CN109438374A - Rufinamide is continuously synthesizing to method - Google Patents
Rufinamide is continuously synthesizing to method Download PDFInfo
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- CN109438374A CN109438374A CN201811178842.0A CN201811178842A CN109438374A CN 109438374 A CN109438374 A CN 109438374A CN 201811178842 A CN201811178842 A CN 201811178842A CN 109438374 A CN109438374 A CN 109438374A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
Abstract
Method is continuously synthesizing to the present invention provides a kind of rufinamide.It includes: in the presence of acid binding agent, by 1,2 that this, which is continuously synthesizing to method, 3- triazole -4- carboxylate methyl ester and 2,6- difluoro benzyl chloride continuously inputs progress serialization condensation reaction in the first continuous reacting device, obtains serialization condensation product, and serialization condensation product is continuously discharged；It is inputted serialization condensation product and ammonia or continuously containing ammonia solution and carries out ammonolysis reaction in the second continuous reacting device, obtain rufinamide, and rufinamide is continuously discharged.Cyclization step in regular course is not only avoided using the method for being continuously synthesizing to and generates isomers, the purification step of finished product is simplified, also reduces process costs, and effectively shorten reaction route；Simultaneously compared to batch equipment, above-mentioned synthetic reaction carries out in being continuously synthesizing to device, and since reaction system is small, rate of heat exchange is higher, so that the condition of reaction is more violent but safer.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, are continuously synthesizing to method in particular to a kind of rufinamide.
Background technique
Rufinamide (trade name Banzel) is the drug for epilepsy adjuvant treatment of Novartis Co., Ltd, Switzerland exploitation,
In November, 2008 lists in the U.S..It is a kind of derivative of triazole type, chemical structure and the anti-epileptic listed at present
Drug is different, is played a role by adjusting brain sodium-ion channel activity.When rufinamide concentration is greater than 10 μm of ol/L, it
To monoamine, adrenaline, histamine, acetylcholine, AMPA-kainate, glycine, NMDA or GABA neurotransmitter-by system
System has no significant effect.The tolerance that clinical research shows that epileptic assists in the treatment of rufinamide is good, epileptic attack number
It reduces.And rufinamide still generates effect to the local or general hair Patients with Epilepsy for the treatment of tolerance, and to focal seizures
Treatment with general hair property tonic-clonic seizures also has booster action, can be administered in combination or be administered alone.
The synthetic route of rufinamide mainly has several following:
Batch route:
In 1988, existing literature was made public for the first time with 2,6-, bis- fluorobenzyl bromide as starting material, warp and reaction of sodium azide,
Triazole carboxylic acid is obtained with propiolic acid cyclization again, then obtains final product with ammonia solution reaction after chloride or at ester.It should
Method uses the sodium azide of high-risk severe toxicity, and route is longer, it is difficult to which large-scale production, totle drilling cost are higher.Then inventor
The route is improved, cyclization is carried out using 2- chloroacrylonitrile substitution propiolic acid, improves reaction yield (64%) and contract
Short reaction route, but still need using sodium azide and expensive 2- chloroacrylonitrile.
A document in 2010 provides a kind of method for synthesizing rufinamide, in this method with 2,6-, bis- fluorobenzyl bromide and
Methyl propiolate is starting material, rufinamide has been made by one kettle way, but yield is only 36%.And there is still a need for use
Sodium azide and expensive Methyl propiolate；In the same year, another document report is using 2,6-, bis- fluorobenzyl bromide through Azide
Prepared by the route for carrying out cyclization with propiolic acid, propine amide or Methyl propiolate under the catalysis of cuprous ion afterwards, reduce
The generation of position isomer, can obtain target product with 64%~77% yield during cyclization.Another piece document report
Existed using price 3- methoxy-methyl acrylate substitution propine acid compounds inexpensively and 2,6- difluorobenzyl nitrine
Ammonolysis obtains the route of object again after solvent-free progress cyclization reaction at 135 DEG C, total yield of products 89%, the route there is still a need for
Use the Sodium azide of high-risk severe toxicity.
A document in 2012 provides a kind of use propilolic alcohol substitution propiolic acid and 2, and 6- difluorobenzyl nitrine is in Asia
It is reoxidised into acid after the lower progress cyclization of copper ion catalysis, finally at the route of amide, product yield 71%.The route still needs
To use Sodium azide and expensive propilolic alcohol.
A document in 2013 provide it is a kind of using cuprous oxide be catalyst, with 2,6-, bis- fluorobenzyl bromide, Sodium azide
It is starting material, the method for one pot process rufinamide, yield 95% with propine amide.Though the route yield is high, use
The Sodium azide of high-risk severe toxicity, and the cuprous catalysis agent used is granatohedron crystal, and price is higher.
