CN103396365A - Synthesis method of pyrazolone - Google Patents
Synthesis method of pyrazolone Download PDFInfo
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- CN103396365A CN103396365A CN2013103406489A CN201310340648A CN103396365A CN 103396365 A CN103396365 A CN 103396365A CN 2013103406489 A CN2013103406489 A CN 2013103406489A CN 201310340648 A CN201310340648 A CN 201310340648A CN 103396365 A CN103396365 A CN 103396365A
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- pyrazolin
- methyl
- substituted
- microwave
- Prior art date
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- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 title description 2
- 238000001308 synthesis method Methods 0.000 title 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 150000004031 phenylhydrazines Chemical class 0.000 claims abstract description 8
- 229940067157 phenylhydrazine Drugs 0.000 claims abstract description 3
- 238000001953 recrystallisation Methods 0.000 claims abstract description 3
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical class CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims abstract 2
- 238000002360 preparation method Methods 0.000 claims description 13
- 230000005855 radiation Effects 0.000 claims description 10
- -1 3-methyl -1-substituted phenyl-2-pyrazolin-5-one Chemical class 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 239000002904 solvent Substances 0.000 abstract description 6
- 230000035484 reaction time Effects 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 3
- 239000012467 final product Substances 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- FTCOWMWIZNVSPP-UHFFFAOYSA-N 2-phenyl-4h-pyrazol-3-one Chemical class O=C1CC=NN1C1=CC=CC=C1 FTCOWMWIZNVSPP-UHFFFAOYSA-N 0.000 abstract 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical class COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000009514 concussion Effects 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 2
- SHXMKDIFGLNJMZ-UHFFFAOYSA-N 1-methyl-2-(3-methylphenyl)hydrazine Chemical compound CNNC1=CC=CC(C)=C1 SHXMKDIFGLNJMZ-UHFFFAOYSA-N 0.000 description 1
- SMYNLUANLYQTDV-UHFFFAOYSA-N CC1=CC=C(C=C1)N1N=CCC1=O.CC1(CC(C(=O)O)=CC=C1)C(=O)O Chemical compound CC1=CC=C(C=C1)N1N=CCC1=O.CC1(CC(C(=O)O)=CC=C1)C(=O)O SMYNLUANLYQTDV-UHFFFAOYSA-N 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- 241001635574 Sabatia angularis Species 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种微波无溶剂快速合成3-甲基-1取代苯基-2-吡唑啉-5-酮的方法。在微波条件下，使用取代苯肼和乙酰乙酸乙酯快速合成，经乙酸乙酯重结晶得最后产物，具有不需溶剂、反应时间短、产率高等特点。The invention relates to a method for rapidly synthesizing 3-methyl-1 substituted phenyl-2-pyrazolin-5-one by microwave without solvent. Under microwave conditions, it is quickly synthesized by using substituted phenylhydrazine and ethyl acetoacetate, and the final product is obtained by recrystallization from ethyl acetate. It has the characteristics of no solvent, short reaction time and high yield.
Description
Technical field
The present invention relates to a kind of non-solvent microwave method of synthetic 3-methyl isophthalic acid-substituted-phenyl-2-pyrazolin-5-one fast.Under microwave condition, use substituted phenylhydrazines and methyl aceto acetate synthetic fast, obtain final product through re-crystallizing in ethyl acetate, having does not need that solvent, reaction times are short, the productive rate high.
Background technology
3-methyl isophthalic acid-substituted-phenyl-2-pyrazolin-5-one; it is a class cerebral protective agent (free-radical scavengers); mechanism research prompting; it can remove free radical; suppress lipid peroxidation; thereby suppress the oxidative damage of brain cell, vascular endothelial cell, neurocyte, particularly the 3-methyl-1-phenyl-2-pyrazolin-5-one effect is best.Therefore by clinical be used to improving the nervous symptoms that cerebral stroke at acute period occurs, action and the dysfunction of daily life.
