CN113072502A - Brain protective agent and preparation method of key impurities thereof - Google Patents
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- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The application relates to a brain protective agent and a preparation method of key impurities thereof. The edaravone and three key impurities thereof are synthesized in the same route by taking phenylhydrazine and ethyl acetoacetate as raw materials: compared with the respective synthesis of edaravone and each impurity, the time and the cost are saved by the transitional-state impurities, the edaravone dimer nitric oxide and the 5-methyl-2-phenyl-4- (propan-2-ylidene) -2, 4-dihydro-3H-pyrazol-3-one, and experiments prove that the yield and the purity of the edaravone are higher than those of the edaravone synthesized directly by firstly controlling the process for synthesizing the transitional-state impurities and then changing the process for synthesizing the edaravone.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a brain protective agent and a preparation method of key impurities thereof.
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.
The preparation method 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 preparation method of phenylhydrazine and ethyl acetoacetate is mainly adopted at present. A synthesis process of the edaravone is improved in a document [ Yidawawa. edaravone ] chemical engineering and equipment, 2013, and the edaravone is obtained by carrying out reflux reaction on phenylhydrazine and ethyl acetoacetate in absolute ethyl alcohol for 7 hours, 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 to perform reflux reaction of acetic acid, shortens the reaction time to 4 hours, and has the yield of 50.3 percent,
patent CN109608398A discloses a preparation method of edaravone, which is characterized in that phenylhydrazine and ethyl acetoacetate react in absolute ethyl alcohol at room temperature, and then the reaction is performed in acetic acid under reflux, so that the total reaction time is long, and the total yield is low after two times of refining.
The edaravone dimer key impurity can be generated in the processes of preparing and storing the edaravone, and the structure is as follows:
when the applicant detects edaravone placed in a long-term test, a part of samples find dimer nitrogen oxide impurities, and the existing documents do not report that the structure is as follows through mass spectrum detection:
the impurities are generated by the edaravone through oxidation in the long-term standing process, and are prepared by the edaravone through oxidation in a laboratory, and the edaravone dimer impurities can be easily obtained and the dimer nitrogen oxide impurities are not easily obtained during the preparation of the impurities.
In the process of synthesizing edaravone from phenylhydrazine and ethyl acetoacetate, transition state impurities are easily generated, and the structure is as follows:
the reason for the generation of the impurities is that the control of the process conditions such as temperature and the like is not accurate enough and is almost unavoidable in the edaravone synthesis process. Due to the difference of the preparation conditions of the transition state impurities and the edaravone, the preparation of the impurities and the preparation of the edaravone need to be carried out independently.
Ethyl acetoacetate readily decarboxylates at high temperatures to produce acetone, which condenses with edaravone to produce the impurity 5-methyl-2-phenyl-4- (propan-2-ylidene) -2, 4-dihydro-3H-pyrazol-3-one, which has the structure:
disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a preparation method of a brain protective agent and key impurities thereof, and the preparation method is realized by the following technical scheme.
A preparation method of a brain protective agent and key impurities thereof comprises the following steps:
(1) adding phenylhydrazine into an alcohol solvent, controlling the temperature to be-5-0 ℃, adding ethyl acetoacetate, controlling the temperature to be-5 ℃, reacting for 1 hour, taking part of reaction liquid after the reaction is finished, adding a sodium bicarbonate solution, quenching the reaction, adding dichloromethane for extraction, carrying out reduced pressure concentration to obtain an oily substance, and purifying by column chromatography to obtain a transition impurity;
heating the rest reaction liquid to 60-65 ℃ for reaction for 1 hour, adding concentrated sulfuric acid solution, heating to 80-85 ℃, controlling the temperature for reaction for 3 hours, cooling to-10-10 ℃ for crystallization, and obtaining the edaravone.
(2) Dissolving the edaravone obtained in the step (1) in an acetic acid solvent, adding hydrogen peroxide with the mass concentration of 50%, reacting for 24 hours at room temperature, filtering, and pulping a filter cake with ethyl acetate to obtain a dimer nitrogen oxide impurity.
(3) Dissolving the edaravone obtained in the step (1) in an acetone solvent, adding acetic acid, adding sodium acetate, heating to reflux reaction, cooling and crystallizing after the reaction is finished, filtering, and drying to obtain the 5-methyl-2-phenyl-4- (propyl-2-subunit) -2, 4-dihydro-3H-pyrazol-3-one.
