A kind of preparation method of trimethoprim

A technology of trimethoprim and benzyloxy, applied in the field of preparation of anticoccidial drugs, can solve the problem that the supply of dimethyl methoxymethylenemalonate is not large, the large-scale mass production is restricted, and the market share is limited. Not high problems, to achieve the effect of improving production safety, sufficient market supply, and cheap prices

Active Publication Date: 2019-10-18
ZHEJIANG GENEBEST PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, in the domestic market, trimethoprim mainly depends on imports. Due to the high price, the market share is not high. If localization can be realized and the cost of use can be effectively reduced, it will definitely promote the development of this type of veterinary drug and animal husbandry in my country. develop
[0004] The manufacturer of this type of coccidiostat produced on a large scale is mainly U.S. Eli Lilly and Company in the world at present, and the main preparation method of trimethoprim is to use methoxymethylene malonate as a condensation agent, and then at high temperature Conditions (greater than 200°C) for ring closure to obtain products (Italian patent IT1320189 and world patent WO9911602), because the domestic supply of dimethylmethoxymethylenemalonate is not large, and the price is relatively expensive, and there are relatively large irritation, which severely limits the mass production of this method
[0005] After consulting a large number of domestic and foreign related documents and patents, we proposed a synthetic route with independent intellectual property rights to synthesize trimethoprim, using domestic cheap and easy-to-obtain ethyl 2-cyano-3-methoxyacrylate as Condensing agent, and the ring-closing solvent has been improved. Although there is an extra step of hydrolysis and esterification, the yield of each step is high, and they are all conventional operations, with good production prospects.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] A. Preparation of ethyl 3-(3-benzyloxy-4-butylanilino)-2-cyanoacrylate (Ⅲ)

[0023] Add 4-butyl-3-benzyloxyaniline (255g, 1.0mol), ethyl 2-cyano-3-methoxyacrylate (186g, 1.2mol) in the reactor, stir and heat up to 30- React at 35°C, continue to stir and react for 8 hours. After the reaction is completed, the temperature is raised to 65°C under normal pressure to distill off the methanol generated by the reaction. The residue contains about 3-(3-benzyloxy-4-butylanilino)-2- Ethyl cyanoacrylate (Ⅲ) was 337.2g, with a yield of about 89.2%, which could be directly used in the next reaction.

[0024] B. Preparation of 7-benzyloxy-6-butyl-4-cyano-3-cyanoquinoline (Ⅱ)

[0025] Add 3-(3-benzyloxy-4-butylanilino)-2-cyanoacrylate ethyl ester (Ⅲ) (378g, 1.0mol) and triethyl phosphate (3000g) into the reactor, stir well at room temperature Afterwards, the temperature was raised to 120° C., and the stirring reaction was continued for 10 hours. After the reaction was completed, it ...

Embodiment 2

[0031] Other steps are the same as in Example 1, except that the preparation method of 3-(3-benzyloxy-4-butylanilino)-2-cyanoacrylate ethyl ester (Ⅲ) of A step is as follows:

[0032] In the reactor, add 4-butyl-3-benzyloxyaniline (255g, 1.0mol), 2-cyano-3-methoxyethyl acrylate (155g, 1.0mol), stir and heat up to 30- React at 35°C and continue to stir for 4 hours. After the reaction is completed, the temperature is raised to 65°C under normal pressure to distill off the methanol generated by the reaction. The residue contains about 3-(3-benzyloxy-4-butylanilino)-2- Ethyl cyanoacrylate (Ⅲ) was 283.6g, with a yield of about 75.0%, which could be directly used in the next reaction.

Embodiment 3

[0034] Other steps are the same as in Example 1, except that the preparation method of 3-(3-benzyloxy-4-butylanilino)-2-cyanoacrylate ethyl ester (Ⅲ) of A step is as follows:

[0035] Add 4-butyl-3-benzyloxyaniline (255g, 1.0mol), ethyl 2-cyano-3-methoxyacrylate (170.5g, 1.1mol) in the reactor, stir and heat up to 30 React at -35°C, continue to stir and react for 5 hours. After the reaction is completed, the temperature is raised to 65°C under normal pressure to distill off the methanol generated by the reaction. The residue contains about 3-(3-benzyloxy-4-butylanilino)-2 - 308.9 g of ethyl cyanoacrylate (Ⅲ), with a yield of about 81.7%, which can be directly used in the next reaction.

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Abstract

The invention discloses a nequinate preparation method, and relates to a broad-spectrum coccidiostat preparation method which sequentially includes the steps: taking 4-butyl-3-benzyloxy aniline as raw materials; sequentially performing substitution reaction on the 4-butyl-3-benzyloxy aniline and 2-cyano-3-methoxy ethyl acrylate; performing ring closing reaction on the 4-butyl-3-benzyloxy aniline and the 2-cyano-3-methoxy ethyl acrylate; performing hydrolysis and esterification reaction on the 4-butyl-3-benzyloxy aniline and the 2-cyano-3-methoxy ethyl acrylate under the acid condition to prepare nequinate. The invention provides a new synthesis route, raw materials such as methoxy methylene are not used, reactions are mild in condition, simple in process and conventional to operate, and extreme reaction conditions are effectively avoided.

Description

technical field [0001] The invention relates to a preparation method of anticoccidial medicine, in particular to a method for preparing trimethoprim. Background technique [0002] In the raising process of modern animal husbandry, livestock and poultry are easily infected by coccidiosis and are attacked by coccidiosis. In recent years, more and more attention has been paid to anti-coccidia drugs, and anti-coccidia veterinary drugs are also widely used. It is used in animal husbandry, and quinoline anticoccidiostats are an important veterinary drug raw material. Since there are mainly quinoline rings in its molecular structure, it is possible to form different types of anticoccidial raw materials by adding different substituents. Among them, there are mainly butyl hydroxyquinoline (Byqyunilate butyl quinoline), ethoquinoline (Decoquinate decoquinate, decanoquinate, decoquinate), trimethoprazil (Methylbenzoquat methylbenzylquinoline, methylbenzene quinoate, benzyl quinoate) ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/56
Inventor 王金银俞关成何晓均潘明
Owner ZHEJIANG GENEBEST PHARMA
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