CN103333103A - Method for preparing flupirtine maleate by one-pot method - Google Patents
Method for preparing flupirtine maleate by one-pot method Download PDFInfo
- Publication number
- CN103333103A CN103333103A CN2013102922767A CN201310292276A CN103333103A CN 103333103 A CN103333103 A CN 103333103A CN 2013102922767 A CN2013102922767 A CN 2013102922767A CN 201310292276 A CN201310292276 A CN 201310292276A CN 103333103 A CN103333103 A CN 103333103A
- Authority
- CN
- China
- Prior art keywords
- toxilic acid
- flupirtine
- amino
- nitro
- reaction
- 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.)
- Granted
Links
Abstract
The invention discloses a method for preparing flupirtine maleate by a one-pot method. The method is characterized in that 2-amino-3-nitro-6-pyridine and 4-fluorobenzylamine serve as starting materials, and condensation, raney nickel reduction, ethyl chloroformate acylation and maleic acid salification are accomplished in a reactor without intermediate separation. The total yield of flupirtine maleate is increased from below 40% of a step-by-step method to above 70%, and the purity of a crude product is greater than 99%. According to the method, the technical flow is shortened, equipment is decreased, and the problem of high oxidation stain possibility of aminopyridine intermediates in a separation process is effectively solved. The feasibility and controllability of the one-pot method is proven by small-scale and pilot-scale studies, and the method is a handleable and environment-friendly manner to prepare flupirtine maleate, and is suitable for industrial production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to the novel process of a kind of " one kettle way " preparation toxilic acid flupirtine.
Background technology
The toxilic acid flupirtine is one of 2,3,6-triamino pyridine derivate, its chemistry 2-amino by name-6-[((4-fluorophenyl) methyl) amino] pyridine-3-urethanum maleate.Its structural formula is:
As a kind of non-opium maincenter anodyne of medium tenacity, the toxilic acid flupirtine does not have the habituation of opium kind analgesics, to breathing and cardiovascular systems unrestraint effect; Also have better tolerance, characteristics such as low neurotoxicity, neuroprotective and lymphocyte simultaneously.Can be used for the treatment of various types of moderate acute pains, also very effective to chronic pain and pain caused by cancer as the acute pain that various entanglement pain, operation, wound cause, show good potential applicability in clinical practice.In recent years, find that also it is expected in cerebral ischemia, senile dementia plays a role in the treatment of brain injury diseases such as parkinsonism.
The preparation document of comprehensive relevant toxilic acid flupirtine; be starting raw material with 2-amino-3-nitro-6-chloropyridine; be the most frequently used route through processes such as condensation, reduction, acidylate, salifies; yet; because reduction, acidylate, the working method difference in three steps of salify; not only synthesis yield differs greatly, and also influential to the quality of product toxilic acid flupirtine.This mainly is that the luorobenzyl aminopyridine of 3-diamino-6-and flupirtine are the polyamino pyridine derivate, very easy deterioration by oxidation because of intermediate 2.So the employing operate continuously not only can easy operation steps, and can improve product quality and yield.
Chinese patent CN102241626 has reported with 2; 6-two chloro-3-nitropyridines are raw material; solve 2-amino-3-nitro-6-chloropyridine through selectivity ammonia, again with the NSC 158269 condensation, obtain the luorobenzyl aminopyridine of yellow solid 2-amino-3-nitro-6-; after the vacuum-drying; adopt hydrogenating reduction, then under nitrogen protection and the Vinyl chloroformate acidylate, behind the filtration catalizer again with the toxilic acid salify; obtain the light green crude product, yield is about 37%(in 2-amino-3-nitro-6-chloropyridine).
