CN103664758B - The synthetic method of Mexidole - Google Patents
The synthetic method of Mexidole Download PDFInfo
- Publication number
- CN103664758B CN103664758B CN201310622873.1A CN201310622873A CN103664758B CN 103664758 B CN103664758 B CN 103664758B CN 201310622873 A CN201310622873 A CN 201310622873A CN 103664758 B CN103664758 B CN 103664758B
- Authority
- CN
- China
- Prior art keywords
- mexidole
- methyl
- grams
- synthetic method
- minutes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
Abstract
The invention belongs to chemosynthesis technical field, be specifically related to a kind of synthetic method of Mexidole.The synthetic method of Mexidole of the present invention, comprises the steps: S1: the synthesis of dimethyl furan; The synthesis of S2:2,3,5,6-tetrafluorobenzamide.The synthetic method of Mexidole of the present invention, adds proper catalyst Secondary ammonium phosphate and tosic acid in cyclization process, under 50 DEG C of condition of normal pressure, obtain product, and raw material reaction is thorough, and the reaction times is short, and yield is high.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to a kind of synthetic method of Mexidole.
Background technology
2-ethyl-6-methyl-3-pyridone hydrochloride, a kind of novel anti-oxidation medicine. be the compound with brand new first developed by S.R.L institute of materia medica, this medicine is improved immunity of organisms, promote lymphopoiesis, improve scavenger cell, NK cell, engulfing and lethality of T cell, increase leukocytic quantity, improve the effect of sudismase, interior free yl can be eliminated, the content reducing mda (M.D.A) in body improves flowing and the closure of cytolemma, reduce body lipid levels of peroxide, improve myocardial metabolism, adjustment blood pressure, blood sugar keeps normal level, thus reach the object for the treatment of.US4486440 reports the clinical application of this medicine, within 1994, has this medicine of report to be applied in Russia.
From product structure and literature survey result, Mexidole and Mexidole have two synthetic technology circuits:
(1) with 2-picoline for starting raw material
With 2-picoline for starting raw material, obtain through the chlorination of 5-position, 6-acetylize, carbonyl reduction, again hydrolysis, four-step reaction altogether, the total recovery 10% in 2-picoline:
Chlorination reaction need use chlorine and a large amount of acid, and inevitably produces methyl ortho position by product, due to less with product characteristics difference, and separation difficulty, yield 45%; Second step using acetic anhydride as acylating reagent, yield 67%; 3rd step adopts the imperial method of yellow ring or metallic reducing agent, yield 50%; Finally be hydrolyzed in the basic conditions, yield 66%.
(2) with 2-first tomb furans for starting raw material
With 2-methyl furan for starting raw material, through propionating, then ring expansion obtains target product in ammonia solution.Two-step reaction is in the document total recovery 25% of 2-methyl furan:
The acidylate of 2-methyl furan needs acid as catalyzer, but furan nucleus is not acidproof, yield 50%; Ring expansion need use polar organic solvent, and owing to being alkaline environment, furan nucleus is opened needs comparatively high temps, is also likely substituted by pyrrole ring, so yield also lower (45-50%), the pressure that causes of Yin Gaowen is higher in addition.
Patent 2010102265672 discloses a kind of production method of Mexidole, belongs to chemosynthesis technical field.Be included in propionic anhydride and add solid acid, stir and heat up, slowly drip 2-methyl furan, react to obtain 2-propionyl-5-methyl furan; Then in 2-propionyl-5-methyl furan, ammoniacal liquor, ammonium chloride and resin is added; Filtration of catalyst after reaction; solvent is removed in decompression; extracted out by ammonia, take out solution left standstill, product is separated out; add recrystallisation from isopropanol; suction filtration, filter after filtrate recrystallization, vacuum-drying obtains Mexidole.But it is that yield is low that this technique exists, High Temperature High Pressure, and the halfway defect of raw material reaction.
Have based on this, the invention reside in the production method of grinding and seeking a kind of new Mexidole.
