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Preparation method of 4-trifluoromethyl nicotinic acid

A technology of trifluoromethylnicotinic acid and synthetic methods, applied in the direction of organic chemistry, etc., can solve the problems of unsuitability for industrial production, long route, low yield, etc., and achieve the effects of low equipment requirements, simple reaction operation, and mild conditions

Active Publication Date: 2020-08-25
ANHUI JINGHE IND
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] After that, the Chinese patent CN109232407A and Lai Liwei et al. (Synthesis of 4-trifluoromethylnicotinic acid [J]. Modern Pesticides, 2014, 13(03): 25-27.) optimized the above method, through cyclization, Chlorination, hydrolysis of cyano group into amide, dechlorination by catalytic hydrogenolysis, and finally hydrolysis to obtain 4-trifluoromethylnicotinic acid. Although this method can avoid the reduction of cyano group, the route is relatively long, and the yield during chlorination Low, not suitable for industrial production

Method used

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  • Preparation method of 4-trifluoromethyl nicotinic acid
  • Preparation method of 4-trifluoromethyl nicotinic acid
  • Preparation method of 4-trifluoromethyl nicotinic acid

Examples

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Embodiment 1

[0038] (1) N Preparation of -(2-methoxycarbonylvinyl)-4,4,4-trifluoro-3-one-1-butenylamine:

[0039]Methyl acrylate (8.00g, 92.93mmol) was dissolved with 50mL of toluene and 50mL of water, palladium chloride (494.35mg, 2.79mmol) and copper chloride (1.50g, 11.15mmol) were added, and oxygen was introduced into the system, and After the completion of the reaction was monitored by gas chromatography, the system was filtered, and the filtrate was slowly added dropwise to 4-amino-1,1,1-trifluoro-3-buten-2-one (10.00g, 71.9 mmol), and the system was heated and refluxed to react After 4.5 hours, when TLC monitors that the reaction is no longer in progress, adjust the pH of the system to 1.2 with 1mol / L HCl after the reaction is completed, and a large amount of solids are precipitated in the system, filtered by suction, and dried (moisture content to 0.5%) to obtain a light yellow solid product N -(2-methoxycarbonylvinyl)-4,4,4-trifluoro-3-keto-1-butenamine (12.84 g, yield: 80%).

...

Embodiment 2

[0043] On the basis of Example 1, methyl 3-oxopropionate is prepared with methyl acrylate, and then methyl 3-oxopropionate is prepared N -(2-methoxycarbonylvinyl)-4,4,4-trifluoro-3-ketone-1-butenamine, the reaction conditions are: dissolving methyl acrylate with toluene and water, adding catalyst and oxidizing agent, After the reaction is finished, remove the solid by filtration, slowly add the above filtrate dropwise to 4-amino-1,1,1-trifluoro-3-buten-2-ketone, after adding the raw materials, the system is heated and refluxed for 4.5 hours, and the reaction After the end, adjust the pH of the mixed solution to 1.5, and a light yellow solid precipitates out, which is the product N -(2-Methoxycarbonylethenyl)-4,4,4-trifluoro-3-one-1-butenamine.

Embodiment 3

[0045] On the basis of embodiment 1 or 2, N -(2-Methoxycarbonylvinyl)-4,4,4-trifluoro-3-ketone-1-butenamine is hydrolyzed by one-pot ring closure under the action of alkali to obtain 4-trifluoromethylnicotinic acid, The reaction conditions are: sodium methoxide, N -(2-Methoxycarbonylvinyl)-4,4,4-trifluoro-3-keto-1-butenamine and anhydrous methanol were added to the reaction flask in turn, and stirred at room temperature until sodium methoxide and N After -(2-methoxycarbonylvinyl)-4,4,4-trifluoro-3-keto-1-butenamine is completely dissolved, the system is heated and refluxed for 6 hours, cooled to room temperature, and sodium hydroxide aqueous solution is added, Heating and hydrolysis, after the reaction is finished, adjust the pH of the solution to 3, a light yellow solid precipitates out, filter, and dry the filter cake to obtain the product which is 4-trifluoromethylnicotinic acid.

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Abstract

The invention relates to a synthetic method of 4-trifluoromethyl nicotinic acid. The method is characterized by comprising the following steps: (1) in a solvent A, enabling methyl acrylate to react for 30-60 minutes at 25-90 DEG C under the action of a catalyst and an oxidizing agent, with the molar ratio of methyl acrylate to the catalyst to the oxidizing agent being 1:(0.01-0.05):(1-1.5), so asto prepare methyl 3-oxopropionate; (2) in a solvent B, controlling the mole ratio of the methyl 3-oxopropionate to 4-amino-1,1,1-trifluoro-3-buten-2-one to be (1-1.5):1, reacting at 25-90 DEG C for 30-60 min to prepare N-(2-methoxycarbonyl vinyl)-4,4,4-trifluoro-3-one-1-butenylamine, then adding an alkali, with the mole ratio of the N-(2-methoxycarbonyl vinyl)-4,4,4-trifluoro-3-one-1-butenylamineto the alkali being 1:1-5, performing ring closing hydrolysis at 25-90 DEG C under the action of the alkali for 30-60 min, subjecting the reaction product to rectification separation after the reaction is finished to obtain a 4-trifluoromethyl nicotinic acid finished product. The method has the advantages that the adopted raw materials are cheap and easy to obtain, the synthesis method is simple to operate, reaction conditions are mild, requirements on equipment are low, and the method is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of chemical drug preparation, relates to the field of preparation of a pharmaceutical intermediate, in particular to a preparation method of 4-trifluoromethyl nicotinic acid. Background technique [0002] 4-Trifluoromethylnicotinic acid is an aromatic compound containing trifluoromethyl and pyridine rings. Because of its unique biological activity, it is widely used in the development of new pesticides and pharmaceutical intermediates. Flonicamid is a pyridine amide insecticide developed by Japan Ishihara Sangyo Co., Ltd. It can effectively control piercing-sucking mouthparts pests on crops, especially for aphids. Its mechanism of action is novel, and it has no cross-resistance with other neonicotinoid insecticides currently on the market, and has low toxicity to bees. 4-Trifluoromethylnicotinic acid is a key intermediate in the synthesis of flonicamid, and it is also the biggest difficulty in the development of flon...

Claims

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Application Information

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IPC IPC(8): C07D213/80C07D213/803
CPCC07D213/80C07D213/803Y02P20/582
Inventor 杨志健徐如健吕祖鹏罗艺飞
Owner ANHUI JINGHE IND
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