CN109438374B - Continuous synthesis method of rufinamide - Google Patents

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

Continuous synthesis method of rufinamide

technical field

The invention relates to the field of drug synthesis, in particular to a continuous synthesis method of rufinamide.

Background technique

Rufinamide (trade name Banzel) is a drug developed by Swiss Novartis for the adjuvant treatment of epilepsy and launched in the United States in November 2008. It is a triazole derivative whose chemical structure is different from that of anti-epileptic drugs currently on the market, and works by regulating the activity of sodium ion channels in the brain. When the concentration of rufinamide was greater than 10 μmol/L, it had no significant effect on monoamines, epinephrine, histamine, acetylcholine, AMPA-kainate, glycine, NMDA or GABA neurotransmitter-receptor system. Clinical studies have shown that adjuvant rufinamide treatment is well tolerated in epilepsy patients and has a reduced number of seizures. Moreover, rufinamide still has an effect on patients with partial or generalized epilepsy who are resistant to treatment, and also has an auxiliary effect on the treatment of partial seizures and generalized tonic-clonic seizures, and can be administered in combination or alone.

The synthetic route of rufinamide mainly includes the following:

Batch route:

In 1988, the existing literature disclosed for the first time that 2,6-difluorobenzyl bromide was used as the starting material, reacted with sodium azide, and then cyclized with propyolic acid to obtain triazole carboxylic acid, and then acyl chloride Or react with ammonia gas solution after ester formation to obtain the final product. The method uses high-risk and highly toxic sodium azide, and the route is long, it is difficult to produce on a large scale, and the total cost is high. Then the inventor improved the route, using 2-chloroacrylonitrile instead of propynoic acid for cyclization, which improved the reaction yield (64%) and shortened the reaction route, but still needed to use sodium azide and was expensive 2-chloroacrylonitrile.

A document in 2010 provides a method for synthesizing rufinamide, in which 2,6-difluorobenzyl bromide and methyl propiolate are used as starting materials to obtain rufinamide by one-pot method, But the yield is only 36%. And still need to use sodium azide and expensive methyl propiolate; in the same year, another literature reported the use of 2,6-difluorobenzyl bromide after azide and propyne under the catalysis of cuprous ion. The cyclization route of acid, propargyl amide or methyl propynoate is used for preparation, which reduces the generation of positional isomers in the cyclization process, and can obtain the target product with a yield of 64% to 77%. Another literature reported the use of cheaper methyl 3-methoxyacrylate instead of propynoic acid and 2,6-difluorobenzyl azide to carry out cyclization reaction without solvent at 135 °C and then ammonolysis. The route to obtain the target product has a total yield of 89%, but this route still requires the use of high-risk and highly toxic sodium azide.

A document in 2012 provides a route of using propynyl alcohol to replace propynoic acid and 2,6-difluorobenzyl azide for cyclization under the catalysis of cuprous ions and then oxidation to acid, and finally to amide, The product yield was 71%. This route still requires the use of sodium azide and expensive propargyl alcohol.

A document in 2013 provides a method for synthesizing rufinamide by one-pot method using cuprous oxide as a catalyst, 2,6-difluorobenzyl bromide, sodium azide and propargyl amide as starting materials. rate 95%. Although the yield of this route is high, high-risk and highly toxic sodium azide is used, and the cuprous catalyst used is a rhombic dodecahedron crystal, which is expensive.

A document in 2014 provides a method for synthesizing rufinamide. In this method, a cheaper 2-bromoacrylate is used to replace the expensive propynoic acid, but the preparation of 2-bromoacrylate requires the use of precursors. And the more toxic bromine as a brominating agent, the post-treatment will generate more wastewater and face huge environmental pressure.

A document in 2015 provides a method for synthesizing rufinamide. In the method, DBU is used as a catalyst, and methyl 3-methoxyacrylate is used to react with 2,6-difluorobenzyl azide to form a ring. Rufinamide was prepared by the method of aminolysis. In the same year, another existing document used 1,1,1-trichloromethyl-4-methoxy-3-buten-2-one and 2,6-difluorobenzyl azide as raw materials, using a The pot method was used to prepare rufinamide with a yield of 50%. 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 document provides a method for the synthesis of rufinamide using methyl 3-methoxyacrylate and 2,6-difluorobenzyl azide using sequential techniques under solvent-free conditions The reaction was carried out, and the rufinamide precursor was finally prepared with a yield of 83%. The precursor is then subjected to aminolysis with ammonia water to obtain rufinamide. Three years later, the proposer of the above method improved the method and proposed a new synthesis method. The new synthesis method uses 2,6-difluorobenzyl alcohol as raw material, and is prepared by continuous three-step continuous reaction. The rufinamide precursor was obtained with an overall yield of 82%.

A document in 2014 provides a method for synthesizing rufinamide. In the method, 2,6-difluorobenzyl bromide and methyl propiolate are used as raw materials, and rufinamide is prepared by continuous technology, and the yield is obtained. rate 98%. This route still requires the use of expensive methyl propiolate and highly toxic sodium azide, and uses a large amount of DMSO and ammonia water, resulting in a large amount of three wastes.

A document in 2017 provided a method for the synthesis of rufinamide, which started with 2,6-difluorobenzyl bromide, substituted with azide, and reacted with a propargyl amide ring under the catalysis of a novel cuprous catalyst. The rufinamide was synthesized in a total yield of 95%. However, this route uses triphenylphosphine copper complexes, which are complicated to prepare and difficult to obtain, as catalysts.

It can be seen from this that the problems existing in the existing synthesis method are:

(1) The use of sodium azide with strong toxicity and explosiveness for the reaction brings great inconvenience to the reaction operation and post-processing, and the process safety risk is high.

(2) Using propynoic acid and derivatives as raw materials, the cost is relatively high.

(3) 5-substituted triazole isomers will be produced during cyclization.

SUMMARY OF THE INVENTION

The main purpose of the present invention is to provide a continuous synthesis method of rufinamide, so as to solve the problems of low safety, high cost and low product yield in the existing method for preparing rufinamide.

In order to achieve the above object, the present invention provides a continuous synthesis method of rufinamide, the continuous synthesis method comprising: in the presence of an acid binding agent, 1,2,3-triazole-4-carboxylic acid is The methyl ester and 2,6-difluorobenzyl chloride are continuously input into the first continuous reaction device for continuous condensation reaction to obtain a continuous condensation product, and the continuous condensation product is continuously discharged; the continuous condensation product is mixed with ammonia gas Or the ammonia-containing solution is continuously input into the second continuous reaction device to carry out the aminolysis reaction to obtain rufinamide, and the rufinamide is continuously discharged.

Further, the ratio of moles of methyl 1,2,3-triazole-4-carboxylate to 2,6-difluorobenzyl chloride and acid binding agent is 1:(1～10):(0.01～10 ).

Further, the ratio of the moles of NH ₃ to the continuous condensation product in the ammonia gas or the ammonia-containing solution is (1-100):1.

Further, the acid binding agent is selected from triethylamine, tri-n-propylamine, diisopropylethylamine, tert-butylamine, triethylenediamine, diazabicyclo, KOH, NaOH, K ₂ CO ₃ , Na ₂ CO ₃ One or more of , NaHCO ₃ , Cs ₂ CO ₃ , KHCO ₃ , MeONa, MeOK, t-BuOK, t-BuONa, sodium acetate, potassium acetate sodium methanesulfonate.

Further, the continuous condensation reaction is carried out under the action of a protective solvent; preferably, the protective solvent is selected from 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,N-dimethylformamide, N , One or more of N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and acetonitrile.

Further, the reaction temperature of the continuous condensation reaction is 30-120 °C, and the reaction time is 10-60 min; preferably, the reaction temperature is 70-90 °C, and the reaction time is 20-30 min.

Further, the reaction temperature of the aminolysis reaction is selected from 25-110° C., and the reaction time is 10-100 min; preferably, the reaction temperature is 40-60° C. and the reaction time is 15-60 min.

Further, the ammonia-containing solution is a solution formed by dissolving NH ₃ 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, the concentration of NH ₃ is 10-20 wt %.

Further, the first continuous reaction device and the second continuous reaction device are respectively selected from continuous coils or CSTR continuous reactors.

By applying the technical solution of the present invention, the continuous synthesis method of rufinamide provided by the present application not only avoids the cyclization step in the conventional route to generate isomers, simplifies the purification step of the final product, but also reduces the process cost. Using the above synthesis method, the target product can be directly synthesized through a two-step reaction, thereby effectively shortening the reaction route; at the same time, compared with batch equipment, the above synthesis reaction is carried out in a continuous synthesis device. Due to the small reaction system, the heat exchange rate is faster. high, thus making the reaction conditions more vigorous but safer. The whole process runs continuously, the scale is controllable, and the total yield is about 86 wt%. In addition, the above-mentioned synthetic method has almost no amplification effect in production, and is suitable for reproducing small-scale yield in industrialization.

Detailed ways

It should be noted that the embodiments in the present application and the features of the embodiments may be combined with each other in the case of no conflict. The present invention will be described in detail below with reference to the embodiments.

As described in the background art, the existing methods for preparing rufinamide have problems such as low safety, high cost and low product yield. In order to solve the above-mentioned technical problems, the present application provides a continuous synthesis method of rufinamide, the continuous synthesis method comprises: in the presence of an acid binding agent, 1,2,3-triazole-4-carboxyl Methyl acid and 2,6-difluorobenzyl chloride are continuously input into the first continuous reaction device for continuous condensation reaction to obtain a continuous condensation product, and the continuous condensation product is continuously discharged; the continuous condensation product is combined with ammonia The gas or the ammonia-containing solution is continuously input into the second continuous reaction device to carry out the aminolysis reaction to obtain rufinamide, and the rufinamide is continuously discharged.

In the first step of the present invention, under the action of acid binding agent, 1,2,3-triazole-4-carboxylate methyl ester and 2,6-difluorobenzyl chloride are continuously fed into the first continuous reaction device The continuous condensation reaction is carried out, and the continuous condensation product is continuously discharged. The above-mentioned continuous condensation reaction is not separated and purified, and is continuously transported with ammonia gas or ammonia-containing solution to the second continuous reaction device for ammonolysis reaction to obtain the desired rufinamide.

The continuous synthesis method of rufinamide provided by the present application not only avoids the cyclization step in the conventional route to generate isomers, simplifies the purification step of the final product, but also reduces the process cost. Using the above synthesis method, the target product can be directly synthesized through a two-step reaction, thereby effectively shortening the reaction route; at the same time, compared with batch equipment, the above synthesis reaction is carried out in a continuous synthesis device. Due to the small reaction system, the heat exchange rate is faster. high, thus making the reaction conditions more vigorous but safer. The whole process runs continuously, the scale is controllable, and the total yield is about 86 wt%. In addition, the above-mentioned synthetic method has almost no amplification effect in production, and is suitable for reproducing small-scale yield in industrialization.

In order to further improve the purity of the product, preferably, the above-mentioned continuous synthesis method further includes the step of post-processing the product of the aminolysis reaction. More preferably, the above-mentioned post-processing step includes: continuously transporting the product system of the above-mentioned ammonolysis reaction to an extraction column for continuous water washing, and then concentrating and crystallizing the organic phase obtained by the water washing to obtain rufinamide.

In order to further improve the yield of the product, the mole ratio of the reaction raw materials can be adjusted.

In a preferred embodiment, the ratio of the moles of methyl 1,2,3-triazole-4-carboxylate to 2,6-difluorobenzyl chloride and the acid binding agent is 1:(1～10 ): (0.5～10). The ratio of moles of 1,2,3-triazole-4-carboxylate methyl ester to 2,6-difluorobenzyl chloride includes but is not limited to the above range, and limiting it within the above range is conducive to further improving The yield of the condensation product is continuously improved, thereby increasing the yield of rufinamide.

In a preferred embodiment, the ratio of the moles of NH ₃ to the continuous condensation product in the ammonia gas or the ammonia-containing solution is (1-100):1. The ratio of the number of moles of ammonia gas to the continuous condensation product in the ammonia gas or the ammonia-containing solution includes but is not limited to the above range, and limiting it within the above range is conducive to further improving the yield of rufinamide.

The addition of acid binding agent is beneficial to improve the reaction rate of continuous condensation reaction. In a preferred embodiment, acid binding agents include but are not limited to triethylamine, tri-n-propylamine, diisopropylethylamine, tert-butylamine, triethylenediamine (DABCO), diazabicyclo (DBU) , KOH, NaOH, K ₂ CO ₃ , Na ₂ CO ₃ , NaHCO ₃ , Cs ₂ CO ₃ , KHCO ₃ , MeONa, MeOK, t-BuOK, t-BuONa, sodium acetate, potassium acetate sodium methanesulfonate one or more. The above-mentioned several acid-binding agents are inexpensive and easy to obtain, so the use of the above-mentioned several acid-binding agents is beneficial to reduce the process cost.