A document in 2014 provides a kind of method for synthesizing rufinamide, uses price inexpensively in this method
2- bromopropene acid esters substitution expensive propiolic acid, but the preparation of 2- bromopropene acid esters is needed using easily system poison and is more toxic
Bromine can generate more waste water, face huge environmental protection pressure as bromating agent, post-processing.
A document in 2015 provides a kind of method for synthesizing rufinamide, and it is catalyst that DBU is used in this method,
Using 3- methoxy-methyl acrylate and 2, Lu Fei has been prepared in the method for ammonolysis again after 6- difluorobenzyl azide reaction cyclization
Amide.The same year, another existing literature use 1,1,1- trichloromethyl-4- methoxyl group-3- butene-2 -one and 2,6- difluorobenzyl
Nitrine is raw material, prepares rufinamide, yield 50% using one kettle way.The route, which has used, to be difficult to prepare and unstable 1,
1,1- trichloromethyl-4- methoxyl group-3- butene-2 -one, and yield is not high.
Flow route:
A document in 2013 provides a kind of method for synthesizing rufinamide, uses 3- methoxyl group propylene in this method
Sour methyl esters and 2,6- difluorobenzyl nitrine are reacted under solvent-free conditions using serialization technology, and finally with 83%
Rufinamide precursor has been prepared in yield.The precursor, which carries out ammonolysis with ammonium hydroxide again, can be obtained rufinamide.It is above-mentioned after 3 years
The presenter of method improves method, proposes a kind of new synthetic method, uses 2,6- difluoro in new synthetic method
Benzylalcohol is raw material, and rufinamide precursor, total recovery 82% has been prepared by continual three steps continuous reaction.
A document in 2014 provides a kind of method for synthesizing rufinamide, uses 2,6-, bis- fluorobenzyl bromide in this method
It is raw material with Methyl propiolate, rufinamide, yield 98% has been prepared by serialization technology.There is still a need for make the route
With the Sodium azide of expensive Methyl propiolate and high-risk severe toxicity, and a large amount of DMSO and ammonium hydroxide are used, quantity of three wastes is larger.
A document in 2017 provides a kind of method for synthesizing rufinamide, uses 2,6-, bis- fluorobenzyl bromide in this method
Rufinamide, total recovery are obtained with propine amide cyclization under novel cuprous catalysis agent catalysis through azide substitution for starting
95%.But the route has used preparation complicated, it is more difficult to which the triphenylphosphine copper complex of acquisition is as catalyst.
It follows that existing synthetic method the problem is that:
(1) it is reacted using toxicity and explosive all very strong Sodium azide, brings pole to operation and post-processing
Big inconvenience, and process safety risk is higher.
It (2) the use of propiolic acid and derivative is raw material, higher cost.
(3) the triazole isomers of 5 substitutions can be generated when cyclization.
Summary of the invention
It is continuously synthesizing to method the main purpose of the present invention is to provide a kind of rufinamide, to solve existing preparation
There is safety is low, at high cost and product yield is low etc. in the method for rufinamide.
To achieve the goals above, it is continuously synthesizing to method the present invention provides a kind of rufinamide, the continuous chemical combination
It include: in the presence of acid binding agent at method, by 1,2,3- triazole -4- carboxylate methyl ester and 2,6- difluoro benzyl chloride is continuously inputted
Serialization condensation reaction is carried out in first continuous reacting device, obtains serialization condensation product, and by serialization condensation product
Continuous discharge；It is inputted serialization condensation product and ammonia or continuously containing ammonia solution and carries out ammonia in the second continuous reacting device
Solution reaction, obtains rufinamide, and rufinamide is continuously discharged.
Further, 1,2,3- triazole -4- carboxylate methyl esters and 2, the ratio between 6- difluoro benzyl chloride and the molal quantity of acid binding agent are
1:(1~10): (0.01~10).
Further, ammonia or containing NH in ammonia solution3It is (1~100) with the ratio between the molal quantity of serialization condensation product: 1.
Further, acid binding agent be selected from triethylamine, Tri-n-Propylamine, diisopropyl ethyl amine, tert-butylamine, triethylene diamine,
Diazabicylo, KOH, NaOH, K2CO3、Na2CO3、NaHCO3、Cs2CO3、KHCO3、MeONa、MeOK、t-BuOK、t-BuONa、
One of sodium acetate, potassium acetate sodium methanesulfonate are a variety of.