In the technology of existing synthetic 3-methyl isophthalic acid-substituted-phenyl-2-pyrazolin-5-one, mostly by substituted phenylhydrazines and Butanonamide or methyl aceto acetate back flow reaction in ethanol or water, obtained.There is the problem in many synthesizing: as the raw material Butanonamide, be difficult to obtain; Make solvent with ethanol, increased cost on the one hand, the prior organic solvent of having introduced does not meet environment protection requirement; Substituted phenylhydrazines is added and is warmed up to 50 ℃ and adds methyl aceto acetate under uniform stirring again, and process is relatively numerous and diverse.Above-mentioned all factors cause being unfavorable for realizing scale operation, the popularization of 3-methyl isophthalic acid-substituted-phenyl-2-pyrazolin-5-one series products.
The present invention under microwave condition, uses substituted phenylhydrazines and methyl aceto acetate synthetic fast, through re-crystallizing in ethyl acetate, obtains 3-methyl isophthalic acid-substituted-phenyl-2-pyrazolin-5-one compounds, and having does not need that solvent, reaction times are short, the productive rate high.
Summary of the invention
The object of the present invention is to provide a kind of fast, 3-methyl isophthalic acid-substituted-phenyl that productive rate is high-2-pyrazolin-5-one preparation method.
Preparation method provided by the invention, under the microwave radiation condition, make substituted phenylhydrazines and methyl aceto acetate reaction, obtains 3-methyl isophthalic acid-substituted-phenyl-2-pyrazolin-5-one.
Reaction formula is as follows:
Wherein, R
1, R
2, R
3, R
4, R
5Can be respectively H, CH
3O or be no more than the alkyl of 3 carbon atoms.
In preparation method of the present invention, react under solvent-free condition.
The substituted phenylhydrazines of indication of the present invention refers to the compound as shown in the formula I:
Wherein, R
1, R
2, R
3, R
4, R
5Can be respectively H, CH
3O or be no more than the alkyl of 3 carbon atoms.
3-methyl isophthalic acid-the substituted-phenyl of indication of the present invention-2-pyrazolin-5-one refers to the compound as shown in the formula II:
Wherein, R
1, R
2, R
3, R
4, R
5Can be respectively H, CH
3O or be no more than the alkyl of 3 carbon atoms.
, through research of the present invention, in preparation method of the present invention, adopt the microwave of power 250 to 400W to carry out radiation.In preferred scheme, the microwave of employing 300 to 350W carries out radiation.In preferred scheme, adopt the microwave of 300W to carry out radiation.
In preparation method of the present invention, microwave irradiation time is controlled at 8 to 20 minutes.In preferred scheme, microwave irradiation time is controlled at 10 to 15 minutes.
In preparation method of the present invention, also comprise the re-crystallization step of using ethyl acetate under low temperature.
Embodiment
Embodiment 1
3-methyl isophthalic acid-p-methylphenyl-2-pyrazolin-5-one
get to procarbazine 12.2g (0.1mol), methyl aceto acetate 17.7ml (0.14mol), add in round-bottomed flask and shake, ultrasonic concussion 2min, connect reflux, put under normal pressure microwave reactor 300W microwave radiation the 10min that refluxes, obtain red thick liquid, add the dilution of 20ml methyl aceto acetate and 0.1g heating activated carbon backflow 5min, filtered while hot, be cooled to room temperature, 1/2 volume distillation washing 3 times, 1/2 volume saturated common salt washing 3 times, anhydrous magnesium sulfate drying, underpressure distillation, be dissolved in the 5ml ethyl acetate under 60 ℃ of gained white solids,-25 ℃ of lower crystallizations 10 hours, decompress filter, vacuum-drying obtained white solid 15.9g (0.0854mol) in 4 hours, productive rate 85.4%.mp134～125.5℃
Embodiment 2
3-methyl isophthalic acid-(2,3-3,5-dimethylphenyl)-2-pyrazolin-5-one
