CN109053563B - Method for preparing flupirtine hydrochloride - Google Patents
Method for preparing flupirtine hydrochloride Download PDFInfo
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Abstract
The invention discloses a method for preparing flupirtine hydrochloride, which specifically comprises the steps of taking 2, 6-dichloro-3-nitropyridine as a starting material, carrying out ammonolysis, substitution and purification of p-fluorobenzylamine, simultaneously carrying out hydrogenation and acylation reactions, filtering, crystallizing, and drying under reduced pressure to obtain the flupirtine hydrochloride. The method is simple to operate, hydrogenation and acylation reactions are carried out simultaneously, the deterioration of the polyaminopyridine derivative can be avoided as much as possible, ethyl chloroformate is not required to be dripped by opening the kettle cover, and the harm to a human body is reduced.
Description
Technical Field
The application belongs to the technical field of chemical medicine preparation, and particularly relates to a method for synthesizing flupirtine hydrochloride.
Background
Flupirtine maleate, chemical name: 2-amino-3-acylethoxyamino-6-p-fluorobenzylpyridine maleate having the formula: c19H21FN4O6(ii) a Molecular weight: 420.21, respectively; the structural formula is as follows:
flupirtine maleate is a central non-opioid analgesic developed by AWD company, Germany, and is a triaminopyridine compound, and the action mechanism of the flupirtine maleate is as follows: flupirtine maleate is a selective central potassium channel opener, has the attribute of an indirect aspartic acid (NMDA) receptor antagonist, can activate a G-protein coupled receptor to stimulate a potassium channel of a nerve cell, causes hyperpolarization of a nerve cell membrane and reduction of neuronal excitability, and stabilizes the resting nerve cell membrane so as to achieve the purpose of analgesia. The analgesic effect is independent of any central opioid, is not antagonized by naloxone, does not induce any dependence or need not to increase the dose to maintain clinical efficacy, and does not have any affinity to known opioid receptors. In addition, serotonin receptor antagonists do not inhibit the analgesic effect thereof, have no affinity with alpha 1-or alpha 2-adrenoceptors, and have good tolerance in clinical use. Flupirtine has few and slight adverse reactions, and is occasionally lack of strength, sleepiness, dizziness, nausea and anorexia.
According to the reported preparation method of flupirtine maleate, at present, 2, 6-dichloro-3-nitropyridine is widely used as a starting material, a key intermediate 2-amino-3-nitro-6-chloropyridine is obtained through ammonolysis, and then the flupirtine maleate is prepared through the processes of 6-p-fluorobenzylamine substitution, reduction, acylation, salification and the like. In this process, some prior arts suggest that flupirtine maleate can be finally obtained by first synthesizing flupirtine hydrochloride, which is a key intermediate for synthesizing flupirtine maleate, and then reacting with maleic acid.
Flupirtine hydrochloride, C15H18FN4O2Cl; chemical name: 2-amino-3-acylethoxyamino-6-p-fluorobenzylpyridine hydrochloride having the formula:
chinese patent CN105541705A discloses a method for preparing flupirtine hydrochloride. 2-amino-3-nitro-6-chloropyridine and p-fluorobenzylamine are used as raw materials, condensation is carried out, di-tert-butyl dicarbonate is used for protecting amino, palladium chloride is used as catalyst for hydrogenation reduction, ethyl chloroformate acylation is carried out, and hydrochloric acid deprotection is carried out to prepare flupirtine hydrochloride. However, 2-amino-3-nitro-6-chloropyridine is expensive and has high production cost. Moreover, the hydrogenation and acylation processes are complicated, and the hydrogenated product is easy to deteriorate and is not beneficial to the subsequent reaction. The ethyl chloroformate is also a dangerous chemical in a highly toxic control class, and is greatly harmful to human bodies and environment-friendly by opening the kettle cover for dropwise adding. The yield of flupirtine hydrochloride of this patent is calculated on the basis of the protected 2-amino-3-nitro-6-p-fluorobenzylamine pyridine. This yield cannot be calculated as the yield of the whole route.
The document J.Med.chem.1994,37, 3016-acid 3022 reports a preparation method of a general formula of a compound containing flupirtine hydrochloride, 2, 6-dichloro-3-nitropyridine is used as a starting material, and the key intermediate 2-amino-3-nitro-6-chloropyridine is obtained through ammonolysis. Then carrying out substitution reaction with benzylamine derivative, carrying out hydrogenation reduction by taking Raney nickel as a catalyst, and acylating agent to prepare flupirtine hydrochloride. The literature provides only one way for synthesizing an intermediate 2-amino-3-nitro-6-p-fluorobenzylaminopyridine derivative, and specific reaction conditions are not disclosed. And the high-risk material Raney nickel is used in the catalytic hydrogenation reaction, and the Raney nickel is inflammable and high in risk.
Therefore, there is still a need in the art to provide a process for preparing flupirtine hydrochloride that is simple in preparation process, less harmful to the human body, and environmentally friendly, and the present invention meets such a need.
Disclosure of Invention
In order to solve the technical problems, the invention provides a method for synthesizing flupirtine hydrochloride, which has the advantages of simple operation in the whole process, reduction in production cost and reduction in harm of ethyl chloroformate to human bodies.
The invention provides a preparation method of flupirtine hydrochloride, which is characterized in that a key intermediate 2-amino-3-nitro-6-p-fluorobenzyl aminopyridine is subjected to a one-pot method, excessive ammonia water is directly used as an acid-binding agent, and the production operation is simplified. In order to reduce the production cost, 2, 6-dichloro-3-nitropyridine is adopted as a starting material; in order to obtain a high-purity product, the key intermediate 2-amino-3-nitro-6-p-fluorobenzyl aminopyridine is purified. In order to avoid the easy oxidation and color change of intermediates 2, 3-diamino-6-p-fluorobenzylamine pyridine and flupirtine caused by step-by-step treatment and reduce the harm of ethyl chloroformate to human bodies, a 'one-pot method' is implemented; ethyl chloroformate, 2-amino-3-nitro-6-p-fluorobenzyl aminopyridine, palladium carbon and fatty alcohol are all put into a reaction kettle to carry out hydrogenation and acylation reactions simultaneously.
The invention is realized by the following technical scheme:
the application adopts the following synthetic route:
the method for preparing flupirtine hydrochloride is characterized in that 2, 6-dichloro-3-nitropyridine reacts with ammonia water to generate 2-amino-3-nitro-6-chloropyridine; excessive ammonia water is used as an acid-binding agent, then reacts with p-fluorobenzylamine to generate a key intermediate 2-amino-3-nitro-6-p-fluorobenzyl aminopyridine, and is refined by fatty alcohol; and putting the obtained wet product, ethyl chloroformate, palladium carbon and n-propanol into a reaction kettle, simultaneously carrying out hydrogenation and acylation reactions, discharging the materials, filtering, cooling and crystallizing to obtain flupirtine hydrochloride.
The method for preparing flupirtine hydrochloride specifically comprises the following steps:
1. a process for the preparation of flupirtine hydrochloride comprising the steps of:
(1) taking 2, 6-dichloro-3-nitropyridine as a starting material, adding ammonia water into methanol, ethanol or n-propanol, reacting for 6-7 h at 30-40 ℃, adding p-fluorobenzylamine, heating to 55-80 ℃, reacting for 4-7 h, cooling to 5-10 ℃, crystallizing for 1-2 h, and filtering to obtain a 2-amino-3-nitro-6-p-fluorobenzylaminopyridine crude product;
(2) heating, refluxing and dissolving the obtained intermediate 2-amino-3-nitro-6-p-fluorobenzyl aminopyridine in fatty alcohol, cooling and crystallizing, and refining;
(3) adding the 2-amino-3-nitro-6-p-fluorobenzyl aminopyridine wet product obtained in the step (2) into n-propanol or isopropanol, adding ethyl chloroformate and Pd/C into a reaction kettle in a pot, introducing hydrogen, heating to 60-70 ℃, simultaneously carrying out hydrogenation and acylation reactions for 5-7 h, filtering while hot, and cooling and crystallizing the filtrate to obtain flupirtine hydrochloride;
wherein the molar charge ratio of the ammonia water to the 2, 6-dichloro-3-nitropyridine in the step (1) is (2.2-4): 1, preferably (2.2-3): 1.
Wherein, the aliphatic alcohol in the step (2) is methanol, ethanol, isopropanol or n-propanol, preferably n-propanol or isopropanol.
Wherein, the weight ratio of the fatty alcohol to the 2, 6-dichloro-3-nitropyridine in the step (2) is (10-20): 1, and the weight ratio of the fatty alcohol to the 2, 6-dichloro-3-nitropyridine is preferably (12-15): 1.
Wherein, the ethyl chloroformate, the 2-amino-3-nitro-6-p-fluorobenzyl aminopyridine and the Pd/C in the step (3) are added into a reaction kettle together, and hydrogenation and acylation reactions are carried out simultaneously. The catalyst Pd/C is 5 percent Pd/C, the weight ratio of the palladium carbon to the 2, 6-dichloro-3-nitropyridine is (0.02-0.1): 1, and the pressure of hydrogen is 1.0-2.0 MPa.
The preparation process of the invention has the following advantages:
1. the ammonolysis reaction and the substitution reaction of p-fluorobenzylamine are carried out in the same reaction vessel, and excessive ammonia water in the ammonolysis reaction can be used as an acid-binding agent of the substitution reaction. The operation is simple, and the production cost is reduced.
2. The intermediate 2-amino-3-nitro-6-p-fluorobenzyl aminopyridine is refined to provide a high-purity raw material for the next reaction. The intermediates 2, 3-diamino-6-p-fluorobenzylaminopyridine and flupirtine are polyaminopyridine derivatives which are very easy to oxidize and deteriorate. Hydrogenation and acylation reactions are carried out simultaneously, so that the deterioration condition can be avoided as much as possible, and the subsequent reaction is not influenced. Ethyl chloroformate was also added dropwise without opening the kettle cover. Reducing the harm to human body. And the catalyst used in the method is palladium carbon, so that the environmental pollution can be reduced.
3. The yield of the flupirtine hydrochloride is about 70 percent, and the flupirtine hydrochloride with the purity of more than 99 percent can be prepared.
Detailed Description
The invention will now be further described by way of examples, which are not intended to limit the scope of the invention. It will be understood by those skilled in the art that equivalent substitutions for the technical features of the present invention, or corresponding modifications, can be made within the scope of the present invention.
In the present invention, NMR spectrometer (1H NMR is Bruker AVANCE-400, nuclear magnetic resonance: (1H NMR) shifts (δ) are given in parts per million (ppm), internal standard Tetramethylsilane (TMS), and chemical shifts are given in 10 "6 (ppm).
Example 1:
adding 2, 6-dichloro-3-nitropyridine (50g, 259.1mmol) into a reaction kettle filled with 200ml of methanol, adding 25% ammonia water (145.3g, 1.036mol) at room temperature, controlling the internal temperature to be 30-35 ℃, carrying out heat preservation reaction for about 7h, stopping the reaction when the raw material reaction is monitored by TLC, adding p-fluorobenzylamine (38.9g, 310.8mmol), heating to 75-80 ℃ for about 4h, stopping the reaction when the raw material reaction is monitored by TLC, cooling to 5-10 ℃, crystallizing for 1-2 h, and filtering. And adding 940ml of n-propanol into the obtained wet product, heating until the mixture is refluxed and dissolved to be clear, cooling to room temperature for crystallization for 2 hours, filtering, and keeping the wet product in the reaction kettle. Adding 750ml of n-propanol, 1.0g of 5% Pd/C and ethyl chloroformate (30g, 276.5mmol) into a reaction kettle, introducing hydrogen, maintaining the pressure at 1.0-1.3 MPa, and controlling the temperature at 60-70 ℃ to react for 5 hours. Filtering, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 2h, and drying under reduced pressure at 60 ℃ for 4h to obtain the white-like flupirtine hydrochloride 59.2g, with the yield of 67.0%, the chromatographic purity of 99.68% and the maximum single impurity of 0.075%.
The nuclear magnetic results were as follows:
1H NMR(400MHz,DMSO)：δ＝1.20(br s,3H,CH3)，4.05(q,J＝6.8Hz,2H)，4.35(s,J＝6.0Hz,2H)，5.80(d,J＝8.0Hz,1H)，7.02(t,J＝6.0Hz,1H)，7.25(m,2H)7.40(m,2H)，8.27(br s,1H)ppm。
13C NMR(400MHz,DMSO):δ＝14.5，44.5，59.4，106.5，114.6，128.9，135.7，137.2，153.2，155.2，155.6，159.7，162.5ppm。
example 2:
adding 2, 6-dichloro-3-nitropyridine (50g, 259.1mmol) into a reaction kettle filled with 250ml of ethanol, adding 25% ammonia water (109.0g, 777.5mmol) at room temperature, controlling the internal temperature to be 35-40 ℃, carrying out heat preservation reaction for about 6 hours, stopping the reaction when the TLC monitors that the raw material reaction is complete, adding p-fluorobenzylamine (38.9g, 310.8mmol), heating to 55-60 ℃ for about 7 hours, stopping the reaction when the TLC monitors that the raw material reaction is complete, cooling to 5-10 ℃ for crystallization for 1-2 hours, and filtering. Adding the obtained wet product into 630ml of methanol, heating to reflux and dissolve, cooling to room temperature for crystallization for 2h, filtering, and keeping the wet product in the reaction kettle. Adding 800ml of isopropanol, 5% Pd/C2 g and ethyl chloroformate (30g, 276.5mmol) into a reaction kettle, introducing hydrogen, maintaining the pressure at 1.2-1.5 MPa, and controlling the temperature at 60-70 ℃ to react for 5 hours. Filtering, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 2h, and drying under reduced pressure at 60 ℃ for 4h to obtain 64.3g of off-white flupirtine hydrochloride, wherein the yield is 72.8 percent and the chromatographic purity is 99.74 percent. The nuclear magnetic data remained substantially consistent with the data of example 1.
Example 3:
adding 2, 6-dichloro-3-nitropyridine (50g, 259.1mmol) into a reaction kettle filled with 300ml of n-propanol, adding 25% ammonia water (76.3g, 544.1mmol) at room temperature, controlling the internal temperature to be 30-35 ℃, carrying out heat preservation reaction for about 6h, stopping the reaction when the TLC monitors that the raw material reaction is complete, adding p-fluorobenzylamine (38.9g, 310.8mmol), heating to 60-65 ℃ for about 6h, stopping the reaction when the TLC monitors that the raw material reaction is complete, cooling to 5-10 ℃ for crystallization for 1-2 h, and filtering. Adding 760ml ethanol into the obtained wet product, heating to reflux and dissolve, cooling to room temperature for crystallization for 2h, filtering, and keeping the wet product in the reaction kettle. Adding 800ml of n-propanol, 5g of 5% Pd/C and ethyl chloroformate (30g, 276.5mmol) into a reaction kettle, introducing hydrogen, maintaining the pressure at 1.8-2.0 MPa, and controlling the temperature at 60-70 ℃ to react for 5 hours. Filtering, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 2h, and drying under reduced pressure at 60 ℃ for 4h to obtain white-like flupirtine hydrochloride 60.4g, with the yield of 68.0% and the chromatographic purity of 99.71%. The nuclear magnetic data remained substantially consistent with the data of example 1.
Example 4:
adding 2, 6-dichloro-3-nitropyridine (5kg, 25.9mol) into a reaction kettle filled with 16kg of methanol, adding 25% ammonia water (10.89kg, 777.7mol) at room temperature, controlling the internal temperature to be 30-35 ℃, carrying out heat preservation reaction for about 6 hours, stopping the reaction when the TLC monitors that the raw material reaction is complete, adding p-fluorobenzylamine (3.89kg, 31.1mmol), heating to 65-70 ℃ for about 5 hours, stopping the reaction when the TLC monitors that the raw material reaction is complete, cooling to 5-10 ℃, crystallizing for 1-2 hours, and filtering. Adding the obtained wet product into 50kg of n-propanol, heating until the solution is clear, cooling to room temperature, crystallizing for 2 hours, filtering, and keeping the wet product in a reaction kettle. Adding 60kg of n-propanol, 5% of Pd/C0.1kg and ethyl chloroformate (3kg, 27.6mol) into a reaction kettle, introducing hydrogen, maintaining the pressure at 1.3-1.6 MPa, and controlling the temperature at 60-70 ℃ to react for 5 hours. Filtering, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 2h, and drying under reduced pressure at 60 ℃ for 4h to obtain 6.12kg of off-white flupirtine hydrochloride, wherein the yield is 69.3% and the chromatographic purity is 99.58%. The nuclear magnetic data remained substantially consistent with the data of example 1.
Example 5:
adding 2, 6-dichloro-3-nitropyridine (5kg, 25.9mol) into a reaction kettle filled with 20kg of ethanol, adding 25% ammonia water (9.07kg, 64.8mol) at room temperature, controlling the internal temperature to be 30-35 ℃, carrying out heat preservation reaction for about 6 hours, stopping the reaction when the TLC monitors that the raw materials are completely reacted, adding p-fluorobenzylamine (3.8kg, 31.1mol), heating to 60-65 ℃ for about 6 hours, stopping the reaction when the TLC monitors that the raw materials are completely reacted, cooling to 5-10 ℃, crystallizing for 1-2 hours, and filtering. Adding 60kg of isopropanol into the obtained wet product, heating until the mixture is refluxed and dissolved to be clear, cooling to room temperature for crystallization for 2 hours, filtering, and keeping the wet product in a reaction kettle. Adding 75kg of isopropanol, 0.3kg of 5% Pd/C and ethyl chloroformate (3kg, 27.6mol) into a reaction kettle, introducing hydrogen, maintaining the pressure at 1.2-1.5 MPa, and controlling the temperature at 60-70 ℃ to react for 5 hours. Filtering, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 2h, and drying under reduced pressure at 60 ℃ for 4h to obtain 6.48kg of off-white flupirtine hydrochloride with yield of 73.4% and chromatographic purity of 99.62%. The nuclear magnetic data remained substantially consistent with the data of example 1.
Example 6:
adding 2, 6-dichloro-3-nitropyridine (5kg, 25.9mol) into a reaction kettle filled with 25kg of n-propanol, adding 25% ammonia water (7.98kg, 57.0mol) at room temperature, controlling the internal temperature to be 35-40 ℃, carrying out heat preservation reaction for about 6 hours, stopping the reaction when the TLC monitors that the raw material reaction is complete, adding p-fluorobenzylamine (3.89kg, 31.1mmol), heating to 55-60 ℃ for about 7 hours, stopping the reaction when the TLC monitors that the raw material reaction is complete, cooling to 5-10 ℃, crystallizing for 1-2 hours, and filtering. Adding the obtained wet product into 100kg of n-propanol, heating until the solution is clear, cooling to room temperature, crystallizing for 2 hours, filtering, and keeping the wet product in the reaction kettle. Adding 100kg of n-propanol, 0.5kg of 5% Pd/C and ethyl chloroformate (3kg, 27.6mol) into a reaction kettle, introducing hydrogen, maintaining the pressure at 1.8-2.0 MPa, and controlling the temperature at 60-70 ℃ to react for 5 hours. Filtering, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 2h, and drying under reduced pressure at 60 ℃ for 4h to obtain 6.28g of off-white flupirtine hydrochloride with yield of 71.1% and chromatographic purity of 99.66%. The nuclear magnetic data remained substantially consistent with the data of example 1.
Therefore, compared with the preparation method of flupirtine in the prior art, the preparation method has the advantages of mild reaction conditions, simple operation, good process reproducibility, small harm to human bodies, environmental friendliness and high purity of the obtained product. The key intermediate 2-amino-3-nitro-6-p-fluorobenzyl aminopyridine is subjected to a one-pot method, excessive ammonia water is directly used as an acid-binding agent, the production operation is simplified, the intermediates 2, 3-diamino-6-p-fluorobenzylamine pyridine and flupirtine are prevented from being easily oxidized and discolored due to step-by-step treatment, the damage of ethyl chloroformate to a human body is reduced, and the one-pot method is implemented; ethyl chloroformate, 2-amino-3-nitro-6-p-fluorobenzyl aminopyridine, palladium carbon and fatty alcohol are all put into a reaction kettle to carry out hydrogenation and acylation reactions simultaneously.
It will be apparent to those skilled in the art that various modifications and variations can be made in the compounds, compositions, and methods of making the same of the present application without departing from the spirit or scope of the application, and it is intended that the scope of the present application cover all modifications and variations of this application provided they come within the scope of the appended claims and their equivalents.
Claims (5)
1. A preparation method of flupirtine hydrochloride is characterized by comprising the following steps:
(1) 2, 6-dichloro-3-nitropyridine is used as a starting material, ammonia water is added into methanol, ethanol or n-propanol at the temperature of 30-40 DEG C
Reacting for 6-7 h, adding p-fluorobenzylamine, heating to 55-80 ℃, reacting for 4-7 h, cooling to 5-10 ℃, crystallizing for 1-2 h, and filtering to obtain a 2-amino-3-nitro-6-p-fluorobenzyl aminopyridine crude product;
(2) heating, refluxing and dissolving the obtained intermediate 2-amino-3-nitro-6-p-fluorobenzyl aminopyridine in fatty alcohol, cooling and crystallizing, and refining;
(3) adding the 2-amino-3-nitro-6-p-fluorobenzyl aminopyridine wet product obtained in the step (2) into n-propanol or isopropanol, adding ethyl chloroformate and Pd/C into a reaction kettle in a pot, introducing hydrogen, heating to 60-70 ℃, simultaneously carrying out hydrogenation and acylation reactions for 5-7 h, filtering while hot, and cooling and crystallizing the filtrate to obtain flupirtine hydrochloride;
wherein the molar charge ratio of the ammonia water to the 2, 6-dichloro-3-nitropyridine in the step (1) is (2.2-4) to 1; the aliphatic alcohol in the step (2) is methanol, ethanol, isopropanol or n-propanol; the weight ratio of the fatty alcohol to the 2, 6-dichloro-3-nitropyridine in the step (2) is (10-20): 1; adding ethyl chloroformate, 2-amino-3-nitro-6-p-fluorobenzyl aminopyridine and Pd/C into a reaction kettle together, and simultaneously carrying out hydrogenation and acylation reactions; the catalyst Pd/C is 5 percent Pd/C, the weight ratio of palladium carbon to 2, 6-dichloro-3-nitropyridine is (0.02-0.1): 1, and the pressure of hydrogen is 1.0-2.0 MPa.
2. The preparation method according to claim 1, wherein the molar charge ratio of the ammonia water to the 2, 6-dichloro-3-nitropyridine in the step (1) is (2.2-3): 1.
3. The method according to claim 1, wherein the aliphatic alcohol in the step (2) is n-propanol or isopropanol.
4. The preparation method according to claim 1, wherein the weight ratio of the fatty alcohol in the step (2) to the 2, 6-dichloro-3-nitropyridine is (12-15): 1.
5. The method of claim 1, comprising the steps of:
adding 5kg and 25.9mol of 2, 6-dichloro-3-nitropyridine into a reaction kettle filled with 20kg of ethanol, adding 9.07kg and 64.8mol of 25% ammonia water at room temperature, controlling the internal temperature to be 30-35 ℃, carrying out heat preservation reaction for about 6 hours, monitoring the reaction of raw materials by TLC (thin layer chromatography), stopping the reaction when the reaction of the raw materials is completed, adding 3.8kg and 31.1mol of p-fluorobenzylamine, heating to 60-65 ℃ for reacting for about 6 hours, monitoring the reaction of the raw materials by TLC, stopping the reaction when the reaction of the raw materials is completed, cooling to 5-10 ℃, crystallizing for 1-2 hours, and filtering; adding the obtained wet product into 60kg of isopropanol, heating until the solution is clear after refluxing, cooling to room temperature, crystallizing for 2 hours, filtering, and keeping the wet product in a reaction kettle; adding 75kg of isopropanol, 0.3kg of 5% Pd/C and 3kg of ethyl chloroformate by 27.6mol into a reaction kettle, introducing hydrogen, maintaining the pressure at 1.2-1.5 MPa, and controlling the temperature at 60-70 ℃ to react for 5 hours; filtering, cooling the filtrate to 0-5 ℃, stirring and crystallizing for 2h, and drying under reduced pressure at 60 ℃ for 4h to obtain 6.48kg of off-white flupirtine hydrochloride.
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| 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 |
| 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 |
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