CN104817494A - Method for synthesizing flupirtine maleate by use of one-pot process - Google Patents
Method for synthesizing flupirtine maleate by use of one-pot process Download PDFInfo
- Publication number
- CN104817494A CN104817494A CN201510192785.1A CN201510192785A CN104817494A CN 104817494 A CN104817494 A CN 104817494A CN 201510192785 A CN201510192785 A CN 201510192785A CN 104817494 A CN104817494 A CN 104817494A
- Authority
- CN
- China
- Prior art keywords
- pot process
- flupirtine maleate
- nitropyridine
- flupirtine
- diamino
- 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
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
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing flupirtine maleate by use of a one-pot process. The method comprises the steps of taking 2,6-dichloro-3-nitropyridine as a starting material and performing ammonolysis to obtain a key intermediate 2,6-diamino-3-nitropyridine, and then condensing the key intermediate with p-fluorobenzaldehyde and performing Pd/C catalytic hydrogenation reduction, ethyl chloroformate acylation and maleic acid salifying to obtain the flupirtine maleate; the selected process route is simple and convenient to operate; the various steps are not separated and one-pot process production is realized; as a result, the production cost is effectively reduced, and the yield and the product purity are improved; in short, the method is suitable for industrial large-scale production.
Description
Technical field
The invention belongs to chemicals preparing technical field, be specifically related to a kind of method of one pot process flupirtine maleate.
Background technology
Flupirtine maleate, chemical name: 2-amino-3-acyl group oxyethyl group amino-6-is to luorobenzyl pyridine maleate, and its structural formula is:
.
Flupirtine maleate is a kind of central nonopioid analgesic developed by German AWD company, for triamino pyridine compounds and their, its mechanism of action is: flupirtine maleate is a kind of selectivity maincenter K ~+Channel Opener, there is indirectly aspartic acid (NMDA) receptor antagonist attribute simultaneously, the potassium-channel of G-protein linked receptor and the cell that excites nerve can be activated, cause the hyperpolarization of neuron membrane and neuronal excitability to reduce, make the neuron membrane stabilization of tranquillization thus reach analgesic purpose.Its analgesic activity does not rely on any central opiate sample material, not by naloxone antagonism, any dependence can not be brought out or there is no need increase dosage to maintain clinical efficacy, and known opiate receptor without any affinity.In addition, serotonin receptor antagonist also can not suppress its analgesic effect, to α 1-or the not relevant affinity of α 2-adrenoceptor, Clinical practice has good tolerance.
The comprehensive flupirtine maleate synthetic method reported; at present; the synthetic route of extensive employing is: with 2; 6-dichloro-3-nitropyridine is starting material; solve key intermediate 2-amino-3-nitro-6-chloropyridine through ammonia, then replace through 6 NSC 158269, reduction; acidylate, the processes such as salify obtain flupirtine maleate sterling.But in the process preparing key intermediate 2-amino-3-nitro-6-chloropyridine, because ammonia solution agent (ammonia or ammoniacal liquor) cannot fixing quantity, very easily excessive response produces 2,6-diamino-3-nitropyridine, need to be further purified process to it in subsequent step and to by 2, the process contaminants of the follow-up generation of 6-diamino-3-nitropyridine carries out quality control, adds the industrial production cost of whole piece route, and this prepares the greatest problem existed in flupirtine maleate process at present.
Chinese patent CN201110112934.0 reports with 2; 6-dichloro-3-nitropyridine is raw material; 2-amino-3-nitro-6-chloropyridine is solved through selectivity ammonia; again with NSC 158269 condensation; obtain 2-amino-3-nitro-6-to fluorobenzylamino pyridine; with Vinyl chloroformate acidylate after hydrogenating reduction, then with toxilic acid salify.Chinese patent CN201210381705.3, CN201310292276.7 and CN201410344088.9 report with 2-amino-3-nitro-6-chloropyridine finished product as raw material; 2-amino-3-nitro-6-is obtained to fluorobenzylamino pyridine with NSC 158269 condensation; with Vinyl chloroformate acidylate after reduction, finally and toxilic acid salify.