The reaction route is as follows:
the alcohol solvent in the step (1) is one or more of ethanol or isopropanol, and the volume mass ratio of the alcohol solvent to phenylhydrazine is 3-8: 1;
the molar ratio of the phenylhydrazine to the ethyl acetoacetate in the step (1) is 1: 1.05;
the mass ratio of the concentrated sulfuric acid to the phenylhydrazine in the residual reaction solution in the step (1) is 0.1-0.3: 1, the concentrated sulfuric acid and the phenylhydrazine in the residual reaction solution are uniformly mixed in a reaction system, and the phenylhydrazine content can be calculated according to the ratio of the residual reaction solution to the total reaction solution.
The crystallization temperature in the step (1) is-10-10 ℃;
the volume-to-mass ratio of the acetic acid to the edaravone in the step (2) is 5: 1;
in the step (2), the molar ratio of the hydrogen peroxide to the edaravone is 5-15: 1;
the volume-to-mass ratio of the acetone to the edaravone in the step (3) is 3: 1; the volume-mass ratio of acetic acid to edaravone is 1:1, and the molar ratio of edaravone to sodium acetate is 8-12: 1.
The invention has the following beneficial technical effects:
edaravone and three key impurities thereof are synthesized in the same route: compared with the respective synthesis of edaravone and each impurity, the time and the cost are saved by the transitional-state impurities, the edaravone dimer nitric oxide and the 5-methyl-2-phenyl-4- (propan-2-ylidene) -2, 4-dihydro-3H-pyrazol-3-one, and experiments prove that the yield and the purity of the edaravone are higher than those of the edaravone synthesized directly by firstly controlling the process for synthesizing the transitional-state impurities and then changing the process for synthesizing the edaravone.
Drawings
FIG. 1 is a transition state impurity LC-MS spectrogram
FIG. 2 is an LC-MS spectrogram of edaravone dimer nitrogen oxide
FIG. 3 is a LC-MS spectrum of 5-methyl-2-phenyl-4- (prop-2-ylidene) -2, 4-dihydro-3H-pyrazol-3-one
The specific implementation mode is as follows:
example 1
(1) Adding 108g of phenylhydrazine into 324mL of ethanol, controlling the temperature to be-5-0 ℃, adding 136.5g of ethyl acetoacetate, controlling the temperature to be-5 ℃ for reaction for 1 hour, taking out half of reaction liquid after the reaction is finished, adding 100mL of sodium bicarbonate solution with the mass fraction of 20%, quenching the reaction, adding dichloromethane for extraction, carrying out reduced pressure concentration at 35 ℃ to obtain an oily substance, purifying and drying by using a column chromatography to obtain 96.59g of transition-state impurities, wherein the yield is 87.7%. LC-MS shows that [ M + H ] at 16.658min is 221.11, the molecular weight of the [ M + H ] is consistent with that of the target product, and the [ M + H ] is determined as a transition state impurity.
Heating the rest half of reaction liquid to 60-65 ℃ for reaction for 1 hour, quickly adding 5.4g of concentrated sulfuric acid solution, heating to 80-85 ℃, controlling the temperature for reaction for 3 hours, cooling for crystallization, performing suction filtration, and drying in vacuum to obtain 78.91g of edaravone with the yield of 90.6%.
(2) And (2) dissolving 17.4g of edaravone obtained in the step (1) in 70mL of acetic acid solvent, adding 34.0g of hydrogen peroxide with the mass concentration of 50%, reacting at room temperature for 24 hours, filtering, pulping a filter cake with ethyl acetate, filtering and drying to obtain 14.53g of dimer nitrogen oxide impurity, wherein the yield is 80.2% calculated by edaravone. LC-MS shows that [ M + H ] at 14.593min is 363.33, is consistent with the molecular weight of a target product, and is determined as edaravone dimer nitrogen oxide impurity.
(3) Dissolving 17.4g of edaravone obtained in the step (1) in 52ml of acetone, adding 17.4ml of acetic acid and 1.03g of sodium acetate, heating to reflux for reaction for 8H, cooling to 0 ℃ after the reaction is finished, crystallizing for 2H, performing suction filtration and drying to obtain 18.51g of 5-methyl-2-phenyl-4- (propyl-2-subunit) -2, 4-dihydro-3H-pyrazol-3-one, wherein the yield is 86.4% by edaravone. LC-MS showed that [ M + H ] at 16.723min was 215.14, consistent with the molecular weight of the target product, and was determined to be 5-methyl-2-phenyl-4- (propan-2-ylidene) -2, 4-dihydro-3H-pyrazol-3-one.
