CN109438374B - Continuous synthesis method of rufinamide - Google Patents

Continuous synthesis method of rufinamide Download PDF

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CN109438374B
CN109438374B CN201811178842.0A CN201811178842A CN109438374B CN 109438374 B CN109438374 B CN 109438374B CN 201811178842 A CN201811178842 A CN 201811178842A CN 109438374 B CN109438374 B CN 109438374B
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rufinamide
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ammonia
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CN109438374A (en
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洪浩
卢江平
张恩选
申慰
闫红磊
张震
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Asymchem Laboratories Tianjin Co Ltd
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D249/00Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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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

卢非酰胺的连续化合成方法Continuous synthesis method of rufinamide

技术领域technical field

本发明涉及药物合成领域,具体而言,涉及一种卢非酰胺的连续化合成方法。The invention relates to the field of drug synthesis, in particular to a continuous synthesis method of rufinamide.

背景技术Background technique

卢非酰胺(商品名为Banzel)是瑞士诺华公司开发的用于癫痫辅助治疗的药物,2008年11月在美国上市。它是一种三唑类的衍生物,其化学结构与目前已经上市的抗癫痫药物不同,通过调节大脑钠离子通道活性而发挥作用。当卢非酰胺浓度大于10μmol/L时,它对单胺类、肾上腺素、组胺、乙酰胆碱、AMPA-kainate、甘氨酸、NMDA或GABA神经递质-受体系统无明显影响。临床研究表明,癫痫患者对卢非酰胺辅助治疗的耐受性良好,癫痫发作次数减少。而且卢非酰胺对治疗耐受的局部或泛发性癫痫患者仍产生作用,且对局部癫痫发作和泛发性强直-阵挛癫痫发作的治疗也有辅助作用,可联合给药或单独给药。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.

卢非酰胺的合成路线主要有如下几条:The synthetic route of rufinamide mainly includes the following:

Batch路线:Batch route:

在1988年,现有文献首次公开了以2,6-二氟苄溴为起始原料,经与叠氮化钠反应,再和丙炔酸环合得三氮唑羧酸,然后经酰氯化或者成酯后与氨气溶液反应得到终产物。该方法使用高危剧毒的叠氮化钠,而且路线较长,难以规模化生产,总成本较高。而后发明人对该路线进行了改进,使用2-氯丙烯腈替代丙炔酸进行环合,提高了反应收率(64%)并缩短了反应路线,但仍然需要使用叠氮化钠和价格昂贵的2-氯丙烯腈。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.

2010年的一篇文献提供了一种合成卢非酰胺的方法,该方法中以2,6-二氟苄溴和丙炔酸甲酯为起始原料,通过一锅法制得了卢非酰胺的,但收率仅为36%。且仍然需要使用叠氮化钠和价格昂贵的丙炔酸甲酯;同年,另一篇文献报道了使用2,6-二氟苄溴经叠氮化后在亚铜离子的催化下与丙炔酸、丙炔酰胺或丙炔酸甲酯进行环合的路线进行制备,减少了环合过程中位置异构体的生成,能以64%~77%的收率得到目标产物。又一篇文献报道了使用价格较为便宜的3-甲氧基丙烯酸甲酯替代丙炔酸类化合物与2,6-二氟苄基叠氮在135℃下无溶剂进行环合反应后再氨解得到目标物的路线,产品总收率89%,该路线仍需要使用高危剧毒的叠氮钠。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.

2012年的一篇文献提供了一种使用丙炔醇替代丙炔酸与2,6-二氟苄基叠氮在亚铜离子催化下进行环合后再氧化成酸,最后成酰胺的路线,产品收率为71%。该路线仍然需要使用叠氮钠和价格昂贵的丙炔醇。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.

2013年的一篇文献提供了一种使用氧化亚铜为催化剂,以2,6-二氟苄溴、叠氮钠和丙炔酰胺为起始原料,一锅法合成卢非酰胺的方法,收率95%。该路线收率虽高,但使用了高危剧毒的叠氮钠,并且使用的亚铜催化剂为菱形十二面体晶体,价格较高。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.

