Synthesis method of 3-fluoro-2-trifluoromethyl isonicotinic acid

Abstract

The invention discloses a synthesis method of a fluorine-containing heterocyclic compound medical intermediate. The method comprises the following steps: (1) taking 2-chloro-3-nitropyridine as a raw material to carry out reacting with trifluoromethyltrimethylsilane in dimethyl formamide (DMF) under catalysis of cuprous iodide and 1,10-phenanthroline to obtain 2-trifluoromethyl-3-nitropyridine; (2)carrying out a reflux reaction on the obtained 2-trifluoromethyl-3-nitropyridine in tetrabutylammonium fluoride by using acetonitrile, dimethyl sulfoxide (DMSO) or DMF as a solvent to obtain 2-trifluoromethyl-3-fluoropyridine; and (3) removing hydrogen from the obtained 2-trifluoromethyl-3-fluoropyridine under action of a lithium reagent, and introducing dry carbon dioxide gas to obtain the 3-fluoro-2-trifluoromethyl isonicotinic acid. The method has the advantages of high product yield, high operability, environmental friendliness, high safety factor and the like.

Description

Technical field [0001] The invention relates to the technical field of compound preparation, and more specifically to a method for preparing 3-fluoro-2-trifluoromethylisonicotinic acid. Background technique [0002] Fluorine-containing heterocyclic compounds have a wide range of biological activities and are a large class of important intermediates in the development of new drugs. The synthesis methods and active molecules of these compounds have been very active; and fluorochemistry has always been very active in the industrial system. An important component, it is very important in the research of materials and new drugs, and has broad prospects in the medicine, pesticide and chemical industries. 3-Fluoro-2-trifluoromethylisonicotinic acid is an important intermediate that is currently being developed for new drugs. So far, there are no specific reports in domestic and foreign literature. For 3-fluoro-2-trifluoromethylpyridine, According to the literature reports of similar co...

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Problems solved by technology

[0010] In Route 1, the trifluoromethylation reaction can be carried out, but only about 10% can be carried out, and no further reaction can be carried out. No matter how the reaction conditions are modified, the system cannot be further carried out.

And the price of methyl chlorodifluoroacetate is as high as 2,000 yuan / kg, which is expensive. With such a low yield and such expensive raw materials, this route is not feasible

[0011] In route two, the trifluoromethylation reaction can be carried out, but the boiling point of dibromodifluoromethane is 24.5°C, and the reaction temperature needs to be 120°C, and the reaction cannot be carried out in an autoclave, and the reaction requires anhydrous and oxygen-free Extremely high, the yield is about 30%, plus there is too much dibromodifluoromethane, the price is 400 yuan / kg, the cost is high, and there is no economic value

Dibromodifluoromethane itself has great damage to the ozone layer and high environmental costs, so this route is also worthless

[0012] Route 3: This route is unique, but there are few suppliers of ethyl 2-trifluoromethyl nicotinate, the price is expensive, and the second step of diazotization thermal decomposition process has a greater safety risk, so this route 2 also has defects

[0013] And for the synthesis of 3-fluoro-2-trifluoromethylisonicotinic acid, there is basically no literature report

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