Summary of the invention
In order to solve above-mentioned technical problem, the invention provides a kind of synthetic method of Mexidole.
The present invention is realized by following technical scheme:
A synthetic method for Mexidole, comprises the steps:
S1: the synthesis of dimethyl furan
At 20 DEG C, by 15 grams of propionic anhydrides and 9.2 grams of 2-methyl furan mixing, add by the ortho-phosphoric acid of 0.45 gram 85% and 0.3 gram of Vanadium Pentoxide in FLAKES, reactant becomes light green, and temperature of reaction was increased to 135 DEG C in 10 minutes simultaneously; In 30 minutes, stir at the temperature of 125-135 DEG C, be cooled to 80 DEG C subsequently, then add 1.6 grams of water, in 15 minutes, be cooled to 60 DEG C; In 30 minutes, add 8 milliliter of 25% ammonia soln subsequently, temperature finally rises to 80 DEG C, and stop cooling and stirring, layering after 10 minutes, obtains 14.430 grams of 5-methyl-2-acetonyl furans;
The synthesis of S2:2,3,5,6-tetrafluorobenzamide
Methyl alcohol 30 milliliters, ammoniacal liquor 0.6 milliliter, catalyzer is diammonium hydrogen phosphate 0.5 gram and tosic acid 0.025 gram, and 5.6 grams of 5-methyl-2-acetonyl furans, 50 DEG C of reactions obtain 4.81 grams of 2-ethyl-6-methyl 3-pyridols for 4 hours.
In the synthetic method of above-mentioned Mexidole, in described step S1, Vanadium Pentoxide in FLAKES is 76.96% for measuring containing P2O5.
In the synthetic method of above-mentioned Mexidole, in described step S2, ammonia concn is 25%.
In the synthetic method of above-mentioned Mexidole, in described step S2, the mass percent concentration of 5-methyl-2-acetonyl furans is 96.5%.
Reaction formula of the present invention is as follows:
Beneficial effect of the present invention is, adds proper catalyst Secondary ammonium phosphate and tosic acid in cyclization process, under 50 DEG C of condition of normal pressure, obtain product, and raw material reaction is thorough, and the reaction times is short, and yield is high.
Embodiment
Below in conjunction with specific embodiment, the present invention is further described, so that those skilled in the art more understands the present invention, but does not therefore limit the present invention.
Embodiment 1
S1: the synthesis of methyl furan
At 20 DEG C, by 15 grams of propionic anhydrides and 9.2 grams of 2-methyl furan mixing, add by the ortho-phosphoric acid of 0.45 gram 85% and 0.3 gram of Vanadium Pentoxide in FLAKES (phosphorus pentoxide content is 76.96%), reactant becomes light green, and temperature of reaction was increased to 135 DEG C in 10 minutes simultaneously; In 30 minutes, stir at the temperature of 125-135 DEG C, be cooled to 80 DEG C subsequently, then add 1.6 grams of water, in 15 minutes, be cooled to 60 DEG C; In 30 minutes, add 8 milliliter of 25% ammonia soln subsequently, temperature finally rises to 80 DEG C, stops cooling and stirring, layering after 10 minutes, obtain 14.430 grams of 5-methyl-2-acetonyl furans, yield is that 93.2%(is in theory by 2-methyl furan), total reaction times is 1 hour 55 minutes.
2. the synthesis of 2,3,5,6-tetrafluorobenzamide
Methyl alcohol 30 milliliters, ammoniacal liquor 0.6 milliliter (25% ammoniacal liquor), catalyzer is diammonium hydrogen phosphate 0.5 gram and tosic acid 0.025 gram, 5.6 grams of 5-methyl-2-acetonyl furans (mass percent concentration of 5-methyl-2-acetonyl furans is 96.5%), 50 DEG C of reactions obtain 4.81 grams of 2-ethyl-6-methyl 3-pyridols for 4 hours.The transformation efficiency of reaction is 96.05%, is 93.18% by the 5-methyl 2-acetonyl furans rate of collecting.It is 99.9% that obtained 2-ethyl-6-methyl 3-pyridol HPLC detects 2-ethyl-6-methyl 3-pyridol content.
TLC(acetone: chloroform: normal hexane: 25% ammoniacal liquor=20:20:0.5:5) detect not impure, sulfated ash (standard regulation be no more than 0.3%) do not detected.
Claims (4)
1. a synthetic method for Mexidole, comprises the steps:
At S1:20 DEG C, by 15 grams of propionic anhydrides and 9.2 grams of 2-methyl furan mixing, add by the ortho-phosphoric acid of 0.45 gram 85% and 0.3 gram of Vanadium Pentoxide in FLAKES, reactant becomes light green, and temperature of reaction was increased to 135 DEG C in 10 minutes simultaneously; In 30 minutes, stir at the temperature of 125-135 DEG C, be cooled to 80 DEG C subsequently, then add 1.6 grams of water, in 15 minutes, be cooled to 60 DEG C; In 30 minutes, add 8 milliliter of 25% ammonia soln subsequently, temperature finally rises to 80 DEG C, and stop cooling and stirring, layering after 10 minutes, obtains 14.430 grams of 5-methyl-2-acetonyl furans;
S2: methyl alcohol 30 milliliters, ammoniacal liquor 0.6 milliliter, catalyzer is Secondary ammonium phosphate 0.5 gram and tosic acid 0.025 gram, and 5.6 grams of 5-methyl-2-acetonyl furans, 50 DEG C of reactions obtain 4.81 grams of 2-ethyl-6-methyl 3-pyridols for 4 hours.
2. the synthetic method of Mexidole according to claim 1, is characterized in that, in described step S1, Vanadium Pentoxide in FLAKES is for containing P
2o
5amount is 76.96%.
3. the synthetic method of Mexidole according to claim 1, is characterized in that, in described step S2, ammonia concn is 25%.
4. the synthetic method of Mexidole according to claim 1, is characterized in that, in described step S2, the mass percent concentration of 5-methyl-2-acetonyl furans is 96.5%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310622873.1A CN103664758B (en) | 2013-11-30 | 2013-11-30 | The synthetic method of Mexidole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310622873.1A CN103664758B (en) | 2013-11-30 | 2013-11-30 | The synthetic method of Mexidole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103664758A CN103664758A (en) | 2014-03-26 |
| CN103664758B true CN103664758B (en) | 2015-11-18 |
Family
ID=50303638
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310622873.1A Active CN103664758B (en) | 2013-11-30 | 2013-11-30 | The synthetic method of Mexidole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103664758B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112724076A (en) * | 2020-12-28 | 2021-04-30 | 浦拉司科技（上海）有限责任公司 | Improved synthesis method of 6-methyl-2-ethyl-3-hydroxypyridine |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992019597A1 (en) * | 1991-04-24 | 1992-11-12 | Medea Research S.R.L. | Gallic acid derivative, and pharmaceutical compositions containing it |
| RU2296123C1 (en) * | 2005-10-27 | 2007-03-27 | Насыбуллин Радик Равильевич | Method for preparing derivatives of 3-hydroxypyridine |
| RU2395498C1 (en) * | 2009-03-10 | 2010-07-27 | Евгений Александрович Савельев | Method of producing 2-ethyl-6-methyl-3-hydroxypyridine |
| CN101891677A (en) * | 2010-07-13 | 2010-11-24 | 绍兴文理学院 | Preparation method of 6-methyl-2-ethyl-3-hydroxy pyridine |
-
2013
- 2013-11-30 CN CN201310622873.1A patent/CN103664758B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992019597A1 (en) * | 1991-04-24 | 1992-11-12 | Medea Research S.R.L. | Gallic acid derivative, and pharmaceutical compositions containing it |
| RU2296123C1 (en) * | 2005-10-27 | 2007-03-27 | Насыбуллин Радик Равильевич | Method for preparing derivatives of 3-hydroxypyridine |
| RU2395498C1 (en) * | 2009-03-10 | 2010-07-27 | Евгений Александрович Савельев | Method of producing 2-ethyl-6-methyl-3-hydroxypyridine |