Relatively above patent, patent CN201110112934.0 is with 2,6-dichloro-3-nitropyridine is raw material, in this intermediate process of synthesis 2-amino-3-nitro-6-chloropyridine, be easy to excessive response produce by product 2,6-diamino-3-nitropyridine, 2-amino-3-nitro-6-the chloropyridine that must obtain ammonia solution carries out purification process and could throw the next step, and therefore whole piece operational path can not accomplish operate continuously.Patent CN201210381705.3, CN201310292276.7 and CN201410344088.9 with 2-amino-3-nitro-6-chloropyridine for raw material, impurity 2 is generated although solve, the problem of 6-diamino-3-nitropyridine, operate continuously can be realized, but 2-amino-3-nitro-6-chloropyridine is obviously than 2,6-dichloro-3-nitropyridine is expensive, and preparation cost is higher.
Summary of the invention
For solving the problems of the technologies described above, the invention provides a kind of method of one pot process flupirtine maleate, whole synthetic mesophase process is without the need to purifying, can operate continuously, simplify operating process, reduce production cost, improve quality product and yield, be applicable to industrialization and generate.
The technical solution used in the present invention is: a kind of method of one pot process flupirtine maleate, comprise the following steps: (1) is with 2,6-dichloro-3-nitropyridine is starting material, passes into ammonia and obtain midbody 2,6-diamino-3-nitropyridine through ammonia solution in fatty alcohol after heating for dissolving; (2) under nitrogen protection, midbody 2,6-diamino-3-nitropyridine and p-Fluorobenzenecarboxaldehyde condensation, obtain intermediate 2-amino-3-nitro-6-for reacting by heating 4-8 hour to the sub-picolilamine of fluorobenzene; (3) catalyst P d/C is added toward 2-amino-3-nitro-6-in the fatty alcohol solution of the sub-picolilamine of fluorobenzene, then hydrogen is passed into, intermediate 2 is obtained after catalytic hydrogen reduction, 3-diamino-6-is to fluorobenzylamino pyridine, or after adding catalyst P d/C, add ammonium formiate under nitrogen protection, within reacting by heating 10-14 hour, obtain intermediate 2,3-diamino-6-to fluorobenzylamino pyridine; (4) under nitrogen protection, flupirtine is obtained to 2,3-diamino-6-to adding in the fatty alcohol solution of fluorobenzylamino pyridine after Vinyl chloroformate and acid binding agent carry out acylation reaction; (5) filtrate will obtained after the fatty alcohol solution of flupirtine under nitrogen protection suction filtration; be added in maleic acid fatty alcoholic solution; flupirtine maleate is obtained with toxilic acid salify after heated and stirred 4-6 hour; wherein; 2; 6-dichloro-3-nitropyridine: p-Fluorobenzenecarboxaldehyde: Vinyl chloroformate: ammonium formiate: the mol ratio of toxilic acid is 1:1.0 ~ 1.2:1.0 ~ 1.2:4 ~ 10:1.5 ~ 3.5, and described acid binding agent is organic bases or mineral alkali.
It is of the present invention that to be collectively referred to as route as follows:
。
Preferably, described fatty alcohol is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol or isopropylcarbinol.
Preferred, described fatty alcohol is ethanol.
Preferably, described Heating temperature is 40 ~ 120 DEG C.
Preferred, described Heating temperature is the reflux temperature of aliphatic alcohol solvent used.
Preferably, the weight ratio of described 2,6-dichloro-3-nitropyridines and catalyst P d/C is 1:0.01 ~ 0.1.
Preferably, described catalyst P d/C is 10%Pd/C.
Preferably, described organic bases is Trimethylamine 99, triethylamine, DIPEA, quadrol or pyridine, and mineral alkali is sodium bicarbonate, sodium carbonate, saleratus or salt of wormwood.
Preferred, described acid binding agent is triethylamine.
Beneficial effect of the present invention: the method for a kind of one pot process flupirtine maleate provided by the invention, realizes whole process " one kettle way " synthesis.The method allows 2, 6-dichloro-3-nitropyridine excessive response, change into 2 completely, 6-diamino-3-nitropyridine, with 2, 6-diamino-3-nitropyridine is that key intermediate directly carries out the next step, so instant invention overcomes the impurity 2 produced in existing technique, 6-diamino-3-nitropyridine is to the detrimentally affect of subsequent step, overcome the intermediate 2 that step-by-step processing is brought, 3-diamino-6-is to problems such as fluorobenzylamino pyridine and flupirtine easy oxidation discolorations, achieve reduced Schiff base to complete with reduction nitro one step, by ammonia solution, condensation, reduction, acidylate, the steps such as salify are integrated into continuous operation, each step intermediate realizes " one kettle way " and produces without sepn process, make whole route pilot process without the need to purifying, can operate continuously, simplify operating process, reduce production cost, improve quality product and yield, be applicable to industrialization generate.
