阅读说明：本技术 一种脑保护剂的制备工艺 (Preparation process of brain protective agent ) 是由 陈相助 刘新泉 刘彦东 李思宇 任崇飞 梁树勇 于 2021-08-20 设计创作，主要内容包括：本发明提供了一种脑保护剂依达拉奉的制备工艺,采用新的起始原料苯胺及(3Z)-3-羟基亚胺丁酸乙酯,先生成中间体化合物II,再生成依达拉奉,反应分两步进行,解决了乙酰乙酸乙酯和苯肼为原料先生成过渡态再生成依达拉奉可控性差的问题,提高了反应收率和纯度。(The invention provides a preparation process of edaravone serving as a brain protective agent, which adopts new initial raw materials of aniline and (3Z) -3-hydroxyiminobutyric acid ethyl ester to generate an intermediate compound II and regenerate edaravone, wherein the reaction is carried out in two steps, so that the problem of poor controllability of the transition state regeneration of edaravone by taking acetoacetic acid ethyl ester and phenylhydrazine as raw materials is solved, and the reaction yield and purity are improved.)

1. A preparation process of a brain protective agent comprises the following steps: the method is characterized by comprising the following steps:

(1) the compound I, aniline and sodium ethoxide are contacted at room temperature to generate a compound II;

(2) generating edaravone by the compound II under the action of sodium hydroxide and paratoluensulfonyl chloride;

the reaction route is as follows:

2. the process according to claim 1, comprising the following steps:

(1) adding aniline and a compound I into an ethanol solvent, adding sodium ethoxide, controlling the room temperature to react, adding hydrochloric acid to adjust the pH value to 4.5-6.0 after the reaction is finished, and adding purified water to crystallize to obtain a compound II;

(2) dissolving the compound II in a dichloromethane solvent, adding sodium hydroxide and p-toluenesulfonyl chloride, refluxing and stirring, adding water after the reaction is finished, extracting with dichloromethane 00, removing the solvent by reduced pressure evaporation, adding ethanol, cooling and crystallizing to obtain the edaravone.

3. The preparation process according to claim 2, wherein the volume-to-mass ratio of ethanol to compound I in step (1) is 4-10: 1.

4. the process according to claim 2, wherein the molar ratio of aniline to compound I in step (1) is 1.1: 1.

5. the process according to claim 2, wherein the molar ratio of sodium ethoxide to compound I in step (1) is 1.1-1.5: 1.

6. the process for preparing the cerebral protective agent according to claim 2, wherein the volume-to-mass ratio of the purified water to the compound I in the step (1) is 6 to 12: 1.

7. the preparation process according to claim 2, wherein the volume-to-mass ratio of the dichloromethane to the compound II in the step (2) is 6-12: 1.

8. the process according to claim 2, wherein the molar ratio of sodium hydroxide to compound II in step (2) is 1.5-2.5: 1.

9. the process according to claim 2, wherein the molar ratio of p-toluenesulfonyl chloride to compound II in step (2) is 1.1 to 1.5: 1.

10. the preparation process according to claim 2, wherein the volume-to-mass ratio of ethanol to compound II in step (2) is 4-12: 1.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a preparation process of a brain protective agent.

Background

Edaravone, chemical name of 3-methyl-1-phenyl-2-pyrazoline-5-ketone, was developed by Mitsubishi pharmaceutical company, and was marketed in Japan in 6 months in 2001, and currently, several imitation pharmaceuticals are on the market in China. The product can be used for treating nervous symptoms related to acute stage of cerebral infarction; the new increase of the approval of Amyotrophic Lateral Sclerosis (ALS) was observed 6 months in 2015; us approved for treatment of ALS in 2017 at 5 months.

Edaravone, chemical name of 3-methyl-1-phenyl-2-pyrazoline-5-ketone, was developed by Mitsubishi pharmaceutical company, and was marketed in Japan in 6 months in 2001, and currently, several imitation pharmaceuticals are on the market in China. The product can be used for treating nervous symptoms related to acute stage of cerebral infarction; the new increase of the approval of Amyotrophic Lateral Sclerosis (ALS) was observed 6 months in 2015; us approved for treatment of ALS in 2017 at 5 months.