Example 2
(1) Adding 108g of phenylhydrazine into 540mL of isopropanol, controlling the temperature to be-5-0 ℃, adding 136.5g of ethyl acetoacetate, controlling the temperature to be-5 ℃ for reaction for 1 hour, taking out half of reaction liquid after the reaction is finished, adding 100mL of sodium bicarbonate solution with the mass fraction of 20%, quenching the reaction, adding dichloromethane for extraction, carrying out reduced pressure concentration at 35 ℃ to obtain an oily substance, purifying and drying by using a column chromatography to obtain 93.50g of transition-state impurities, wherein the yield is 84.9%.
Heating the rest half of reaction liquid to 60-65 ℃ for reaction for 1 hour, quickly adding 10.8g of concentrated sulfuric acid solution, heating to 80-85 ℃, controlling the temperature for reaction for 3 hours, cooling for crystallization, performing suction filtration, and performing vacuum drying to obtain 79.35g of edaravone with the yield of 91.1%.
(2) And (2) dissolving 17.4g of edaravone obtained in the step (1) in 104mL of acetic acid solvent, adding 68.0g of hydrogen peroxide with the mass concentration of 50%, reacting at room temperature for 24 hours, filtering, pulping a filter cake with ethyl acetate, filtering, and drying to obtain 15.69g of dimer nitrogen oxide impurity, wherein the yield is 86.6% in terms of edaravone.
(3) Dissolving 17.4g of edaravone obtained in the step (1) in 52ml of acetone, adding 17.4ml of acetic acid and 1.03g of sodium acetate, heating to reflux for reaction for 8H, cooling to 0 ℃ after the reaction is finished, crystallizing for 2H, performing suction filtration and drying to obtain 19.09g of 5-methyl-2-phenyl-4- (propyl-2-subunit) -2, 4-dihydro-3H-pyrazol-3-one, wherein the yield is 89.1% by edaravone.
Example 3
(1) Adding 108g of phenylhydrazine into 864mL of ethanol, controlling the temperature to be-5-0 ℃, adding 136.5g of ethyl acetoacetate, controlling the temperature to be-5 ℃ for reaction for 1 hour, taking out half of reaction liquid after the reaction is finished, adding 100mL of sodium bicarbonate solution with the mass fraction of 20%, quenching the reaction, adding dichloromethane for extraction, carrying out reduced pressure concentration at 35 ℃ to obtain an oily substance, purifying and drying by using a column chromatography to obtain 99.76g of transition-state impurities, wherein the yield is 90.4%.
Heating the rest half of reaction liquid to 60-65 ℃ for reaction for 1 hour, quickly adding 16.2g of concentrated sulfuric acid solution, heating to 80-85 ℃, controlling the temperature for reaction for 3 hours, cooling for crystallization, performing suction filtration, and drying in vacuum to obtain 78.04g of edaravone with the yield of 89.6%.
(2) And (2) dissolving 17.4g of edaravone obtained in the step (1) in 139mL of acetic acid solvent, adding 102.0g of hydrogen peroxide with the mass concentration of 50%, reacting at room temperature for 24 hours, filtering, pulping a filter cake with ethyl acetate, filtering, and drying to obtain 16.16g of dimer nitrogen oxide impurity, wherein the yield is 89.2% in terms of edaravone.
(3) Dissolving 17.4g of edaravone obtained in the step (1) in 52ml of acetone, adding 17.4ml of acetic acid and 1.03g of sodium acetate, heating to reflux for reaction for 8H, cooling to 0 ℃ after the reaction is finished, crystallizing for 2H, performing suction filtration and drying to obtain 18.95g of 5-methyl-2-phenyl-4- (propyl-2-subunit) -2, 4-dihydro-3H-pyrazol-3-one, wherein the yield is 88.3% by edaravone.
Comparative example 1 for directly preparing edaravone, the yield and the purity are lower
Adding 108g of phenylhydrazine into 324mL of ethanol, controlling the temperature to be-5-0 ℃, adding 136.5g of ethyl acetoacetate, heating to 60-65 ℃ for reaction for 1 hour, after the reaction is finished, quickly adding 5.4g of concentrated sulfuric acid solution, heating to 80-85 ℃, controlling the temperature for reaction for 3 hours, cooling for crystallization, performing suction filtration, and performing vacuum drying to obtain 129.43g of edaravone, wherein the yield is 74.3%.
