CN102558133B - Industrialized synthetic technology of 3-(3',4'-methylidynel dioxo phenyl)-acrylyl piperidine - Google Patents
Industrialized synthetic technology of 3-(3',4'-methylidynel dioxo phenyl)-acrylyl piperidine Download PDFInfo
- Publication number
- CN102558133B CN102558133B CN201210030127.9A CN201210030127A CN102558133B CN 102558133 B CN102558133 B CN 102558133B CN 201210030127 A CN201210030127 A CN 201210030127A CN 102558133 B CN102558133 B CN 102558133B
- Authority
- CN
- China
- Prior art keywords
- inferior
- dimethylbenzene
- reaction
- dioxy phenyl
- piperidines
- 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.)
- Expired - Fee Related
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Abstract
The invention belongs to an industrialized synthetic technology of 3-(3',4'-methylidynel dioxo phenyl)-acrylyl piperidine. The compound has anti-epileptic, anti-convulsions, anti-depression and other pharmacological activities, and the compound has been applied in treatment of epilepsy. The 3-(3',4'-methylidynel dioxo phenyl)-acrylyl piperidine is obtained by using heliotropin 2 as an initial raw material, carrying out condensation reaction on heliotropin 2 and propane diacid, and carrying out amidation reaction on heliotropin 2 and piperidine. The synthetic technology has the advantages of high yield, good purity, and easy operation, and is convenient for industrialized production, etc. The synthesis of the compound comprises the following equations.
Description
Technical field
The present invention relates to the industrial synthesis technique of a kind of compound 3-(3 ', 4 '-inferior first dioxy phenyl)-Antiepilepsirin, this compound has the pharmacologically actives such as anti-epileptic, anticonvulsion, antidepressant.
Background technology
Piperine (Piperine) is one of main effective constituent of plant pepper, and its chemical structure belongs to Cinnamamides, and research shows, this compounds has calmness, hypnosis, anticonvulsion and myorelaxant effects.3-(3 ', 4 '-inferior first dioxy phenyl)-Antiepilepsirin (I) is the derivative of piperine, the antiepileptic drug that a kind of China that to be the eighties in last century Beijing scientific research personnel of department of pharmacy of medical college develop through piperine is carried out to composition optimizes has complete independent intellectual property right, clinical for the treatment of epilepsy.Clinical experiment shows, this medicine is applicable to various types of epilepticss, has the characteristics such as the anti-epilepsy of wide spectrum, high-efficiency low-toxicity, and the patient can relieved long-term taking, is particularly useful for children epilepsy patient and teenager epileptic.Further research shows, this compound also has stronger anticonvulsion, antidepressant activity, and Pharmacological Mechanism studies have shown that, this compound has the nerve ending of promotion to discharge 5-HT, increase the effect of the interior 5-HT of brain and DOPAMINE CONTENT IN RABBIT, thereby there is anticonvulsion, antidepressant effect.Therefore, this compound is with a wide range of applications.
Document has been reported the synthetic of various Cinnamamides.Yang Hui in 1999 etc. have reported and have replaced the synthetic of Cinnamamide Deriv A Tives, under piperidines catalysis, substituted benzaldehyde and propanedioic acid are used the sulfur oxychloride chloride after condensation reaction generation replacement TRANSCINNAMIC ACID occurs in pyridine in benzene, obtain the Cinnamamide Deriv A Tives replaced through aminolysis reaction.Dish hawks in 2004 etc. have been reported intermediate 3-(3 ', 4 '-inferior first dioxy phenyl)-acrylic acid improvement synthetic method, take toluene as solvent, replace propanedioic acid with diethyl malonate, with piperonylaldehyde generation condensation reaction, under the catalysis of acetic acid and piperidines, through condensation, hydrolysis decarboxylation, synthesize and obtain.Zhang Qunying in 2006 etc. have reported the synthetic route improvement of aryl pyrimidines, take phenyl aldehyde as raw material, with the diacetyl oxide condensation, obtain TRANSCINNAMIC ACID, with after the sulfur oxychloride chloride, synthesizing and obtain aryl pyrimidines with the piperidines aminolysis again.In sum, Cinnamamides is to take aromatic aldehyde first to pass through the corresponding TRANSCINNAMIC ACID of condensation reaction synthetic intermediate as starting raw material, and then changes acyl chlorides into and carry out aminolysis with corresponding amine and obtain target compound.Therefore, 3-(3 ', 4 '-inferior first dioxy phenyl)-Antiepilepsirin (I) can be synthesized through condensation reaction and amidate action two steps: the first step condensation reaction synthetic intermediate 3-(3 ', 4 '-inferior first dioxy phenyl)-vinylformic acid (III), second step changes acyl chlorides into and carries out amidate action with piperidines again and obtain target compound.The synthetic method of two-step reaction is summarized as follows respectively:
One, take piperonylaldehyde (II) as raw material carries out condensation reaction synthetic intermediate 3-(3 ', 4 '-inferior first dioxy phenyl)-vinylformic acid (III), can adopt three kinds of methods: diacetyl oxide method, diethyl malonate method and propanedioic acid method.In the diacetyl oxide method, adopt diacetyl oxide and piperonylaldehyde to carry out condensation, this step reaction needs comparatively high temps (approximately 140 ℃), long period (about 10h), strict anhydrous condition, and intermediate III need be carried out purifying through processes such as alkalization salify, decolouring, acidifying washings.In the diethyl malonate method, adopt toluene solvant can take away the water that reaction generates, reaction times, about 4h can complete condensation reaction, but obtaining is 3-(3 ', 4 '-inferior first dioxy phenyl)-diethyl malonate, still need to just can obtain intermediate III at hydrolysis decarboxylation under acidic conditions, increase reactions steps, operate complicated.In the propanedioic acid method, the temperature of reaction that propanedioic acid and piperonylaldehyde carry out condensation lower (lower than 100 ℃), reaction times shortens (about 2h) greatly, one step both can complete, and intermediate III only needs the acidifying washing to get final product purifying, and technique is simple, but decarboxylic reaction needs high temperature to complete (straight fire heating 0.5h left and right), there is certain danger in this reaction, is difficult for realizing industrialization.
Method one: diacetyl oxide method
Method two: diethyl malonate method
Method three: propanedioic acid method
In the second step amidate action, generally use the solvent of benzene as synthetic this class acid amides, but, because benzene is easy to be absorbed by human body alimentary canal, skin also there is a small amount of absorption, and be difficult to processing after discharge, cause environmental pollution.Bibliographical information is all to adopt sulfur oxychloride to carry out chloride to intermediate III, then obtains product with the piperylhydrazine solution.Usually the acyl chlorinating agent of carboxylic acid mainly contains sulfur oxychloride, phosphorus trichloride, phosphorus oxychloride, phosgene, oxalyl chloride etc., laboratory generally adopts sulfur oxychloride as acyl chlorinating agent, this reaction can be carried out at a lower temperature, byproduct of reaction is sulfurous gas and hydrogen chloride gas, be easy to remove from reaction, but the sulfur oxychloride activity is higher, remaining excess chlorination sulfoxide must be removed and just can carry out lower step aminolysis process, otherwise causes more by product to produce.Industrial normal employing phosphorus trichloride carries out chloride, and this reaction can be carried out equally at a lower temperature, and the by product phosphorous acid of reaction is easy to separate, and excessive a little phosphorus trichloride can not separate, and directly carries out aminolysis.
Summary of the invention
The object of the present invention is to provide the industrial synthesis technique of the 3-that a kind of step is few, reaction efficiency is high (3 ', 4 '-inferior first dioxy phenyl)-Antiepilepsirin.
Technical scheme of the present invention:
Adopting piperonylaldehyde (II) be starting raw material, through with the propanedioic acid condensation, obtaining intermediate 3-(3 ', 4 '-inferior first dioxy phenyl)-vinylformic acid (III), then passes through chloride, reacts with piperidine amides and obtain target compound (I).
It has following reaction formula:
1) condensation reaction: suction dimethylbenzene and pyridine in reactor, start stirring, drop into successively the piperidines of piperonylaldehyde (II), propanedioic acid and catalytic amount, open condenser condenses water, progressively heat up, 1～2h temperature rises to 80 ℃～100 ℃, keep temperature to stir 5～10h, change logical cold water temperature is down to below 50 ℃, stop stirring the whizzer rejection filter, it is 1～2 that filter cake is acidified to pH with concentrated hydrochloric acid, wash with water again to neutrality, rejection filter, be drying to obtain intermediate 3-(3 ', 4 '-inferior first dioxy phenyl)-vinylformic acid (III);
2) amidate action: suction dimethylbenzene in reactor, start stirring, add successively again the first step intermediate 3-(3 ', 4 '-inferior first dioxy phenyl)-vinylformic acid (III) and acylating agent, open condenser condenses water, progressively heat up, 1～2h temperature rises to 70 ℃～90 ℃, insulated and stirred 4-6h, be cooled to below 45 ℃, slowly drip piperidines under stirring, control temperature and be no more than 45 ℃, after adding, make temperature remain on 50～55 ℃ and stir 2h, stop heating, put to room temperature, reaction solution is first washed with weak ammonia, with dilute hydrochloric acid, wash again, finally remove dimethylbenzene under reduced pressure, the cooling crude product of separating out, crude product obtains required high purity 3-(3 ' with the dimethylbenzene recrystallization, 4 '-inferior first dioxy phenyl)-Antiepilepsirin (I).