The preparation process of edaravone mainly comprises the reaction of phenylhydrazine and butanone amide or ethyl acetoacetate, and the ethyl acetoacetate is easier to react with phenylhydrazine and is easier to obtain, and the price is cheaper, so the prior art mainly adopts the preparation process of phenylhydrazine and ethyl acetoacetate. The reaction route of phenylhydrazine and ethyl acetoacetate is as follows:

although the route can be completed in one pot, transition-state impurities are generated in the reaction process and then edaravone is generated, in order to avoid the transition-state impurities generated in the process of generating edaravone from the transition state in the actual reaction, quenching reaction is generally required after the transition state is generated, and because the quenching reaction needs a period of time, the time for quenching reaction is difficult to control accurately, and the influence on the yield and purity of the final product due to insufficient reaction or impurity residue caused by early or untimely quenching is difficult to avoid.

For example, the synthesis process of the edaravone in the document [ invar dawn. edaravone is improved [ J ] chemical engineering and equipment, 2013 ], the reaction is carried out for 7 hours by refluxing the phenylhydrazine and the ethyl acetoacetate in absolute ethyl alcohol, and the edaravone is obtained by cooling and crystallizing, wherein the yield of the edaravone is 50.6%.

The synthesis of yaoaipin edaravone [ J ] china journal of modern applied pharmacy 2003,20(7) ] uses phenylhydrazine and ethyl acetoacetate in acetic acid reflux reaction to shorten the reaction time to 4 hours, with a yield of 50.3%.

Patent CN109608398A discloses a preparation method of edaravone, which comprises the steps of firstly reacting phenylhydrazine and ethyl acetoacetate in absolute ethyl alcohol at room temperature, then carrying out reflux reaction in acetic acid, wherein the total reaction time is long, and the crude product is refined by two times of ethyl alcohol and two times of ethyl acetate, and the yield of the refined two times of ethyl alcohol and the yield of the refined two times of ethyl acetate are both about 50%.

In conclusion, the one-pot reaction of phenylhydrazine and ethyl acetoacetate does not have the advantage of high yield in most one-pot reactions due to the presence of transition impurities.

Disclosure of Invention

In order to overcome the defects in the prior art, the invention provides a process for preparing the brain protective agent edaravone with higher yield and purity by adopting new raw materials.

A preparation process of a brain protective agent comprises the following steps:

(1) the compound I, aniline and sodium ethoxide are contacted at room temperature to generate a compound II;

(2) generating edaravone by the compound II under the action of sodium hydroxide and paratoluensulfonyl chloride;

the reaction route is as follows:

the compound I is (3Z) -3-hydroxyiminobutyric acid ethyl ester, is sourced from Henan Tianfu chemical industry Co., Ltd, and has the purity of 99%, and the applicant finds that the compound can react with aniline at room temperature to generate an edaravone precursor compound II and further generate edaravone, so that the problem of transition state impurities in one-step synthesis of edaravone by taking ethyl acetoacetate and phenylhydrazine as starting materials in the prior art is solved.

A preparation process of a brain protective agent specifically comprises the following steps:

(1) adding aniline and a compound I into an ethanol solvent, adding sodium ethoxide, controlling the room temperature to react, adding hydrochloric acid to adjust the pH value to 4.5-6.0 after the reaction is finished, and adding purified water to crystallize to obtain a compound II;

(2) and dissolving the compound II in a dichloromethane solvent, adding sodium hydroxide and p-toluenesulfonyl chloride, heating to reflux and stirring, reacting for 1 hour, then finishing, adding water, extracting with dichloromethane, evaporating under reduced pressure to remove the solvent, adding ethanol, cooling and crystallizing to obtain the edaravone.