Patent CN102838534 has reported that with 2-amino-3-nitro-6-chloropyridine be raw material; adopt the method for step-by-step processing; in first reactor and the NSC 158269 condensation; get the luorobenzyl aminopyridine of intermediate 2-amino-3-nitro-6-after the vacuum-drying; in second reactor, be catalyzer with the Raney's nickel; the reduction of hydrazine hydrate catalytic hydrogenation; filter the back steam desolventize solid shape intermediate 2; the luorobenzyl aminopyridine of 3-diamino-6-; in the 3rd reactor with the Vinyl chloroformate acidylate; underpressure distillation must be consolidated shape intermediate flupirtine; with refining behind the toxilic acid aqueous solution salify, total recovery 25%～30%.
Patent WO2012004391 discloses the method that a kind of high yield prepares the toxilic acid flupirtine.Be raw material with 2-amino-3-nitro-6-chloropyridine and NSC 158269; condensation gets the luorobenzyl aminopyridine of 2-amino-3-nitro-6-, adopts high-pressure hydrogenation reduction then, will reduce, the acidylate step concentrates in the high-pressure hydrogenation still and finish; salify behind the filtration catalizer again, the crude product yield is greater than 70%.This method preparation process adopts High-pressure Hydrogenation Unit, has security risk and consuming time long, is not suitable for industrial production.
It is raw material that patent CN102260209 discloses with the luorobenzyl aminopyridine of 2-amino-3-nitro-6-, and reduction, acidylate and salify step are carried out continuous operation, synthesis yield is brought up to about 58% not mentioned product purity.Because the acidylate step takes Vinyl chloroformate, organic bases to add simultaneously, and side reaction is increased, product yield reduces; Simultaneously, be raw material with the luorobenzyl aminopyridine of 2-amino-3-nitro-6-, preparation cost is higher.
Among the present invention; we consider intermediate 2 by emphasis; the chemical property of the luorobenzyl aminopyridine of 3-diamino-6-and flupirtine concentrates on condensation, reduction, acidylate, salt-forming reaction in the same popular response device and to finish, and each goes on foot intermediate without separation; simplify operational path and operation; raise the efficiency, reduce cost, the crude product total recovery is brought up to below 40% more than 70% by the substep operation; crude product purity reaches more than 99%, is suitable for industrial scale production.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of toxilic acid flupirtine, realize that " one kettle way " is synthetic, the intermediate 2 of avoiding step-by-step processing to bring, problems such as the luorobenzyl aminopyridine of 3-diamino-6-and flupirtine easy oxidation discoloration, overcome troublesome operation such as existing technology mesohigh hydrogenation, reduce production cost, improved quality product and yield, be suitable for industrial production.
The present invention is achieved by the following technical solutions:
The present invention adopts following synthetic route:
" one kettle way " of the present invention prepares the method for toxilic acid flupirtine, is that raw material makes the toxilic acid flupirtine through condensation, Raney's nickel reduction, Vinyl chloroformate acidylate, toxilic acid salify with 2-amino-3-nitro-6-chloropyridine and NSC 158269.The invention is characterized in that condensation, reduction, acidylate, the salify step-by-step processing that will report in the prior art are improved to continuous operation, each goes on foot intermediate and realizes " one kettle way " production without sepn process.
The method that " one kettle way " of the present invention prepares the toxilic acid flupirtine specifically may further comprise the steps:
2-amino-3-nitro-6-chloropyridine in the presence of organic bases with NSC 158269 generation condensation reaction, use the C1-C3 lower alcohol as reaction solvent, organic bases comprises pyridine, triethylamine, quadrol, diisopropylethylamine etc., under refluxad reacted 2～4 hours, after purified water crystallization, washing making beating, the wet product that obtain 2-amino-luorobenzyl aminopyridine of 3-nitro-6-are directly used in the next step.
The luorobenzyl aminopyridine of compound 2-amino-3-nitro-6-is under raney ni catalysis; be hydroborating reagent with 80% hydrazine hydrate; the C1-C3 lower alcohol is as reaction solvent; under refluxad reacted 2～4 hours; after nitrogen protection drops to room temperature; add Vinyl chloroformate fast; reacted at ambient temperature 2～3 hours; get flupirtine hydrochloride solution; add ammoniacal liquor or organic bases again, organic bases comprises triethylamine, quadrol etc., free 1～2 hour; get flupirtine solution, filter the not treated the next step that is directly used in of rear filtrate.
