CN-122010831-A - Preparation method of 4-trifluoromethyl nicotinic acid

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of 4-trifluoromethyl nicotinic acid. The invention takes 4, 4-trifluoro-2-butynal and beta-enamine ester as raw materials, and 4-trifluoromethyl nicotinic acid ester intermediate is generated through cyclization reaction under the action of catalyst, and then 4-trifluoromethyl nicotinic acid is obtained through hydrolysis reaction. The method has the advantages of easily available raw materials, mild reaction conditions, high atom economy, excellent yield and the like, is suitable for industrial production, and solves the problems of complex synthesis steps and high cost of the 4-trifluoromethyl nicotinic acid in the prior art.

Inventors

• ZHU KAIMING
• SONG YING
• LIANG YUMENG
• HE BIN
• ZHENG ZHENZHEN
• QIU HUIQIANG
• LIU DIYU
• TONG ZHENPING

Assignees

• 衢州凯沃化工有限公司

Dates

Publication Date

20260512

Application Date

20260202

Claims (9)

1. 1. The preparation method of the 4-trifluoromethyl nicotinic acid is characterized by comprising the following steps of: Taking 4, 4-trifluoro-2-butynal and beta-enamine ester shown in formula 1 as raw materials, carrying out alkynyl cyclization reaction on the 4, 4-trifluoro-2-butynal and the beta-enamine ester shown in formula 1 under the action of a catalyst to obtain a 4-trifluoromethyl nicotinic acid ester intermediate, wherein the catalyst is Lewis acid; the 4-trifluoromethyl nicotinic acid ester intermediate is subjected to alkaline hydrolysis reaction to obtain 4-trifluoromethyl nicotinic acid, and the specific synthetic route is as follows: ; Wherein R 1 is an alkyl group of C 1 ～C 4 .
2. 2. The method for preparing 4-trifluoromethyl nicotinic acid according to claim 1, wherein R 1 is methyl, ethyl, isopropyl or tert-butyl.
3. 3. The method for preparing 4-trifluoromethyl nicotinic acid according to claim 1 or 2, wherein the method for preparing 4-trifluoromethyl nicotinic acid is as follows: Mixing 4, 4-trifluoro-2-butynal, beta-enamine ester shown in a formula 1, a catalyst and a first solvent, and carrying out alkynyl cyclization reaction under a reflux condition to obtain a 4-trifluoromethyl nicotinic acid ester intermediate; And mixing the 4-trifluoromethyl nicotinic acid ester intermediate, a second solvent and an alkali solution, and performing alkaline hydrolysis reaction to obtain the 4-trifluoromethyl nicotinic acid.
4. 4. The method for producing 4-trifluoromethylnicotinic acid according to claim 3, wherein the molar ratio of 4, 4-trifluoro-2-butynal to beta-enamine ester represented by formula 1 is 1:1 to 3; the molar quantity of the catalyst is 10% -20% of the molar quantity of the 4, 4-trifluoro-2-butynal.
5. 5. The method for producing 4-trifluoromethylnicotinic acid according to claim 4, wherein the beta-enamine ester represented by formula 1 is at least one of ethyl 3-aminoacrylate ‌, isopropyl 3-aminoacrylate, t-butyl 3-aminoacrylate, and methyl 3-aminoacrylate.
6. 6. The method for preparing 4-trifluoromethyl nicotinic acid according to claim 4, wherein the catalyst is ZnBr 2 、ZnCl 2 or ZnI 2 .
7. 7. The method for preparing 4-trifluoromethyl nicotinic acid according to claim 3, wherein the alkaline solution is an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous lithium hydroxide solution, an aqueous cesium hydroxide solution, an aqueous sodium carbonate solution or an aqueous potassium carbonate solution, and the mass concentration of the alkaline solution is 10wt% to 30wt%.
8. 8. The method for preparing 4-trifluoromethyl nicotinic acid according to claim 3, wherein the molar ratio of the base to the 4-trifluoromethyl nicotinic acid ester intermediate is 1-6:1.
9. 9. The method for preparing 4-trifluoromethyl nicotinic acid according to claim 3, wherein the first solvent is toluene, 1, 4-dioxane, xylene, ethanol, N-dimethylformamide or dimethyl sulfoxide, and the second solvent is an alcohol solvent.