Compare with the preparation method of existing 3-(3 ', 4 '-inferior first dioxy phenyl)-Antiepilepsirin, the invention has the advantages that:
1. in condensation reaction, the present invention is improved on the basis of traditional propanedioic acid method, take piperidines as catalyzer, adopt pyridine and dimethylbenzene mixed solvent, make piperonylaldehyde and propanedioic acid generation condensation reaction and remove carboxyl to obtain intermediate III, reaction process relaxes, and a step completes, and has avoided the high temperature decarboxylation reaction of traditional propanedioic acid method;
2. in condensation reaction, the present invention adopts pyridine and dimethylbenzene mixed solvent, adopts the method for applying mechanically continuously, suitably adding, and has both reduced cost, has improved again yield.In mixed solvent, the volume ratio of pyridine and dimethylbenzene is 40～55%: 45～60%, and the use of mixed solvent can make two kinds of reactants all be easy to dissolve, to promote fully carrying out of reaction.The water generated in reaction constantly separates through water trap, to promote reaction, carries out fully.In production, mixed solvent adopts the method for applying mechanically continuously, suitably adding, and has both reduced cost, has improved again yield;
3. amidate action, the present invention selects dimethylbenzene as reaction solvent, can reduce as far as possible the harm of noxious solvent to people and environment;
4. in amidate action, piperidines drips excessively 100%～500%, both as reactant, participates in reaction, again as acid scavenger except the hydrogenchloride generated in dereaction, to impel acyl chlorides, react completely as far as possible, improve yield;
5. the mixed solvent that the present invention uses is reusable, and other reagent also is conventional reagent, and therefore production technique cost of the present invention is low, has good application prospect;
6. the invention provides the synthetic 3-(3 ' of an industrialization, the method of 4 '-inferior first dioxy phenyl)-Antiepilepsirin, the synthetic route design is easy, reasonable, obtain product by two-step reaction, each step reaction conditions gentleness, overall yield of reaction can reach more than 60%, is easy to scale operation, and has the stability of good suitability for industrialized production.
Embodiment
Following embodiment illustrates content of the present invention better.But the present invention is not limited to following embodiment.
3-(3 ', 4 '-inferior first dioxy phenyl)-acrylic acid synthetic
In the 300L reactor, suction 66L dimethylbenzene and 66L pyridine, start stirring, then drop into successively 72Kg piperonylaldehyde, 75Kg propanedioic acid and 5Kg piperidines, opens condenser condenses water.Start to heat up, the 1h left and right is warming up to 80 ℃ (interior temperature), and interior temperature remains on 80-85 ℃ and stirs 8h.Change logical cold water and make, below interior temperature drop to 45 ℃, to stop stirring, reaction mixture is put to the 60L plastic tank, cooling, placement is spent the night.Second day whizzer rejection filter, collect in order to the reaction of leaving office and apply mechanically filtrate merging.The white solid leached is put into to plastic tank, add 40L water, after mixing, under stirring, slowly add concentrated hydrochloric acid to adjust mixture pH=1～2, place 30min.Use the whizzer rejection filter, with tap water, be washed till filtrate pH=7, filter cake dries in shady and cool ventilation, and pulverizing, airtight package, obtain the 84Kg white solid, yield 91.1%.
