CN103274998B - Preparation method of flupirtine maleate - Google Patents
Preparation method of flupirtine maleate Download PDFInfo
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- CN103274998B CN103274998B CN201310247965.6A CN201310247965A CN103274998B CN 103274998 B CN103274998 B CN 103274998B CN 201310247965 A CN201310247965 A CN 201310247965A CN 103274998 B CN103274998 B CN 103274998B
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- flupirtine
- toxilic acid
- virahol
- flupirtine maleate
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Abstract
The invention relates to a preparation method of flupirtine maleate, which takes flupirtine as a raw material, and obtains flupirtine maleate pure products through salification and fine purification steps. By strictly controlling the use level and the reaction condition of maleic acid, the method greatly improves the yield of crude products, adopts a fine purification method integrating ultrafiltration and recrystallization, avoids product loss caused by adopting activated carbon, and greatly improves the purity and the yield of the flupirtine maleate pure products.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, be specifically related to a kind of preparation method of flupirtine maleate.
Background technology
Flupirtine maleate, chemistry 2-amino-3-ethoxy amido-6-NSC 158269 yl pyridines maleate by name, structural formula is as follows:
。
Flupirtine is that HomBurg is synthesized in the Yi Ge institute of materia medica at Frankfurt, Germany in 1981, and Aster Medica company sells on market with trade(brand)name Katabolic, is a kind of non-opium maincenter anodyne of medium tenacity.Compare with the analgesic drug product that acts on opiate receptor, flupirtine has advantages of the habituation of being difficult for, and this focus and difficult point at present anodyne research and development just.
At present, for synthesizing of flupirtine maleate, the mode extensively adopting is by flupirtine (i.e. " 2-amino-3-ethoxy amido-6-NSC 158269 yl pyridines ") salify after toxilic acid acidifying, obtains flupirtine maleate crude product, then through further refining and obtain flupirtine maleate sterling.
The salify mode of existing flupirtine be mainly the direct suction filtration of flupirtine that toxilic acid is added drop-wise in flupirtine or reaction is generated in toxilic acid, obtain flupirtine maleate crude product.In the product making through aforesaid method, tend to contain a large amount of impurity, purity often only has 70 ~ 80%, needs just can obtain highly purified product through refining.
For process for purification, in prior art mainly in the following ways: by flupirtine maleate crude product with obtaining flupirtine after the reduction of the alkali such as strong aqua; By flupirtine activated carbon decolorizing, to remove impurity; By decolouring after flupirtine with obtaining flupirtine maleate after toxilic acid again acidifying.This method of purification step is many, wastes time and energy, and cost is high, and product loss is very large, and yield often only has 10 ~ 15% of former crude product weight, is not suitable for industrial production.
In order to overcome the shortcoming of aforesaid method, researchist simplifies it, and flupirtine maleate is directly obtained to sterling with recrystallization after activated carbon decolorizing.Method after simplification has been saved reduction step and the secondary salify step in first method, operates easylier, and product loss is relatively little, and yield can reach 75 ~ 85% of former crude product weight, but its purification effect is poor, and purity is lower.
Summary of the invention
In order to overcome the deficiencies in the prior art, the invention provides a kind of preparation method of highly purified flupirtine maleate, its have advantages of easy and simple to handle, yield is high, product purity is high, is very suitable for large industrial production.
We find through research, cause the reason that occurs a large amount of impurity in flupirtine salification process to mainly contain 2 points:
1), contain free amido in flupirtine, unstable under normal temperature and neutrality or alkaline condition, easily oxidized;
2) in the molecular structure, due to flupirtine, contain four amidos, and toxilic acid is dihydric acid, the result more complicated of the two salify, tends to contain half maleate, 2-maleate and the free impurity such as flupirtine in product.
In order to reduce the generation of impurity in flupirtine salification process, the generation of oxidizing reaction be need in salification process, reduce, and consumption and the salify process of toxilic acid strictly controlled, reduce the generation of half toxilic acid and 2-maleate.