Comparative example 2 No sulfuric acid and little hydrogen peroxide
Adding 108g of phenylhydrazine into 324mL of ethanol, controlling the temperature to be-5-0 ℃, adding 136.5g of ethyl acetoacetate, controlling the temperature to be-5 ℃ for reaction for 1 hour, taking out half of reaction liquid after the reaction is finished, adding 100mL of sodium bicarbonate solution with the mass fraction of 20%, quenching the reaction, adding dichloromethane for extraction, carrying out reduced pressure concentration at 35 ℃ to obtain an oily substance, purifying and drying by using a column chromatography to obtain 96.59g of transition-state impurities, wherein the yield is 87.7%.
Heating the rest half of the reaction solution to 60-65 ℃ for reaction for 1 hour, heating to 80-85 ℃, controlling the temperature for reaction for 3 hours, cooling for crystallization, filtering, and drying in vacuum to obtain 44.07g of edaravone with the yield of 50.6%.
Dissolving 17.4g of edaravone in 70mL of acetic acid solvent, adding 17.0g of 50% hydrogen peroxide, reacting at room temperature for 24 hours, filtering, pulping a filter cake by using ethyl acetate, filtering and drying to obtain 11.20g of dimer nitrogen oxide impurity, wherein the yield is 61.8% in terms of edaravone.
Comparative example 3 No sodium acetate
Dissolving 17.4g of edaravone obtained in example 1 in 52ml of acetone, adding 17.4ml of acetic acid, heating to reflux reaction for 10H, cooling to 0 ℃ after the reaction is finished, crystallizing for 2H, carrying out suction filtration and drying to obtain 12.98g of 5-methyl-2-phenyl-4- (propyl-2-subunit) -2, 4-dihydro-3H-pyrazol-3-one, wherein the yield is 60.6% in terms of edaravone.
Experimental example 1 influence factor test
High-temperature test: the edaravone sample in example 1 is taken, put into a clean culture dish through an opening, spread into a thin layer with the thickness less than or equal to 5mm, placed at the temperature of 60 ℃ for 10 days, sampled on the 5 th day and the 10 th day, detected according to the key stability items, and the test result is compared with 0 day. The results are shown in Table 1.
In the high-humidity test, the edaravone sample in example 1 is taken, placed in a clean culture dish through an opening, spread into a thin layer with the thickness of less than or equal to 5mm, placed in a constant-humidity closed container, placed for 10 days under the condition of the relative humidity of 92.5% at 25 ℃, sampled on the 5 th day and the 10 th day, tested according to the stability focus examination item, and the test result is compared with the test result on the 0 day. The results are shown in Table 1.
In the illumination test, the edaravone sample in example 1 is taken, placed in a clean culture dish at an opening, spread into a thin layer with the thickness of less than or equal to 5mm, placed for 10 days under the condition that the illumination intensity is 4500lx, samples are taken on the 5 th day and the 10 th day, the detection is carried out according to the key stability investigation items, and the test result is compared with the 0 day. The results are shown in Table 1.
Table 1 example 1 edaravone effect factor test results
Experimental example 2 accelerated test
The edaravone sample of example 1 was packaged in a package as commercially available, placed at 40 ± 2 ℃ and 75% ± 5% relative humidity for 6 months, sampled at the end of 1, 2, 3 and 6 months, and measured according to the stability stress item. The test results are shown in Table 2.
Table 2 example 1 edaravone accelerated test results
| Time/month | Traits | Content/% | Maximum single impurity/%) | Total impurities/%) |
| 0 | White-like crystalline powder | 99.78 | 0.05 | 0.07 |
| 1 | White-like crystalline powder | 100.03 | 0.04 | 0.08 |
| 2 | White-like crystalline powder | 99.91 | 0.05 | 0.09 |
| 3 | White-like crystalline powder | 99.88 | 0.05 | 0.09 |
| 6 | White-like crystalline powder | 99.68 | 0.06 | 0.10 |
The test result shows that the product has no obvious change in various inspection indexes after being inspected for 6 months by an accelerated test, and the product is basically stable under the conditions of the temperature of 40 +/-2 ℃ and the relative humidity of 75 +/-5%.
Experimental example 3 Long-term test
The edaravone sample of example 1 was packaged in a package that was prepared on the market, placed at 25 ℃. + -. 2 ℃ and 60%. + -. 10% relative humidity for 36 months, sampled at the end of 3 rd, 6 th, 9 th, 12 th, 18 th, 24 th and 36 th months, and measured according to the stability stress test item. The results are shown in Table 3.