| CN101891677A (en) * | 2010-07-13 | 2010-11-24 | 绍兴文理学院 | Preparation method of 6-methyl-2-ethyl-3-hydroxy pyridine |
Non-Patent Citations (1)
| Title |
|---|
| 一种3-羟基-2,6-二烷基类吡啶合成方法的优化;周泽建;《北京化工大学学报》;20080430;第35卷(第4期);全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103664758A (en) | 2014-03-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3004047B1 (en) | Compounds of '3-(5-substituted oxy-2,4-dinitro-phenyl)-2-oxo-propionic acid ester', process and applications thereof | |
| CN104356146B (en) | A kind of preparation method of cefotiam chloride | |
| CN103772432B (en) | A kind of production method of benfotiamine | |
| CN101880240B (en) | Ornithine and aspartate compound and novel method thereof | |
| CN104311597A (en) | Industrial production method of s-(-)-ornidazole disodium phosphate | |
| CN105330582A (en) | Preparation method for (R)-4-hydroxy-2-oxo-1-pyrrolidine acetamide | |
| CN102485723A (en) | Semi-synthesis of vinpocetine through one kettle way and preparation of water-soluble vinpocetine salt | |
| CN103664758B (en) | The synthetic method of Mexidole | |
| CN102442972B (en) | Industrial preparation method for pramipexole and its dihydrochloride monohydrate | |
| CN101979395B (en) | Method for preparing topiramate | |
| CN101475539A (en) | Refining method for preparing high-purity oteracil potassium | |
| CN102391186A (en) | Method for preparing ozagrel intermediate (E)-4-(methyl imidazolyl) methyl cinnamate | |
| CN104725422A (en) | Minodronic acid preparation method | |
| CN101781264B (en) | Production method of 1-methyl-5-mercapto-1,2,3,4-tetrazole | |
| CN110003238A (en) | A kind of preparation method of cefotiam | |
| CN103012437A (en) | Method for preparing cefoxitin acid as antibacterial medicament | |
| CN105175355B (en) | A kind of preparation method of 2- cyano-phenothiazines | |
| CN103351346A (en) | Preparation method of impurity HP1 in bendamustine hydrochloride | |
| CN105294734B (en) | A kind of method for preparing cefonicid dibenzylethylenediamsalt salt | |
| CN106565776A (en) | Separating and purifying method for 4-(methyl hydroxyl phosphoryl)-2-carbonyl butyric acid | |
| CN103833660B (en) | The preparation method of lamotrigine and intermediate thereof | |
| CN101492388A (en) | Method for synthesis of Miqujing medicament material | |
| CN110698419A (en) | Preparation method of cycleanine | |
| CN104447273B (en) | A kind of recovery method of Zopiclone resolving agent D-(+)-oxysuccinic acid | |
| EP3026047A1 (en) | Method for producing heterocyclic compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20171220 Address after: The torch Park HII1201-217 No. 1789 Xinxiang 453600 Henan province high tech Zone Frestech Avenue (2109) Patentee after: Henan plain public intellectual property operation and Management Co., Ltd. Address before: 257335 Guangrao City, Dongying Province town of Rubber Industrial Park Patentee before: Shandong Yongtai Chemical Co., Ltd. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20180703 Address after: 226000 Jiangsu Tongzhou District Nantong science and Technology Industrial Park, north of Wu Tong Road, west of tipping Road, south of dandelion Road, east of Zhang Zhishan river. Patentee after: Nantong Rui Environmental Protection Technology Co., Ltd. Address before: 453600 HII1201-217 (2109), torch Park, No. 1789, Xinfei Avenue, Xinxiang new high tech Zone, Henan. Patentee before: Henan plain public intellectual property operation and Management Co., Ltd. |
|
| TR01 | Transfer of patent right |