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A method for synthesizing 2-halogenated nicotinic acid esters and intermediates thereof by microwave method

A technology of halogenated nicotinic acid ester and microwave method, which is applied in chemical instruments and methods, preparation of organic compounds, preparation of carboxylic acid nitrile, etc., can solve problems such as difficult to handle, difficult, multi-treatment of waste liquid, etc., and achieve synthesis energy consumption Low, short reaction time, less side effects

Active Publication Date: 2018-05-04
SHANDONG NORMAL UNIV
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Problems solved by technology

This synthetic route malondialdehyde is unstable and raw material is not easy to get, so this synthetic route is also not suitable for industrialized production
[0006] (3) Use acetaldehyde, sodium methoxide, and methyl formate as raw materials to generate sodium aldehyde vinyl alcoholate, which is then reacted with methanol to generate 1,1-dimethoxypropionaldehyde, and then reacted with malononitrile to generate cyclized precursor body, and then undergo cyclization, chlorination, and cyanohydrolysis to generate 2-chloronicotinic acid (Gao Qian, Qian Yong, Xue Yi, etc. A method for preparing 2-chloronicotinic acid [P].CN 104592104 A, 2015 ), the disadvantage of this method is that there is a lot of waste liquid and it is difficult to handle
The disadvantage of this method is that the raw material 2-chloro-3-picoline is not easy to get, and the environmental pollution is large, so it is not suitable for large-scale industrial production.
[0009] (6) 3-cyanopyridine-chlorination-hydrolysis method (Fumiya H.Preparation of 2-Chloro-3-cyanopyridine and 2-Chloronicotinic Acid: JP, 56-169672[P].1981; Naoi Kacheng.2- Preparation of Chloronicotinic Acid: JP, 59-144759 [P].1984) This route converts 3-cyanopyridine through H 2 o 2 Oxidation to generate N-oxide, then use POCl 3 As a chlorination reagent, it undergoes a nucleophilic substitution reaction, and then hydrolyzes and neutralizes the product, but the disadvantage of this method is that there is a lot of waste liquid and it is difficult to handle
[0010] It can be seen that the existing 2-halogenated nicotinic acid preparation methods generally have many "three wastes" and are difficult to handle. Therefore, it is very useful to develop green and environmentally friendly synthetic methods for 2-halogenated nicotinic acid esters and 2-halogenated nicotinic acid. necessary

Method used

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  • A method for synthesizing 2-halogenated nicotinic acid esters and intermediates thereof by microwave method
  • A method for synthesizing 2-halogenated nicotinic acid esters and intermediates thereof by microwave method
  • A method for synthesizing 2-halogenated nicotinic acid esters and intermediates thereof by microwave method

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Example 1 Synthesis of methyl 2-chloronicotinate

[0035] In a 500mL three-necked flask equipped with a thermometer, first add 69mL (0.5mol) of N,N-dibutylaminoacrolein and KHCO 3 5.0 g, and then add 65 mL (0.6 mol) of methyl cyanoacetate, and put the prepared device into a microwave apparatus. Set microwave radiation conditions, react under the conditions of temperature 60°C, microwave power 100W and frequency 915MHz, TLC detection (petroleum ether: dichloromethane 1:2, sublimation iodine color development) N,N-dibutylamine The reaction of acrolein is complete. Afterwards, HCl gas was introduced again, and the microwave irradiation conditions were the same as above, and the reaction was carried out for about 30 minutes, and the reaction was tracked by HPLC until the reaction was completed. Then after the reaction, add sodium carbonate solution to adjust the pH=5-6, separate the layers, extract the aqueous layer with ethyl acetate 20mL×3 times, combine the organic lay...