Embodiment
Below will the invention will be further described by embodiment, these descriptions are not be further limited content of the present invention.One skilled in the art will understand that the equivalent replacement that technical characteristic of the present invention is done, or improve accordingly, still belong within protection scope of the present invention.
Embodiment 1:
2,6-dichloro-3-nitropyridine (5kg, 25.9mol) is added in the reactor that 50L methyl alcohol is housed, be stirred at 50-60 DEG C entirely molten after, pass into ammonia gas react 10 hours, TLC monitors the completely i.e. stopped reaction of raw material reaction, generates yellow suspension.Question response is cooled to room temperature, and pass in reaction solution in nitrogen discharge reactor after remaining ammonia, under nitrogen protection, slowly drip p-Fluorobenzenecarboxaldehyde (3.5kg, 28.5mol), back flow reaction about 8 hours, TLC monitors the completely i.e. stopped reaction of raw material reaction.Question response liquid is cooled to room temperature, adds the Pd/C 400g of 10%, passes into hydrogen 25 DEG C reaction 20 hours, and TLC monitors the completely i.e. stopped reaction of raw material reaction.Under nitrogen protection, drip Vinyl chloroformate (3.1kg, 28.5mol) and triethylamine (3.9kg, 38.8mol), react 4 hours at 25 DEG C, TLC monitors the completely i.e. stopped reaction of raw material reaction.Filtered under nitrogen, filtrate is added in toxilic acid (4.5kg, the 38.8mol) methanol solution of 50L, and reflux dissolves 4 hours; cooling is stirred cooling crystallization and is obtained off-white color solid, vacuum-drying at 35 DEG C, net weight 6.7kg; yield 61.3%, detect through HPLC, product purity is 97.4%.
Embodiment 2:
2,6-dichloro-3-nitropyridine (5kg, 25.9mol) is added in the reactor that 40L ethanol is housed, be stirred at 50-60 DEG C entirely molten after, pass into ammonia gas react 8 hours, TLC monitors the completely i.e. stopped reaction of raw material reaction, generates yellow suspension.Question response is cooled to room temperature, and pass in reaction solution in nitrogen discharge reactor after remaining ammonia, under nitrogen protection, drip p-Fluorobenzenecarboxaldehyde (3.8kg, 31.1mol), back flow reaction about 4 hours, TLC monitors the completely i.e. stopped reaction of raw material reaction.Question response liquid is cooled to room temperature, adds Pd/C 500g and the ammonium formiate 9.8kg of 10%, continues heating reflux reaction about 14 hours under nitrogen protection, and TLC monitors the completely i.e. stopped reaction of raw material reaction.Question response liquid is cooled to room temperature, under nitrogen protection, drips Vinyl chloroformate (3.4kg, 31.1mol) and DIPEA (4.7kg, 36.3mol), reacts 2 hours at 25 DEG C, and TLC monitors the completely i.e. stopped reaction of raw material reaction.Filtered under nitrogen, filtrate is added in toxilic acid (4.5kg, the 38.8mol) ethanolic soln of 40L, and reflux dissolves 2 hours; cooling is stirred cooling crystallization and is obtained off-white color solid, vacuum-drying at 35 DEG C, net weight 8.4kg; yield 76.4%, detect through HPLC, product purity is 96.5%.
Embodiment 3:
2,6-dichloro-3-nitropyridine (5kg, 25.9mol) is added in the reactor that 60L Virahol is housed, be stirred at 50-60 DEG C entirely molten after, pass into ammonia gas react 8 hours, TLC monitors the completely i.e. stopped reaction of raw material reaction, generates yellow suspension.Question response is cooled to room temperature, and pass in reaction solution in nitrogen discharge reactor after remaining ammonia, under nitrogen protection, drip p-Fluorobenzenecarboxaldehyde (3.5kg, 28.5mol), back flow reaction about 5 hours, TLC monitors the completely i.e. stopped reaction of raw material reaction.Question response liquid is cooled to room temperature, adds Pd/C 450g and the ammonium formiate 9.6kg of 10%, continues heating reflux reaction about 14 hours under nitrogen protection, and TLC monitors the completely i.e. stopped reaction of raw material reaction.Question response liquid is cooled to room temperature, under nitrogen protection, drips Vinyl chloroformate (3.1kg, 28.5mol) and triethylamine (3.9kg, 38.8mol), reacts 4 hours at 25 DEG C, and TLC monitors the completely i.e. stopped reaction of raw material reaction.Filtered under nitrogen, filtrate is added in toxilic acid (4.5kg, the 38.8mol) aqueous isopropanol of 50L, and reflux dissolves 2 hours; cooling is stirred cooling crystallization and is obtained off-white color solid, vacuum-drying at 35 DEG C, net weight 8.6kg; yield 78.2%, detect through HPLC, product purity is 95.2%.
Embodiment 4:
2,6-dichloro-3-nitropyridine (5kg, 25.9mol) is added in the reactor that 40L ethanol is housed, be stirred at 50-60 DEG C entirely molten after, pass into ammonia gas react 8 hours, TLC monitors the completely i.e. stopped reaction of raw material reaction, generates yellow suspension.Question response is cooled to room temperature, and pass in reaction solution in nitrogen discharge reactor after remaining ammonia, under nitrogen protection, drip p-Fluorobenzenecarboxaldehyde (3.5kg, 28.5mol), back flow reaction about 4 hours, TLC monitors the completely i.e. stopped reaction of raw material reaction.Question response liquid is cooled to room temperature, adds Pd/C 500g and the ammonium formiate 9.8kg of 10%, continues heating reflux reaction about 14 hours under nitrogen protection, and TLC monitors the completely i.e. stopped reaction of raw material reaction.Question response liquid is cooled to room temperature, adds sodium carbonate (4.1kg, 38.9mol), then under nitrogen protection, drips Vinyl chloroformate (3.1kg, 28.5mol), reacts 6 hours at 25 DEG C, and TLC monitors the completely i.e. stopped reaction of raw material reaction.Filtered under nitrogen, filtrate is added in toxilic acid (4.5kg, the 38.8mol) ethanolic soln of 50L, and reflux dissolves 2 hours; cooling is stirred cooling crystallization and is obtained off-white color solid, vacuum-drying at 35 DEG C, net weight 7.5kg; yield 68.7%, detect through HPLC, product purity is 96.1%.
Embodiment 5:
2,6-dichloro-3-nitropyridine (5kg, 25.9mol) is added in the reactor that 50L ethanol is housed, be stirred at 50-60 DEG C entirely molten after, pass into ammonia gas react 8 hours, TLC monitors the completely i.e. stopped reaction of raw material reaction, generates yellow suspension.Question response is cooled to room temperature, and pass in reaction solution in nitrogen discharge reactor after remaining ammonia, under nitrogen protection, drip p-Fluorobenzenecarboxaldehyde (3.2kg, 25.9mol), back flow reaction about 4 hours, TLC monitors the completely i.e. stopped reaction of raw material reaction.Question response liquid is cooled to room temperature, adds Pd/C 50g and the ammonium formiate 6.5kg of 10%, continues heating reflux reaction about 14 hours under nitrogen protection, and TLC monitors the completely i.e. stopped reaction of raw material reaction.Question response liquid is cooled to room temperature, adds sodium carbonate (3.7kg, 35.4mol), then under nitrogen protection, drips Vinyl chloroformate (2.8kg, 25.9mol), reacts 6 hours at 25 DEG C, and TLC monitors the completely i.e. stopped reaction of raw material reaction.Filtered under nitrogen, filtrate is added in toxilic acid (6.0kg, the 51.8mol) ethanolic soln of 40L, and reflux dissolves 2 hours; cooling is stirred cooling crystallization and is obtained off-white color solid, vacuum-drying at 35 DEG C, net weight 7.6kg; yield 70%, detect through HPLC, product purity is 96.3%.
Embodiment 6:
2,6-dichloro-3-nitropyridine (5kg, 25.9mol) is added in the reactor that 60L Virahol is housed, be stirred at 50-60 DEG C entirely molten after, pass into ammonia gas react 8 hours, TLC monitors the completely i.e. stopped reaction of raw material reaction, generates yellow suspension.Question response is cooled to room temperature, and pass in reaction solution in nitrogen discharge reactor after remaining ammonia, under nitrogen protection, drip p-Fluorobenzenecarboxaldehyde (3.5kg, 28.5mol), back flow reaction about 5 hours, TLC monitors the completely i.e. stopped reaction of raw material reaction.Question response liquid is cooled to room temperature, adds Pd/C 500g and the ammonium formiate 16.3kg of 10%, continues heating reflux reaction about 14 hours under nitrogen protection, and TLC monitors the completely i.e. stopped reaction of raw material reaction.Question response liquid is cooled to room temperature, under nitrogen protection, drips Vinyl chloroformate (3.1kg, 28.5mol) and triethylamine (3.9kg, 38.8mol), reacts 4 hours at 25 DEG C, and TLC monitors the completely i.e. stopped reaction of raw material reaction.Filtered under nitrogen, filtrate is added in toxilic acid (10.5kg, the 90.7mol) aqueous isopropanol of 60L, and reflux dissolves 2 hours; cooling is stirred cooling crystallization and is obtained off-white color solid, vacuum-drying at 35 DEG C, net weight 8.2kg; yield 75%, detect through HPLC, product purity is 95.3%.
Claims (9)
1. the method for an one pot process flupirtine maleate, it is characterized in that: comprise the following steps: (1) is with 2,6-dichloro-3-nitropyridine is starting material, passes into ammonia and obtain midbody 2,6-diamino-3-nitropyridine through ammonia solution in fatty alcohol after heating for dissolving; (2) under nitrogen protection, midbody 2,6-diamino-3-nitropyridine and p-Fluorobenzenecarboxaldehyde condensation, obtain intermediate 2-amino-3-nitro-6-for reacting by heating 4-8 hour to the sub-picolilamine of fluorobenzene; (3) catalyst P d/C is added toward 2-amino-3-nitro-6-in the fatty alcohol solution of the sub-picolilamine of fluorobenzene, then hydrogen is passed into, intermediate 2 is obtained after catalytic hydrogen reduction, 3-diamino-6-is to fluorobenzylamino pyridine, or after adding catalyst P d/C, add ammonium formiate under nitrogen protection, within reacting by heating 10-14 hour, obtain intermediate 2,3-diamino-6-to fluorobenzylamino pyridine; (4) under nitrogen protection, flupirtine is obtained to 2,3-diamino-6-to adding in the fatty alcohol solution of fluorobenzylamino pyridine after Vinyl chloroformate and acid binding agent carry out acylation reaction; (5) filtrate will obtained after the fatty alcohol solution of flupirtine under nitrogen protection suction filtration; be added in maleic acid fatty alcoholic solution; flupirtine maleate is obtained with toxilic acid salify after heated and stirred 4-6 hour; wherein; 2; 6-dichloro-3-nitropyridine: p-Fluorobenzenecarboxaldehyde: Vinyl chloroformate: ammonium formiate: the mol ratio of toxilic acid is 1:1.0 ~ 1.2:1.0 ~ 1.2:4 ~ 10:1.5 ~ 3.5, and described acid binding agent is organic bases or mineral alkali.
2. the method for a kind of one pot process flupirtine maleate according to claim 1, is characterized in that: described fatty alcohol is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol or isopropylcarbinol.
3. the method for a kind of one pot process flupirtine maleate according to claim 2, is characterized in that: described fatty alcohol is ethanol.
4. the method for a kind of one pot process flupirtine maleate according to claim 1, is characterized in that: described Heating temperature is 40 ~ 120 DEG C.
5. the method for a kind of one pot process flupirtine maleate according to claim 1 or 4, is characterized in that: described Heating temperature is the reflux temperature of aliphatic alcohol solvent used.
6. the method for a kind of one pot process flupirtine maleate according to claim 1, is characterized in that: the weight ratio of described 2,6-dichloro-3-nitropyridines and catalyst P d/C is 1:0.01 ~ 0.1.
7. the method for a kind of one pot process flupirtine maleate according to claim 1, is characterized in that: described catalyst P d/C is 10%Pd/C.
8. the method for a kind of one pot process flupirtine maleate according to claim 1, it is characterized in that: described organic bases is Trimethylamine 99, triethylamine, N, N-diisopropylethylamine, quadrol or pyridine, mineral alkali is sodium bicarbonate, sodium carbonate, saleratus or salt of wormwood.