2014年的一篇文献提供了一种合成卢非酰胺的方法,该方法中使用价格较为便宜的2-溴丙烯酸酯替代昂贵的丙炔酸,但2-溴丙烯酸酯的制备需要使用易制毒和毒性较大的溴素做为溴化剂,后处理会产生较多的废水,面临巨大的环保压力。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.

2015年的一篇文献提供了一种合成卢非酰胺的方法,该方法中使用DBU为催化剂,使用3-甲氧基丙烯酸甲酯与2,6-二氟苄基叠氮反应成环后再氨解的方法制备得到了卢非酰胺。同年,另一篇现有文献使用1,1,1-三氯甲基-4-甲氧基-3-丁烯-2-酮和2,6-二氟苄基叠氮为原料,采用一锅法制备卢非酰胺,收率为50%。该路线使用了难以制备且不稳定的1,1,1-三氯甲基-4-甲氧基-3-丁烯-2-酮,且收率不高。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路线:Flow route:

2013年的一篇文献提供了一种合成卢非酰胺的方法,该方法中使用3-甲氧基丙烯酸甲酯和2,6-二氟苄基叠氮使用连续化技术在无溶剂条件下进行了反应,并最终以83%的收率制备得到了卢非酰胺前体。该前体再和氨水进行氨解即可得到卢非酰胺。三年后,上述方法的提出者对方法进行改进,提出了一种新的合成方法,新的合成方法中使用2,6-二氟苄醇为原料,经过不间断的三步连续化反应制备得到了卢非酰胺前体,总收率82%。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%.

2014年的一篇文献提供了一种合成卢非酰胺的方法,该方法中使用2,6-二氟苄溴和丙炔酸甲酯为原料,通过连续化技术制备得到了卢非酰胺,收率98%。该路线仍然需要使用昂贵的丙炔酸甲酯和高危剧毒的叠氮钠,并且使用了大量DMSO和氨水,三废量较大。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.

2017年的一篇文献提供了一种合成卢非酰胺的方法,该方法中使用2,6-二氟苄溴为起始,经叠氮取代,在新型亚铜催化剂催化下与丙炔酰胺环合得到卢非酰胺,总收率95%。但该路线使用了制备复杂,较难获得的三苯基膦铜配合物做为催化剂。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.

由此可知,现有的合成方法存在的问题是:It can be seen from this that the problems existing in the existing synthesis method are:

(1)使用毒性和爆炸性都很强的叠氮钠进行反应,给反应操作和后处理带来了极大的不便,且工艺安全风险较高。(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)使用丙炔酸及衍生物为原料,成本较高。(2) Using propynoic acid and derivatives as raw materials, the cost is relatively high.

(3)环合时会产生5位取代的三氮唑异构体。(3) 5-substituted triazole isomers will be produced during cyclization.

发明内容SUMMARY OF THE INVENTION

本发明的主要目的在于提供一种卢非酰胺的连续化合成方法,以解决现有的制备卢非酰胺的方法存在安全性低、成本高及产品收率低等的问题。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.

为了实现上述目的,本发明提供了一种卢非酰胺的连续化合成方法,该连续化合成方法包括:在缚酸剂的存在下,将1,2,3-三氮唑-4-羧酸甲酯与2,6-二氟苄氯连续地输入第一连续化反应装置中进行连续化缩合反应,得到连续化缩合产物,并将连续化缩合产物连续排出;将连续化缩合产物与氨气或含氨溶液连续地输入第二连续化反应装置中进行氨解反应,得到卢非酰胺,并将卢非酰胺连续排出。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.

进一步地,1,2,3-三氮唑-4-羧酸甲酯与2,6-二氟苄氯及缚酸剂的摩尔数之比为1:(1~10):(0.01~10)。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 ).

进一步地,氨气或含氨溶液中NH3与连续化缩合产物的摩尔数之比为(1~100):1。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.