In a preferred embodiment, the sequential condensation reaction is carried out under the action of a protective solvent. Carrying out the continuous condensation reaction under the action of a protective solvent is beneficial to make the reaction raw materials fully contact and improve the reaction efficiency of the continuous condensation reaction. More preferably, protective solvents include but are not limited to 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,N-dimethylformamide, N,N-dimethylacetamide, N,N - One or more of diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and acetonitrile.

In order to further improve 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, 30-120° C., and the reaction time is 10-60 min. The reaction time of the reaction temperature of the continuous condensation reaction includes but is not limited to the above range, and limiting it within the above range is beneficial to further improve the reaction rate of the continuous condensation reaction and the yield of the product. In order to further improve the reaction efficiency of the continuous condensation reaction, preferably, the reaction temperature of the continuous condensation reaction is 40-60° C., and the reaction time is 15-60 min.

In a preferred embodiment, the reaction temperature of the aminolysis reaction includes, but is not limited to, 25-110° C., and the reaction time is 10-100 min. The reaction temperature of the aminolysis reaction includes but is not limited to the above range, and limiting it within the above range is beneficial to further improve the reaction rate of the aminolysis reaction and the yield of the aminolysis reaction product. In order to further improve the reaction efficiency of the hydrazine reaction and the yield of the aminolysis reaction product, more preferably, the reaction temperature of the aminolysis reaction is 40-60° C., and the reaction time is 15-60 min.

In a preferred embodiment, the ammonia _- containing solution is NH dissolved in one or more of methanol, water, ethanol, ethyl acetate, acetonitrile, dichloromethane, chloroform, tetrahydrofuran and methyl tert-butyl ether formed solution. Using ammonia-containing solution as the reaction raw material for the ammonolysis reaction is beneficial to adjust the reaction rate of the ammonolysis reaction and reduce the intensity of the reaction.

Preferably, in the ammonia-containing solution, the concentration of NH ₃ is 10-20 wt %. The concentration of NH ₃ includes but is not limited to the above range, and limiting it to the above range is beneficial to further improve the reaction rate of the reaction.

The above continuous synthesis method has the advantages of low cost, controllable scale and high product yield. In a preferred embodiment, the first continuous reaction unit and the second continuous reaction unit are selected from continuous coils or CSTR continuous reactors (continuously stirred reaction units), respectively.

The present application will be described in further detail below with reference to specific embodiments, which should not be construed as limiting the scope of protection claimed by the present application.

Example 1

即直径3mm)盘管中，2,6-二氟苄氯(8.1g，0.05mol)溶解在氯仿中(19g，2V)用泵B以1.86g/min的速度泵入第一连续化反应装置中，并将第一连续化反应装置浸没在75℃油浴中，反应原料的保留时间为30min，第一连续化反应装置中压力为0.6MPa，得到连续化缩合产物体系，其中1,2,3-三氮唑-4-羧酸甲酯、三乙胺及2,6-二氟苄氯的摩尔数之比为1:1.2:1。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 used Pump A is pumped into the first continuous reaction device (coil, 25.5 meters long, 1.81 g/min)

2,6-difluorobenzyl chloride (8.1g, 0.05mol) was dissolved in chloroform (19g, 2V) in the coil tube with a diameter of 3mm) and pumped into the first continuous reaction device with pump B at a speed of 1.86g/min , and the first continuous reaction device was immersed in an oil bath at 75°C, the retention time of the reaction raw materials was 30 min, and the pressure in the first continuous reaction device was 0.6 MPa to obtain a continuous condensation product system, wherein 1, 2, The molar ratio of methyl 3-triazole-4-carboxylate, triethylamine and 2,6-difluorobenzyl chloride is 1:1.2:1.

即直径3mm)中，同时用泵C以0.27g/min的速度将20wt％的氨甲醇溶液泵入第二连续化反应装置中，并将第二连续化反应装置浸没在45℃油浴中，保留时间为15min，第二连续化反应装置中的压力为0.6MPa，得到氨解产物体系。The above-mentioned continuous condensation product system is directly entered into the second continuous reaction device (coil, 14.3 meters long,

That is, the diameter of 3mm), at the same time, the 20wt% ammonia methanol solution was pumped into the second continuous reaction device at a speed of 0.27 g/min with the pump C, and the second continuous reaction device was immersed in a 45 ℃ oil bath, The retention time was 15 min, and the pressure in the second continuous reaction device was 0.6 MPa to obtain an aminolysis product system.

The outlet was sampled for HPLC, the effluent aminolysis product system entered from the upper end of the extraction column, and was pumped into water at 3.01 g/min from the lower end for continuous water washing. After stirring and crystallization for 2 hours, 10.2 g of off-white solid product (rufinamide) was obtained by filtration, with a purity of 99% and a yield of 86wt%.

Example 2

即直径3mm)盘管中，2,6-二氟苄氯(8.1g，0.05mol)溶解在氯仿中(19g，2V)用泵B以1.86g/min的速度泵入第一连续化反应装置中，并将第一连续化反应装置浸没在100℃油浴中，反应原料的保留时间为30min，第一连续化反应装置中压力为0.6MPa，得到连续化缩合产物体系，其中1,2,3-三氮唑-4-羧酸甲酯、三乙胺及2,6-二氟苄氯的摩尔数之比为1:1.2:1。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 used Pump A is pumped into the first continuous reaction device (coil, 25.5 meters long, 1.81 g/min)

2,6-difluorobenzyl chloride (8.1g, 0.05mol) was dissolved in chloroform (19g, 2V) in the coil tube with a diameter of 3mm) and pumped into the first continuous reaction device with pump B at a speed of 1.86g/min , the first continuous reaction device was immersed in an oil bath at 100 °C, the retention time of the reaction raw materials was 30 min, and the pressure in the first continuous reaction device was 0.6 MPa to obtain a continuous condensation product system, wherein 1, 2, The molar ratio of methyl 3-triazole-4-carboxylate, triethylamine and 2,6-difluorobenzyl chloride is 1:1.2:1.

即直径3mm)中，同时用泵C以0.27g/min的速度将20wt％的氨甲醇溶液泵入第二连续化反应装置中，并将第二连续化反应装置浸没在45℃油浴中，保留时间为15min，第二连续化反应装置中的压力为0.6MPa，得到氨解产物体系。The above-mentioned continuous condensation product system is directly entered into the second continuous reaction device (coil, 14.3 meters long,

That is, the diameter of 3mm), at the same time, the 20wt% ammonia methanol solution was pumped into the second continuous reaction device at a speed of 0.27 g/min with the pump C, and the second continuous reaction device was immersed in a 45 ℃ oil bath, The retention time was 15 min, and the pressure in the second continuous reaction device was 0.6 MPa to obtain an aminolysis product system.

The outlet was sampled for HPLC, the effluent aminolysis product system entered from the upper end of the extraction column, and was pumped into water at 3.01 g/min from the lower end for continuous water washing. After stirring and crystallization for 2 hours, 9.5 g of off-white solid product (rufinamide) was obtained by filtration, with a purity of 98% and a yield of 80% by weight.

The difference from Example 1 is that the first continuous reaction device was immersed in an oil bath at 100°C.

Example 3

即直径3mm)盘管中，2,6-二氟苄氯(8.1g，0.05mol)溶解在氯仿中(19g，2V)用泵B以1.86g/min的速度泵入第一连续化反应装置中，并将第一连续化反应装置浸没在75℃油浴中，反应原料的保留时间为30min，第一连续化反应装置中压力为0.6MPa，得到连续化缩合产物体系，其中1,2,3-三氮唑-4-羧酸甲酯、三乙胺及2,6-二氟苄氯的摩尔数之比为1:1.2:1。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 used Pump A is pumped into the first continuous reaction device (coil, 25.5 meters long, 1.81 g/min)

2,6-difluorobenzyl chloride (8.1g, 0.05mol) was dissolved in chloroform (19g, 2V) in the coil tube with a diameter of 3mm) and pumped into the first continuous reaction device with pump B at a speed of 1.86g/min , and the first continuous reaction device was immersed in an oil bath at 75°C, the retention time of the reaction raw materials was 30 min, and the pressure in the first continuous reaction device was 0.6 MPa to obtain a continuous condensation product system, wherein 1, 2, The molar ratio of methyl 3-triazole-4-carboxylate, triethylamine and 2,6-difluorobenzyl chloride is 1:1.2:1.

即直径3mm)中，同时用泵C以0.27g/min的速度将20wt％的氨甲醇溶液泵入第二连续化反应装置中，并将第二连续化反应装置浸没在80℃油浴中，保留时间为15min，第二连续化反应装置中的压力为0.6MPa，得到氨解产物体系。The above-mentioned continuous condensation product system is directly entered into the second continuous reaction device (coil, 14.3 meters long,

That is, the diameter of 3mm), at the same time, the 20wt% ammonia methanol solution was pumped into the second continuous reaction device at a speed of 0.27 g/min with the pump C, and the second continuous reaction device was immersed in the 80 ℃ oil bath, The retention time was 15 min, and the pressure in the second continuous reaction device was 0.6 MPa to obtain an aminolysis product system.

The outlet was sampled for HPLC, the effluent aminolysis product system entered from the upper end of the extraction column, and was pumped into water at 3.01 g/min from the lower end for continuous water washing. After stirring and crystallization for 2 hours, 8.9 g of off-white solid product (rufinamide) was obtained by filtration, with a purity of 98% and a yield of 75% by weight.

The difference from Example 1 is that the second continuous reaction device is immersed in an oil bath at 80°C.

Example 4

即直径3mm)盘管中，2,6-二氟苄氯(8.1g，0.05mol)溶解在氯仿中(19g，2V)用泵B以1.86g/min的速度泵入第一连续化反应装置中，并将第一连续化反应装置浸没在75℃油浴中，反应原料的保留时间为30min，第一连续化反应装置中压力为0.6MPa，得到连续化缩合产物体系，其中1,2,3-三氮唑-4-羧酸甲酯、三乙胺及2,6-二氟苄氯的摩尔数之比为1:1.2:1。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 used Pump A is pumped into the first continuous reaction device (coil, 25.5 meters long, 1.81 g/min)

2,6-difluorobenzyl chloride (8.1g, 0.05mol) was dissolved in chloroform (19g, 2V) in the coil tube with a diameter of 3mm) and pumped into the first continuous reaction device with pump B at a speed of 1.86g/min , and the first continuous reaction device was immersed in an oil bath at 75°C, the retention time of the reaction raw materials was 30 min, and the pressure in the first continuous reaction device was 0.6 MPa to obtain a continuous condensation product system, wherein 1, 2, The molar ratio of methyl 3-triazole-4-carboxylate, triethylamine and 2,6-difluorobenzyl chloride is 1:1.2:1.

即直径3mm)中，同时用泵C以0.27g/min的速度将5wt％的氨甲醇溶液泵入第二连续化反应装置中，并将第二连续化反应装置浸没在45℃油浴中，保留时间为15min，第二连续化反应装置中的压力为0.6MPa，得到氨解产物体系。The above-mentioned continuous condensation product system is directly entered into the second continuous reaction device (coil, 14.3 meters long,

That is, the diameter of 3mm), at the same time, the 5wt% ammonia methanol solution was pumped into the second continuous reaction device at a speed of 0.27g/min with pump C, and the second continuous reaction device was immersed in a 45 ℃ oil bath, The retention time was 15 min, and the pressure in the second continuous reaction device was 0.6 MPa to obtain an aminolysis product system.

The outlet was sampled for HPLC, the effluent aminolysis product system entered from the upper end of the extraction column, and was pumped into water at 3.01 g/min from the lower end for continuous water washing. After stirring and crystallization for 2 hours, 5.0 g of off-white solid product (rufinamide) was obtained by filtration, with a purity of 98% and a yield of 42% by weight.

The difference from Example 1 is that the concentration of ammonia gas is 5 wt %.

Example 5

即直径3mm)盘管中，2,6-二氟苄氯(4.1g，0.03mol)溶解在氯仿中(19g，2V)用泵B以1.86g/min的速度泵入第一连续化反应装置中，并将第一连续化反应装置浸没在75℃油浴中，反应原料的保留时间为30min，第一连续化反应装置中压力为0.6MPa，得到连续化缩合产物体系，其中1,2,3-三氮唑-4-羧酸甲酯、三乙胺及2,6-二氟苄氯的摩尔数之比为1:0.12:0.5。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 then used Pump A is pumped into the first continuous reaction device (coil, 25.5 meters long, 1.81 g/min)

2,6-difluorobenzyl chloride (4.1g, 0.03mol) was dissolved in chloroform (19g, 2V) in the coil tube with a diameter of 3mm) and pumped into the first continuous reaction device with pump B at a speed of 1.86g/min , and the first continuous reaction device was immersed in an oil bath at 75°C, the retention time of the reaction raw materials was 30 min, and the pressure in the first continuous reaction device was 0.6 MPa to obtain a continuous condensation product system, wherein 1, 2, The molar ratio of methyl 3-triazole-4-carboxylate, triethylamine and 2,6-difluorobenzyl chloride was 1:0.12:0.5.

即直径3mm)中，同时用泵C以0.27g/min的速度将20wt％的氨甲醇溶液泵入第二连续化反应装置中，并将第二连续化反应装置浸没在45℃油浴中，保留时间为15min，第二连续化反应装置中的压力为0.6MPa，得到氨解产物体系。The above-mentioned continuous condensation product system is directly entered into the second continuous reaction device (coil, 14.3 meters long,

That is, the diameter of 3mm), at the same time, the 20wt% ammonia methanol solution was pumped into the second continuous reaction device at a speed of 0.27 g/min with the pump C, and the second continuous reaction device was immersed in a 45 ℃ oil bath, The retention time was 15 min, and the pressure in the second continuous reaction device was 0.6 MPa to obtain an aminolysis product system.

The outlet was sampled for HPLC, the effluent aminolysis product system entered from the upper end of the extraction column, and was pumped into water at 3.01 g/min from the lower end for continuous water washing. After stirring and crystallization for 2 hours, 2.2 g of off-white solid product (rufinamide) was obtained by filtration, with a purity of 98% and a yield of 18.5 wt%.

The difference from Example 1 is that the ratio of the moles of methyl 1,2,3-triazole-4-carboxylate to 2,6-difluorobenzyl chloride and acid binding agent is 1:0.5:0.12.

Example 6

即直径3mm)盘管中，2,6-二氟苄氯(8.1g，0.05mol)溶解在氯仿中(19g，2V)用泵B以1.86g/min的速度泵入第一连续化反应装置中，并将第一连续化反应装置浸没在75℃油浴中，反应原料的保留时间为30min，第一连续化反应装置中压力为0.6MPa，得到连续化缩合产物体系，其中1,2,3-三氮唑-4-羧酸甲酯、三乙胺及2,6-二氟苄氯的摩尔数之比为1:1.2:1。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 used Pump A is pumped into the first continuous reaction device (coil, 25.5 meters long, 1.81 g/min)

2,6-difluorobenzyl chloride (8.1g, 0.05mol) was dissolved in chloroform (19g, 2V) in the coil tube with a diameter of 3mm) and pumped into the first continuous reaction device with pump B at a speed of 1.86g/min , and the first continuous reaction device was immersed in an oil bath at 75°C, the retention time of the reaction raw materials was 30 min, and the pressure in the first continuous reaction device was 0.6 MPa to obtain a continuous condensation product system, wherein 1, 2, The molar ratio of methyl 3-triazole-4-carboxylate, triethylamine and 2,6-difluorobenzyl chloride is 1:1.2:1.

即直径3mm)中，同时用泵C以0.027g/min的速度将20wt％的氨甲醇溶液泵入第二连续化反应装置中，并将第二连续化反应装置浸没在45℃油浴中，保留时间为15min，第二连续化反应装置中的压力为0.6MPa，得到氨解产物体系。The above-mentioned continuous condensation product system is directly entered into the second continuous reaction device (coil, 14.3 meters long,

That is, the diameter of 3mm), at the same time, the 20wt% ammonia methanol solution was pumped into the second continuous reaction device at a speed of 0.027g/min with the pump C, and the second continuous reaction device was immersed in a 45 ℃ oil bath, The retention time was 15 min, and the pressure in the second continuous reaction device was 0.6 MPa to obtain an aminolysis product system.

The outlet was sampled for HPLC, the effluent aminolysis product system entered from the upper end of the extraction column, and was pumped into water at 3.01 g/min from the lower end for continuous water washing. After stirring and crystallization for 2 hours, 4.1 g of off-white solid product (rufinamide) was obtained by filtration, with a purity of 98% and a yield of 35wt%.

The difference from Example 1 is that the ratio of the continuous condensation product to the moles of ammonia in the ammonia methanol solution is 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 set aside. in the reaction flask. 2,6-Difluorobenzyl chloride (8.1g, 0.05mol) was dissolved in chloroform (19g, 2V) and dropped into the reaction flask with a constant pressure dropping funnel. It was detected that the reaction was complete, and the system was brought to room temperature. A condensation product system prepared in batches is obtained, wherein the ratio of the moles of 1,2,3-triazole-4-carboxylate methyl ester, triethylamine and 2,6-difluorobenzyl chloride is 1:1.2:1 .

At room temperature, 20wt% ammonia methanol solution was directly added to the above batch condensation product system, and the system was heated to 30°C for reaction.

The system was brought to room temperature, washed with water to separate the liquids, concentrated most of the solvent, stirred and crystallized at room temperature for 2 h, and filtered to obtain 6.2 g of off-white solid product (rufinamide) with a purity of 98% and a yield of 52.3 wt%.

The difference from Example 1 is that the reaction device is a batch reaction device.

From the above description, it can be seen that the above-mentioned embodiments of the present invention achieve the following technical effects:

Comparing Example 1 and Comparative Example 1, it can be known that the continuous synthesis method provided by the present application is beneficial to improve the yield of rufinamide.

Comparing Examples 1 to 3, it can be seen that limiting the temperature of the first continuous reaction device and the second continuous reaction device within the preferred range of the present application is beneficial to improve the yield of rufinamide.

Comparing Examples 1 and 4, it can be seen that limiting the concentration of ammonia gas in the ammonia-containing solution within the preferred range of the present application is beneficial to improve the yield of rufinamide.

Comparing Examples 1 and 5, it can be seen that the ratio of the moles of methyl 2,3-triazole-4-carboxylate to 2,6-difluorobenzyl chloride and acid binding agent is limited within the preferred range of the present application It is beneficial to improve the yield of rufinamide.

Comparing Examples 1 and 6, it can be seen that the ratio of the continuous condensation product to the moles of ammonia in the ammonia methanol solution is limited to the preferred range of the present application, which is beneficial to improve the yield of rufinamide.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims (10)

1. a continuous synthesis method of Rufinamide, is characterized in that, the continuous synthesis method of described Rufinamide comprises: In the presence of acid binding agent, 1,2,3-triazole-4-carboxylate methyl ester and 2,6-difluorobenzyl chloride are continuously input into the first continuous reaction device for continuous condensation reaction, obtaining a continuous condensation product, and continuously discharging the continuous condensation product; The continuous condensation product and ammonia or ammonia-containing solution are continuously input into the second continuous reaction device to carry out an aminolysis reaction to obtain the rufinamide, and the rufinamide is continuously discharged; the 1, The ratio of the moles of methyl 2,3-triazole-4-carboxylate to the 2,6-difluorobenzyl chloride and the acid binding agent is 1:(1～10):(0.01～10) ; The ratio of the moles _of NH to the continuous condensation product in the ammonia gas or the ammonia-containing solution is (1～100):1; The reaction temperature of the continuous condensation reaction is 70-90°C, and the reaction temperature of the aminolysis reaction is 40-60°C; The first continuous reaction unit and the second continuous reaction unit are respectively selected from a continuous coil or a CSTR continuous reactor. 2. the continuous synthesis method of rufinamide according to claim 1, is characterized in that, described acid binding agent is selected from triethylamine, tri-n-propylamine, diisopropylethylamine, tert-butylamine, triethylenediamine Amine, Diazabicycle, KOH, _NaOH , K2CO3, _Na2CO3 , _NaHCO3 , _Cs2CO3 , _KHCO3 , _MeONa , _MeOK , _t -BuOK, t-BuONa, Sodium Acetate, Potassium Acetate , one or more of sodium methanesulfonate. 3. the continuous synthesis method of rufinamide according to claim 1 is characterized in that, described continuous condensation reaction is carried out under the effect of protective solvent. 4. the continuous synthesis method of rufinamide according to claim 3, is characterized in that, described protective solvent is selected from water, chloroform, dichloromethane, ethyl acetate, triethylamine, tri-n-propylamine, diisopropylamine Propylethylamine, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, N,N-di One or more of methylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-methylpyrrolidone, dimethylsulfoxide, and acetonitrile. 5. the continuous synthesis method of rufinamide according to claim 1, is characterized in that, the reaction time of described continuous condensation reaction is 10～60min. 6 . The continuous synthesis method of rufinamide according to claim 5 , wherein the reaction time of the continuous condensation reaction is 20 to 30 min. 7 . 7. the continuous synthesis method of rufinamide according to claim 1, is characterized in that, the reaction time of described aminolysis reaction is 10～100min. 8. the continuous synthesis method of rufinamide according to claim 7, is characterized in that, the reaction time of described aminolysis reaction is 15～60min. 9. the continuous synthesis method of rufinamide according to claim ₁ , is characterized in that, described ammoniacal solution is NH be dissolved in methanol, water, ethanol, ethyl acetate, acetonitrile, dichloromethane, chloroform, A solution formed after one or more of tetrahydrofuran and methyl tert-butyl ether. 10 . The continuous synthesis method of rufinamide according to claim 9 , wherein, in the ammonia-containing solution, the concentration of NH ₃ is 10-20 wt %. 11 .