CN101830852B - Edaravone compound of new route - Google Patents
Edaravone compound of new route Download PDFInfo
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- CN101830852B CN101830852B CN2010101283175A CN201010128317A CN101830852B CN 101830852 B CN101830852 B CN 101830852B CN 2010101283175 A CN2010101283175 A CN 2010101283175A CN 201010128317 A CN201010128317 A CN 201010128317A CN 101830852 B CN101830852 B CN 101830852B
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- 229950009041 edaravone Drugs 0.000 title claims abstract description 30
- -1 Edaravone compound Chemical class 0.000 title claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 16
- JOVOSQBPPZZESK-UHFFFAOYSA-N phenylhydrazine hydrochloride Chemical compound Cl.NNC1=CC=CC=C1 JOVOSQBPPZZESK-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229940038531 phenylhydrazine hydrochloride Drugs 0.000 claims abstract description 13
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 238000010992 reflux Methods 0.000 claims abstract description 7
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims description 13
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 239000013078 crystal Substances 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 238000010792 warming Methods 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 abstract description 21
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 abstract description 12
- 229940067157 phenylhydrazine Drugs 0.000 abstract description 12
- 239000012043 crude product Substances 0.000 abstract 2
- 239000000047 product Substances 0.000 abstract 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000000843 powder Substances 0.000 abstract 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 abstract 1
- 238000001179 sorption measurement Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 239000002994 raw material Substances 0.000 description 4
- OTCCIMWXFLJLIA-UHFFFAOYSA-N N-acetyl-DL-aspartic acid Natural products CC(=O)NC(C(O)=O)CC(O)=O OTCCIMWXFLJLIA-UHFFFAOYSA-N 0.000 description 3
- OTCCIMWXFLJLIA-BYPYZUCNSA-N N-acetyl-L-aspartic acid Chemical compound CC(=O)N[C@H](C(O)=O)CC(O)=O OTCCIMWXFLJLIA-BYPYZUCNSA-N 0.000 description 3
- 206010008118 cerebral infarction Diseases 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 206010048962 Brain oedema Diseases 0.000 description 1
- FXXMNCZOYVUJEE-UHFFFAOYSA-N C1(=CC=CC=C1)N1N=CCC1=O.CC1(CC(C(=O)O)=CC=C1)C(=O)O Chemical compound C1(=CC=CC=C1)N1N=CCC1=O.CC1(CC(C(=O)O)=CC=C1)C(=O)O FXXMNCZOYVUJEE-UHFFFAOYSA-N 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N Methyl ethyl ketone Natural products CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- FZRKAZHKEDOPNN-UHFFFAOYSA-N Nitric oxide anion Chemical compound O=[N-] FZRKAZHKEDOPNN-UHFFFAOYSA-N 0.000 description 1
- 150000004729 acetoacetic acid derivatives Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to edaravone of a new route, said method regards phenylhydrazine hydrochloride as the initial material, react with sodium hydroxide and produce phenylhydrazine; then, mixing phenylhydrazine and ethyl acetoacetate for reflux reaction to prepare an edaravone crude product; and dissolving the edaravone crude product in an isopropanol-water solution, adding activated carbon for adsorption, and filtering to obtain a white crystalline powder refined product. The method has the advantages of low cost, high product yield and high purity.
Description
Technical field
The present invention relates to a kind of Edaravone compound of variation route, belong to medical technical field.
Background technology
Edaravone, chemical name is: 3-methyl isophthalic acid-phenyl-2-pyrazolin-5-one, molecular formula is: molecular formula: C
10H
10N
2O, molecular weight: 174.20, structural formula is:
Edaravone is a kind of cerebral protective agent (free-radical scavengers).Clinical study prompting N-acetyl Aspartic Acid (NAA) is the sign of specific survival neurocyte, and cerebral infarction their early stage content sharply reduces.Acute period of cerebral infarction the patient give Edaravone, can suppress to block the minimizing of RCBF on every side, makes that NAA content obviously raises than the glycerine control group in the 28th day brain in morbidity back.The preclinical study prompting, rat gives Edaravone at ischemic/ischemia-reperfusion posterior vein, can stop the progress of cerebral edema and cerebral infarction, and alleviates the nervous symptoms of being followed, and suppresses delayed neuronal death.Mechanism research prompting, Edaravone can be removed radical, suppresses lipid peroxidation, thereby suppresses the oxidative damage of brain cell, vascular endothelial cell, neurocyte.