Wherein the molar ratio of aniline to compound I in step (1) is 1.1: 1, the volume-to-mass ratio of the ethanol to the compound I is 4-10: 1;

the molar ratio of the sodium ethoxide to the compound I in the step (1) is 1.1-1.5: 1;

the volume mass ratio of the purified water to the compound I in the step (1) is 6-12: 1;

the volume mass ratio of the dichloromethane to the compound II in the step (2) is 6-12: 1;

the molar ratio of the sodium hydroxide to the compound II in the step (2) is 1.5-2.5: 1;

the molar ratio of the p-toluenesulfonyl chloride to the compound II in the step (2) is 1.1 to 1.5: 1;

the volume mass ratio of the ethanol to the compound II in the step (2) is 4-12: 1.

the invention has the following beneficial effects:

new reaction raw materials are adopted, the intermediate compound II is firstly generated, the edaravone is regenerated, the reaction is carried out in two steps, the problem that the controllability of the transition state regeneration of the edaravone is poor when ethyl acetoacetate and phenylhydrazine are used as raw materials is solved, and the reaction yield and the purity are improved.

Detailed Description

Example 1 preparation of edaravone

14.52g of the compound I and 10.24g of aniline are added into 58mL of ethanol solvent, 7.49g of sodium ethoxide is added, the reaction is controlled at room temperature, concentrated hydrochloric acid is added to adjust the pH value to 4.5 after the HPLC monitoring reaction is finished, 87mL of purified water is added, and the mixture is stirred and crystallized at room temperature for 2 hours to obtain 17.74g of the compound II with the yield of 92.3%.

Adding 19.22g of the compound II into 115mL of dichloromethane solvent, adding 6.0g of sodium hydroxide and 20.97g of p-toluenesulfonyl chloride, refluxing and stirring for 1 hour, adding 150mL of purified water, adding 150mL of dichloromethane for extraction, evaporating the solvent under reduced pressure by using an organic phase, adding 77mL of ethanol, cooling to 0-5 ℃, and crystallizing for 2 hours to obtain 15.96g of edaravone, wherein the yield is 91.6%, and the purity is 99.92%.

Example 2 preparation of edaravone

14.52g of the compound I and 10.24g of aniline are added into 87mL of ethanol solvent, 8.17g of sodium ethoxide is added, the reaction is controlled at room temperature, concentrated hydrochloric acid is added to adjust the pH value to 5.0 after the HPLC monitoring reaction is finished, 116mL of purified water is added, and the mixture is stirred and crystallized at room temperature for 2 hours to obtain 17.45g of the compound II with the yield of 90.8%.

Adding 19.22g of the compound II into 154mL of dichloromethane solvent, adding 8.0g of sodium hydroxide and 22.88g of p-toluenesulfonyl chloride, refluxing and stirring for 1 hour, adding 150mL of purified water, adding 150mL of dichloromethane for extraction, evaporating the solvent under reduced pressure by an organic phase, adding 135mL of ethanol, cooling to 0-5 ℃, and crystallizing for 2 hours to obtain 15.92g of edaravone, wherein the yield is 91.4%, and the purity is 99.89%.

Example 3 preparation of edaravone

14.52g of the compound I and 10.24g of aniline are added into 116mL of ethanol solvent, 8.85g of sodium ethoxide is added, the reaction is controlled at room temperature, concentrated hydrochloric acid is added to adjust the pH value to 5.5 after the HPLC monitoring reaction is finished, 145mL of purified water is added, and the mixture is stirred and crystallized at room temperature for 2 hours to obtain 17.68g of the compound II, wherein the yield is 92.0%.

Adding 19.22g of the compound II into 192mL of dichloromethane solvent, adding 10.0g of sodium hydroxide and 24.78g of p-toluenesulfonyl chloride, refluxing and stirring for 1 hour, adding 150mL of purified water, adding 150mL of dichloromethane for extraction, evaporating the solvent under reduced pressure by an organic phase, adding 192mL of ethanol, cooling to 0-5 ℃, and crystallizing for 2 hours to obtain 15.66g of edaravone, wherein the yield is 89.9%, and the purity is 99.90%.

Example 4 preparation of edaravone

14.52g of the compound I and 10.24g of aniline are added into 145mL of ethanol solvent, 10.21g of sodium ethoxide is added, the reaction is controlled at room temperature, concentrated hydrochloric acid is added to adjust the pH value to 6.0 after the HPLC monitoring reaction is finished, 174mL of purified water is added, and the mixture is stirred and crystallized at room temperature for 2 hours to obtain 17.78g of the compound II, wherein the yield is 92.5%.

Adding 19.22g of the compound II into 230mL of dichloromethane solvent, adding 8.0g of sodium hydroxide and 28.60g of p-toluenesulfonyl chloride, refluxing and stirring for 1 hour, adding 150mL of purified water, adding 150mL of dichloromethane for extraction, evaporating the solvent under reduced pressure by an organic phase, adding 230mL of ethanol, cooling to 0-5 ℃, and crystallizing for 2 hours to obtain 15.99g of edaravone, wherein the yield is 91.8%, and the purity is 99.90%.

Comparative example 1

14.52g of the compound I and 10.24g of aniline are added into 116mL of ethanol solvent, 8.85g of sodium ethoxide is added, the reaction is controlled at room temperature, concentrated hydrochloric acid is added to adjust the pH value to 4.0 after the HPLC monitoring reaction is finished, 145mL of purified water is added, and the mixture is stirred and crystallized at room temperature for 2 hours to obtain 14.79g of the compound II with the yield of 84.9%.

Comparative example 2

14.52g of the compound I and 10.24g of aniline are added into 116mL of ethanol solvent, 8.85g of sodium ethoxide is added, the reaction is controlled at room temperature, concentrated hydrochloric acid is added to adjust the pH value to 6.5 after the HPLC monitoring reaction is finished, 145mL of purified water is added, and the mixture is stirred and crystallized at room temperature for 2 hours to obtain 15.03g of the compound II with the yield of 86.3%.

Comparative example 3

14.52g of the compound I and 10.24g of aniline are added into 116mL of ethanol solvent, 8.85g of sodium ethoxide is added, the reaction is controlled at room temperature, concentrated hydrochloric acid is added to adjust the pH value to 5.5 after the HPLC monitoring reaction is finished, 145mL of purified water is added, and the mixture is stirred and crystallized at room temperature for 2 hours to obtain 17.68g of the compound II, wherein the yield is 92.0%.

Adding 19.22g of the compound II into 192mL of dichloromethane solvent, adding 24.78g of p-toluenesulfonyl chloride, refluxing and stirring for 1 hour, adding 150mL of purified water, adding 150mL of dichloromethane for extraction, distilling off the solvent by organic phase under reduced pressure, adding 192mL of ethanol, cooling to 0-5 ℃ and crystallizing for 2 hours to obtain 10.85g of edaravone, wherein the yield is 62.3%, and the purity is 96.8%.

Comparative example 4

14.52g of the compound I and 10.24g of aniline are added into 116mL of ethanol solvent, 8.85g of sodium ethoxide is added, the reaction is controlled at room temperature, concentrated hydrochloric acid is added to adjust the pH value to 5.5 after the HPLC monitoring reaction is finished, 145mL of purified water is added, and the mixture is stirred and crystallized at room temperature for 2 hours to obtain 17.68g of the compound II, wherein the yield is 92.0%.

Adding 19.22g of the compound II into 192mL of dichloromethane solvent, adding 10.0g of sodium hydroxide, refluxing and stirring for 1 hour, adding 150mL of purified water, adding 150mL of dichloromethane for extraction, distilling off the solvent by organic phase under reduced pressure, adding 192mL of ethanol, cooling to 0-5 ℃ and crystallizing for 2 hours to obtain 8.64g of edaravone, wherein the yield is 49.6% and the purity is 95.4%.