The preparation method who the present invention relates to a kind of flupirtine maleate, it comprises the steps:
(1) salify: flupirtine is dissolved in cold Virahol, open and stir, slowly drip the aqueous isopropanol of toxilic acid, after every batch of toxilic acid dropwises in batches, continue to stir 1 ~ 2 hour, then standing crystallization is 1 ~ 2 hour, filters to isolate solid and reaction solution, and reaction solution continues to drip the aqueous isopropanol of next batch toxilic acid, repeat aforesaid operations, until toxilic acid all adds in reaction solution, merge the solid filtering out, obtain flupirtine maleate crude product.
(2) refining: flupirtine maleate crude product is dissolved again with hot Virahol, solution is removed fine impurities after ultrafiltration, filtrate is standing crystallization at normal temperatures, cold washed with isopropyl alcohol for the solid of separating out, and the solid after washing obtains flupirtine maleate sterling after drying.
The temperature of the cold Virahol that step (1) is described is 0 ~ 10 ℃.Step (1) is described refers to minutes 2 ~ 5 batches in batches.
In step (1), the time for adding of each batch is 1 ~ 2 hour.
The salify step of step (1) is carried out under nitrogen protection.
In step (1), the total amount of toxilic acid used and the mol ratio of flupirtine are 1:1.
The temperature of the hot Virahol that step (2) is described is 30 ~ 50 ℃.
The described ultrafiltration of step (2) refers to ultrafilter filters.
The time of the standing crystallization of step (2) is 2 ~ 4 hours.
The washing times of the washed with isopropyl alcohol that the described use of step (2) is cold is 1 ~ 3 time, and the temperature of Virahol is 0 ~ 5 ℃.
The present invention carries out salt-forming reaction under the environment of low temperature and nitrogen protection; avoided the oxidation of flupirtine; strictly control the add-on of toxilic acid simultaneously; and adopt the mode in batches slowly dripping; avoided the generation of half maleate and 2-maleate; greatly improved purity and the yield of flupirtine maleate crude product, its crude product purity 90 ~ 95%, crude product yield reaches 95 ~ 97%.
In the purification step of product, the mode that the present invention has adopted ultrafiltration and recrystallization to combine, easy and simple to handle, product purity is high, and avoided the problem because adopting product yield that gac causes to reduce, refining yield can reach 97 ~ 99%, and product purity reaches 99.5 ~ 99.7%.
Embodiment
With prior art, as a comparison case and in conjunction with the embodiments preparation method of the present invention is elaborated below, but it does not limit the present invention.
Comparative example 1
Flupirtine (2.88Kg, 10mol) is added in the reactor that 20L Virahol is housed, open and stir and pass into nitrogen, rotating speed is controlled at 2000 ~ 2500 revs/min.Toxilic acid (1.16Kg, 10mol), with being added drop-wise in reactor after 2L isopropanol, after dropwising, is continued to stir 1 hour, and then standing crystallization is 1 hour, separates out a large amount of white solids.Filter, solid vacuum-drying, obtains flupirtine maleate crude product 3.1Kg, yield 75%.Through HPLC, detect, the purity of crude product is 74.2%.
Comparative example 2
Toxilic acid (1.16Kg, 10mol) is added in the reactor that 10L Virahol is housed, open and stir and pass into nitrogen, rotating speed is controlled at 2000 ~ 2500 revs/min.Flupirtine (2.88Kg, 10mol), with adding in reactor after 20L isopropanol, is stirred under room temperature 1 hour, and then standing crystallization is 1 hour, separates out a large amount of white solids.Filter, solid vacuum-drying, obtains flupirtine maleate crude product 2.5Kg, yield 62.5%.Through HPLC, detect, the purity of crude product is 70.2%.