About the compound method of Edaravone, employing phenylhydrazine that report has and the reaction of butanone acid amides make, and the Dante keto-amide is difficult to obtain, and sluggish, and this method is abandoned now basically; Employing phenylhydrazine that has and methyl aceto acetate at ethanol (referring to US4857542A; Synthesize embodiment 1) or water (Dykhanov NN.Ethyl and buty1 acetoacetates, Med Prom SSSR, 1961; 15 (1): back flow reaction makes 42-45); The Edaravone purity that this reaction makes is relatively poor, and yield is not high, has only about 70%.
The compound method of the Edaravone that a kind of yield is high, purity is high, cost is low becomes the present invention's emphasis of research at present.
Summary of the invention
The object of the present invention is to provide a kind of compound method of Edaravone compound of variation route, is starting raw material with the phenylhydrazine hydrochloride, and purity is high, yield is high, cost is low, has solved the problems referred to above that the preparation Edaravone exists in the prior art.
For realizing the foregoing invention purpose, technical scheme of the present invention is following:
A kind of compound method of Edaravone compound of variation route, synthetic route comprises following process:
Particularly, Edaravone compound method of the present invention is characterized in that comprising following synthesis step:
(1) be that the reaction of starting raw material and sodium hydroxide generates phenylhydrazine with the phenylhydrazine hydrochloride;
(2) phenylhydrazine mixes back flow reaction with methyl aceto acetate again, makes the Edaravone bullion.
Above-mentioned described synthesis step, the mol ratio of described phenylhydrazine hydrochloride, sodium hydroxide and methyl aceto acetate are 2～1: 1～2: 1, be preferably 1.04: 1.04: 1.
Above-mentioned described synthesis step, phenylhydrazine mixed back flow reaction 2～4 hours with methyl aceto acetate again, were preferably 2.5 hours.
The compound method of above-mentioned described Edaravone also comprises purification step: the Edaravone bullion is dissolved in Virahol-aqueous solution, adds charcoal absorption, filter, make white crystals sprills highly finished product.Wherein the volume ratio of Virahol and water is 1～3: 1 in Virahol-aqueous solution, is preferably 2: 1.
As the present invention's one preferred embodiment, the compound method of Edaravone provided by the invention comprises the steps:
(1) is starting raw material with the phenylhydrazine hydrochloride, is added to the water, stirred 0.5 hour, add equimolar sodium hydroxide, stirred 0.5 hour, generate phenylhydrazine;
(2) in above-mentioned reaction solution, drip methyl aceto acetate, exothermic heat of reaction was warming up to back flow reaction 2.5 hours, stopped heating, stirred and was as cold as room temperature, filtered, and obtained faint yellow particulate state bullion after the drying;
(3) the adding volume ratio is Virahol-aqueous solution of 2: 1, adds activated carbon, and absorption refluxed 1 hour, and heat filtering is cooled to room temperature and separates out white solid, and filtration drying gets white crystals sprills highly finished product.
Compare with the preparation method of existing Edaravone; The inventive method is that starting raw material replaces phenylhydrazine that production cost is reduced with the phenylhydrazine hydrochloride; Present commercially available phenylhydrazine price is 45000 yuan/ton, and the price of phenylhydrazine hydrochloride is 36000 yuan/ton, and makes High Purity Phenylhydrazine and reduced the influence of impurity to reaction through adding sodium hydroxide reaction original position; Through reaction makes the Edaravone bullion with methyl aceto acetate, yield is significantly improved again.Further, the present invention adopts Virahol-aqueous solution to carry out recrystallization, makes the purity of Edaravone significantly improve, and has reached more than 99%.The conventional absolute ethyl alcohol recrystallization product purity only about 96% that adopts., therefore, use the inventive method to prepare Edaravone, cost reduces, and product yield and purity all significantly improve, and have solved present technological difficulties.
Embodiment
Below further explain or explanation content of the present invention, but embodiment should not be understood that the restriction to protection domain of the present invention through embodiment.
