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Industrial preparation method for 4-chlorine-5-fluorine-2-methyl pyrimidine

A technology of methylpyrimidine and methyltetrahydrofuran, which is applied in the field of preparation of 4-chloro-5-fluoro-2-methylpyrimidine, can solve the problems of toxicity, tear gas and corrosion, and the large amount of phosphorus oxychloride used as a solvent, etc. , to achieve the effect of reducing the generation of related impurities, facilitating the scale-up of production, and making the process safe and controllable

Inactive Publication Date: 2015-09-23
SHANGHAI STA PHARMA R&D CO LTD +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of this invention is to provide a kind of industrialized preparation method of 4-chloro-5-fluoro-2-methylpyrimidine, which mainly solves the safety problem that the existing preparation method uses sodium hydrogen as base to carry out enlarged production and phosphorus oxychloride is The large amount of solvent used has technical problems of toxicity, tear gas and corrosiveness

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] 5-Fluoro-2-methylpyrimidin-4(3H)-one Synthesis

[0016] 109 g of ethyl formate and 100 g of ethyl fluoroacetate were dissolved in 300 ml of tetrahydrofuran, and 114 g of potassium tert-butoxide and 600 ml of tetrahydrofuran were added. After the drop was completed, the mixture was stirred overnight at room temperature, and the reaction was completed to obtain the intermediate sodium salt of ethyl 2-fluoro-3-oxopropionate. Add 1200 ml of ethanol, 80 g of sodium ethylate, and 97 g of acetamidine hydrochloride, heat the system to reflux and stir overnight, and the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure, dissolved with a minimum amount of water, extracted with 2-methyltetrahydrofuran, concentrated, added ethyl acetate, stirred at room temperature, filtered to obtain 54 grams of 5-fluoro-2-methylpyrimidine-4( 3H)-ketone.

Embodiment 2

[0018] 5-Fluoro-2-methylpyrimidin-4(3H)-one Synthesis

[0019] 109 g of ethyl formate and 100 g of ethyl fluoroacetate were dissolved in 300 ml of isopropyl ether, and 114 g of potassium tert-butoxide and 600 ml of isopropyl ether were added. After the drop was completed, the mixture was stirred overnight at room temperature, and the reaction was completed to obtain the intermediate sodium salt of ethyl 2-fluoro-3-oxopropionate. Add 1200 ml of methanol, 80 g of sodium ethoxide, and 97 g of acetamidine hydrochloride, heat the system to reflux and stir overnight, and the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure, dissolved with a minimum amount of water, extracted with 2-methyltetrahydrofuran, concentrated, added ethyl acetate, stirred at room temperature, filtered to obtain 40 grams of 5-fluoro-2-methylpyrimidine-4( 3H)-ketone.

Embodiment 3

[0021] 5-Fluoro-2-methylpyrimidin-4(3H)-one Synthesis

[0022] 109 g of ethyl formate and 100 g of ethyl fluoroacetate were dissolved in 300 ml of toluene, and 114 g of potassium tert-butoxide and 600 ml of tetrahydrofuran were added. After the drop was completed, the mixture was stirred overnight at room temperature, and the reaction was completed to obtain the intermediate sodium salt of ethyl 2-fluoro-3-oxopropionate. Add 1200 ml of isopropanol, 80 g of sodium ethoxide, and 97 g of acetamidine hydrochloride, heat the system to reflux and stir overnight, and the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure, dissolved with a minimum amount of water, extracted with 2-methyltetrahydrofuran, concentrated, added ethyl acetate, stirred at room temperature, filtered to obtain 30 grams of 5-fluoro-2-methylpyrimidine-4( 3H)-ketone.

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Abstract

The invention relates to an industrial preparation method for 4-chlorine-5-fluorine-2-methyl pyrimidine, and the problems that existing 4-chlorine-5-fluorine-2-methyl pyrimidine is not easy to amplify and low in yield coefficient are solved. According to the technical scheme, the industrial preparation method for the 4-chlorine-5-fluorine-2-methyl pyrimidine comprises the steps that 1 ethyl formate and ethyl fluoroacetate are reacted by potassium tert-butoxide in an alkali mode, and after a midbody of 2-fluorine-3-oxo, ethyl propionate sodium salt is obtained and reacted with acetamidine hydrochloride in a ring closing mode, 5-fluorine-2-methyl pyrimidine-4(3H)-ketone is obtained; 2 chlorination is conducted, phosphorus oxychloride serves as a chloride agent, organic alkali serves as an additive, and the 4-chlorine-5-fluorine-2-methyl pyrimidine is obtained in solvent through a reaction. The invention is used for the industrial preparation method for the 4-chlorine-5-fluorine-2-methyl pyrimidine.

Description

technical field [0001] The invention relates to a preparation method of 4-chloro-5-fluoro-2-methylpyrimidine, in particular to an industrialized preparation method of 4-chloro-5-fluoro-2-methylpyrimidine. Background technique [0002] 4-Chloro-5-fluoro-2-methylpyrimidine is an important pharmaceutical and chemical intermediate. Both WO2006072831A1 and WO2008096260A1 reported that ethyl formate and ethyl fluoroacetate were used as a base to obtain sodium 2-fluoro-3-oxopropionate sodium salt intermediate, and then ring-closed with acetamidine hydrochloride to obtain 5-fluoro -2-Methylpyrimidin-4(3H)-one. 5-Fluoro-2-methylpyrimidin-4(3H)-one, using phosphorus oxychloride as solvent and N,N-dimethylaniline as additive, chlorination at 110°C to obtain 4-chloro-5-fluoro -2-methylpyrimidine. [0003] Sodium hydride is a flammable substance, and it will release extremely flammable gas when it meets water, so it is not suitable for safe scale-up production. In the second step of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/30
CPCC07D239/30
Inventor 杨少辉赖正茂杨伟峰黄平傅小勇陈民章
Owner SHANGHAI STA PHARMA R&D CO LTD
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