Description

Preparation method of 4-trifluoromethyl nicotinic acid Technical Field The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of 4-trifluoromethyl nicotinic acid. Background 4-Trifluoromethyl nicotinic acid is a key intermediate for synthesizing various important compounds, and has irreplaceable application value in the fields of pesticides and medicines. In the field of pesticides, 4-trifluoromethyl nicotinic acid is a core synthetic raw material of a high-efficiency pesticide flonicamid, and the pesticide can realize quick antifeedant by interfering insect nerve conduction and has obvious control effect on sucking pests such as aphids and the like. In the medical field, 4-trifluoromethyl nicotinic acid as a synthesis precursor of an HCV NS5B polymerase inhibitor and a CRAC channel regulator has potential application prospect in antiviral and cardiovascular drug development. At present, the preparation methods of 4-trifluoromethyl nicotinic acid are mainly divided into two types, namely a pyridine ring direct trifluoromethyl method and a trifluoromethyl building block method. Specifically, the method comprises a trifluoro-acetoacetate method, a trifluoro-acetyl chloride/trifluoro-acetic anhydride method, a direct cyanation method and a direct carbonylation method. The method for synthesizing the ethyl trifluoroacetoacetate takes ethyl trifluoroacetoacetate and cyanoacetamide as starting materials and synthesizes a target product through four steps of reactions of cyclization, chlorination, hydrogenolysis and hydrolysis. Wherein, the key chlorination step in the ethyl trifluoroacetoacetate method needs to use highly toxic phosphorus oxychloride, thereby generating phosphorus-containing wastewater, having serious environmental pollution and low total yield of only 38.6 percent. The trifluoroacetyl chloride/trifluoroacetic anhydride method uses trifluoroacetyl chloride or trifluoroacetic anhydride having strong corrosiveness as a raw material. In the ammonification process, byproducts such as 3-methoxy methyl acrylate and the like are easy to generate, and the purity and the yield of the target product are reduced. For example, european patent application publication No. EP0744400A2 and Japanese patent application publication No. JP2007210923A both report that 4-trifluoromethyl nicotinic acid is obtained by using trifluoroacetyl chloride or trifluoroacetic anhydride as a starting material, and by performing acylation, ammonolysis, condensation under alkaline conditions, ring closure and hydrolysis. In the trifluoroacetyl chloride/trifluoroacetic anhydride method, as the trifluoroacetyl chloride or the trifluoroacetic anhydride with strong corrosiveness is used as the raw material, byproducts are easy to generate in the reaction process, the purity and the yield of the product are influenced, and the strong corrosiveness raw material brings potential safety hazard. Although the direct cyanation method avoids the use of a highly toxic chloridizing reagent, toxic cyanide is used, and cyano groups are easy to be excessively reduced in the hydrogenolysis process, so that the pyridine ring structure is damaged by up to 15%, and the yield of target products is reduced. The direct carbonylation process is to take 4-trifluoromethyl pyridine compound as initial material, react with carbon dioxide under the action of strong alkali such as lithium diisopropylamide, and then acidify to obtain the target product. The direct carbonylation method needs to react with carbon dioxide under strict anhydrous low-temperature conditions, has strict reaction conditions, expensive raw materials and low yield, and is difficult to industrialize. In summary, the existing preparation method of 4-trifluoromethyl nicotinic acid generally has the problems of low yield and incapability of meeting the efficiency requirement of industrial production, poor environmental compatibility, or the use of extremely toxic or highly corrosive reagents or the generation of a large amount of pollutants, and in addition, the production difficulty and the cost are high due to the strict reaction conditions or insufficient operation safety. Disclosure of Invention In order to solve the technical problems, the invention provides a preparation method of 4-trifluoromethyl nicotinic acid, which has the advantages of excellent yield, environmental protection, mild reaction and safety and controllability. The method solves the technical problems of severe conditions, complicated steps and low yield of the existing synthesis method by using a highly toxic or highly corrosive reagent. Based on the Bohlmann-Rahtz heterocyclic reaction principle, 4-trifluoro-2-butynal is used as a trifluoromethyl synthetic building block, and is cyclized with beta-enamine ester to generate a 4-trifluoromethyl nicotinic acid ester intermediate, and then alkaline hydrolysis is carried out to obtain the 4-trifluoromethyl nicot