Above-mentioned filtrate is joined in the low-alcohol solution of toxilic acid, be cooled to 0-4 ℃ of crystallization and get the off-white color solid, i.e. toxilic acid flupirtine crude product, the crude product yield is greater than 70%, and purity is greater than 99%.
" one kettle way " of the present invention prepares the method for toxilic acid flupirtine; in the concrete implementation step; the acylation reaction process is directly to add Vinyl chloroformate, and does not additionally add base catalysis, is because the alkali in the first step condensation reaction just can provide alkaline environment suddenly for acylation step; guarantee carrying out smoothly of acidylate step; after treating that acidylate is finished, add alkali again and dissociate, namely obtain flupirtine solution; thereby effectively avoided the generation of too much by product, improved yield.
" one kettle way " of the present invention prepares the method for toxilic acid flupirtine, it is characterized in that reacting solvent for use and is the single fat alcoholic solvent, and described Fatty Alcohol(C12-C14 and C12-C18) is the C1-C3 lower alcohol, comprises methyl alcohol, ethanol, n-propyl alcohol, Virahol.
" one kettle way " of the present invention prepares the method for toxilic acid flupirtine, it is characterized in that: used main molar ratio of material is 2-amino-3-nitro-6-chloropyridine: NSC 158269: 80% hydrazine hydrate: Vinyl chloroformate: toxilic acid=1:1.1～2:3～8:1.1～2:1.5～3.
" one kettle way " of the present invention prepares the method for toxilic acid flupirtine, it is characterized in that: weight ratio=1:0.1～0.5 of used 2-amino-3-nitro-6-chloropyridine and reducing catalyst Raney's nickel.
The selected operational path of the present invention is simple, and is easy to operate, and each step is realized " one kettle way " production without sepn process, effectively avoided polyamino pyridine derivate oxidization of intermediates, has improved yield and product purity, is suitable for industrial scale production.
Specific embodiment
Below will the invention will be further described by embodiment, these descriptions are not that content of the present invention is done further to limit.One skilled in the art will understand that to be equal to replacement to what technical characterictic of the present invention was done, or corresponding the improvement, still belong within protection scope of the present invention.
Embodiment 1:
4Kg2-amino-3-nitro-6-chloropyridine, 4Kg quadrol, 40L Virahol are put in the reactor, opened and stir and be heated to backflow; The 3.6Kg NSC 158269 is joined in the reactor, and reaction is 3 hours under the reflux conditions.After stopping heating, add the 40L purified water in reaction solution, a large amount of yellow solids are separated out after-filtration, and the wet product of gained are retained in the reactor.In reactor, add 1.2Kg Raney's nickel, 40L Virahol, open and stir and be heated to backflow, drip the 8Kg80% hydrazine hydrate; back flow reaction 2 hours; drop to room temperature in nitrogen protection after reacting completely, add the 4Kg Vinyl chloroformate fast, reaction is 3 hours under the room temperature condition.Add the 3.2Kg strong aqua, free 1 hour, to filter, filtrate joins in the 6Kg/120L toxilic acid aqueous isopropanol, and the cooling crystallization gets the off-white color solid, 60 ℃ of forced air dryings, net weight 7.3Kg, yield are 75.3%, purity 99.5%.