synthesizing of 3-(3 ', 4 '-inferior first dioxy phenyl)-Antiepilepsirin
In the 300L reactor, suction 180L dimethylbenzene, start stirring, drops into 14Kg 3-(3 ', 4 '-inferior first dioxy phenyl)-vinylformic acid, opens condenser condenses water, then drops into the 9Kg phosphorus trichloride.Start to heat up, the 1h left and right is warming up to 75 ℃, and temperature remains on 75-80.℃ stir 4h.Change logical cold water and make, below interior temperature drop to 45 ℃, slowly to drip the 25Kg piperidines under stirring, control temperature and be no more than 45 ℃, after finishing, make interior temperature remain on 50-55 ℃ and stir 2h, stop heating, placement is spent the night.Second day adds 100L water in reactor, stirs 5min, standing 10min, after discarding water layer, organic phase is successively respectively with 95L water+5L ammoniacal liquor and 96L water+4L concentrated hydrochloric acid washing, and finally, with 100L washing twice, 5min is all stirred in each washing, standing 10min, discard water layer.Wash to finish the dimethylbenzene layer is proceeded in the 300L still kettle, start and stir and condenser condenses water, start heating, open reliever and carry out underpressure distillation, collect dimethylbenzene in order to reclaiming use.After collecting about 150L dimethylbenzene, resistates is put into to the 50L stainless steel cask, stir crystallisation by cooling, placement is spent the night.Within the 3rd day, use the whizzer rejection filter, dry the shady and cool ventilation of filter cake, pulverizes and obtain yellow solid 16Kg.Above-mentioned crude product is put in 48L dimethylbenzene, stirred and be heated to 60 ℃, insulation 30min after all dissolving, put into the 50L stainless steel cask, stir cooling crystallization, the whizzer rejection filter, naturally dry and obtain the 14.5Kg light yellow crystal, HPLC detects purity 99.8%, yield 76.8%.
1H?NMR(600MHz，CDCl
3)：δ＝1.61(m，4H)；1.68(m，2H)；3.61(d，4H)；5.98(s，2H)；6.73(d，1H)；6.79(d，1H)；6.99(dd，1H)；7.03(d，1H)；7.56(d，1H)。
13C?NMR(150MHz，CDCl
3)：δ＝24.9，25.8，27.0，43.5，47.2，101.6，106.6，108.7，115.9，123.8，130.2，142.1，148.4，149.0，165.6；CI-MS(m/z)：260(M+1)。
Claims (3)
1. a 3-(3 ', the industrial synthesis technique of 4 '-inferior first dioxy phenyl)-Antiepilepsirin, it is characterized in that: adopt piperonylaldehyde (II) for starting raw material, through with the propanedioic acid condensation, obtaining intermediate 3-(3 ', 4 '-inferior first dioxy phenyl)-vinylformic acid (III), then pass through chloride, react with piperidine amides and obtain 3-(3 ', 4 '-inferior first dioxy phenyl)-Antiepilepsirin (I), synthetic route is as follows:
1) condensation reaction: suction dimethylbenzene and pyridine in reactor, the volume ratio of pyridine and dimethylbenzene is 40～55%:45～60%, start stirring, drop into successively piperonylaldehyde (II), the piperidines of propanedioic acid and catalytic amount, open condenser condenses water, progressively heat up, 1～2h temperature rises to 80 ℃～100 ℃, keep temperature to stir 5～10h, changing logical cold water is down to below 50 ℃ temperature, stop stirring, the whizzer rejection filter, it is 1～2 that filter cake is acidified to pH with concentrated hydrochloric acid, wash with water again to neutrality, rejection filter, be drying to obtain intermediate 3-(3 ', 4 '-inferior first dioxy phenyl)-vinylformic acid (III),
2) amidate action: suction dimethylbenzene in reactor, start stirring, add successively again the first step intermediate 3-(3 ', 4 '-inferior first dioxy phenyl)-vinylformic acid (III) and acylating agent, open condenser condenses water, progressively heat up, 1～2h temperature rises to 70 ℃～90 ℃, insulated and stirred 4-6h, be cooled to below 45 ℃, slowly drip piperidines under stirring, piperidines excessive 100～500%, control temperature and be no more than 45 ℃, after adding, make temperature remain on 50～55 ℃ and stir 2h, stop heating, put to room temperature, reaction solution is first washed with weak ammonia, with dilute hydrochloric acid, wash again, finally remove dimethylbenzene under reduced pressure, the cooling crude product of separating out, crude product obtains required high purity 3-(3 ' with the dimethylbenzene recrystallization, 4 '-inferior first dioxy phenyl)-Antiepilepsirin (I).
2. the industrial synthesis technique of 3-as claimed in claim 1 (3 ', 4 '-inferior first dioxy phenyl)-Antiepilepsirin, it is characterized in that: in described condensation reaction, the volume ratio of pyridine and dimethylbenzene mixed solvent is 40～55%: 45～60%; The feed ratio of propanedioic acid, piperonylaldehyde and piperidines is 14:15:1～20:15:1; The mixed solvent that reaction leaches after finishing can be applied mechanically continuously in the reaction of leaving office.