进一步地,缚酸剂选自三乙胺、三正丙胺、二异丙基乙基胺、叔丁胺、三乙烯二胺、二氮杂二环、KOH、NaOH、K2CO3、Na2CO3、NaHCO3、Cs2CO3、KHCO3、MeONa、MeOK、t-BuOK、t-BuONa、乙酸钠、乙酸钾甲基磺酸钠中的一种或多种。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.

进一步地,连续化缩合反应在保护溶剂的作用下进行;优选地,保护溶剂选自水、氯仿、二氯甲烷、乙酸乙酯、三乙胺、三正丙胺、二异丙基乙基胺、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙二醇二甲醚、二乙二醇二甲醚、苯、甲苯、二甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜、乙腈中的一种或多种。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.

进一步地,连续化缩合反应的反应温度为30~120℃,反应时间为10~60min;优选地,反应温度为70~90℃,反应时间为20~30min。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.

进一步地,氨解反应的反应温度选自25~110℃,反应时间为10~100min;优选地,反应温度为40~60℃,反应时间为15~60min。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.

进一步地,含氨溶液为NH3溶解在甲醇、水、乙醇、乙酸乙酯、乙腈、二氯甲烷、氯仿、四氢呋喃和甲基叔丁基醚中的一种或多种后形成的溶液。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.

进一步地,含氨溶液中,NH3的浓度为10~20wt%。Further, in the ammonia-containing solution, the concentration of NH 3 is 10-20 wt %.

进一步地,第一连续化反应装置和第二连续化反应装置分别选自连续盘管或CSTR连续反应器。Further, the first continuous reaction device and the second continuous reaction device are respectively selected from continuous coils or CSTR continuous reactors.

应用本发明的技术方案,本申请提供的卢非酰胺的连续化合成方法不仅避免了常规路线中的环合步骤产生异构体,简化了终产品的纯化步骤,还降低了工艺成本。采用上述合成方法通过两步反应就能够直接合成目标产物,从而有效缩短了反应路线;同时相比于批次设备,上述合成反应在连续化合成装置中进行,由于反应体系小,热交换速度更高,从而使得反应的条件更加剧烈,但更加安全。整个过程连续运行,规模可控,总收率在86wt%左右。此外上述合成方法在生产上几乎没有放大效应,适合工业化重现小试收率。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.

具体实施方式Detailed ways

需要说明的是,在不冲突的情况下,本申请中的实施例及实施例中的特征可以相互组合。下面将结合实施例来详细说明本发明。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.

正如背景技术所描述的,现有的制备卢非酰胺的方法存在安全性低、成本高及产品收率低等的问题。为了解决上述技术问题,本申请提供了一种卢非酰胺的连续化合成方法,该连续化合成方法包括:在缚酸剂的存在下,将1,2,3-三氮唑-4-羧酸甲酯与2,6-二氟苄氯连续地输入第一连续化反应装置中进行连续化缩合反应,得到连续化缩合产物,并将连续化缩合产物连续排出;将连续化缩合产物与氨气或含氨溶液连续地输入第二连续化反应装置中进行氨解反应,得到卢非酰胺,并将卢非酰胺连续排出。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.

本发明第一步在缚酸剂的作用下,将1,2,3-三氮唑-4-羧酸甲酯与2,6-二氟苄氯连续地通入第一连续化反应装置中进行连续化缩合反应,并将连续缩合产物连续排出。上述连续化缩合反应不经分离纯化,与氨气或含氨溶液连续地输送至第二连续化反应装置中进行氨解反应,得到所需的卢非酰胺。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.

本申请提供的卢非酰胺的连续化合成方法不仅避免了常规路线中的环合步骤产生异构体,简化了终产品的纯化步骤,还降低了工艺成本。采用上述合成方法通过两步反应就能够直接合成目标产物,从而有效缩短了反应路线;同时相比于批次设备,上述合成反应在连续化合成装置中进行,由于反应体系小,热交换速度更高,从而使得反应的条件更加剧烈,但更加安全。整个过程连续运行,规模可控,总收率在86wt%左右。此外上述合成方法在生产上几乎没有放大效应,适合工业化重现小试收率。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.