Embodiment 2:
4Kg2-amino-3-nitro-6-chloropyridine, 3Kg triethylamine, 50L dehydrated alcohol are put in the reactor, opened and stir and be heated to backflow; The 4Kg NSC 158269 is joined in the reactor, and reaction is 2 hours under the reflux conditions.After stopping heating, add the 50L purified water in reaction solution, a large amount of yellow solids are separated out after-filtration, and the wet product of gained are retained in the reactor.In reactor, add 1Kg Raney's nickel, 50L dehydrated alcohol, open and stir and be heated to backflow, drip the 8.8Kg80% hydrazine hydrate; back flow reaction 2 hours; drop to room temperature in nitrogen protection after reacting completely, add the 4.5Kg Vinyl chloroformate fast, reaction is 2 hours under the room temperature condition.Add the 3Kg triethylamine, free 1 hour, to filter, filtrate joins in the 6Kg/180L toxilic acid ethanolic soln, and the cooling crystallization gets the off-white color solid, 60 ℃ of forced air dryings, net weight 6.9Kg, yield are 71.2%, purity 99.2%.
Embodiment 3:
4Kg2-amino-3-nitro-6-chloropyridine, 3Kg pyridine, 20L methyl alcohol are put in the reactor, opened and stir and be heated to backflow; The 4.4Kg NSC 158269 is joined in the reactor, and reaction is 4 hours under the reflux conditions.After stopping heating, add the 20L purified water in reaction solution, a large amount of yellow solids are separated out after-filtration, and the wet product of gained are retained in the reactor.In reactor, add 500g Raney's nickel, 20L methyl alcohol, open and stir and be heated to backflow, drip the 7Kg80% hydrazine hydrate; back flow reaction 4 hours; drop to room temperature in nitrogen protection after reacting completely, add the 3.6Kg Vinyl chloroformate fast, reaction is 3 hours under the room temperature condition.Add the 3.6Kg strong aqua, free 2 hours, to filter, filtrate joins in the 5Kg/50L toxilic acid methanol solution, and the cooling crystallization gets the off-white color solid, 60 ℃ of forced air dryings, net weight 7.1Kg, yield are 73.3%, purity 99.4%.
Embodiment 4:
4Kg2-amino-3-nitro-6-chloropyridine, 4.5Kg triethylamine, 40L Virahol are put in the reactor, opened and stir and be heated to backflow; The 4.4Kg NSC 158269 is joined in the reactor, and reaction is 3 hours under the reflux conditions.After stopping heating, add the 40L purified water in reaction solution, a large amount of yellow solids are separated out after-filtration, and the wet product of gained are retained in the reactor.In reactor, add 1.8Kg Raney's nickel, 40L Virahol, open and stir and be heated to backflow, drip the 7Kg80% hydrazine hydrate; back flow reaction 3 hours; drop to room temperature in nitrogen protection after reacting completely, add the 3.6Kg Vinyl chloroformate fast, reaction is 3 hours under the room temperature condition.Add the 3Kg triethylamine, free 2 hours, to filter, filtrate joins in the 5Kg/100L toxilic acid aqueous isopropanol, and the cooling crystallization gets the off-white color solid, 50 ℃ of forced air dryings, net weight 7.8Kg, yield are 80.5%, purity 99.6%.
Comparative example---step-by-step processing technical study and data
According to Chinese patent CN102838534 disclosed method, preparation toxilic acid flupirtine, concrete operations step and data see the following form:
By above-described embodiment result as can be known, prior art (comparative example) adopts the method for step-by-step processing, and total recovery only is 34%, and obtains toxilic acid flupirtine crude product and be the light green solid, and impurity is more, and content only is 96%.Simultaneously, substep complex operation, big, the consuming time length of aftertreatment workload.
Technical scheme of the present invention adopts the advantage of " one kettle way " preparation toxilic acid flupirtine to be: by reducing reprocessing loss and the problem of avoiding the easy oxidation of polyamino pyridine derivate intermediate, to improve combined coefficient greatly and improved product purity; Condensation, reduction, acidylate, salify step-by-step processing are improved to " one kettle way " of serialization, have simplified operating procedure, reduced production cost.
Claims (6)
1. one kind " one kettle way " prepares the method for toxilic acid flupirtine; it is characterized in that: be that raw material makes the toxilic acid flupirtine through condensation, Raney's nickel reduction, Vinyl chloroformate acidylate, toxilic acid salify with 2-amino-3-nitro-6-chloropyridine and NSC 158269, each goes on foot intermediate and purifies and realize that " one kettle way " produce without separating.
