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Method for synthesizing 2-halogenated ester nicotinate and 2-halogenated ester nicotinate intermediate according to ultrasonic method

A technology of halogenated nicotinic acid ester and ultrasonic method, which is applied in chemical instruments and methods, preparation of organic compounds, preparation of carboxylic acid nitrile, etc. It can solve the problems of unsuitable industrial production, unstable raw materials of malondialdehyde, and many wastes, etc. Problems, to achieve the effect of environmental protection, promote organic synthesis reaction, speed up the reaction speed

Active Publication Date: 2015-09-30
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
[0005] (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 104592104A, 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 there is a lot of waste liquid and it is difficult to handle
[0009] It can be seen that the existing 2-halogenated nicotinic acid preparation methods all have many "three wastes" and are difficult to handle. Therefore, it is necessary to develop green and environmentally friendly synthetic methods for 2-halogenated nicotinic acid esters and 2-halogenated nicotinic acid is very necessary

Method used

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  • Method for synthesizing 2-halogenated ester nicotinate and 2-halogenated ester nicotinate intermediate according to ultrasonic method
  • Method for synthesizing 2-halogenated ester nicotinate and 2-halogenated ester nicotinate intermediate according to ultrasonic method
  • Method for synthesizing 2-halogenated ester nicotinate and 2-halogenated ester nicotinate intermediate according to ultrasonic method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1 5-(N,N-dimethyl)amino-2-cyano-2,4-pentadienoic acid ethyl ester

[0033] In a 500mL three-necked round-bottom flask, add 62mL (0.5mol) of 3-dimethylaminoacrolein, 10mL of triethylamine and 65mL (0.6mol) of ethyl cyanoacetate, and put the prepared device into a sonicator . Set the ultrasonic radiation conditions, react under the conditions of temperature 120°C, ultrasonic power 350W, and frequency 100KHz, high-performance liquid phase tracking and detection of the reaction process until the end of the reaction, add 10mL of deionized water to remove impurities, filter to obtain crude products, and then use 90.4 g of white powder was obtained by recrystallization from absolute ethanol, with a melting point of 134-135° C. and a product yield of 93.1%. The product has passed HRMS, 1 H NMR, 13 C NMR spectrum characterization, namely ethyl 5-(N,N-dimethyl)amino-2-cyano-2,4-pentadienoate. ESI-MS: m / z Calcd for C 10 h 14 N 2 o 2 217.0947[M+Na] + ,found 217.095...

Embodiment 2

[0037] Example 2 Butyl 5-(N,N-diethyl)amino-2-cyano-2,4-pentadienoate

[0038] In a 500 mL three-neck round bottom flask, add 61 mL (0.5 mol) of 3-diethylaminoacrolein, 10 mL of sodium ethoxide and 67 mL (0.6 mol) of butyl cyanoacetate, and put the prepared device into a sonicator. Set the ultrasonic radiation conditions, react under the conditions of temperature 100°C, ultrasonic power 300W, and frequency 80KHz, high-performance liquid phase tracking and detection of the reaction process until the end of the reaction, add 10mL of deionized water to remove impurities, and distill to obtain a light brown oil 113.5 g, yield 90.7%. The product was characterized by HRMS as butyl 5-(N,N-diethyl)amino-2-cyano-2,4-pentadienoate. ESI-MS: m / z Calcd for C 14 h 22 N 2 o 2 273.3265[M+Na] + ,found 273.3261[M+Na] + .

Embodiment 3

[0042] Example 3 Synthesis of ethyl 2-chloronicotinate

[0043] In a 500mL three-neck 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 ultrasonic instrument. Set the ultrasonic radiation conditions, react under the conditions of temperature 100°C, ultrasonic power 250W and frequency 40KHz, TLC detection (petroleum ether: dichloromethane 1:2, sublimation iodine color development) 3-dimethylaminoacrolein The response is complete. Afterwards, HCl gas was introduced again, the conditions of ultrasonic radiation were as above, and the reaction was tracked by HPLC until the end of the reaction. Then after the reaction is over, add a mass fraction of 10% sodium hydroxide 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...

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Abstract

The invention discloses a method for synthesizing 2-halogenated ester nicotinate and a 2-halogenated ester nicotinate intermediate according to an ultrasonic method. The method comprises the following steps: adding substituent amino acrolein, a catalyst and cyanacetic ester into a reactor for a reaction under ultrasonic radiation; tracing the reaction till substituent amino acrolein is disappeared, thereby obtaining a reaction solution I containing the 2-halogenated ester nicotinate intermediate; then, adding halogen hydride into the reaction solution I for another reaction to obtain a reaction solution II; tracing and monitoring the reaction till completion; adding a lye into the reaction solution II to adjust the pH value of the reaction solution II to be 5-6; carrying out standing stratification to obtain a water layer and an organic layer; conducting extraction on the water layer by utilizing an organic solvent, and then combining the extraction solution with the organic layer; carrying out refining to obtain 2-halogenated ester nicotinate. Through the adoption of the method, an organic synthesis reaction can be effectively facilitated, the reaction speed and yield can be improved, and the environmental protection can be promoted; the reaction time is short and the operation is simple, that is, the organic synthesis reaction can be finished within 2 hours in general; the product yield and quality are high; specifically, the product yield can reach 90% or higher, and exceed that achieved according to the conventional solvent heating reflux method.

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 an ultrasonic method. Background technique [0002] 2-halogenated nicotinic acid esters can be hydrolyzed to prepare 2-halogenated nicotinic acid, among which, 2-chloronicotinic acid is an important drug and pesticide intermediate, mainly used for the preparation of highly effective anti-inflammatory and analgesic drugs niflumic acid, Pranoprofen, HIV reverse transcriptase inhibitor nevirapine and new high-efficiency herbicide nicosulfuron, etc. The main preparation methods of 2-chloronicotinic acid in the prior art are: [0003] (1) Ethyl cyanoacetate chlorination method (Tony Y Z, Eric F V, Scriven.Processes for Producing 2-Halonicotonic Acid Derivatives and Precursors Thereto: US, 5493028[P].1994; Mayer J.Process of Preparing 2-Halogenonicotinic acids: US, 4081451[P].1977; Liang Wa...

Claims

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Application Information

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IPC IPC(8): C07D213/803C07D213/80C07C253/30C07C255/30
CPCC07C253/30C07D213/80C07D213/803C07C255/30
Inventor 刘玉法毛霏霏顾巧莲程桂英毕珊珊安方云
Owner SHANDONG NORMAL UNIV
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