Embodiment 1
Flupirtine (2.88Kg, 10mol) is added in the reactor that 20L Virahol is housed, open and stir and pass into nitrogen, rotating speed is controlled at 2000 ~ 2500 revs/min, then reactor is cooled to 0 ℃.By toxilic acid (1.16Kg, 10mol) 2L isopropanol, after mixing, be divided into 4 parts, every part of 500mL.First part of toxilic acid aqueous isopropanol is slowly added drop-wise in reactor, and time for adding is controlled at 50 ~ 70 minutes, after dropwising, continues to stir 1 hour, and then standing crystallization is 1 hour, separates out a large amount of white solids.Filter to isolate solid and reaction solution, reaction solution continues to drip the aqueous isopropanol of second part of toxilic acid, repeats aforesaid operations, until 4 parts of toxilic acids all add in reaction solution.Merge the solid filtering out, vacuum-drying, obtains flupirtine maleate crude product 3.8Kg, yield 95%.Through HPLC, detect, the purity of crude product is 95.3%.
3.8Kg flupirtine maleate crude product is added in 1L Virahol, be heated to 40 ℃ of dissolvings, solution filters through ultrafilter, and filtrate standing 3 hours at normal temperatures, separates out a large amount of white crystals.The washed with isopropyl alcohol of 0 ℃ 2 times for the crystal of separating out, each 200mL.Solid after washing obtains flupirtine maleate sterling 3.75Kg after vacuum-drying, refining yield 98.7%, and fusing point is 176 ~ 177 ℃.Through HPLC, detect, product purity is 99.7%.
Embodiment 2
Flupirtine (2.88Kg, 10mol) is added in the reactor that 20L Virahol is housed, open and stir and pass into nitrogen, rotating speed is controlled at 2000 ~ 2500 revs/min, then reactor is cooled to 5 ℃.By toxilic acid (1.16Kg, 10mol) 2L isopropanol, after mixing, be divided into 4 parts, every part of 500mL.First part of toxilic acid aqueous isopropanol is slowly added drop-wise in reactor, and time for adding is controlled at 50 ~ 70 minutes, after dropwising, continues to stir 2 hours, and then standing crystallization is 2 hours, separates out a large amount of white solids.Filter to isolate solid and reaction solution, reaction solution continues to drip the aqueous isopropanol of second part of toxilic acid, repeats aforesaid operations, until 4 parts of toxilic acids all add in reaction solution.Merge the solid filtering out, vacuum-drying, obtains flupirtine maleate crude product 3.75Kg, yield 93.7%.Through HPLC, detect, the purity of crude product is 95.0%.
3.75Kg flupirtine maleate crude product is added in 1L Virahol, be heated to 40 ℃ of dissolvings, solution filters through ultrafilter, and filtrate standing 3 hours at normal temperatures, separates out a large amount of white crystals.The washed with isopropyl alcohol of 5 ℃ 2 times for the crystal of separating out, each 200mL.Solid after washing obtains flupirtine maleate sterling 3.70Kg after vacuum-drying, refining yield 98.7%, and fusing point is 176 ~ 177 ℃.Through HPLC, detect, product purity is 99.5%.
Comparative example 3
The 3.85Kg flupirtine maleate crude product that embodiment 1 is prepared dissolves with 1L Virahol, adds 25% strong aqua (1.35L, 20mol) under stirring, obtains the flupirtine of unbound state.In reaction solution, add 0.5Kg gac, reflux, stops heating after 30 minutes, remove by filter gac, and under room temperature, standing crystallization is 2 hours, removes by filter solvent and obtains white solid 1.8Kg.Above-mentioned white solid is added in the reactor that 10L Virahol is housed, open and stir and pass into nitrogen, rotating speed is controlled at 2000 ~ 2500 revs/min.Toxilic acid (0.725Kg, 6.25mol), with being added drop-wise in reactor after 1L isopropanol, after dropwising, is continued to stir 1 hour, and then standing crystallization is 1 hour, separates out white solid, filters.The washed with isopropyl alcohol of 0 ℃ 2 times for filter cake, each 200mL.Solid vacuum-drying, obtains flupirtine maleate sterling 2.3Kg, and fusing point is 176 ~ 177.5 ℃, refining yield 59.7%.Through HPLC, detect, the purity of product is 94.2%.