Further, serialization condensation reaction carries out under the action of protecting solvent；Preferably, protection solvent be selected from water,
Chloroform, methylene chloride, ethyl acetate, triethylamine, Tri-n-Propylamine, diisopropyl ethyl amine, tetrahydrofuran, 2- methyl tetrahydro furan
Mutter, 1,4- dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, benzene,toluene,xylene, N,N-dimethylformamide,
DMAC N,N' dimethyl acetamide, N, one of N- diethylformamide, N-Methyl pyrrolidone, dimethyl sulfoxide, acetonitrile or more
Kind.
Further, the reaction temperature of serialization condensation reaction is 30~120 DEG C, and the reaction time is 10~60min；It is preferred that
Ground, reaction temperature are 70~90 DEG C, and the reaction time is 20~30min.
Further, the reaction temperature of ammonolysis reaction is selected from 25~110 DEG C, and the reaction time is 10~100min；Preferably,
Reaction temperature is 40~60 DEG C, and the reaction time is 15~60min.
It further, is NH containing ammonia solution3Be dissolved in methanol, water, ethyl alcohol, ethyl acetate, acetonitrile, methylene chloride, chloroform,
One of tetrahydrofuran and methyl tertiary butyl ether(MTBE) or a variety of rear solution formed.
Further, contain in ammonia solution, NH3Concentration be 10~20wt%.
Further, the first continuous reacting device and the second continuous reacting device are respectively selected from continuous coil pipe or CSTR
Flow reactor.
It applies the technical scheme of the present invention, the method that is continuously synthesizing to of rufinamide provided by the present application not only avoids often
The cyclization step advised in route generates isomers, simplifies the purification step of finished product, also reduces process costs.Using above-mentioned
Synthetic method can directly synthesize target product by two-step reaction, to effectively shorten reaction route；While compared to
Batch equipment, above-mentioned synthetic reaction carry out in being continuously synthesizing to device, and since reaction system is small, rate of heat exchange is higher, from
And make the condition of reaction more violent but safer.Whole process continuous operation, scale is controllable, and total recovery is in 86wt%
Left and right.Furthermore above-mentioned synthetic method is suitble to industrialization to reappear lab scale yield almost without enlarge-effect in production.
Specific embodiment
It should be noted that in the absence of conflict, the features in the embodiments and the embodiments of the present application can phase
Mutually combination.Below in conjunction with embodiment, the present invention will be described in detail.
As described in background technique, the existing method for preparing rufinamide there are safeties it is low, at high cost and produce
The problem of product yield is low equal.In order to solve the above-mentioned technical problem, this application provides a kind of sides of being continuously synthesizing to of rufinamide
Method, it includes: in the presence of acid binding agent, by 1,2,3- triazole -4- carboxylate methyl ester and 2,6- difluoro that this, which is continuously synthesizing to method,
Benzyl chloride continuously inputs progress serialization condensation reaction in the first continuous reacting device, obtains serialization condensation product, and will
Serialization condensation product is continuously discharged；It is anti-that serialization condensation product is continuously inputted with ammonia or containing ammonia solution to the second serialization
It answers and carries out ammonolysis reaction in device, obtain rufinamide, and rufinamide is continuously discharged.
The first step of the present invention is under the action of acid binding agent, by 1,2,3- triazole -4- carboxylate methyl ester and 2,6- difluoro benzyl chloride
It is continuously passed through progress serialization condensation reaction in the first continuous reacting device, and continuous condensating product is continuously discharged.On
It states serialization condensation reaction to purify without isolation, be continuously delivered in the second continuous reacting device with ammonia or containing ammonia solution
Ammonolysis reaction is carried out, required rufinamide is obtained.
The cyclization step that method not only avoids in regular course that is continuously synthesizing to of rufinamide provided by the present application produces
Raw isomers, simplifies the purification step of finished product, also reduces process costs.Two-step reaction is passed through using above-mentioned synthetic method
Target product can be directly synthesized, to effectively shorten reaction route；Simultaneously compared to batch equipment, above-mentioned synthetic reaction
It is carried out in being continuously synthesizing to device, since reaction system is small, rate of heat exchange is higher, so that the condition of reaction is more aggravated
It is strong but safer.Whole process continuous operation, scale is controllable, and total recovery is in 86wt% or so.Furthermore above-mentioned synthetic method exists
Almost without enlarge-effect in production, industrialization is suitble to reappear lab scale yield.
