CN109438374B - Continuous synthesis method of rufinamide - Google Patents
Continuous synthesis method of rufinamide Download PDFInfo
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Abstract
The invention provides a continuous synthesis method of rufinamide. The continuous synthesis method comprises the following steps: continuously inputting 1,2, 3-triazole-4-methyl carboxylate and 2, 6-difluorobenzyl chloride into a first continuous reaction device for continuous condensation reaction in the presence of an acid-binding agent to obtain a continuous condensation product, and continuously discharging the continuous condensation product; continuously inputting the continuous condensation product and ammonia gas or ammonia-containing solution into a second continuous reaction device for aminolysis reaction to obtain the rufinamide, and continuously discharging the rufinamide. By adopting the continuous synthesis method, isomers generated in the cyclization step in the conventional route are avoided, the purification step of the final product is simplified, the process cost is reduced, and the reaction route is effectively shortened; compared with batch equipment, the synthesis reaction is carried out in a continuous synthesis device, and the reaction conditions are more violent and safer due to the small reaction system and higher heat exchange speed.
Description
Technical Field
The invention relates to the field of drug synthesis, and particularly relates to a continuous synthesis method of rufinamide.
Background
Rufinamide (trade name Banzel) is a drug developed by norwalk, switzerland for the adjuvant treatment of epilepsy and is marketed in the us 11 months in 2008. It is a triazole derivative, has a chemical structure different from that of the antiepileptic drugs on the market at present, and plays a role by regulating the activity of a cerebral sodium ion channel. When the concentration of rufinamide is more than 10. mu. mol/L, it has no significant effect on monoamines, epinephrine, histamine, acetylcholine, AMPA-kainate, glycine, NMDA or GABA neurotransmitter-receptor systems. Clinical studies show that the tolerance of the epileptic to the adjuvant therapy of the rufinamide is good, and the frequency of epileptic seizures is reduced. Furthermore, the rufinamide still has the effect of treating patients with tolerant partial or generalized epilepsy, has auxiliary effect on the treatment of partial epilepsy and generalized tonic-clonic epilepsy, and can be jointly or independently administered.
The synthetic route of rufinamide mainly comprises the following steps:
batch route:
in 1988, the prior literature discloses that 2, 6-difluorobenzyl bromide is used as an initial raw material, is reacted with sodium azide, is cyclized with propiolic acid to obtain triazole carboxylic acid, and is subjected to acyl chlorination or ester formation and then is reacted with an ammonia solution to obtain a final product. The method uses high-risk and virulent sodium azide, has a long route, is difficult to produce in a large scale, and has high total cost. The inventors then modified the route by using 2-chloroacrylonitrile instead of propiolic acid for the cyclization, increasing the reaction yield (64%) and shortening the reaction route, but still requiring the use of sodium azide and the expensive 2-chloroacrylonitrile.
A 2010 document provides a method for synthesizing rufinamide, in which rufinamide is obtained by a one-pot method starting from 2, 6-difluorobenzyl bromide and methyl propiolate, but the yield is only 36%. And still need to use sodium azide and methyl propiolate that is expensive; in the same year, another document reports that 2, 6-difluorobenzyl bromide is subjected to azide and then is subjected to cyclization with propiolic acid, propiolamide or methyl propiolate under the catalysis of cuprous ions, so that the generation of position isomers in the cyclization process is reduced, and the target product can be obtained at a yield of 64-77%. Another document reports a route for obtaining a target substance by using cheap 3-methoxy methyl acrylate instead of a propiolic acid compound and 2, 6-difluorobenzyl azide for solvent-free cyclization reaction at 135 ℃, wherein the total yield of the product is 89%, and the route still needs high-risk and virulent sodium azide.
2012 provides a route of using propiolic alcohol to replace propiolic acid to perform cyclization with 2, 6-difluorobenzyl azide under the catalysis of cuprous ions, then oxidizing the product into acid and finally forming amide, wherein the product yield is 71%. This route still requires the use of sodium azide and the expensive propargyl alcohol.
2013, which provides a method for synthesizing rufinamide by using cuprous oxide as a catalyst and 2, 6-difluorobenzyl bromide, sodium azide and propioamide as starting materials through a one-pot method, wherein the yield is 95%. Although the yield of the route is high, high-risk and virulent sodium azide is used, and the used cuprous catalyst is a rhombic dodecahedron crystal and is high in price.
2014 provides a method for synthesizing rufinamide, in the method, expensive propiolic acid is replaced by cheaper 2-bromoacrylate, but bromine which is easy to prepare and has high toxicity is used as a brominating agent for preparing the 2-bromoacrylate, and more waste water is generated in the post-treatment process, so that great environmental protection pressure is faced.
A document in 2015 provides a method for synthesizing rufinamide, in the method, DBU is used as a catalyst, methyl 3-methoxyacrylate and 2, 6-difluorobenzyl azide are reacted to form a ring and then aminolyzed to prepare the rufinamide. In the same year, another prior document uses 1,1, 1-trichloromethyl-4-methoxy-3-buten-2-one and 2, 6-difluorobenzyl azide as raw materials to prepare rufinamide in a 50% yield by a one-pot method. This route uses 1,1, 1-trichloromethyl-4-methoxy-3-buten-2-one which is difficult to prepare and unstable, and the yield is not high.
Flow route:
a 2013 reference provides a method for synthesizing rufinamide, in which methyl 3-methoxyacrylate and 2, 6-difluorobenzyl azide are used to perform reaction under solvent-free condition using continuous technology, and rufinamide precursor is finally prepared in 83% yield. The precursor is ammonolyzed with ammonia water to obtain rufinamide. After three years, the method is improved by the method, a new synthesis method is provided, 2, 6-difluorobenzyl alcohol is used as a raw material in the new synthesis method, and the rufinamide precursor is prepared through uninterrupted three-step continuous reaction, wherein the total yield is 82%.
2014 provides a method for synthesizing the rufinamide, which uses 2, 6-difluorobenzyl bromide and methyl propiolate as raw materials, and prepares the rufinamide by a continuous technology with the yield of 98%. The route still needs to use expensive methyl propiolate and high-risk virulent sodium azide, and uses a large amount of DMSO and ammonia water, so that the amount of three wastes is large.
2017, a document provides a method for synthesizing rufinamide, in the method, 2, 6-difluorobenzyl bromide is used as an initial, substituted by azide, and cyclized with propynylamide under the catalysis of a novel cuprous catalyst to obtain the rufinamide, wherein the total yield is 95%. But the route uses triphenylphosphine copper complex which is complex to prepare and difficult to obtain as the catalyst.
From this, it is clear that the conventional synthesis method has problems:
(1) sodium azide with strong toxicity and explosiveness is used for reaction, great inconvenience is brought to reaction operation and aftertreatment, and the process safety risk is high.
(2) The propiolic acid and the derivative are used as raw materials, so the cost is high.
(3) Ring closure results in the formation of the 5-substituted triazole isomer.
Disclosure of Invention
The invention mainly aims to provide a continuous synthesis method of rufinamide, which aims to solve the problems of low safety, high cost, low product yield and the like of the existing preparation method of rufinamide.
In order to achieve the above object, the present invention provides a continuous synthesis method of rufinamide, comprising: continuously inputting 1,2, 3-triazole-4-methyl carboxylate and 2, 6-difluorobenzyl chloride into a first continuous reaction device for continuous condensation reaction in the presence of an acid-binding agent to obtain a continuous condensation product, and continuously discharging the continuous condensation product; continuously inputting the continuous condensation product and ammonia gas or ammonia-containing solution into a second continuous reaction device for aminolysis reaction to obtain the rufinamide, and continuously discharging the rufinamide.
Furthermore, the molar ratio of the methyl 1,2, 3-triazole-4-carboxylate to the 2, 6-difluorobenzyl chloride and the acid-binding agent is 1 (1-10) to 0.01-10.
Further, NH in ammonia gas or ammonia-containing solution3The ratio of the amount of the continuous condensation product to the number of moles of the continuous condensation product is (1-100): 1.
Further, the acid-binding agent is selected from triethylamine, tri-n-propylamine, diisopropylethylamine, tert-butylamine, triethylenediamine, diazabicyclo, KOH, NaOH, K2CO3、Na2CO3、NaHCO3、Cs2CO3、KHCO3One or more of MeONa, MeOK, t-BuOK, t-BuONa, sodium acetate and potassium acetate sodium methyl sulfonate.
Further, the continuous condensation reaction is carried out under the action of a protective solvent; preferably, the protective solvent is selected from one or more of water, chloroform, dichloromethane, ethyl acetate, triethylamine, tri-N-propylamine, diisopropylethylamine, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile.
Further, the reaction temperature of the continuous condensation reaction is 30-120 ℃, and the reaction time is 10-60 min; preferably, the reaction temperature is 70-90 ℃, and the reaction time is 20-30 min.
Further, the reaction temperature of the ammonolysis reaction is 25-110 ℃, and the reaction time is 10-100 min; preferably, the reaction temperature is 40-60 ℃, and the reaction time is 15-60 min.
Further, the ammonia-containing solution is NH3A solution formed after dissolving in one or more of methanol, water, ethanol, ethyl acetate, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, and methyl tert-butyl ether.
Further, in the ammonia-containing solution, NH3In a concentration of10～20wt％。
Further, the first continuous reaction device and the second continuous reaction device are respectively selected from a continuous coil or a CSTR continuous reactor.
By applying the technical scheme provided by the invention, the continuous synthesis method of the rufinamide not only avoids the generation of isomers in the cyclization step in the conventional route, simplifies the purification step of the final product, but also reduces the process cost. The target product can be directly synthesized by adopting the synthesis method through two-step reaction, so that the reaction route is effectively shortened; compared with batch equipment, the synthesis reaction is carried out in a continuous synthesis device, and the reaction conditions are more violent and safer due to the small reaction system and higher heat exchange speed. The whole process is operated continuously, the scale is controllable, and the total yield is about 86 wt%. In addition, the synthesis method has almost no amplification effect on production, and is suitable for industrial reproduction of small test yield.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.
As described in the background art, the existing method for preparing rufinamide has the problems of low safety, high cost, low product yield and the like. In order to solve the above technical problem, the present application provides a continuous synthesis method of rufinamide, including: continuously inputting 1,2, 3-triazole-4-methyl carboxylate and 2, 6-difluorobenzyl chloride into a first continuous reaction device for continuous condensation reaction in the presence of an acid-binding agent to obtain a continuous condensation product, and continuously discharging the continuous condensation product; continuously inputting the continuous condensation product and ammonia gas or ammonia-containing solution into a second continuous reaction device for aminolysis reaction to obtain the rufinamide, and continuously discharging the rufinamide.
In the first step of the method, 1,2, 3-triazole-4-carboxylic acid methyl ester and 2, 6-difluorobenzyl chloride are continuously introduced into a first continuous reaction device for continuous condensation reaction under the action of an acid binding agent, and continuous condensation products are continuously discharged. The continuous condensation reaction is not separated and purified, and is continuously conveyed to a second continuous reaction device together with ammonia gas or ammonia-containing solution for ammonolysis reaction to obtain the required rufinamide.
The continuous synthetic method of the rufinamide provided by the application not only avoids the generation of isomers in the cyclization step in the conventional route, simplifies the purification step of the final product, but also reduces the process cost. The target product can be directly synthesized by adopting the synthesis method through two-step reaction, so that the reaction route is effectively shortened; compared with batch equipment, the synthesis reaction is carried out in a continuous synthesis device, and the reaction conditions are more violent and safer due to the small reaction system and higher heat exchange speed. The whole process is operated continuously, the scale is controllable, and the total yield is about 86 wt%. In addition, the synthesis method has almost no amplification effect on production, and is suitable for industrial reproduction of small test yield.
In order to further improve the purity of the product, preferably, the continuous synthesis method further comprises a step of post-treating the product of the ammonolysis reaction. More preferably, the post-processing step includes: and (3) continuously conveying the product system of the ammonolysis reaction to an extraction column for continuous water washing, and then concentrating and crystallizing the organic phase obtained by water washing to obtain the rufinamide.
The ratio of the number of moles of the reaction raw materials can be adjusted to further increase the yield of the product.
In a preferred embodiment, the mole ratio of the methyl 1,2, 3-triazole-4-carboxylate to the 2, 6-difluorobenzyl chloride and the acid-binding agent is 1 (1-10) to 0.5-10. The molar ratio of the methyl 1,2, 3-triazole-4-carboxylate to the 2, 6-difluorobenzyl chloride includes, but is not limited to, the above range, and limiting the molar ratio to the above range is advantageous for further increasing the yield of the continuous condensation product, and thus the yield of the rufinamide.
In a preferred embodiment, the ammonia gas or the NH in the ammoniacal solution3The ratio of the amount of the continuous condensation product to the number of moles of the continuous condensation product is (1-100): 1. Condensation of ammonia gas or ammonia gas in ammonia-containing solution with continuous condensationThe ratio of the number of moles of the product includes, but is not limited to, the above range, and it is defined in the above range to be advantageous to further improve the yield of the rufinamide.
The addition of the acid-binding agent is beneficial to improving the reaction rate of the continuous condensation reaction. In a preferred embodiment, acid scavengers include, but are not limited to, triethylamine, tri-n-propylamine, diisopropylethylamine, tert-butylamine, triethylenediamine (DABCO), Diazabicyclo (DBU), KOH, NaOH, K2CO3、Na2CO3、NaHCO3、Cs2CO3、KHCO3One or more of MeONa, MeOK, t-BuOK, t-BuONa, sodium acetate and potassium acetate sodium methyl sulfonate. The acid-binding agents are low in price and easy to obtain, so that the process cost is reduced by adopting the acid-binding agents.
In a preferred embodiment, the continuous condensation reaction is carried out under the action of a protective solvent. The continuous condensation reaction is carried out under the action of the protective solvent, which is favorable for fully contacting the reaction raw materials and improving the reaction efficiency of the continuous condensation reaction. More preferably, the protective solvent includes, but is not limited to, one or more of water, chloroform, dichloromethane, ethyl acetate, triethylamine, tri-N-propylamine, diisopropylethylamine, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile.
In order to further increase the reaction rate of the continuous reaction and the yield of the product, the reaction temperature of each stage in the continuous synthesis reaction can be adjusted.
In a preferred embodiment, the reaction temperature of the continuous condensation reaction includes, but is not limited to, 30 to 120 ℃ and the reaction time is 10 to 60 min. The reaction time of the reaction temperature of the continuous condensation reaction includes, but is not limited to, the above range, and it is advantageous to further increase the reaction rate of the continuous condensation reaction and the yield of the product by limiting the reaction time to the above range. In order to further improve the reaction efficiency of the continuous condensation reaction, the reaction temperature of the continuous condensation reaction is preferably 40 to 60 ℃ and the reaction time is preferably 15 to 60 min.
In a preferred embodiment, the reaction temperature of the ammonolysis reaction includes, but is not limited to, 25 to 110 ℃ and the reaction time is 10 to 100 min. The reaction temperature of the aminolysis reaction includes, but is not limited to, the above range, and it is preferable to limit it to the above range to further increase the reaction rate of the continuous aminolysis reaction and the yield of the product of the aminolysis reaction. In order to further improve the reaction efficiency of continuous ammonolysis reaction and the yield of products of ammonolysis reaction, the reaction temperature of ammonolysis reaction is more preferably 40-60 ℃, and the reaction time is 15-60 min.
In a preferred embodiment, the ammoniated solution is NH3A solution formed by dissolving in one or more of methanol, water, ethanol, ethyl acetate, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, and methyl tert-butyl ether. The ammonia-containing solution is adopted as the reaction raw material of the ammonolysis reaction, so that the reaction rate of the ammonolysis reaction is favorably regulated, and the reaction severity is reduced.
Preferably, in an ammonia-containing solution, NH3The concentration of (A) is 10-20 wt%. NH (NH)3The concentration of (b) includes, but is not limited to, the above range, and it is preferable to limit it to the above range to further increase the reaction rate of the reaction.
The continuous synthesis method has the advantages of low cost, controllable scale, high product yield and the like. In a preferred embodiment, the first and second continuous reaction units are each selected from a continuous coil or a CSTR continuous reactor (continuous stirred reaction unit).
The present application is described in further detail below with reference to specific examples, which should not be construed as limiting the scope of the invention as claimed.
Example 1
Methyl 1,2, 3-triazole-4-carboxylate (6.4g, 0.05mol) and triethylamine (6.1g, 0.06mol) were dissolved in chloroform (19g, 2V), stirred and clarified, and then pumped into a first continuous reaction apparatus (coil, length 25.5 m,
namely, the diameter is 3mm), 2, 6-difluorobenzyl chloride (8.1g, 0.05mol) is dissolved in chloroform (19g, 2V), the solution is pumped into a first continuous reaction device by a pump B at the speed of 1.86g/min, the first continuous reaction device is immersed in an oil bath at the temperature of 75 ℃, the retention time of reaction raw materials is 30min, and the pressure in the first continuous reaction device is 0.6MPa, so that a continuous condensation product system is obtained, wherein the molar ratio of the methyl 1,2, 3-triazole-4-carboxylate, the triethylamine and the 2, 6-difluorobenzyl chloride is 1:1.2: 1.
The continuous condensation product system directly enters a second continuous reaction device (a coil pipe with the length of 14.3 meters,
i.e. diameter 3mm), and simultaneously pumping 20 wt% of ammonia methanol solution into a second continuous reaction device by a pump C at the speed of 0.27g/min, immersing the second continuous reaction device in an oil bath at 45 ℃, wherein the retention time is 15min, and the pressure in the second continuous reaction device is 0.6MPa, thus obtaining an ammonolysis product system.
And (3) sampling at an outlet for HPLC, feeding an effluent ammonolysis product system from the upper end of an extraction column, pumping water from the lower end at a rate of 3.01g/min for continuous water washing, keeping for 10min, concentrating an organic phase flowing out of the lower opening of the extraction column to remove most of solvent, stirring at room temperature for crystallization for 2h, and filtering to obtain a white-like solid product (rufinamide) 10.2g, wherein the purity is 99% and the yield is 86 wt%.
Example 2
Methyl 1,2, 3-triazole-4-carboxylate (6.4g, 0.05mol) and triethylamine (6.1g, 0.06mol) were dissolved in chloroform (19g, 2V), stirred and clarified, and then pumped into a first continuous reaction apparatus (coil, length 25.5 m,
i.e., 3mm in diameter), 2, 6-difluorobenzyl chloride (8.1g, 0.05mol) dissolved in chloroform (19g, 2V) was pumped into the first continuous reaction apparatus at a rate of 1.86g/min by means of a pump B, and the first continuous reaction apparatus was immersed in an oil bath at 100 ℃ to react the starting materialsThe retention time of (3) is 30min, the pressure in the first continuous reaction device is 0.6MPa, and a continuous condensation product system is obtained, wherein the molar ratio of the 1,2, 3-triazole-4-carboxylic acid methyl ester to the triethylamine to the 2, 6-difluorobenzyl chloride is 1:1.2: 1.
The continuous condensation product system directly enters a second continuous reaction device (a coil pipe with the length of 14.3 meters,
i.e. diameter 3mm), and simultaneously pumping 20 wt% of ammonia methanol solution into a second continuous reaction device by a pump C at the speed of 0.27g/min, immersing the second continuous reaction device in an oil bath at 45 ℃, wherein the retention time is 15min, and the pressure in the second continuous reaction device is 0.6MPa, thus obtaining an ammonolysis product system.
Sampling from an outlet and carrying out HPLC, feeding an effluent ammonolysis product system from the upper end of an extraction column, pumping water from the lower end at a rate of 3.01g/min for continuous water washing, keeping the time for 10min, concentrating an organic phase flowing out of the lower opening of the extraction column to remove most of solvent, stirring at room temperature for crystallization for 2h, and filtering to obtain a white-like solid product (rufinamide) 9.5g, wherein the purity is 98 percent, and the yield is 80 percent by weight.
The differences from example 1 are: the first continuous reaction apparatus was immersed in an oil bath at 100 ℃.
Example 3
Methyl 1,2, 3-triazole-4-carboxylate (6.4g, 0.05mol) and triethylamine (6.1g, 0.06mol) were dissolved in chloroform (19g, 2V), stirred and clarified, and then pumped into a first continuous reaction apparatus (coil, length 25.5 m,
namely, the diameter is 3mm) in a coil pipe, 2, 6-difluorobenzyl chloride (8.1g, 0.05mol) is dissolved in chloroform (19g, 2V), the solution is pumped into a first continuous reaction device by a pump B at the speed of 1.86g/min, the first continuous reaction device is immersed in an oil bath at the temperature of 75 ℃, the retention time of reaction raw materials is 30min, the pressure in the first continuous reaction device is 0.6MPa, a continuous condensation product system is obtained, wherein, 1,2, 3-triazole-4-carboxylic acid methyl ester, triethylamine and 2, 6-difluorobenzyl chloride are mixed into the reaction product, and the reaction product is a continuous condensation product systemThe ratio of the number of moles of (a) to (b) is 1:1.2: 1.
The continuous condensation product system directly enters a second continuous reaction device (a coil pipe with the length of 14.3 meters,
i.e. diameter 3mm), and simultaneously pumping 20 wt% of ammonia methanol solution into a second continuous reaction device by a pump C at the speed of 0.27g/min, immersing the second continuous reaction device in an oil bath at 80 ℃, wherein the retention time is 15min, and the pressure in the second continuous reaction device is 0.6MPa, thus obtaining an ammonolysis product system.
And (3) sampling at an outlet for HPLC, feeding an effluent ammonolysis product system from the upper end of an extraction column, pumping water from the lower end at a rate of 3.01g/min for continuous water washing, keeping the time for 10min, concentrating an organic phase flowing out of the lower opening of the extraction column to remove most of solvent, stirring at room temperature for crystallization for 2h, and filtering to obtain a white-like solid product (rufinamide) of 8.9g, wherein the purity is 98% and the yield is 75 wt%.
The differences from example 1 are: the second continuous reaction apparatus was immersed in an oil bath at 80 ℃.
Example 4
Methyl 1,2, 3-triazole-4-carboxylate (6.4g, 0.05mol) and triethylamine (6.1g, 0.06mol) were dissolved in chloroform (19g, 2V), stirred and clarified, and then pumped into a first continuous reaction apparatus (coil, length 25.5 m,
namely, the diameter is 3mm), 2, 6-difluorobenzyl chloride (8.1g, 0.05mol) is dissolved in chloroform (19g, 2V), the solution is pumped into a first continuous reaction device by a pump B at the speed of 1.86g/min, the first continuous reaction device is immersed in an oil bath at the temperature of 75 ℃, the retention time of reaction raw materials is 30min, and the pressure in the first continuous reaction device is 0.6MPa, so that a continuous condensation product system is obtained, wherein the molar ratio of the methyl 1,2, 3-triazole-4-carboxylate, the triethylamine and the 2, 6-difluorobenzyl chloride is 1:1.2: 1.
The continuous condensation product system directly enters a second continuous reaction device (a coil pipe with the length of 14.3 meters,
i.e. diameter 3mm), simultaneously pumping 5 wt% ammonia methanol solution into a second continuous reaction device by a pump C at the speed of 0.27g/min, immersing the second continuous reaction device in an oil bath at 45 ℃, and keeping the time for 15min, wherein the pressure in the second continuous reaction device is 0.6MPa, thus obtaining an ammonolysis product system.
Sampling from an outlet and carrying out HPLC, feeding an effluent ammonolysis product system from the upper end of an extraction column, pumping water from the lower end at a rate of 3.01g/min for continuous water washing, keeping the time for 10min, concentrating an organic phase flowing out of the lower opening of the extraction column to remove most of solvent, stirring at room temperature for crystallization for 2h, and filtering to obtain a white-like solid product (rufinamide) 5.0g, wherein the purity is 98 percent, and the yield is 42 percent by weight.
The differences from example 1 are: the concentration of ammonia gas was 5 wt%.
Example 5
Methyl 1,2, 3-triazole-4-carboxylate (6.4g, 0.05mol) and triethylamine (0.61g, 0.006mol) were dissolved in chloroform (19g, 2V), stirred and clarified, and pumped into a first continuous reaction apparatus (coil, length 25.5 m,
namely, the diameter is 3mm), 2, 6-difluorobenzyl chloride (4.1g, 0.03mol) is dissolved in chloroform (19g, 2V), the solution is pumped into a first continuous reaction device by a pump B at the speed of 1.86g/min, the first continuous reaction device is immersed in an oil bath at the temperature of 75 ℃, the retention time of reaction raw materials is 30min, and the pressure in the first continuous reaction device is 0.6MPa, so that a continuous condensation product system is obtained, wherein the molar ratio of the methyl 1,2, 3-triazole-4-carboxylate, the triethylamine and the 2, 6-difluorobenzyl chloride is 1:0.12: 0.5.
The continuous condensation product system directly enters a second continuous reaction device (a coil pipe with the length of 14.3 meters,
i.e., 3mm in diameter), while pumping a 20 wt% methanolic ammonia solution at a rate of 0.27g/min with pump CAnd putting the mixture into a second continuous reaction device, immersing the second continuous reaction device in an oil bath at 45 ℃, keeping the time for 15min, and keeping the pressure in the second continuous reaction device at 0.6MPa to obtain an ammonolysis product system.
And (3) sampling at an outlet for HPLC, feeding an effluent ammonolysis product system from the upper end of an extraction column, pumping water from the lower end at a rate of 3.01g/min for continuous water washing, keeping the time for 10min, concentrating an organic phase flowing out of the lower opening of the extraction column to remove most of solvent, stirring at room temperature for crystallization for 2h, and filtering to obtain a white-like solid product (rufinamide) 2.2g, wherein the purity is 98% and the yield is 18.5 wt%.
The differences from example 1 are: the mol ratio of the 1,2, 3-triazole-4-carboxylic acid methyl ester to the 2, 6-difluorobenzyl chloride and the acid-binding agent is 1: 0.5: 0.12.
example 6
Methyl 1,2, 3-triazole-4-carboxylate (6.4g, 0.05mol) and triethylamine (6.1g, 0.06mol) were dissolved in chloroform (19g, 2V), stirred and clarified, and then pumped into a first continuous reaction apparatus (coil, length 25.5 m,
namely, the diameter is 3mm), 2, 6-difluorobenzyl chloride (8.1g, 0.05mol) is dissolved in chloroform (19g, 2V), the solution is pumped into a first continuous reaction device by a pump B at the speed of 1.86g/min, the first continuous reaction device is immersed in an oil bath at the temperature of 75 ℃, the retention time of reaction raw materials is 30min, and the pressure in the first continuous reaction device is 0.6MPa, so that a continuous condensation product system is obtained, wherein the molar ratio of the methyl 1,2, 3-triazole-4-carboxylate, the triethylamine and the 2, 6-difluorobenzyl chloride is 1:1.2: 1.
The continuous condensation product system directly enters a second continuous reaction device (a coil pipe with the length of 14.3 meters,
i.e., 3mm in diameter), while pumping a 20 wt% ammonia methanol solution into the second continuous reaction apparatus at a rate of 0.027g/min by means of a pump C, and immersing the second continuous reaction apparatus in an oil bath at 45 ℃ for a retention time of 15min, the second continuous reaction apparatusThe pressure in the reaction device is 0.6MPa, and an ammonolysis product system is obtained.
And (3) sampling at an outlet for HPLC, feeding an effluent ammonolysis product system from the upper end of an extraction column, pumping water from the lower end at a rate of 3.01g/min for continuous water washing, keeping the time for 10min, concentrating an organic phase flowing out of the lower opening of the extraction column to remove most of solvent, stirring at room temperature for crystallization for 2h, and filtering to obtain a white-like solid product (rufinamide) of 4.1g, wherein the purity is 98% and the yield is 35 wt%.
The differences from example 1 are: the molar ratio of the continuous condensation product to ammonia in the methanolic ammonia solution was 1: 0.5.
Comparative example 1
Methyl 1,2, 3-triazole-4-carboxylate (6.4g, 0.05mol) and triethylamine (6.1g, 0.06mol) were dissolved in chloroform (19g, 2V), stirred and clarified, and then placed in a reaction flask. Dissolving 2, 6-difluorobenzyl chloride (8.1g, 0.05mol) in chloroform (19g, 2V), dropping into a reaction bottle by using a constant-pressure dropping funnel, heating to 61 ℃ by an external bath after adding, carrying out reflux reaction, detecting that the reaction is complete after 10h, and turning the system to room temperature. Obtaining a condensation product system prepared in batches, wherein the molar ratio of the 1,2, 3-triazole-4-carboxylic acid methyl ester to the triethylamine to the 2, 6-difluorobenzyl chloride is 1:1.2: 1.
And at room temperature, directly adding 20 wt% of ammonia methanol solution into the condensation product system of the batch, heating the system to 30 ℃ for reaction, and detecting that the reaction is complete after 10 hours to obtain an ammonolysis product system.
And (3) washing and separating the system at room temperature, concentrating most of solvent, stirring and crystallizing for 2 hours at room temperature, and filtering to obtain a white-like solid product (rufinamide) 6.2g with the purity of 98% and the yield of 52.3 wt%.
The differences from example 1 are: the reaction device is a batch reaction device.
From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:
comparing example 1 with comparative example 1, it can be seen that the continuous synthesis method provided by the present application is beneficial to increase the yield of rufinamide.
As is clear from comparison of examples 1 to 3, limiting the temperatures of the first and second continuous reaction apparatuses within the preferable range of the present application is advantageous for increasing the yield of rufinamide.
Comparing examples 1 and 4, it is found that limiting the concentration of ammonia gas in the ammonia-containing solution to the preferable range in the present application is advantageous for increasing the yield of rufinamide.
Comparing examples 1 and 5, it is found that limiting the molar ratio of methyl 2, 3-triazole-4-carboxylate to 2, 6-difluorobenzyl chloride and acid-binding agent to the preferred range of the present application is advantageous for increasing the yield of rufinamide.
Comparing examples 1 and 6, it is found that limiting the molar ratio of the continuous condensation product to ammonia in the ammonia methanol solution to the range preferred in the present application is advantageous in increasing the yield of rufinamide.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A continuous synthetic method of rufinamide is characterized by comprising the following steps:
continuously inputting 1,2, 3-triazole-4-methyl carboxylate and 2, 6-difluorobenzyl chloride into a first continuous reaction device for continuous condensation reaction in the presence of an acid-binding agent to obtain a continuous condensation product, and continuously discharging the continuous condensation product;
continuously inputting the continuous condensation product and ammonia gas or ammonia-containing solution into a second continuous reaction device for aminolysis reaction to obtain the rufinamide, and continuously discharging the rufinamide; the molar ratio of the 1,2, 3-triazole-4-carboxylic acid methyl ester to the 2, 6-difluorobenzyl chloride to the acid-binding agent is 1 (1-10) to 0.01-10; NH in the ammonia gas or the ammonia-containing solution3The ratio of the number of moles of the continuous condensation product to the number of moles of the continuous condensation product is (1-100): 1;
the reaction temperature of the continuous condensation reaction is 70-90 ℃, and the reaction temperature of the ammonolysis reaction is 40-60 ℃;
the first continuous reaction device and the second continuous reaction device are respectively selected from a continuous coil or a CSTR continuous reactor.
2. The continuous rufinamide synthesis method according to claim 1, wherein the acid-binding agent is selected from triethylamine, tri-n-propylamine, diisopropylethylamine, tert-butylamine, triethylenediamine, diazabicyclo, KOH, NaOH, K2CO3、Na2CO3、NaHCO3、Cs2CO3、KHCO3One or more of MeONa, T-BuOK, t-BuONa, sodium acetate, potassium acetate and sodium methanesulfonate.
3. The continuous synthesis method of rufinamide according to claim 1, wherein the continuous condensation reaction is performed under the action of a protective solvent.
4. The continuous synthesis method of rufinamide according to claim 3, wherein the protective solvent is selected from one or more of water, chloroform, dichloromethane, ethyl acetate, triethylamine, tri-N-propylamine, diisopropylethylamine, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and acetonitrile.
5. The continuous synthesis method of rufinamide according to claim 1, wherein the reaction time of the continuous condensation reaction is 10-60 min.
6. The continuous synthesis method of rufinamide according to claim 5, wherein the reaction time of the continuous condensation reaction is 20-30 min.
7. The continuous rufinamide synthesis method according to claim 1, wherein the aminolysis reaction is performed for 10-100 min.
8. The continuous rufinamide synthesis method according to claim 7, wherein the aminolysis reaction is performed for 15-60 min.
9. The continuous synthesis method of rufinamide according to claim 1, wherein the ammonia-containing solution is NH3A solution formed after dissolving in one or more of methanol, water, ethanol, ethyl acetate, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, and methyl tert-butyl ether.
10. The continuous synthesis method of rufinamide according to claim 9, wherein in the ammonia-containing solution, NH is contained3The concentration of (A) is 10-20 wt%.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010043849A1 (en) * | 2008-10-13 | 2010-04-22 | Cipla Limited | Process for the preparation of rufinamide |
| CN103539750A (en) * | 2012-07-09 | 2014-01-29 | 旭和（天津）医药科技有限公司 | Synthesis process of rufinamide |
| WO2014121383A1 (en) * | 2013-02-11 | 2014-08-14 | Apotex Technologies Inc. | A process for the preparation of rufinamide and intermediates thereof |
| CN104955332A (en) * | 2013-01-30 | 2015-09-30 | 住友化学株式会社 | Method for controlling arthropod pest |
-
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- 2018-10-10 CN CN201811178842.0A patent/CN109438374B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010043849A1 (en) * | 2008-10-13 | 2010-04-22 | Cipla Limited | Process for the preparation of rufinamide |
| CN103539750A (en) * | 2012-07-09 | 2014-01-29 | 旭和（天津）医药科技有限公司 | Synthesis process of rufinamide |
| CN104955332A (en) * | 2013-01-30 | 2015-09-30 | 住友化学株式会社 | Method for controlling arthropod pest |
| WO2014121383A1 (en) * | 2013-02-11 | 2014-08-14 | Apotex Technologies Inc. | A process for the preparation of rufinamide and intermediates thereof |
Non-Patent Citations (2)
| Title |
|---|
| Regioselective Oxo-Amination of Alkenes and Enol Ethers with N-Bromosuccinimide-Dimethyl Sulfoxide Combination: A Facile Synthesis of α-Amino-Ketones and Esters;Pragati K. Prasad,等;《Organic Letters》;20160122;第18卷(第3期);第500-503页尤其是方案3 * |
| 抗癫痫药Rufinamide的合成;王俊敏,等;《延边大学医学学报》;20041231;第27卷(第4期);第264-266页 * |
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