为了进一步提高产品的纯度,优选地,上述连续化合成方法还包括对氨解反应的产物进行后处理的步骤。更优选地,上述后处理步骤包括:将上述氨解反应的产物体系连续地输送至萃取柱中进行连续水洗,然后将水洗得到的有机相进行浓缩、析晶处理,得到卢非酰胺。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.

为了进一步提高产品的收率,可以对反应原料的摩尔数之比进行调整。In order to further improve the yield of the product, the mole ratio of the reaction raw materials can be adjusted.

在一种优选的实施方式中,1,2,3-三氮唑-4-羧酸甲酯与2,6-二氟苄氯及缚酸剂的摩尔数之比为1:(1~10):(0.5~10)。1,2,3-三氮唑-4-羧酸甲酯与2,6-二氟苄氯反应的摩尔数之比包括但不限于上述范围,而将其限定在上述范围内有利于进一步提高连续化缩合产物的收率,进而提高卢非酰胺的收率。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.

在一种优选的实施方式中,氨气或含氨溶液中NH3与连续化缩合产物的摩尔数之比为(1~100):1。氨气或含氨溶液中氨气与连续化缩合产物的摩尔数之比包括但不限于上述范围,而将其限定在上述范围内有利于进一步提高卢非酰胺的收率。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.

缚酸剂的加入有利于提高连续化缩合反应的反应速率。在一种优选的实施方式中,缚酸剂包括但不限于三乙胺、三正丙胺、二异丙基乙基胺、叔丁胺、三乙烯二胺(DABCO)、二氮杂二环(DBU)、KOH、NaOH、K2CO3、Na2CO3、NaHCO3、Cs2CO3、KHCO3、MeONa、MeOK、t-BuOK、t-BuONa、乙酸钠、乙酸钾甲基磺酸钠中的一种或多种。上述几种缚酸剂价格低廉、易于获取,因而采用上述几种缚酸剂有利于降低工艺成本。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.

在一种优选的实施方式中,连续化缩合反应在保护溶剂的作用下进行。将连续化缩合反应在保护溶剂的作用下进行有利于使反应原料充分接触,提高连续化缩合反应的反应效率。更优选地,保护溶剂包括但不限于水、氯仿、二氯甲烷、乙酸乙酯、三乙胺、三正丙胺、二异丙基乙基胺、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙二醇二甲醚、二乙二醇二甲醚、苯、甲苯、二甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜、乙腈中的一种或多种。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.

为了进一步提高连续化反应的反应速率和产品的收率,可以调整连续化合成反应中各阶段的反应温度。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.

在一种优选的实施方式中,连续化缩合反应的反应温度包括但不限于30~120℃,反应时间为10~60min。连续化缩合反应的反应温度的反应时间包括但不限于上述范围,而将其限定在上述范围内有利于进一步提高连续化缩合反应的反应速率和产品的收率。为了更进一步提高连续化缩合反应的反应效率,优选地,连续化缩合反应的反应温度为40~60℃,反应时间为15~60min。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.

在一种优选的实施方式中,氨解反应的反应温度包括但不限于25~110℃,反应时间为10~100min。氨解反应的反应温度包括但不限于上述范围,而将其限定在上述范围内有利于进一步提高连氨解反应的反应速率和氨解反应产物的收率。为了更进一步提高连氨解反应的反应效率和氨解反应产物的收率,更优选,氨解反应的反应温度为40~60℃,反应时间为15~60min。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.

在一种优选的实施方式中,含氨溶液为NH3溶解在甲醇、水、乙醇、乙酸乙酯、乙腈、二氯甲烷、氯仿、四氢呋喃和甲基叔丁基醚中的一种或多种形成的溶液。采用含氨溶液作为氨解反应的反应原料有利于调节氨解反应的反应速率,并降低反应的激烈程度。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.

优选地,含氨溶液中,NH3的浓度为10~20wt%。NH3的浓度包括但不限于上述范围,而将其限定在上述范围内有利于进一步提高反应的反应速率。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.

上述连续化合成方法具有成本低、规模可控和产品收率高等优点。在一种优选的实施方式中,第一连续化反应装置和第二连续化反应装置分别选自连续盘管或CSTR连续反应器(连续搅拌反应装置)。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.