2. prepare the method for toxilic acid flupirtine according to claims 1 described " one kettle way ", it is characterized in that described concrete steps are:
(1) in the Fatty Alcohol(C12-C14 and C12-C18) solvent under the reflux condition, 2-amino-3-nitro-6-chloropyridine in the presence of organic bases with NSC 158269 generation condensation reaction, reaction is finished, in reaction solution, add water, separate out a large amount of solids, elimination liquid, gained solid are the luorobenzyl aminopyridine of 2-amino-3-nitro-6-;
(2) in the Fatty Alcohol(C12-C14 and C12-C18) solvent under the reflux condition, the luorobenzyl aminopyridine of 2-amino-3-nitro-6-and 80% hydrazine hydrate are reduced to the luorobenzyl aminopyridine of 2,3-diamino-6-under raney ni catalysis;
(3) under nitrogen protection, step (2) reaction solution is down to room temperature, add Vinyl chloroformate, reaction is finished, and adds alkali and dissociates, and obtains flupirtine solution;
(4) with step (3) reacting liquid filtering, filtrate joins the maleic acid fatty alcoholic solution, salify, and the cooling crystallization obtains toxilic acid flupirtine crude product.
3. prepare the method for toxilic acid flupirtine according to claims 2 described " one kettle way ", it is characterized in that: the direct and Vinyl chloroformate generation acylation reaction of the luorobenzyl aminopyridine of 2,3-diamino-6-, add alkali afterwards again and dissociate, obtain flupirtine solution.
4. prepare the method for toxilic acid flupirtine according to claims 2 described " one kettle way ", it is characterized in that: the reaction solvent for use is the single fat alcoholic solvent, and described Fatty Alcohol(C12-C14 and C12-C18) is the C1-C3 lower alcohol, comprises methyl alcohol, ethanol, n-propyl alcohol, Virahol.
5. prepare the method for toxilic acid flupirtine according to claims 2 described " one kettle way ", it is characterized in that: used main molar ratio of material is 2-amino-3-nitro-6-chloropyridine: NSC 158269: 80% hydrazine hydrate: Vinyl chloroformate: toxilic acid=1:1.1～2:3～8:1.1～2:1.5～3.
6. prepare the method for toxilic acid flupirtine according to claims 2 described " one kettle way ", it is characterized in that: weight ratio=1:0.1～0.5 of used 2-amino-3-nitro-6-chloropyridine and reducing catalyst Raney's nickel.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310292276.7A CN103333103B (en) | 2013-07-12 | 2013-07-12 | Method for preparing flupirtine maleate by one-pot method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310292276.7A CN103333103B (en) | 2013-07-12 | 2013-07-12 | Method for preparing flupirtine maleate by one-pot method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103333103A true CN103333103A (en) | 2013-10-02 |
| CN103333103B CN103333103B (en) | 2015-07-22 |
Family
ID=49241328
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310292276.7A Active CN103333103B (en) | 2013-07-12 | 2013-07-12 | Method for preparing flupirtine maleate by one-pot method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103333103B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817494A (en) * | 2015-04-22 | 2015-08-05 | 江苏海岸药业有限公司 | Method for synthesizing flupirtine maleate by use of one-pot process |
| CN106397313A (en) * | 2016-08-31 | 2017-02-15 | 安徽省润生医药股份有限公司 | High efficient synthesis method of flupirtine maleate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102241626A (en) * | 2011-05-03 | 2011-11-16 | 北京华睿鼎信科技有限公司 | Synthesis process of flupirtine maleate |
| WO2012004391A1 (en) * | 2010-07-09 | 2012-01-12 | K.H.S. Pharma Holding Gmbh | Process for the preparation of flupirtine maleate |
