shortening the reaction steps, improving economic benefits, and reducing emissions

Active Publication Date: 2021-09-24
SHANDONG GUOBANG PHARMA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesis process of the existing diclazuril and samizuril triazine rings is to add diethoxycarbonyl malonamide to the aniline compound under acetic acid solvent, add dropwise sodium nitrite aqueous solution to carry out diazonium, and then keep warm for coupling. Cyclization under the condition of sodium acetate, adding hydrochloric acid for hydrolysis, final separation for decarboxylation, plus the preparation of a cyclizing agent, a total of six steps of reaction, in the conventional synthesis process of 1,2,4 triazine ring of diclazuril and samizuril The cyclizing agent diethoxycarbonyl malonamide used in the method is very easy to hydrolyze and the yield is low, only 50%, which leads to a high unit consumption of raw materials, resulting in a large amount of intermediate in the process of diazo, coupling, and cyclization under conventional conditions. In the end, the purity of the product is not high, and the yield is low. The yield of the existing technical means in the triazine ring synthesis process is only 40%, and it needs complicated refining means to obtain qualified products, which is not suitable for industrial production.

Method used

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  • A method for preparing 2-[phenyl]-1,2,4-triazine-3,5(2h,4h)-dione compounds
  • A method for preparing 2-[phenyl]-1,2,4-triazine-3,5(2h,4h)-dione compounds
  • A method for preparing 2-[phenyl]-1,2,4-triazine-3,5(2h,4h)-dione compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (1) Add 720g of toluene to a 1000ml four-necked bottle, add 120g of dichloroacetyl chloride, 25.89g of 0.3 equivalent of sodium carbonate, and accurately drop 79.79g of 1.1 equivalent of molten ethyl carbamate using a peristaltic pump for 0.5h. Insulate at 65°C, monitor the end of the reaction by liquid phase monitoring, and isolate (2,2-dichloroacetyl) ethyl carbamate 156.27g after the end of the reaction, with a yield of 93.20% and a purity of 97.13%;

[0030] (2) Add 500g of N-(4-(4-amino-2-methylphenoxy)phenyl)acetamide into a 10000ml four-necked flask, add 2250g of hydrochloric acid, cool down to 5-15°C, and add 1.05 equivalents dropwise 20wt% sodium nitrite aqueous solution 706.61g, after 0.5 hours of dropping, keep warm for 1h and the reaction is completed, add 3.5 equivalents of 20wt% sodium bisulfite aqueous solution 3552.44g to a 10000ml four-neck flask and heat up to 90°C, and the above diazotized feed solution Use a peristaltic pump to add dropwise to the aq...

Embodiment 2

[0033] (1) Add 720g of p-xylene to a 1000ml four-necked bottle, add 120g of dichloroacetyl chloride, 47.46g of 0.55 equivalent of sodium carbonate, and accurately drop 79.79g of 1.1 equivalent of molten ethyl carbamate using a peristaltic pump, dropwise adding 0.5 h, keep warm at 65°C, monitor the end of the reaction by liquid phase monitoring, and isolate (2,2-dichloroacetyl) ethyl carbamate 159.41g after the end of the reaction, with a purity of 96.25% and a yield of 94.21%;

[0034] (2) Add 500g of N-(4-(4-amino-2-methylphenoxy)phenyl)acetamide into a 10000ml four-necked flask, add 2250g of hydrochloric acid, cool down to 5-15°C, and add 1.05 equivalents dropwise 20wt% sodium nitrite aqueous solution 706.61g for 0.5 hours, after the dropwise addition, keep warm for 1h and the reaction is completed. Add 3.5 equivalents of 20wt% sodium bisulfite aqueous solution 3552.44g to a 10000ml four-neck flask and heat up to 90°C. The solution was added dropwise to the aqueous solution ...

Embodiment 3

[0037] (1) Add 720g of m-xylene to a 1000ml four-necked bottle, add 120g of dichloroacetyl chloride, 47.46g of 0.55 equivalent of sodium carbonate, and accurately drop 79.79g of 1.1 equivalent of molten ethyl carbamate using a peristaltic pump, drop 0.5 h, keep warm at 65°C, monitor the end of the reaction by liquid phase monitoring, and isolate (2,2-dichloroacetyl) ethyl carbamate 156.84g after the end of the reaction, with a purity of 95.71% and a yield of 92.17%;

[0038] (2) Add 500g of N-(4-(4-amino-2-methylphenoxy)phenyl)acetamide into a 10000ml four-necked flask, add 2250g of hydrochloric acid, cool down to 5-15°C, and add 1.05 equivalents dropwise 20wt% sodium nitrite aqueous solution 706.61g for 0.5 hours, after the dropwise addition, keep warm for 1h and the reaction is completed. Add 3.5 equivalents of 20wt% sodium bisulfite aqueous solution 3552.44g to a 10000ml four-neck flask and heat up to 90°C. The solution was added dropwise to the aqueous solution of sodium b...

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Abstract

The present invention relates to the technical field of veterinary medicine, in particular to a method for preparing 2-[phenyl]-1,2,4-triazine-3,5(2H,4H)-diketone compounds, comprising the following steps: (1 ) using dichloroacetyl chloride and ethyl carbamate as reaction raw materials, adding an acid-binding agent and a reaction solvent, heating and undergoing heat preservation reaction, distillation and rectification to obtain (2,2-dichloroacetyl) ethyl carbamate; (2) adding the aniline compound shown in structural formula 2 into hydrochloric acid, after being treated with diazotization reagent, reducing reagent, and acid precipitation reagent, and then washing with neutralization water to obtain the phenylhydrazine compound shown in structural formula 3; (3) Add phenylhydrazine compounds and (2,2-dichloroacetyl) ethyl carbamate into anhydrous acetic acid, add reaction aids, heat until the reaction is complete, and then undergo distillation to obtain 2-[phenyl]-1, 2,4‑triazine‑3,5(2H,4H)‑diones. By using the method, the overall reaction steps are shortened, the economic benefit is improved, and the discharge of three wastes is reduced.

Description

technical field [0001] The invention relates to the technical field of veterinary medicine, in particular to a method for preparing 2-[phenyl]-1,2,4-triazine-3,5(2H,4H)-dione compounds. Background technique [0002] The triazine ring veterinary drugs salizuril and diclazuril are broad-spectrum anticoccidiostats with high efficiency and low toxicity. It can be used clinically for the control of poultry coccidiosis. Existing anticoccidial drugs such as toltrazuril, diclazuril, and samizuril generally have good anticoccidial properties, diclazuril has a lower dosage, and samizuril has a lower The drug resistance makes it widely used in the control of poultry coccidiosis. The synthesis process of the existing diclazuril and samizuril triazine rings is to add diethoxycarbonyl malonamide to the aniline compound under acetic acid solvent, add dropwise sodium nitrite aqueous solution to carry out diazonium, and then keep warm for coupling. Cyclization under the condition of sodiu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D253/075A61P33/02
CPCA61P33/02C07D253/075
Inventor 王兴国廖仕学李琦斌刘聪杨志豪
Owner SHANDONG GUOBANG PHARMA
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