Embodiment 2

[0044] Example 2 Synthesis of methyl 2-bromonicotinate

[0045] In a 500mL three-neck flask equipped with a thermometer, first add 61mL (0.5mol) of 3-diethylaminoacrolein and 20mL of diethanolamine, then add 65mL (0.6mol) of methyl cyanoacetate, and put the prepared device into the microwave instrument. Set up the microwave radiation conditions, react at a temperature of 60°C, a microwave power of 200W, and a frequency of 915MHz, TLC detection (petroleum ether: dichloromethane 1:2, sublimation iodine color development) 3-diethylaminopropene Aldehydes react completely. Afterwards, HBr gas was introduced, and the microwave irradiation conditions were the same as above, and the reaction was performed for about 35 minutes, and the reaction was tracked by HPLC until the reaction was completed. Then after the reaction is finished, add a mass fraction of 10% potassium hydroxide solution to adjust the pH=5-6, separate the layers, extract the aqueous layer with 20 mL of ethyl acetate...

Embodiment 3

[0047] Example 3 Synthesis of ethyl 2-chloronicotinate

[0048] In a 500mL three-necked flask equipped with a thermometer, first add 62mL (0.5mol) of 3-dimethylaminoacrolein and 10mL of piperidine, then add 65mL (0.6mol) of ethyl cyanoacetate, and put the prepared device into the microwave instrument. Set microwave radiation conditions, react under the conditions of temperature 120°C, microwave power 350W and frequency 2450MHz, TLC detection (petroleum ether: dichloromethane 1:2, sublimation iodine color development) 3-dimethylaminoacrolein The response is complete. Afterwards, HCl gas was introduced again, the microwave irradiation conditions were as above, and the reaction was tracked by HPLC until the reaction was completed. Then after the reaction is over, add potassium carbonate solution to adjust the pH=5-6, separate the layers, extract the aqueous layer with 20 mL of dichloromethane×3 times, combine the organic layers, add anhydrous Na 2 SO 4 Dry, filter, evaporate ...

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Abstract

The invention discloses a method for synthesizing 2-halogenated nicotinic acid ester and intermediates thereof through microwave method. The method comprises the following steps: adding substitute amino acrolein, a catalyst and cyan-acetic ester into a reactor, carrying out reaction under microwave radiation, and tracking the reaction till substitute amino acrolein disappears to prepare and obtain reaction liquid of the intermediates of 2-halogenated nicotinic acid ester; adding hydrogen halide into the reaction liquid, continuously carrying out reaction, and tracking and monitoring the reaction till the reaction is complete; adding alkali liquor into the reaction liquid to adjust the pH value to 5-6; carrying out standing delamination to obtain an aqueous layer and an organic layer; extracting the aqueous layer with an organic solvent, combining the extracted aqueous layer with the organic layer, and carrying out refinement to prepare and obtain 2-halogenated nicotinic acid ester. The synthesis method of 2-halogenated nicotinic acid ester related to the invention has the advantages of beingenvironment-friendly, short in reaction time, simple to operate, high in product yield and good in quality.

Description

technical field [0001] The invention relates to the technical field of organic chemistry, in particular to a method for synthesizing 2-halogenated nicotinic acid ester and its intermediate by microwave method. Background technique [0002] Many traditional organic reactions are carried out in organic solvents, and most solvents are flammable, explosive, toxic, and unfriendly to the environment. Organic reactions carried out under microwave radiation conditions have low energy consumption, short time, and With the characteristics of few side reactions, easy purification, and high yield, it has become a new technology of organic synthesis that emerged in the late 1980s and has been developed rapidly. [0003] 2-Chloronicotinic acid aspergne lactone ester has medicinal effect on tomato cinerea (Liu Yong. Derivative synthesis and antibacterial activity of aspergne lactone esters[D]. Northwest Agriculture and Forestry University, 2011 , 12-22.), 2-halogenated nicotinic acid can ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/803C07D213/80C07C253/30C07C255/30
CPCC07C253/30C07D213/80C07D213/803C07C255/30
Inventor 刘玉法李得超顾巧莲孙琳徐俊赵建霞程桂英
Owner SHANDONG NORMAL UNIV
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