Comparative example 4
The 3.85Kg flupirtine maleate crude product that embodiment 1 is prepared adds in 1L Virahol, and reflux is dissolved, after flupirtine maleate all dissolves, cooling, add gac 1.1Kg, continue reflux, after 30 minutes, stop heating, filtering gac, obtain limpid filtrate, 0 ℃ of cooling crystallization, filtered and obtains flupirtine maleate sterling 2.7Kg after 5 hours, 176 ~ 177 ℃ of fusing points, refining yield 70%.
By above contrast, can find, the yield of salify step of the present invention and purification step and product purity are all far away higher than prior art, and method of the present invention operation is easier, is very suitable for industrial production.
Claims (2)
1. a preparation method for flupirtine maleate, it comprises the steps:
(1) salify: flupirtine is dissolved in cold Virahol, open and stir, slowly drip the aqueous isopropanol of toxilic acid in batches, after every batch of toxilic acid dropwises, continue to stir 1 ~ 2 hour, then standing crystallization is 1 ~ 2 hour, filter to isolate solid and reaction solution, reaction solution continues to drip the aqueous isopropanol of next batch toxilic acid, repeat aforesaid operations, until toxilic acid all adds in reaction solution, merge the solid filtering out, obtain flupirtine maleate crude product, the temperature of described cold Virahol is 0 ~ 10 ℃, salify step is carried out under nitrogen protection, described refer to minutes 2 ~ 5 batches in batches, the time for adding of each batch is 1 ~ 2 hour, the total amount of toxilic acid used and the mol ratio of flupirtine are 1:1,
(2) refining: flupirtine maleate crude product is dissolved again with hot Virahol, solution is removed fine impurities after ultrafiltration, filtrate is standing crystallization at normal temperatures, cold washed with isopropyl alcohol for the solid of separating out, solid after washing obtains flupirtine maleate sterling after drying, and the temperature of described hot Virahol is 30 ~ 50 ℃, and described ultrafiltration refers to ultrafilter filters, the washing times of the washed with isopropyl alcohol that described use is cold is 1 ~ 3 time, and the temperature of Virahol is 0 ~ 5 ℃.
2. a preparation method for flupirtine maleate, its operation steps is:
Flupirtine is added in the reactor that Virahol is housed, open and stir and pass into nitrogen, rotating speed is controlled at 2000 ~ 2500 revs/min, then reactor is cooled to 0 ~ 5 ℃; By the toxilic acid isopropanol with flupirtine equimolar amount, after mixing, be divided into 2 ~ 5 parts; First part of toxilic acid aqueous isopropanol is slowly added drop-wise in reactor, and time for adding is controlled at 50 ~ 70 minutes, after dropwising, continues to stir 1 ~ 2 hour, and then standing crystallization is 1 ~ 2 hour, separates out a large amount of white solids; Filter to isolate solid and reaction solution, reaction solution continues to drip the aqueous isopropanol of second part of toxilic acid, repeats aforesaid operations, until toxilic acid all adds in reaction solution; Merge the solid filtering out, vacuum-drying, obtains flupirtine maleate crude product; Flupirtine maleate crude product is added in Virahol, be heated to 30 ~ 50 ℃ of dissolvings, solution filters through ultrafilter, and filtrate standing 1 ~ 3 hour at normal temperatures, separates out a large amount of white crystals; The washed with isopropyl alcohol of 0 ~ 5 ℃ 1 ~ 3 time for the crystal of separating out; Solid after washing obtains flupirtine maleate sterling after vacuum-drying; Wherein, crude product yield is 95 ~ 97%, and refining yield reaches 97 ~ 99%, and the product purity after refining reaches 99.5 ~ 99.7%.
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