| CN102838534A (en) * | 2012-10-10 | 2012-12-26 | 苏州二叶制药有限公司 | Preparation method of flupirtine maleate |
| WO2013080215A1 (en) * | 2011-11-30 | 2013-06-06 | Arch Pharmalabs Limited | An improved process for the preparation of flupirtine and pharmaceutically acceptable salts thereof |
-
2013
- 2013-07-12 CN CN201310292276.7A patent/CN103333103B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012004391A1 (en) * | 2010-07-09 | 2012-01-12 | K.H.S. Pharma Holding Gmbh | Process for the preparation of flupirtine maleate |
| CN102241626A (en) * | 2011-05-03 | 2011-11-16 | 北京华睿鼎信科技有限公司 | Synthesis process of flupirtine maleate |
| WO2013080215A1 (en) * | 2011-11-30 | 2013-06-06 | Arch Pharmalabs Limited | An improved process for the preparation of flupirtine and pharmaceutically acceptable salts thereof |
| CN102838534A (en) * | 2012-10-10 | 2012-12-26 | 苏州二叶制药有限公司 | Preparation method of flupirtine maleate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817494A (en) * | 2015-04-22 | 2015-08-05 | 江苏海岸药业有限公司 | Method for synthesizing flupirtine maleate by use of one-pot process |
| CN104817494B (en) * | 2015-04-22 | 2017-09-29 | 江苏海岸药业有限公司 | A kind of method of one pot process flupirtine maleate |
| CN106397313A (en) * | 2016-08-31 | 2017-02-15 | 安徽省润生医药股份有限公司 | High efficient synthesis method of flupirtine maleate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103333103B (en) | 2015-07-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110357853B (en) | Synthesis method of (R, S-) nicotine | |
| CN105237467A (en) | Preparation method of doxylamine succinate | |
| CN102241626B (en) | Synthesis process of flupirtine maleate | |
| CN103333103B (en) | Method for preparing flupirtine maleate by one-pot method | |
| CN102311394B (en) | Preparation method for 5-ethyl-5-phenyl barbituric acid | |
| CN113336629B (en) | Preparation process of 1,3 cyclohexanedione | |
| CN103044468B (en) | Preparation method of N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid | |
| CN108752184B (en) | Preparation method of SGLT2 inhibitor intermediate | |
| WO2013040750A1 (en) | Method for preparing β-artemether | |
| CN108164423B (en) | Preparation method of naftifine hydrochloride | |
| CN113024389B (en) | Preparation method of substituted phenoxybenzylamine compound and pyrazole carboxamide compound | |
| CN109651234B (en) | Synthesis method of donepezil hydrochloride | |
| WO2016078584A1 (en) | Emtricitabine purification method | |
| CN106542958A (en) | A kind of preparation method of adjacent Iodoaniline | |
| CN101538212A (en) | Method for preparing 4-hydroxy-3-methoxybenzylamine hydrochloride | |
| CN101412678B (en) | Method for synthesizing memantine hydrochloride | |
| CN104817494A (en) | Method for synthesizing flupirtine maleate by use of one-pot process | |
| CN112341340B (en) | Green and efficient preparation method of medicine for treating Alzheimer's disease | |
| CN103319373B (en) | The preparation method of 1 [2 amino 1 (4 benzyloxy-phenyl) ethyl] hexamethylene alkanol and related intermediate | |
| CN109879775A (en) | A kind of environment-friendly preparation method of 5-ALA hydrochloride intermediate | |
| KR101383246B1 (en) | Novel method for prepararing voglibose | |
| CN103145692A (en) | Preparation method of 4, 5-dihydro-6H-cyclopenta[b]thiophene-6-ketone | |
| CN102229541A (en) | Method for preparing Agomelatine N-[2-(7-methoxynaphthalene-1-yl)ethyl] acetamide | |
| CN113185419B (en) | Synthetic method of oxybuprocaine hydrochloride | |
| CN108069846B (en) | Method for resolving cis-1-hydroxy- [1,1' -bis (cyclohexyl) ] -2-formic acid and intermediate |
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 |