In order to further increase the purity of product, it is preferable that the above-mentioned method that is continuously synthesizing to further includes to ammonolysis reaction
The step of product is post-processed.It is highly preferred that above-mentioned post-processing step includes: that the product system of above-mentioned ammonolysis reaction is continuous
Ground, which is delivered in extraction column, carries out continuous washing, then the organic phase that washing obtains is concentrated, crystallization processing, obtains Lu Fei
Amide.
In order to further increase the yield of product, can the ratio between the molal quantity to reaction raw materials be adjusted.
In a preferred embodiment, 1,2,3- triazole -4- carboxylate methyl esters and 2,6- difluoro benzyl chloride and acid binding agent
The ratio between molal quantity be 1:(1~10): (0.5~10).1,2,3- triazole -4- carboxylate methyl ester is reacted with 2,6- difluoro benzyl chloride
The ratio between molal quantity includes but is not limited to above range, and is limited and be conducive to further increase serialization contracting within the above range
The yield of product is closed, and then improves the yield of rufinamide.
In a preferred embodiment, ammonia or containing NH in ammonia solution3With the molal quantity of serialization condensation product it
Than for (1~100): 1.On the ratio between ammonia or the molal quantity containing ammonia in ammonia solution and serialization condensation product include but is not limited to
Range is stated, and is limited the yield for being conducive to further increase rufinamide within the above range.
The addition of acid binding agent is conducive to improve the reaction rate of serialization condensation reaction.In a kind of preferred embodiment
In, acid binding agent include but is not limited to triethylamine, Tri-n-Propylamine, diisopropyl ethyl amine, tert-butylamine, triethylene diamine (DABCO),
Diazabicylo (DBU), KOH, NaOH, K2CO3、Na2CO3、NaHCO3、Cs2CO3、KHCO3、MeONa、MeOK、t-BuOK、t-
One of BuONa, sodium acetate, potassium acetate sodium methanesulfonate are a variety of.Above-mentioned several acid binding agents are cheap, are easily obtained,
Thus process costs are advantageously reduced using above-mentioned several acid binding agents.
In a preferred embodiment, serialization condensation reaction carries out under the action of protecting solvent.By serialization
Condensation reaction carries out being conducive to come into full contact with reaction raw materials under the action of protecting solvent, improves the anti-of serialization condensation reaction
Answer efficiency.It is highly preferred that protection solvent includes but is not limited to water, chloroform, methylene chloride, ethyl acetate, triethylamine, three positive third
Amine, diisopropyl ethyl amine, tetrahydrofuran, 2- methyltetrahydrofuran, 1,4- dioxane, glycol dimethyl ether, diethylene glycol
Dimethyl ether, benzene,toluene,xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N- first
One of base pyrrolidones, dimethyl sulfoxide, acetonitrile are a variety of.
It is adjustable to be continuously synthesizing to react in order to further increase the reaction rate of continuous reaction and the yield of product
In each stage reaction temperature.
In a preferred embodiment, the reaction temperature of serialization condensation reaction includes but is not limited to 30~120 DEG C,
Reaction time is 10~60min.The reaction time of the reaction temperature of serialization condensation reaction includes but is not limited to above range, and
Limited the yield of the reaction rate and product that are conducive to further increase serialization condensation reaction within the above range.In order to
Further improve the reaction efficiency of serialization condensation reaction, it is preferable that the reaction temperature of serialization condensation reaction is 40~60
DEG C, the reaction time is 15~60min.
In a preferred embodiment, the reaction temperature of ammonolysis reaction includes but is not limited to 25~110 DEG C, when reaction
Between be 10~100min.The reaction temperature of ammonolysis reaction includes but is not limited to above range, and is limited within the above range
Be conducive to the reaction rate of the company's of further increasing ammonolysis reaction and the yield of ammonolysis reaction product.For the further company's of raising ammonia
The reaction efficiency of reaction and the yield of ammonolysis reaction product are solved, it is further preferred that the reaction temperature of ammonolysis reaction is 40~60 DEG C, reaction
Time is 15~60min.
It in a preferred embodiment, is NH containing ammonia solution3Be dissolved in methanol, water, ethyl alcohol, ethyl acetate, acetonitrile,
One of methylene chloride, chloroform, tetrahydrofuran and methyl tertiary butyl ether(MTBE) or the solution of a variety of formation.Using conduct containing ammonia solution
The reaction raw materials of ammonolysis reaction are conducive to adjust the reaction rate of ammonolysis reaction, and reduce the severity of reaction.
Preferably, contain in ammonia solution, NH3Concentration be 10~20wt%.NH3Concentration include but is not limited to above range,
And limited the reaction rate for being conducive to further increase reaction within the above range.
The above-mentioned method that is continuously synthesizing to has many advantages, such as that at low cost, scale is controllable and product yield is high.A kind of preferred
In embodiment, the first continuous reacting device and the second continuous reacting device is respectively selected from continuous coil pipe or CSTR is continuously anti-
Answer device (continuously stirring reaction unit).
The application is described in further detail below in conjunction with specific embodiment, these embodiments should not be understood as limitation originally
Apply for range claimed.
Embodiment 1
1,2,3- triazole -4- carboxylate methyl ester (6.4g, 0.05mol) and triethylamine (6.1g, 0.06mol) are dissolved in chloroform
In in (19g, 2V) after stirring clarification, with pump A with the speed of 1.81g/min be pumped into the first continuous reacting device (coil pipe, it is long
25.5 rice,That is diameter 3mm) in coil pipe, 2,6- difluoro benzyl chlorides (8.1g, 0.05mol) are dissolved in chloroform (19g, 2V) use
Pump B is pumped into the first continuous reacting device with the speed of 1.86g/min, and the first continuous reacting device is immersed in 75 DEG C
In oil bath, the retention time of reaction raw materials is 30min, and pressure is 0.6MPa in the first continuous reacting device, obtains serialization
Condensation product system, wherein 1,2,3- triazole -4- carboxylate methyl ester, triethylamine and 2, the ratio between molal quantity of 6- difluoro benzyl chloride is 1:
1.2:1。
By above-mentioned serialization condensation product system be directly entered the second continuous reacting device (coil pipe, it is 14.3 meters long,
That is diameter 3mm) in, while the methanolic ammonia solution of 20wt% is pumped by the second continuous reaction with the speed of 0.27g/min with pump C
In device, and the second continuous reacting device is immersed in 45 DEG C of oil baths, retention time 15min, the second continuous reaction
Pressure in device is 0.6MPa, obtains ammonia products system.
Outlet sampling carries out HPLC, and the ammonia products system of outflow enters from extraction column upper end, from lower end with 3.01g/min
It is pumped into water and carries out continuous washing, retention time 10min, after most of solvent is fallen in the organic phase concentration that mouth flows out under extraction column, room
Warm stirring and crystallizing 2h filters to obtain off-white powder product (rufinamide) 10.2g, purity 99%, yield 86wt%.
Embodiment 2
1,2,3- triazole -4- carboxylate methyl ester (6.4g, 0.05mol) and triethylamine (6.1g, 0.06mol) are dissolved in chloroform
In in (19g, 2V) after stirring clarification, with pump A with the speed of 1.81g/min be pumped into the first continuous reacting device (coil pipe, it is long
25.5 rice,That is diameter 3mm) in coil pipe, 2,6- difluoro benzyl chlorides (8.1g, 0.05mol) are dissolved in chloroform (19g, 2V) use
Pump B is pumped into the first continuous reacting device with the speed of 1.86g/min, and the first continuous reacting device is immersed in 100
In DEG C oil bath, the retention time of reaction raw materials is 30min, and pressure is 0.6MPa in the first continuous reacting device, is obtained continuous
Change condensation product system, wherein 1,2,3- triazole -4- carboxylate methyl ester, triethylamine and 2, the ratio between the molal quantity of 6- difluoro benzyl chloride are
1:1.2:1。
By above-mentioned serialization condensation product system be directly entered the second continuous reacting device (coil pipe, it is 14.3 meters long,That is diameter 3mm) in, while the methanolic ammonia solution of 20wt% is pumped into second continuously with the speed of 0.27g/min with pump C
Change in reaction unit, and the second continuous reacting device is immersed in 45 DEG C of oil baths, retention time 15min, second is continuous
The pressure changed in reaction unit is 0.6MPa, obtains ammonia products system.
Outlet sampling carries out HPLC, and the ammonia products system of outflow enters from extraction column upper end, from lower end with 3.01g/min
It is pumped into water and carries out continuous washing, retention time 10min, after most of solvent is fallen in the organic phase concentration that mouth flows out under extraction column, room
Warm stirring and crystallizing 2h filters to obtain off-white powder product (rufinamide) 9.5g, purity 98%, yield 80wt%.
With the difference of embodiment 1 are as follows: be immersed in the first continuous reacting device in 100 DEG C of oil bath.
Embodiment 3
1,2,3- triazole -4- carboxylate methyl ester (6.4g, 0.05mol) and triethylamine (6.1g, 0.06mol) are dissolved in chloroform
In in (19g, 2V) after stirring clarification, with pump A with the speed of 1.81g/min be pumped into the first continuous reacting device (coil pipe, it is long
25.5 rice,That is diameter 3mm) in coil pipe, 2,6- difluoro benzyl chlorides (8.1g, 0.05mol) are dissolved in chloroform (19g, 2V) use
Pump B is pumped into the first continuous reacting device with the speed of 1.86g/min, and the first continuous reacting device is immersed in 75 DEG C
In oil bath, the retention time of reaction raw materials is 30min, and pressure is 0.6MPa in the first continuous reacting device, obtains serialization
Condensation product system, wherein 1,2,3- triazole -4- carboxylate methyl ester, triethylamine and 2, the ratio between molal quantity of 6- difluoro benzyl chloride is 1:
1.2:1。
By above-mentioned serialization condensation product system be directly entered the second continuous reacting device (coil pipe, it is 14.3 meters long,
That is diameter 3mm) in, while the methanolic ammonia solution of 20wt% is pumped by the second continuous reaction with the speed of 0.27g/min with pump C
In device, and the second continuous reacting device is immersed in 80 DEG C of oil baths, retention time 15min, the second continuous reaction
Pressure in device is 0.6MPa, obtains ammonia products system.
Outlet sampling carries out HPLC, and the ammonia products system of outflow enters from extraction column upper end, from lower end with 3.01g/min
It is pumped into water and carries out continuous washing, retention time 10min, after most of solvent is fallen in the organic phase concentration that mouth flows out under extraction column, room
Warm stirring and crystallizing 2h filters to obtain off-white powder product (rufinamide) 8.9g, purity 98%, yield 75wt%.
With the difference of embodiment 1 are as follows: be immersed in the second continuous reacting device in 80 DEG C of oil bath.
Embodiment 4
1,2,3- triazole -4- carboxylate methyl ester (6.4g, 0.05mol) and triethylamine (6.1g, 0.06mol) are dissolved in chloroform
In in (19g, 2V) after stirring clarification, with pump A with the speed of 1.81g/min be pumped into the first continuous reacting device (coil pipe, it is long
25.5 rice,That is diameter 3mm) in coil pipe, 2,6- difluoro benzyl chlorides (8.1g, 0.05mol) are dissolved in chloroform (19g, 2V) use
Pump B is pumped into the first continuous reacting device with the speed of 1.86g/min, and the first continuous reacting device is immersed in 75 DEG C
In oil bath, the retention time of reaction raw materials is 30min, and pressure is 0.6MPa in the first continuous reacting device, obtains serialization
Condensation product system, wherein 1,2,3- triazole -4- carboxylate methyl ester, triethylamine and 2, the ratio between molal quantity of 6- difluoro benzyl chloride is 1:
1.2:1。
By above-mentioned serialization condensation product system be directly entered the second continuous reacting device (coil pipe, it is 14.3 meters long,
That is diameter 3mm) in, while the methanolic ammonia solution of 5wt% is pumped by the second continuous reaction with the speed of 0.27g/min with pump C
In device, and the second continuous reacting device is immersed in 45 DEG C of oil baths, retention time 15min, the second continuous reaction
Pressure in device is 0.6MPa, obtains ammonia products system.
Outlet sampling carries out HPLC, and the ammonia products system of outflow enters from extraction column upper end, from lower end with 3.01g/min
It is pumped into water and carries out continuous washing, retention time 10min, after most of solvent is fallen in the organic phase concentration that mouth flows out under extraction column, room
Warm stirring and crystallizing 2h filters to obtain off-white powder product (rufinamide) 5.0g, purity 98%, yield 42wt%.
With the difference of embodiment 1 are as follows: the concentration of ammonia is 5wt%.
Embodiment 5
1,2,3- triazole -4- carboxylate methyl ester (6.4g, 0.05mol) and triethylamine (0.61g, 0.006mol) are dissolved in chlorine
In imitating in (19g, 2V) after stirring clarification, the first continuous reacting device (coil pipe, length are pumped into the speed of 1.81g/min with pump A
25.5 rice,That is diameter 3mm) in coil pipe, 2,6- difluoro benzyl chlorides (4.1g, 0.03mol) are dissolved in chloroform (19g, 2V) use
Pump B is pumped into the first continuous reacting device with the speed of 1.86g/min, and the first continuous reacting device is immersed in 75 DEG C
In oil bath, the retention time of reaction raw materials is 30min, and pressure is 0.6MPa in the first continuous reacting device, obtains serialization
Condensation product system, wherein 1,2,3- triazole -4- carboxylate methyl ester, triethylamine and 2, the ratio between molal quantity of 6- difluoro benzyl chloride is 1:
0.12:0.5。
By above-mentioned serialization condensation product system be directly entered the second continuous reacting device (coil pipe, it is 14.3 meters long,That is diameter 3mm) in, while the methanolic ammonia solution of 20wt% is pumped into second continuously with the speed of 0.27g/min with pump C
Change in reaction unit, and the second continuous reacting device is immersed in 45 DEG C of oil baths, retention time 15min, second is continuous
The pressure changed in reaction unit is 0.6MPa, obtains ammonia products system.
Outlet sampling carries out HPLC, and the ammonia products system of outflow enters from extraction column upper end, from lower end with 3.01g/min
It is pumped into water and carries out continuous washing, retention time 10min, after most of solvent is fallen in the organic phase concentration that mouth flows out under extraction column, room
Warm stirring and crystallizing 2h filters to obtain off-white powder product (rufinamide) 2.2g, purity 98%, yield 18.5wt%.
With the difference of embodiment 1 are as follows: mole of 1,2,3- triazole -4- carboxylate methyl ester and 2,6- difluoro benzyl chloride and acid binding agent
The ratio between number is 1:0.5:0.12.
Embodiment 6
1,2,3- triazole -4- carboxylate methyl ester (6.4g, 0.05mol) and triethylamine (6.1g, 0.06mol) are dissolved in chloroform
In in (19g, 2V) after stirring clarification, with pump A with the speed of 1.81g/min be pumped into the first continuous reacting device (coil pipe, it is long
25.5 rice,That is diameter 3mm) in coil pipe, 2,6- difluoro benzyl chlorides (8.1g, 0.05mol) are dissolved in chloroform (19g, 2V) use
Pump B is pumped into the first continuous reacting device with the speed of 1.86g/min, and the first continuous reacting device is immersed in 75 DEG C
In oil bath, the retention time of reaction raw materials is 30min, and pressure is 0.6MPa in the first continuous reacting device, obtains serialization
Condensation product system, wherein 1,2,3- triazole -4- carboxylate methyl ester, triethylamine and 2, the ratio between molal quantity of 6- difluoro benzyl chloride is 1:
1.2:1。
By above-mentioned serialization condensation product system be directly entered the second continuous reacting device (coil pipe, it is 14.3 meters long,
That is diameter 3mm) in, while it is anti-with pump C with the speed of 0.027g/min the methanolic ammonia solution of 20wt% to be pumped into the second serialization
It answers in device, and the second continuous reacting device is immersed in 45 DEG C of oil baths, retention time 15min, the second serialization is anti-
Answering the pressure in device is 0.6MPa, obtains ammonia products system.
Outlet sampling carries out HPLC, and the ammonia products system of outflow enters from extraction column upper end, from lower end with 3.01g/min
It is pumped into water and carries out continuous washing, retention time 10min, after most of solvent is fallen in the organic phase concentration that mouth flows out under extraction column, room
Warm stirring and crystallizing 2h filters to obtain off-white powder product (rufinamide) 4.1g, purity 98%, yield 35wt%.
With the difference of embodiment 1 are as follows: the ratio between molal quantity of ammonia is 1:0.5 in serialization condensation product and methanolic ammonia solution.
Comparative example 1
1,2,3- triazole -4- carboxylate methyl ester (6.4g, 0.05mol) and triethylamine (6.1g, 0.06mol) are dissolved in chloroform
In in (19g, 2V) after stirring clarification, be placed in a reaction flask.2,6- difluoro benzyl chlorides (8.1g, 0.05mol) are dissolved in chloroform
(19g, 2V) is instilled in reaction flask with constant pressure funnel, is finished outer bathe and is warming up to 61 DEG C of back flow reactions, after 10h, detection reaction
Completely, the near room temperature of system.The condensation product system of batch preparation is obtained, wherein 1,2,3- triazole -4- carboxylate methyl ester, three second
The ratio between amine and the molal quantity of 2,6- difluoro benzyl chloride are 1:1.2:1.
At room temperature, Xiang Shangshu batch condensation product system is directly added into the methanolic ammonia solution of 20wt%, and system is heated up
30 DEG C are reacted, and after 10h, are detected fully reacting, are obtained ammonia products system.
The near room temperature of system washes liquid separation, and concentration falls most of solvent, crystallization 2h is stirred at room temperature, filter off-white color is solid
Body product (rufinamide) 6.2g, purity 98%, yield 52.3wt%.
With the difference of embodiment 1 are as follows: reaction unit is batch reaction unit.
It can be seen from the above description that the above embodiments of the present invention realized the following chievements:
Comparing embodiment 1 and comparative example 1 using the method provided by the present application that is continuously synthesizing to it is found that be conducive to improve Lu Fei
The yield of amide.
Comparing embodiment 1 to 3 is it is found that by the limit temperature of the first continuous reacting device and the second continuous reacting device
Be conducive to improve the yield of rufinamide in the preferred range of the application.
Comparing embodiment 1,4 is it is found that the concentration containing ammonia in ammonia solution is limited in the preferred range of the application favorably
In the yield for improving rufinamide.
Comparing embodiment 1,5 is it is found that general, 2,3- triazole -4- carboxylate methyl esters and 2,6- difluoro benzyl chloride and acid binding agent rub
The ratio between your number is limited to the yield for being conducive to improve rufinamide in the preferred range of the application.
Comparing embodiment 1,6 is it is found that the ratio between serialization condensation product and the molal quantity of ammonia in methanolic ammonia solution are limited to
Be conducive to improve the yield of rufinamide in the preferred range of the application.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of rufinamide is continuously synthesizing to method, which is characterized in that the rufinamide is continuously synthesizing to method packet
It includes:
In the presence of acid binding agent, by 1,2,3- triazole -4- carboxylate methyl ester and 2,6- difluoro benzyl chloride continuously inputs the first company
Serialization condensation reaction is carried out in continuousization reaction unit, obtains serialization condensation product, and the serialization condensation product is connected
Continuous discharge；
It is inputted the serialization condensation product and ammonia or continuously containing ammonia solution and carries out ammonia in the second continuous reacting device
Solution reaction, obtains the rufinamide, and the rufinamide is continuously discharged.
2. rufinamide according to claim 1 is continuously synthesizing to method, which is characterized in that described 1,2,3- tri- nitrogen
The ratio between molal quantity of azoles -4- carboxylate methyl ester and the 2,6- difluoro benzyl chloride and the acid binding agent is 1:(1~10): (0.01~
10)。
3. rufinamide according to claim 1 or 2 is continuously synthesizing to method, which is characterized in that the ammonia or institute
It states containing NH in ammonia solution3It is (1~100) with the ratio between the molal quantity of the serialization condensation product: 1.
4. rufinamide according to any one of claim 1 to 3 is continuously synthesizing to method, which is characterized in that described
Acid binding agent be selected from triethylamine, Tri-n-Propylamine, diisopropyl ethyl amine, tert-butylamine, triethylene diamine, diazabicylo, KOH,
NaOH、K2CO3、Na2CO3、NaHCO3、Cs2CO3、KHCO3, MeONa, MeOK, t-BuOK, t-BuONa, sodium acetate, potassium acetate first
One of base sodium sulfonate is a variety of.
5. rufinamide according to claim 1 is continuously synthesizing to method, which is characterized in that the serialization condensation is anti-
It should be carried out under the action of protecting solvent；Preferably, the protection solvent is selected from water, chloroform, methylene chloride, ethyl acetate, three
Ethamine, Tri-n-Propylamine, diisopropyl ethyl amine, tetrahydrofuran, 2- methyltetrahydrofuran, 1,4- dioxane, glycol dinitrate
Ether, diethylene glycol dimethyl ether, benzene,toluene,xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethyl
One of formamide, N-Methyl pyrrolidone, dimethyl sulfoxide, acetonitrile are a variety of.
6. rufinamide according to any one of claim 1 to 3 is continuously synthesizing to method, which is characterized in that described
The reaction temperature of serialization condensation reaction is 30~120 DEG C, and the reaction time is 10~60min；
Preferably, the reaction temperature is 70~90 DEG C, and the reaction time is 20~30min.
7. rufinamide according to any one of claim 1 to 3 is continuously synthesizing to method, which is characterized in that described
The reaction temperature of ammonolysis reaction is selected from 25~110 DEG C, and the reaction time is 10~100min；
Preferably, the reaction temperature is 40~60 DEG C, and the reaction time is 15~60min.
8. rufinamide according to claim 1 is continuously synthesizing to method, which is characterized in that the ammonia solution that contains is NH3
It is dissolved in one of methanol, water, ethyl alcohol, ethyl acetate, acetonitrile, methylene chloride, chloroform, tetrahydrofuran and methyl tertiary butyl ether(MTBE)
Or a variety of rear solution formed.
9. rufinamide according to claim 8 is continuously synthesizing to method, which is characterized in that it is described to contain in ammonia solution,
NH3Concentration be 10~20wt%.
10. rufinamide according to any one of claim 1 to 9 is continuously synthesizing to method, which is characterized in that described
First continuous reacting device and second continuous reacting device are respectively selected from continuous coil pipe or CSTR flow reactor.
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