Synthesizing of embodiment 1 Edaravone
(1) takes by weighing 13.5g phenylhydrazine hydrochloride (94mmol), join in the 100ml water, stirred 0.5 hour, add equimolar sodium hydroxide 3.76g, stirred 0.5 hour;
(2) in above-mentioned reaction solution, drip 11.7g methyl aceto acetate (90mmol), exothermic heat of reaction was warming up to back flow reaction 2.5 hours, stopped heating, stirred and was as cold as room temperature, filtered, and obtained faint yellow particulate state bullion 15.5g after the drying;
(3) above-mentioned bullion being added the 30ml volume ratio is Virahol-aqueous solution of 2: 1, adds the 2g activated carbon, refluxes 1 hour, and heat filtering is cooled to room temperature and separates out white solid, must white crystals sprills 14.8g, and yield is 90%, mp129 ℃, purity is 99.9%.
Synthesizing of embodiment 2 Edaravones
(1) takes by weighing 15g phenylhydrazine hydrochloride (104mmol), join in the 120ml water, stirred 0.5 hour, add equimolar sodium hydroxide 4.16g, stirred 0.5 hour;
(2) in above-mentioned reaction solution, drip 13g methyl aceto acetate (100mmol), exothermic heat of reaction was warming up to back flow reaction 2.5 hours, stopped heating, stirred and was as cold as room temperature, filtered, and obtained faint yellow particulate state bullion 16.7g after the drying;
(3) above-mentioned bullion being added the 40ml volume ratio is Virahol-aqueous solution of 2: 1, adds the 2.5g activated carbon, refluxes 1 hour; Heat filtering is cooled to room temperature and separates out white solid, gets white crystals sprills 16.1g; Yield is 88.9%, and mp128 ℃, purity is 99.9%.
Synthesizing of embodiment 3 Edaravones
(1) takes by weighing 22g phenylhydrazine hydrochloride (152mmol), join in the 200ml water, stirred 0.5 hour, add equimolar sodium hydroxide 6.08g, stirred 0.5 hour;
(2) in above-mentioned reaction solution, drip 19g methyl aceto acetate (146mmol), exothermic heat of reaction was warming up to back flow reaction 3 hours, stopped heating, stirred and was as cold as room temperature, filtered, and obtained faint yellow particulate state bullion 24.8g after the drying;
(3) above-mentioned bullion being added the 50ml volume ratio is Virahol-aqueous solution of 2: 1, adds the 3g activated carbon, refluxes 1 hour, and heat filtering is cooled to room temperature and separates out white solid, must white crystals sprills 23.2g, and yield is 87.8%, mp128 ℃, purity is 99.9%.
The comparative example
Methyl aceto acetate 65g (0.5mol) and absolute ethyl alcohol 180ml are mixed, in 50 ℃ of solution that drip phenylhydrazine 54g (0.5mol) and absolute ethyl alcohol 30ml composition, dripped Bi Huiliu 2 hours under stirring; Steam ethanol 60ml; Cooling, suction filtration, crystal is with cold absolute ethanol washing 2 times; Vacuum-drying gets faint yellow crystallization 70g.Absolute ethyl alcohol recrystallization 2 times gets yellowish white crystal 5 6g (yield 65%).
Claims (3)
1. the compound method of an Edaravone compound is characterized in that comprising following synthesis step:
(1) takes by weighing the 13.5g phenylhydrazine hydrochloride, join in the 100ml water, stirred 0.5 hour, add equimolar sodium hydroxide 3.76g, stirred 0.5 hour;
(2) in above-mentioned reaction solution, drip the 11.7g methyl aceto acetate, exothermic heat of reaction was warming up to back flow reaction 2.5 hours, stopped heating, stirred and was as cold as room temperature, filtered, and obtained faint yellow particulate state bullion 15.5g after the drying;
(3) above-mentioned bullion being added the 30ml volume ratio is Virahol-aqueous solution of 2: 1, adds the 2g activated carbon, refluxes 1 hour, and heat filtering is cooled to room temperature and separates out white solid, must white crystals sprills 14.8g, and yield is 90%, mp129 ℃, purity is 99.9%.
2. the compound method of an Edaravone compound is characterized in that comprising following synthesis step:
(1) takes by weighing the 15g phenylhydrazine hydrochloride, join in the 120ml water, stirred 0.5 hour, add equimolar sodium hydroxide 4.16g, stirred 0.5 hour;
(2) in above-mentioned reaction solution, drip the 13g methyl aceto acetate, exothermic heat of reaction was warming up to back flow reaction 2.5 hours, stopped heating, stirred and was as cold as room temperature, filtered, and obtained faint yellow particulate state bullion 16.7g after the drying;
(3) above-mentioned bullion being added the 40ml volume ratio is Virahol-aqueous solution of 2: 1, adds the 2.5g activated carbon, refluxes 1 hour; Heat filtering is cooled to room temperature and separates out white solid, gets white crystals sprills 16.1g; Yield is 88.9%, and mp128 ℃, purity is 99.9%.