Table 3 example 1 edaravone long term test results
| Time/month | Traits | Content/% | Maximum single impurity/%) | Total impurities/%) |
| 0 | White-like crystalline powder | 99.78 | 0.05 | 0.07 |
| 3 | White-like crystalline powder | 100.18 | 0.04 | 0.08 |
| 6 | White-like crystalline powder | 100.08 | 0.03 | 0.08 |
| 9 | White-like crystalline powder | 99.81 | 0.05 | 0.11 |
| 12 | White-like crystalline powder | 99.92 | 0.04 | 0.09 |
Claims (10)
1. A preparation method of a brain protective agent and key impurities thereof is characterized by comprising the following steps:
adding phenylhydrazine into an alcohol solvent, controlling the temperature to be-5-0 ℃, adding ethyl acetoacetate, controlling the temperature to be-5 ℃, reacting for 1 hour, taking part of reaction liquid after the reaction is finished, adding a sodium bicarbonate solution, quenching the reaction, adding dichloromethane for extraction, carrying out reduced pressure concentration to obtain an oily substance, and purifying by column chromatography to obtain a transition impurity;
heating the rest reaction liquid to 60-65 ℃ for reaction for 1 hour, adding concentrated sulfuric acid solution, heating to 80-85 ℃, controlling the temperature for reaction for 3 hours, cooling to-10-10 ℃ for crystallization, and obtaining the edaravone.
2. The method of claim 1 for preparing a brain protective agent and its key impurities, further comprising the steps of: dissolving the edaravone in an acetic acid solvent, adding hydrogen peroxide with the mass concentration of 50%, reacting for 24 hours at room temperature, filtering, and pulping a filter cake by using ethyl acetate to obtain dimer nitrogen oxide impurities.
3. The method of claim 1 for preparing a brain protective agent and its key impurities, further comprising the steps of: dissolving the edaravone in an acetone solvent, adding acetic acid, adding sodium acetate, heating to reflux reaction, cooling and crystallizing after the reaction is finished, filtering, and drying to obtain the 5-methyl-2-phenyl-4- (propyl-2-subunit) -2, 4-dihydro-3H-pyrazol-3-one.
4. The brain protective agent and the preparation method of the key impurities thereof according to claim 1, wherein the alcohol solvent is one or two of ethanol or isopropanol, and the volume mass ratio of the alcohol solvent to the phenylhydrazine is 3-8: 1.
5. The method for preparing the brain protective agent and the key impurities thereof according to claim 1, wherein the mass ratio of the concentrated sulfuric acid solution to the phenylhydrazine in the residual reaction solution is as follows: 0.1-0.3: 1.
6. The preparation method of the brain protective agent and the key impurities thereof according to claim 2, wherein the volume-to-mass ratio of the acetic acid to the edaravone is 4-8: 1.
7. The preparation method of the brain protective agent and the key impurities thereof according to claim 2, wherein the molar ratio of the hydrogen peroxide to the edaravone is 5-15: 1.
8. the preparation method of the brain protective agent and the key impurities thereof according to claim 3, wherein the volume-to-mass ratio of the acetone to the edaravone is 3: 1.
9. The preparation method of the brain protective agent and the key impurities thereof according to claim 3, wherein the volume-to-mass ratio of the acetic acid to the edaravone is 1:1.
10. The cerebral protective agent and the preparation method of key impurities thereof according to claim 3, wherein the molar ratio of edaravone to sodium acetate is 8-12: 1.
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| WO2020212748A1 (en) * | 2019-04-17 | 2020-10-22 | СИА Эмтеко Холдинг | Phenylmethylpyrazolone compound having a novel crystal form, and method for producing same |
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| WO2020212748A1 (en) * | 2019-04-17 | 2020-10-22 | СИА Эмтеко Холдинг | Phenylmethylpyrazolone compound having a novel crystal form, and method for producing same |
Non-Patent Citations (2)
| Title |
|---|
| D.S.RAJ ET AL: "Synthesis and Physico-chemical Studies on Nickle(II) Chelates of Some Tetradentate Bisketimino Derivatives of 4-Acyl-2-pyrazolin-5-ones", 《SYNTHESIS AND REACTIVITY IN INORGANIC AND METAL-ORGANIC CHEMISTRY》, vol. 34, no. 4, 30 April 2004 (2004-04-30), pages 699 * |
| GLORIA RASSU ET AL: "Direct and Enantioselective Vinylogous Michael Addition of α-Alkylidenepyrazolinones to Nitroolefins Catalyzed by Dual Cinchona Alkaloid Thioureas", 《ADVANCED SYNTHESIS & CATALYSIS 》, vol. 356, no. 10, 28 May 2014 (2014-05-28), pages 2, XP072351988, DOI: 10.1002/adsc.201300964 * |
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