get 2, 3-dimethyl hydrazinobenzene 13.6g (0.1mol), methyl aceto acetate 17.7ml (0.14mol), add in round-bottomed flask and shake, ultrasonic concussion 2min, connect reflux, put under normal pressure microwave reactor 300W microwave radiation the 10min that refluxes, obtain the scarlet thick liquid, add the dilution of 20ml methyl aceto acetate and 0.1g heating activated carbon backflow 5min, filtered while hot, be cooled to room temperature, 1/2 volume distillation washing 3 times, 1/2 volume saturated common salt washing 3 times, anhydrous magnesium sulfate drying, underpressure distillation, be dissolved in the 5ml ethyl acetate under 60 ℃ of gained white solids,-25 ℃ of lower crystallizations 10 hours, decompress filter, vacuum-drying obtained white solid 16.2g (0.0807mol) in 4 hours, productive rate 80.7%.mp152～154.℃
Embodiment 3
3-methyl-1-phenyl-2-pyrazolin-5-one
get phenylhydrazine 10.8g (0.1mol), methyl aceto acetate 17.7ml (0.14mol), add in round-bottomed flask and shake, ultrasonic concussion 2min, connect reflux, put under normal pressure microwave reactor 300W microwave radiation the 10min that refluxes, obtain rose pink thick liquid, add the dilution of 20ml methyl aceto acetate and 0.1g heating activated carbon backflow 5min, filtered while hot, be cooled to room temperature, 1/2 volume distillation washing 3 times, 1/2 volume saturated common salt washing 3 times, anhydrous magnesium sulfate drying, underpressure distillation, be dissolved in the 5ml ethyl acetate under 60 ℃ of gained white solids,-25 ℃ of lower crystallizations 10 hours, decompress filter, vacuum-drying obtained white solid 14.3g (0.0821mol) in 4 hours, productive rate 82.1%.Mp126～128. ℃ (document: 127.5～128.5 ℃)
Embodiment 4
Take 3-methyl-1-phenyl-2-pyrazolin-5-one as example, investigated the impact on reaction yield of different microwave and reaction times, reaction process is with embodiment 1-3.
Claims (7)
Priority Applications (1)
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|---|---|---|---|
| CN2013103406489A CN103396365A (en) | 2013-08-06 | 2013-08-06 | Synthesis method of pyrazolone |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013103406489A CN103396365A (en) | 2013-08-06 | 2013-08-06 | Synthesis method of pyrazolone |
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|---|---|
| CN103396365A true CN103396365A (en) | 2013-11-20 |
Family
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| CN2013103406489A Pending CN103396365A (en) | 2013-08-06 | 2013-08-06 | Synthesis method of pyrazolone |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107652237A (en) * | 2017-11-15 | 2018-02-02 | 天津瑞岭化工有限公司 | A kind of synthetic method of pyrazolone and its derivative |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101213189A (en) * | 2005-04-28 | 2008-07-02 | 拜耳医药保健股份公司 | 4-(pyridin-3-yl)-2-(pyridin-2-yl)-1,2-dihydro-3h-pyrazol-3-one derivatives as specific hif-prolyl-4-hydroxylase inhibitors for treating cardiovascular and haematological diseases |
| WO2010068717A2 (en) * | 2008-12-10 | 2010-06-17 | Auspex Pharmaceutical, Inc | Pyrazolinone scavengers of free radicals |
-
2013
- 2013-08-06 CN CN2013103406489A patent/CN103396365A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101213189A (en) * | 2005-04-28 | 2008-07-02 | 拜耳医药保健股份公司 | 4-(pyridin-3-yl)-2-(pyridin-2-yl)-1,2-dihydro-3h-pyrazol-3-one derivatives as specific hif-prolyl-4-hydroxylase inhibitors for treating cardiovascular and haematological diseases |
| WO2010068717A2 (en) * | 2008-12-10 | 2010-06-17 | Auspex Pharmaceutical, Inc | Pyrazolinone scavengers of free radicals |
Non-Patent Citations (1)
| Title |
|---|
| MOJTAHEDI, MOHAMMAD M.等: "Microwave-assisted synthesis of substituted pyrazolones under solvent-free conditions", 《HETEROCYCLIC COMMUNICATIONS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107652237A (en) * | 2017-11-15 | 2018-02-02 | 天津瑞岭化工有限公司 | A kind of synthetic method of pyrazolone and its derivative |
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Application publication date: 20131120 |