以下结合具体实施例对本申请作进一步详细描述,这些实施例不能理解为限制本申请所要求保护的范围。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.

实施例1Example 1

将1,2,3-三氮唑-4-羧酸甲酯(6.4g,0.05mol)和三乙胺(6.1g,0.06mol)溶在氯仿中(19g,2V)中搅拌澄清后,用泵A以1.81g/min的速度泵入第一连续化反应装置(盘管,长25.5米,

Figure BDA0001824482220000051
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)
Figure BDA0001824482220000051
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.

将上述连续化缩合产物体系直接进入第二连续化反应装置(盘管,长14.3米,

Figure BDA0001824482220000061
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,
Figure BDA0001824482220000061
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.

出口取样进行HPLC,流出的氨解产物体系从萃取柱上端进入,从下端以3.01g/min泵入水进行连续水洗,保留时间10min,萃取柱下口流出的有机相浓缩掉大部分溶剂后,室温搅拌析晶2h,过滤得类白色固体产物(卢非酰胺)10.2g,纯度99%,收率86wt%。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%.

实施例2Example 2

将1,2,3-三氮唑-4-羧酸甲酯(6.4g,0.05mol)和三乙胺(6.1g,0.06mol)溶在氯仿中(19g,2V)中搅拌澄清后,用泵A以1.81g/min的速度泵入第一连续化反应装置(盘管,长25.5米,

Figure BDA0001824482220000062
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)
Figure BDA0001824482220000062
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.

将上述连续化缩合产物体系直接进入第二连续化反应装置(盘管,长14.3米,

Figure BDA0001824482220000063
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,
Figure BDA0001824482220000063
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.

出口取样进行HPLC,流出的氨解产物体系从萃取柱上端进入,从下端以3.01g/min泵入水进行连续水洗,保留时间10min,萃取柱下口流出的有机相浓缩掉大部分溶剂后,室温搅拌析晶2h,过滤得类白色固体产物(卢非酰胺)9.5g,纯度98%,收率80wt%。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.

与实施例1的区别为:将第一连续化反应装置浸没在100℃的油浴中。The difference from Example 1 is that the first continuous reaction device was immersed in an oil bath at 100°C.

实施例3Example 3

将1,2,3-三氮唑-4-羧酸甲酯(6.4g,0.05mol)和三乙胺(6.1g,0.06mol)溶在氯仿中(19g,2V)中搅拌澄清后,用泵A以1.81g/min的速度泵入第一连续化反应装置(盘管,长25.5米,

Figure BDA0001824482220000064
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)
Figure BDA0001824482220000064
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.

将上述连续化缩合产物体系直接进入第二连续化反应装置(盘管,长14.3米,

Figure BDA0001824482220000065
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,
Figure BDA0001824482220000065
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.

出口取样进行HPLC,流出的氨解产物体系从萃取柱上端进入,从下端以3.01g/min泵入水进行连续水洗,保留时间10min,萃取柱下口流出的有机相浓缩掉大部分溶剂后,室温搅拌析晶2h,过滤得类白色固体产物(卢非酰胺)8.9g,纯度98%,收率75wt%。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.

与实施例1的区别为:将第二连续化反应装置浸没在80℃的油浴中。The difference from Example 1 is that the second continuous reaction device is immersed in an oil bath at 80°C.

实施例4Example 4

将1,2,3-三氮唑-4-羧酸甲酯(6.4g,0.05mol)和三乙胺(6.1g,0.06mol)溶在氯仿中(19g,2V)中搅拌澄清后,用泵A以1.81g/min的速度泵入第一连续化反应装置(盘管,长25.5米,

Figure BDA0001824482220000071
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)
Figure BDA0001824482220000071
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.

将上述连续化缩合产物体系直接进入第二连续化反应装置(盘管,长14.3米,

Figure BDA0001824482220000072
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,
Figure BDA0001824482220000072
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.

出口取样进行HPLC,流出的氨解产物体系从萃取柱上端进入,从下端以3.01g/min泵入水进行连续水洗,保留时间10min,萃取柱下口流出的有机相浓缩掉大部分溶剂后,室温搅拌析晶2h,过滤得类白色固体产物(卢非酰胺)5.0g,纯度98%,收率42wt%。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.

与实施例1的区别为:氨气的浓度为5wt%。The difference from Example 1 is that the concentration of ammonia gas is 5 wt %.

实施例5Example 5

将1,2,3-三氮唑-4-羧酸甲酯(6.4g,0.05mol)和三乙胺(0.61g,0.006mol)溶在氯仿中(19g,2V)中搅拌澄清后,用泵A以1.81g/min的速度泵入第一连续化反应装置(盘管,长25.5米,

Figure BDA0001824482220000073
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)
Figure BDA0001824482220000073
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.

将上述连续化缩合产物体系直接进入第二连续化反应装置(盘管,长14.3米,

Figure BDA0001824482220000074
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,
Figure BDA0001824482220000074
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.

出口取样进行HPLC,流出的氨解产物体系从萃取柱上端进入,从下端以3.01g/min泵入水进行连续水洗,保留时间10min,萃取柱下口流出的有机相浓缩掉大部分溶剂后,室温搅拌析晶2h,过滤得类白色固体产物(卢非酰胺)2.2g,纯度98%,收率18.5wt%。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%.

与实施例1的区别为:1,2,3-三氮唑-4-羧酸甲酯与2,6-二氟苄氯及缚酸剂的摩尔数之比为1:0.5:0.12。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.

实施例6Example 6

将1,2,3-三氮唑-4-羧酸甲酯(6.4g,0.05mol)和三乙胺(6.1g,0.06mol)溶在氯仿中(19g,2V)中搅拌澄清后,用泵A以1.81g/min的速度泵入第一连续化反应装置(盘管,长25.5米,

Figure BDA0001824482220000081
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)
Figure BDA0001824482220000081
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.

将上述连续化缩合产物体系直接进入第二连续化反应装置(盘管,长14.3米,

Figure BDA0001824482220000082
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,
Figure BDA0001824482220000082
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.

出口取样进行HPLC,流出的氨解产物体系从萃取柱上端进入,从下端以3.01g/min泵入水进行连续水洗,保留时间10min,萃取柱下口流出的有机相浓缩掉大部分溶剂后,室温搅拌析晶2h,过滤得类白色固体产物(卢非酰胺)4.1g,纯度98%,收率35wt%。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%.

与实施例1的区别为:连续化缩合产物与氨甲醇溶液中氨的摩尔数之比为1:0.5。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.

对比例1Comparative Example 1

将1,2,3-三氮唑-4-羧酸甲酯(6.4g,0.05mol)和三乙胺(6.1g,0.06mol)溶在氯仿中(19g,2V)中搅拌澄清后,置于反应瓶中。2,6-二氟苄氯(8.1g,0.05mol)溶解在氯仿中(19g,2V)用恒压滴液漏斗滴入反应瓶中,加毕外浴升温至61℃回流反应,10h后,检测反应完全,体系将至室温。得到批次制备的缩合产物体系,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 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 .

室温下,向上述批次缩合产物体系直接加入20wt%的氨甲醇溶液,并将体系升温30℃反应,10h后,检测反应完全,得到氨解产物体系。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.

体系将至室温,水洗分液,浓缩掉大部分溶剂,室温搅拌析晶2h,过滤得类白色固体产物(卢非酰胺)6.2g,纯度98%,收率52.3wt%。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%.

与实施例1的区别为:反应装置为批次性反应装置。The difference from Example 1 is that the reaction device is a batch reaction device.

从以上的描述中,可以看出,本发明上述的实施例实现了如下技术效果:From the above description, it can be seen that the above-mentioned embodiments of the present invention achieve the following technical effects:

比较实施例1和对比例1可知,采用本申请提供的连续化合成方法有利于提高卢非酰胺的收率。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.

比较实施例1至3可知,将第一连续化反应装置和第二连续化反应装置的温度限定在本申请优选的范围内有利于提高卢非酰胺的收率。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.

比较实施例1、4可知,将含氨溶液中氨气的浓度限定在本申请优选的范围内有利于提高卢非酰胺的收率。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.

比较实施例1、5可知,将,2,3-三氮唑-4-羧酸甲酯与2,6-二氟苄氯及缚酸剂的摩尔数之比限定在本申请优选的范围内有利于提高卢非酰胺的收率。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.

比较实施例1、6可知,将连续化缩合产物与氨甲醇溶液中氨的摩尔数之比限定在本申请优选的范围内有利于提高卢非酰胺的收率。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.

以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。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)

1.一种卢非酰胺的连续化合成方法,其特征在于,所述卢非酰胺的连续化合成方法包括:1. a continuous synthesis method of Rufinamide, is characterized in that, the continuous synthesis method of described Rufinamide comprises: 在缚酸剂的存在下,将1,2,3-三氮唑-4-羧酸甲酯与2,6-二氟苄氯连续地输入第一连续化反应装置中进行连续化缩合反应,得到连续化缩合产物,并将所述连续化缩合产物连续排出;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; 将所述连续化缩合产物与氨气或含氨溶液连续地输入第二连续化反应装置中进行氨解反应,得到所述卢非酰胺,并将所述卢非酰胺连续排出;所述1,2,3-三氮唑-4-羧酸甲酯与所述2,6-二氟苄氯及所述缚酸剂的摩尔数之比为1:(1~10):(0.01~10);所述氨气或所述含氨溶液中NH3与所述连续化缩合产物的摩尔数之比为(1~100):1;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; 所述连续化缩合反应的反应温度为70~90℃,所述氨解反应的反应温度为40~60℃;The reaction temperature of the continuous condensation reaction is 70-90°C, and the reaction temperature of the aminolysis reaction is 40-60°C; 所述第一连续化反应装置和所述第二连续化反应装置分别选自连续盘管或CSTR连续反应器。The first continuous reaction unit and the second continuous reaction unit are respectively selected from a continuous coil or a CSTR continuous reactor. 2.根据权利要求1所述的卢非酰胺的连续化合成方法,其特征在于,所述缚酸剂选自三乙胺、三正丙胺、二异丙基乙基胺、叔丁胺、三乙烯二胺、二氮杂二环、KOH、NaOH、K2CO3、Na2CO3、NaHCO3、Cs2CO3、KHCO3、MeONa、MeOK、t-BuOK、t-BuONa、乙酸钠、乙酸钾、 甲基磺酸钠中的一种或多种。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.根据权利要求1所述的卢非酰胺的连续化合成方法,其特征在于,所述连续化缩合反应在保护溶剂的作用下进行。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.根据权利要求3所述的卢非酰胺的连续化合成方法,其特征在于,所述保护溶剂选自水、氯仿、二氯甲烷、乙酸乙酯、三乙胺、三正丙胺、二异丙基乙基胺、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙二醇二甲醚、二乙二醇二甲醚、苯、甲苯、二甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二乙基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜、乙腈中的一种或多种。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.根据权利要求1所述的卢非酰胺的连续化合成方法,其特征在于,所述连续化缩合反应的反应时间为10~60min。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.根据权利要求5所述的卢非酰胺的连续化合成方法,其特征在于,所述连续化缩合反应的反应时间为20~30min。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.根据权利要求1所述的卢非酰胺的连续化合成方法,其特征在于,所述氨解反应的反应时间为10~100min。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.根据权利要求7所述的卢非酰胺的连续化合成方法,其特征在于,所述氨解反应的反应时间为15~60min。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.根据权利要求1所述的卢非酰胺的连续化合成方法,其特征在于,所述含氨溶液为NH3溶解在甲醇、水、乙醇、乙酸乙酯、乙腈、二氯甲烷、氯仿、四氢呋喃和甲基叔丁基醚中的一种或多种后形成的溶液。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.根据权利要求9所述的卢非酰胺的连续化合成方法,其特征在于,所述含氨溶液中,NH3的浓度为10~20wt%。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 .
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