3. the compound method of an Edaravone compound is characterized in that comprising following synthesis step:
(1) takes by weighing the 22g phenylhydrazine hydrochloride, join in the 200ml water, stirred 0.5 hour, add equimolar sodium hydroxide 6.08g, stirred 0.5 hour;
(2) in above-mentioned reaction solution, drip the 19g methyl aceto acetate, exothermic heat of reaction was warming up to back flow reaction 3 hours, stopped heating, stirred and was as cold as room temperature, filtered, and obtained faint yellow particulate state bullion 24.8g after the drying;
(3) above-mentioned bullion being added the 50ml volume ratio is Virahol-aqueous solution of 2: 1, adds the 3g activated carbon, refluxes 1 hour, and heat filtering is cooled to room temperature and separates out white solid, must white crystals sprills 23.2g, and yield is 87.8%, mp128 ℃, purity is 99.9%.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010101283175A CN101830852B (en) | 2010-03-22 | 2010-03-22 | Edaravone compound of new route |
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| CN2010101283175A CN101830852B (en) | 2010-03-22 | 2010-03-22 | Edaravone compound of new route |
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| CN101830852A CN101830852A (en) | 2010-09-15 |
| CN101830852B true CN101830852B (en) | 2012-05-09 |
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Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101982463B (en) * | 2010-09-21 | 2013-01-09 | 广西壮族自治区化工研究院 | Method for preparing aryl 5-pyrazolone |
| CN102127020B (en) * | 2010-12-02 | 2012-11-21 | 海南美兰史克制药有限公司 | Refining method of Edaravone compound |
| CN102285920B (en) * | 2011-09-21 | 2014-07-23 | 湖南科技大学 | Optimal edaravone synthesis method |
| CN102432540A (en) * | 2011-10-11 | 2012-05-02 | 沈阳药科大学 | Preparation and application of bisedaravone and pharmaceutical salt thereof |
| CN102643234B (en) * | 2012-04-02 | 2015-09-30 | 浙江大学 | Edaravone polymorphic substance and preparation method thereof |
| CN102766097B (en) * | 2012-06-27 | 2014-11-05 | 江苏正大丰海制药有限公司 | Edaravone A-type crystal and preparation method thereof |
| CN103833640B (en) * | 2012-11-16 | 2016-06-22 | 国药集团国瑞药业有限公司 | A kind of Edaravone crystal, its preparation method and application thereof |
| CN105753785B (en) * | 2016-03-23 | 2018-03-02 | 海南合瑞制药股份有限公司 | A kind of crystal formation of Edaravone and preparation method thereof |
| CN105820121A (en) * | 2016-03-26 | 2016-08-03 | 上海大学 | Preparation method of 1-aryl-3-substituent-5-pyrazolone compound |
| CN106117144B (en) * | 2016-06-24 | 2019-01-29 | 合肥久诺医药科技有限公司 | A kind of synthesis technology of high-purity Edaravone |
| CN108203410B (en) * | 2016-12-20 | 2022-03-18 | 江苏先声药业有限公司 | Synthesis and application of edaravone impurity |
| CN107216289B (en) * | 2017-06-16 | 2020-01-17 | 江苏天晟药业股份有限公司 | Preparation method of edaravone |
| CN107501182A (en) * | 2017-07-10 | 2017-12-22 | 中国农业大学 | The trifluoromethyl of 1 substituted-phenyl 5（Difluoromethyl）4 pyrazole carboxylic acid synthetic methods |
| CN112321454B (en) * | 2020-11-25 | 2023-03-17 | 长沙创新药物工业技术研究院有限公司 | Eltrombopag intermediate, preparation method thereof and method for preparing Ai Qubo Pa by using same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DK169672B1 (en) * | 1985-05-20 | 1995-01-09 | Mitsubishi Chem Ind | Pharmaceutical preparations containing pyrazolone derivatives as active ingredient and the use of pyrazolone derivatives for the preparation of pharmaceutical preparations |
| CN101367763B (en) * | 2007-08-17 | 2012-06-27 | 深圳泛胜塑胶助剂有限公司 | Synthesis process of 1-phenyl-3-methyl-5-pyrazolone |
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