3. the industrial synthesis technique of 3-as claimed in claim 1 (3 ', 4 '-inferior first dioxy phenyl)-Antiepilepsirin, is characterized in that: in described amidate action, take dimethylbenzene as solvent; Acylating agent is a kind of in sulfur oxychloride, phosphorus trichloride, phosphorus oxychloride; Piperidines excessive 100～500%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210030127.9A CN102558133B (en) | 2012-02-13 | 2012-02-13 | Industrialized synthetic technology of 3-(3',4'-methylidynel dioxo phenyl)-acrylyl piperidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210030127.9A CN102558133B (en) | 2012-02-13 | 2012-02-13 | Industrialized synthetic technology of 3-(3',4'-methylidynel dioxo phenyl)-acrylyl piperidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102558133A CN102558133A (en) | 2012-07-11 |
| CN102558133B true CN102558133B (en) | 2014-01-08 |
Family
ID=46404889
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210030127.9A Expired - Fee Related CN102558133B (en) | 2012-02-13 | 2012-02-13 | Industrialized synthetic technology of 3-(3',4'-methylidynel dioxo phenyl)-acrylyl piperidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102558133B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103910709A (en) * | 2014-03-05 | 2014-07-09 | 甘肃省农业科学院植物保护研究所 | High-activity compound (E)-3-(3,4-methylenedioxophenyl)acrylic cyclohexanecarboxamide, and preparation method and application thereof |
| CN109867656A (en) * | 2017-12-01 | 2019-06-11 | 北京斯利安药业有限公司 | A kind of preparation method of Ilepcimide |
| CN110742077B (en) * | 2019-11-11 | 2020-07-17 | 甘肃省农业科学院植物保护研究所 | Application of cinnamate compound in preventing and treating crop fungal diseases |
| CA3213592A1 (en) * | 2021-05-28 | 2022-12-01 | Xiaohui Ma | Antidepressant and anxiolytic substituted cinnamamide compound |
| CN113480513A (en) * | 2021-06-24 | 2021-10-08 | 北京斯利安健康科技有限公司 | Preparation method of ilexlyamine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05262646A (en) * | 1992-03-23 | 1993-10-12 | Takeda Chem Ind Ltd | Hepatic disorder-inhibiting agent |
-
2012
- 2012-02-13 CN CN201210030127.9A patent/CN102558133B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN102558133A (en) | 2012-07-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102558133B (en) | Industrialized synthetic technology of 3-(3',4'-methylidynel dioxo phenyl)-acrylyl piperidine | |
| CN104610250A (en) | 1,2,3-thiadiazole-5-formamidine compound containing three N-heterocycles and synthesis | |
| CN103755688A (en) | Preparation method for afatinib compound | |
| CN101891649A (en) | Novel 3-cyano methyl benzoate preparing method | |
| CN103420881B (en) | A kind of preparation method of medicinal racemization hydroxyl Methionine calcium salt newly | |
| CN106365986A (en) | Compounds and preparation methods thereof, and uses of compounds in synthesis of brivaracetam | |
| CN103694167A (en) | Method for synthesizing flunixin meglumine | |
| CN102558080B (en) | Method for synthesizing thiotriazinone | |
| CN100361972C (en) | Synthesis of tenuazonic acid and iso-tenuazonic acid | |
| CN103664923B (en) | The preparation method of Nifuratel | |
| CN102020584A (en) | Method for synthesizing intermediate L-2-aminobutyrylamide hydrochloride of chiral drug levetiracetam | |
| CN102101830A (en) | Method for preparing trinexapac-ethyl | |
| CN102391128B (en) | Production method of antibiotic pharmaceutical intermediate mono-p-nitro benzyl malonate | |
| WO2016037588A2 (en) | New intermediate for synthesis of anti-aids drug enhancer cobicistat | |
| CN111943862A (en) | Preparation method of heart failure resistant drug Entresto key component Shakuba koji | |
| CN102180864B (en) | Preparation method of strontium ranelate | |
| CN104497048A (en) | Preparation method of minodronic acid | |
| CN101585778A (en) | A kind of preparation method of lyrica | |
| CN103980144A (en) | Nesting method for pregabalin intermediate mother liquor | |
| CN105017158B (en) | A kind of preparation method of cis Rosuvastatin calcium impurities | |
| CN104876911A (en) | Simple method for synthesizing delafloxacin | |
| CN103172497A (en) | Industrialized production process of new medicament benvitimod for treating psoriasis | |
| CN101492388A (en) | Method for synthesis of Miqujing medicament material | |
| CN101891737A (en) | Method for ammonolyzing and synthesizing meloxicam under catalysis of Lewis acid | |
| CN109369494B (en) | Preparation method of N-phenylacetyl-L-proline |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | 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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140108 Termination date: 20170213 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |