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Synthetic method for 6-trifluoromethyl-nicotinic acid

A technology of trifluoromethylnicotinic acid and trifluoromethylnicotinonitrile, which is applied in the field of synthesis of 6-trifluoromethylnicotinic acid, and can solve problems such as inconvenient operation, low yield, and low process yield

Inactive Publication Date: 2019-01-08
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are many synthetic routes of 4-trifluoromethylnicotinic acid, mainly containing the following: 1) by reacting and acidifying the compound containing trifluoromethylpyridine in the presence of a strong base such as LDA with CO2, but The raw materials of this method are expensive, the yield is low, and strict anhydrous conditions are required, so it is difficult to realize industrial production; 2) react with vinyl ethyl ether with trifluoroacetyl chloride or trifluoroacetic anhydride, and then react with methyl 3-methoxyacrylate , and finally the target product is obtained by cyclic hydrolysis. Trifluoroacetyl chloride is a poisonous strong irritating gas, which is inconvenient to operate, and the yield of the process is low; 3) using ethyl trifluoroacetoacetate and cyanoacetamide as raw materials, the Synthesis, chlorination, hydrolysis of cyano group, catalytic hydrogenolysis 4-step reaction to prepare 4-trifluoromethyl nicotinic acid, the route is not mature at present, the yield is low during chlorination, cyano group is easily reduced during catalytic hydrogenolysis, pyridine The ring is susceptible to partial reduction

Method used

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  • Synthetic method for 6-trifluoromethyl-nicotinic acid
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  • Synthetic method for 6-trifluoromethyl-nicotinic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Add 376g (5.2mol) of vinyl ethyl ether, 826g of pyridine and 5000mL of dichloromethane in sequence in a 10L three-necked flask, stir well, then add 1084g (5.2mol) of phosphorus pentachloride, and pass through the constant pressure funnel at 0°C Slowly add 460g (4mol) of trifluoroacetic acid dropwise, and then stir and react at room temperature for 20h; after the reaction, the reaction system is washed once with 2000mL of water and 1000mL of 10% hydrochloric acid, and then washed with 1500mL of saturated sodium bicarbonate solution until the reaction solution The aqueous phase is neutral, and then dried over anhydrous magnesium sulfate and concentrated by suction to obtain the crude product, which is recrystallized in 2000 mL of a mixed solvent of acetone and water (V acetone: V water = 3:1) to obtain 4-ethoxy Pure 1,1,1-trifluoro-3-buten-2-one 542.0g; 1 H NMR (400MHz, CDCl 3 )δ7.89(d, J=12.3Hz, 1H), 5.85(d, J=12.3Hz, 1H), 4.10(q, J=7.1Hz, 2H), 1.40(t, J=7.1Hz, 3H) . ...

Embodiment 2

[0019] Add 376g (5.2mol) of vinyl ethyl ether, 826g of pyridine and 5000mL of dichloromethane in sequence into a 10L three-necked flask, stir well, then add 712g (5.2mol) of phosphorus trichloride, and pass through the constant pressure funnel at 0°C Slowly add 460g (4mol) of trifluoroacetic acid dropwise, and then stir and react at room temperature for 20h; after the reaction, the reaction system is washed once with 2000mL of water and 1000mL of 10% hydrochloric acid, and then washed with 1500mL of saturated sodium bicarbonate solution until the reaction solution The aqueous phase is neutral, and then dried over anhydrous magnesium sulfate and concentrated by suction to obtain the crude product, which is recrystallized in 2000 mL of a mixed solvent of acetone and water (V acetone: V water = 3:1) to obtain 4-ethoxy 536.0 g of pure 1,1,1-trifluoro-3-buten-2-one.

Embodiment 3

[0021] Add 376g (5.2mol) of vinyl ether, 826g of pyridine and 5000mL of dichloromethane in sequence into a 10L three-necked flask, stir evenly, and then add 200g of silicotungstic acid / silica gel (msilicotungstic acid: msilica gel=1:3), 460g (4mol) of trifluoroacetic acid was slowly added dropwise through a constant pressure funnel at 0°C, and after the dropwise addition was completed, the reaction was stirred at room temperature for 20h; Wash with 1500 mL of saturated sodium bicarbonate solution until the aqueous phase of the reaction solution is neutral, and then concentrate with suction after drying over anhydrous magnesium sulfate to obtain the crude product. 1) Recrystallize in 2000mL to obtain 660.0g of pure 4-ethoxy-1,1,1-trifluoro-3-buten-2-one.

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Abstract

The invention discloses a method for synthesizing 6-trifluoromethyl-nicotinic acid. The method comprises the specific steps: carrying out addition-elimination reaction reactions on trifluoroacetic acid and vinyl ethyl ether under the action of phosphorus pentachloride to obtain 4-ethoxyl-1,1,1-trifluoro-3-butene-2-one; carrying out addition-elimination reaction reactions on ethidene diamine and cyanoacetic acid in a heating condition to obtain 3-(diethyl amino) acrylonitrile first; carrying out an Stork alkylation reaction on 3-(diethyl amino) acrylonitrile and 4-ethoxyl-1,1,1-trifluoro-3-butene-2-one to obtain 2-((diethyl amino) methylene)-6,6,6-trifluoro-5-oxo-3-hexenenitrile; carrying out exocondensation on 2-((diethyl amino) methylene)-6,6,6-trifluoro-5-oxo-3-hexenenitrile under the action of ammonium acetate to obtain 6-trifluoromethyl cyanopyridine; and carrying out cyano hydrolysis reaction on the 6-trifluoromethyl cyanopyridine t obtain 6-trifluoromethyl-nicotinic acid. The synthetic method is more economic, environmentally friendly, efficient and simple.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a synthesis method of 6-trifluoromethyl nicotinic acid. Background technique [0002] The introduction of fluorine atoms into organic molecules can significantly improve their physical and chemical properties, which promotes the rapid development of fluorine-containing drugs. The development of a convenient method for synthesizing fluorine-containing aromatic heterocyclic compounds can promote the wide application of such compounds in the fields of pesticides and medicine. Pyridine-containing heterocyclic compounds have been successfully used in many commercial insecticides due to their strong physiological activity in vivo, such as imidacloprid, acetamiprid, nitenpyrid and other insecticides. Trifluoromethylnicotinic acid is a very typical and important fluorine-containing pyridine compound. For example, 2-trifluoromethylnicotinic acid can be used as a cal...

Claims

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Application Information

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IPC IPC(8): C07D213/80C07D213/803
CPCC07D213/80C07D213/803
Inventor 徐桂清周应杰毛龙飞王家豪
Owner HENAN NORMAL UNIV
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