9. the method for a kind of one pot process flupirtine maleate according to claim 1, is characterized in that: described acid binding agent is triethylamine.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510192785.1A CN104817494B (en) | 2015-04-22 | 2015-04-22 | A kind of method of one pot process flupirtine maleate |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510192785.1A CN104817494B (en) | 2015-04-22 | 2015-04-22 | A kind of method of one pot process flupirtine maleate |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104817494A true CN104817494A (en) | 2015-08-05 |
CN104817494B CN104817494B (en) | 2017-09-29 |
Family
ID=53727999
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510192785.1A Active CN104817494B (en) | 2015-04-22 | 2015-04-22 | A kind of method of one pot process flupirtine maleate |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104817494B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109053563A (en) * | 2018-07-20 | 2018-12-21 | 四川青木制药有限公司 | A method of preparing hydrochloric acid Flupirtine |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102838534A (en) * | 2012-10-10 | 2012-12-26 | 苏州二叶制药有限公司 | Preparation method of flupirtine maleate |
CN103333103A (en) * | 2013-07-12 | 2013-10-02 | 南京正大天晴制药有限公司 | Method for preparing flupirtine maleate by one-pot method |
WO2014128465A1 (en) * | 2013-02-20 | 2014-08-28 | Cancer Therapeutics Crc Pty Ltd | 2-(hetero)aryl-benzimidazole and imidazopyridine derivatives as inhibitors of asparagime emethyl transferase |
-
2015
- 2015-04-22 CN CN201510192785.1A patent/CN104817494B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102838534A (en) * | 2012-10-10 | 2012-12-26 | 苏州二叶制药有限公司 | Preparation method of flupirtine maleate |
WO2014128465A1 (en) * | 2013-02-20 | 2014-08-28 | Cancer Therapeutics Crc Pty Ltd | 2-(hetero)aryl-benzimidazole and imidazopyridine derivatives as inhibitors of asparagime emethyl transferase |
CN103333103A (en) * | 2013-07-12 | 2013-10-02 | 南京正大天晴制药有限公司 | Method for preparing flupirtine maleate by one-pot method |
Non-Patent Citations (1)
Title |
---|
ZAHID H. CHOHAN 等: "TRANSITION METAL ION COMPLEXES OF SCHIFF-BASES. SYNTHESIS, CHARACTERIZATION AND ANTIBACTERIAL PROPERTIES", 《METAL BASED DRUGS》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109053563A (en) * | 2018-07-20 | 2018-12-21 | 四川青木制药有限公司 | A method of preparing hydrochloric acid Flupirtine |
CN109053563B (en) * | 2018-07-20 | 2022-03-29 | 四川青木制药有限公司 | Method for preparing flupirtine hydrochloride |
Also Published As
Publication number | Publication date |
---|---|
CN104817494B (en) | 2017-09-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105820110B (en) | Mo Fanselin synthetic methods | |
CN112062767B (en) | Preparation method and intermediate of rumepilone | |
CN104356092A (en) | Preparation method for vortioxetine | |
CN106366022A (en) | Intermediate used for AZD9291 preparation, and preparation method and application thereof | |
CN107365275A (en) | The Sai Lexipa of high-purity | |
CN105566162B (en) | The preparation technology of rilpivirine intermediate | |
CN106279175A (en) | A kind of preparation method of Ertapenem Sodium | |
CN101654419A (en) | Preparation method of fluvoxamine maleate | |
CN105348220A (en) | Synthetic method for vortioxetine hydrobromide | |
CN104817494A (en) | Method for synthesizing flupirtine maleate by use of one-pot process | |
CN110950795A (en) | N-ethylpyridine methylamine methanesulfonate crystal, preparation process and application thereof in preparation of tropicamide | |
CN102675201A (en) | Method for preparing 2-methyl-8-aminoquinoline from o-nitrophenol | |
CN103333103B (en) | Method for preparing flupirtine maleate by one-pot method | |
CN102070513B (en) | Synthesis method of 1-teriary butoxy carbonyl-4-piperidone | |
CN113336761B (en) | Preparation method of JAK inhibitor key intermediate | |
CN112552184B (en) | Synthetic method of cyclopropyl-containing chiral amine hydrochloride | |
US20160304452A1 (en) | Method for preparing silodosin and intermediate thereof | |
CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
CN102702196B (en) | Method for synthesizing 3-methyl-7-diazaindene | |
CN109879800B (en) | Preparation process of bepotastine drug intermediate | |
WO2016078584A1 (en) | Emtricitabine purification method | |
CN112250615A (en) | Preparation method of tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride | |
CN102010386B (en) | Method for preparing trimetazidine hydrochloride | |
CN112851519A (en) | Synthesis method of N-methylisopropylamine | |
CN106883166A (en) | 4-(3- piperidyls)The preparation method of aniline and its tartrate |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
EXSB | Decision made by sipo to initiate substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |