WO2021120064A1 - 乙氧基亚甲基丙二腈的连续合成方法 - Google Patents

乙氧基亚甲基丙二腈的连续合成方法 Download PDF

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WO2021120064A1
WO2021120064A1 PCT/CN2019/126378 CN2019126378W WO2021120064A1 WO 2021120064 A1 WO2021120064 A1 WO 2021120064A1 CN 2019126378 W CN2019126378 W CN 2019126378W WO 2021120064 A1 WO2021120064 A1 WO 2021120064A1
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malononitrile
reaction
continuous
pump
ethoxymethylene
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PCT/CN2019/126378
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English (en)
French (fr)
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洪浩
卢江平
包登辉
刘超杰
贾晓童
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凯莱英医药集团（天津）股份有限公司
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Priority to PCT/CN2019/126378 priority Critical patent/WO2021120064A1/zh
Priority to US17/772,660 priority patent/US20220340517A1/en
Publication of WO2021120064A1 publication Critical patent/WO2021120064A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/15—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same unsaturated acyclic carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups

Definitions

  • the present invention relates to the technical field of organic synthesis, in particular to a continuous synthesis method of ethoxymethylene malononitrile.
  • Ethoxymethylene malononitrile is white to off-white crystalline powder, insoluble in water, soluble in organic solvents such as methanol, ethanol, melting point 65 ⁇ 67°C, boiling point 160°C(12mmHg), commonly used in the preparation of industrial chemicals , Intermediates of pharmaceutical chemicals, such as intermediates for the preparation of milrinone. Therefore, ethoxymethylenemalononitrile has a very broad field and very broad development prospects, and it is of great significance to develop a high-efficiency and low-cost synthesis process of ethoxymethylenemalonitrile.
  • the preparation method of ethoxymethylene malononitrile includes the following steps: triethyl orthoformate and malononitrile are refluxed until the reaction is complete in the presence of an organic solvent and a catalyst.
  • the organic solvent is usually It is a toxic solvent with high boiling point such as toluene. According to the regulations of the International Coordinating Council for Pharmaceuticals for Human Use (ICH), toluene belongs to the second category of restricted solvents.
  • Liu Qiming et al. Liu Qiming, Su Yuyong, Chen Bangyin, Zhang Hanping. Synthesis and structure identification of phosphodiesterase inhibitor Milrinone[J]. Journal of Huazhong University of Science and Technology (Medical Edition), 2005, 34(1): 74-75).
  • a preparation method of ethoxymethylene malononitrile uses a large amount of toxic toluene as a solvent.
  • the catalyst zinc chloride used is insoluble in organic solvents (toluene) and is difficult to fully contact with the reactants, resulting in poor catalytic effect. Ideally, it affects the reaction rate and the reaction effect, and the yield is only 79% (calculated as malononitrile), so there are disadvantages such as unfavorable environmental protection, high production cost, difficulty in solvent recovery, and low yield.
  • the Chinese patent (CN102584626) provides a method for preparing ethoxymethylene malononitrile.
  • the method uses malononitrile and triethyl orthoformate as starting materials, zinc chloride as a catalyst, and the catalyst used is insoluble in zinc chloride. It is difficult to make full contact with the reacting substances due to organic solvents, which leads to unsatisfactory catalytic effect, which affects the reaction speed and reaction effect.
  • the amount of triethyl ester as the raw material is relatively large, and the yield is only 85% (calculated as malononitrile).
  • the method still has the problems of low yield, high cost, slow reaction speed and low production efficiency.
  • WO2014/2111, 2014 provides a new method for preparing ethoxymethylenemalononitrile, using acetic anhydride as a reagent for the reaction, and the reaction temperature is 110 ⁇ 140°C, but the process is recommended to be safe
  • the operating temperature is T ⁇ 107°C (Td24)
  • the Stoessel level of this reaction is 5, and the risk level is relatively high.
  • the use of traditional tank reactors for scale-up production has high safety risks and cannot be scaled up.
  • the main purpose of the present invention is to provide a continuous synthesis method of ethoxymethylene malononitrile to solve the problem of low yield, environmental pollution and safety by toxic solvents when preparing ethoxymethylene malononitrile in the prior art.
  • a continuous synthesis method of ethoxymethylene malononitrile comprises the following steps: continuously combining malononitrile, triethyl orthoformate and acetic anhydride Into the continuous reaction equipment for substitution reaction to obtain ethoxymethylenemalononitrile, and in the process of the substitution reaction, the generated ethoxymethylenemalononitrile is continuously discharged; among them, malononitrile,
  • the molar ratio of triethyl orthoformate to acetic anhydride is 1:(0.9 ⁇ 6.0):(2.0 ⁇ 6.0).
  • the molar ratio of malononitrile, triethyl orthoformate and acetic anhydride is 1:(1.1-1.5):(2.1-2.5).
  • reaction temperature of the substitution reaction is 110-150°C
  • reaction pressure is 0.3-10 MPa.
  • reaction temperature of the substitution reaction is 110-120°C
  • reaction pressure is 0.3-10 MPa.
  • substitution reaction is carried out under solvent-free or solvent-free conditions.
  • the solvent is selected from ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, One or more of toluene, xylene, acetone, acetonitrile, methanol, ethanol, isopropanol, and ethylene glycol.
  • the residence time of malononitrile, triethyl orthoformate and acetic anhydride in the continuous reaction equipment is 30-400 min.
  • the residence time of malononitrile, triethyl orthoformate and acetic anhydride in the continuous reaction equipment is 90-120 min.
  • the continuous reaction equipment is a tubular continuous reactor or a columnar continuous reactor.
  • the malononitrile, triethyl orthoformate, acetic anhydride and optionally the solvent are pumped into the continuous reaction device through a pump, and the total pumping speed is 20ml/min-5L/min.
  • the invention realizes the continuous production of ethoxymethylene malononitrile by adopting continuous reaction equipment and continuous substitution reaction of malononitrile, triethyl orthoformate and acetic anhydride.
  • the continuous reactor can instantly heat the raw materials to the reaction temperature, avoiding the decomposition of the raw materials caused by the long-term heating process, and the yield is significantly improved.
  • the second type of toxic solvent such as toluene is not needed in the reaction process of the present invention.
  • the use of continuous processes and continuous reaction equipment can significantly reduce the safety risks of the process, and scale-up production can be realized.
  • the prior art has the problems of low yield, environmental pollution by toxic solvents and poor safety when preparing ethoxymethylene malononitrile.
  • the present invention provides a continuous synthesis method of ethoxymethylene malononitrile, which includes the following steps: continuously passing malononitrile, triethyl orthoformate and acetic anhydride into continuous reaction equipment Substitution reaction is carried out in the process to obtain ethoxymethylene malononitrile, and in the process of the substitution reaction, the generated ethoxymethylene malononitrile is continuously discharged; among them, malononitrile and triethyl orthoformate
  • the molar ratio with acetic anhydride is 1:(0.9 ⁇ 6.0):(2.0 ⁇ 6.0).
  • the invention realizes the continuous production of ethoxymethylene malononitrile by adopting continuous reaction equipment and continuous substitution reaction of malononitrile, triethyl orthoformate and acetic anhydride.
  • the continuous reactor can instantly heat the raw materials to the reaction temperature, avoiding the decomposition of the raw materials caused by the long-term heating process, and the yield is significantly improved (the highest can reach more than 98.5%).
  • the second type of toxic solvent such as toluene is not needed in the reaction process of the present invention.
  • the use of continuous processes and continuous reaction equipment can significantly reduce the safety risks of the process, and scale-up production can be realized.
  • the present invention compared with the traditional kettle-type production process, also has the advantages of low cost and small amount of three wastes, and the continuous reaction greatly shortens the reaction time, thereby significantly improving the production efficiency.
  • the post-processing is simple, and the product purity is high, even reaching more than 99.5%.
  • the molar ratio of malononitrile, triethyl orthoformate and acetic anhydride is 1:(1.1-1.5):(2.1-2.5).
  • the raw materials can be heated to the reaction temperature instantaneously through the continuous reactor, avoiding the decomposition of the raw materials caused by the long-term heating process, and the yield is significantly improved.
  • the reaction temperature of the substitution reaction is 110-150° C.
  • the reaction pressure is 0.3-10 MPa. More preferably, the reaction temperature of the substitution reaction is 110-120°C, and the reaction pressure is 0.3-10 MPa.
  • the above-mentioned malononitrile, triethyl orthoformate and acetic anhydride can be directly reacted in a solvent-free state.
  • the reaction can also be carried out in the presence of solvents.
  • solvents are non-toxic solvents of the second type.
  • the solvent is selected from ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, One or more of xylene, acetone, acetonitrile, methanol, ethanol, isopropanol, and ethylene glycol.
  • the amount of solvent relative to malononitrile is 1-50 mg/g.
  • the residence time of malononitrile, triethyl orthoformate and acetic anhydride in the continuous reaction equipment is 30-400 min, more preferably 90-120 min. Under this residence time, the substitution reaction is more sufficient, which is beneficial to further increase the reaction yield.
  • the total pumping rate is 20ml/ min to 5 L/min, preferably 100 to 300 mL/min. It should be noted that the above-mentioned pumping speed refers to the total pumping speed of all raw materials, and those skilled in the art can convert the feed speed of each raw material according to the required amount ratio of each raw material, and will not be repeated here.
  • Method 1 under solvent-free conditions, mix malononitrile and acetic anhydride to form raw material A, use triethyl orthoformate as raw material B, and feed raw material A through pump A and pump B, respectively. It is pumped into the continuous reactor at the same time as the raw material B for the reaction; mode two, when a solvent is involved, dissolve malononitrile and acetic anhydride compound in a part of the solvent to form raw material A, and dissolve triethyl orthoformate in another part of the solvent In, raw material B is formed; then raw material A and raw material B are simultaneously pumped into the continuous reactor through pump A and pump B, respectively, for reaction.
  • the above-mentioned continuous reactor may preferably be a tubular continuous reactor or a columnar continuous reactor. More preferably, the continuous reactor is a coil type reactor, and the special structure of the coil inside it helps to increase the reaction effect. More preferably, the continuous reactor includes coils, heat exchange equipment, temperature detection equipment, pressure detection equipment, liquid flow controllers, online PAT equipment, and automated control systems; coils are used to provide reaction sites; heat exchange equipment is used for regulation The temperature inside the coil; the temperature detection device is used to monitor the reaction temperature in the coil; the pressure detection device is used to monitor the reaction pressure in the coil; the liquid flow controller is connected between the pump and the inlet of the coil, and It is used to adjust and control the feed volume; the online PAT equipment is used to detect the product composition in the coil; the automatic control system is electrically connected with the pump, the liquid flow controller, the heat exchange equipment, the temperature detection equipment, the pressure detection equipment and the online PAT equipment.
  • the use of an automated control system enables precise control and real-time feedback of reaction related parameters such as
  • the above-mentioned synthesis method further includes a step of purifying it.
  • the purification step includes: vacuum concentrating the discharged product, and then adding n-heptane dropwise to the system. Alkane is used to precipitate ethoxymethylenemalononitrile, and filtered to obtain an ethoxymethylenemalononitrile product.
  • the feed amount is 1.0kg, and malononitrile (1.0kg, 15.14mol) and acetic anhydride (3.25kg, 31.79mol) are mixed uniformly at room temperature, which is recorded as material A; triethyl orthoformate (2.47kg, 16.65mol) is recorded It is material B.
  • the speed of pump A is: 248g/min, and the speed of pump B is: 157g/min.
  • the temperature is controlled at 120°C, and the outlet of the continuous reactor is prepared.
  • the pressure is 0.3-0.5MPa, the residence time is 100min, and the outlet sampling GC analysis shows that the remaining raw material is 0.0-0.5%.
  • Pump A system is malononitrile (100g, 1.51mol) + acetic anhydride (325g, 3.18mol), pump B is triethyl orthoformate (247g, 1.67mol), pump A speed is: 24.8g/min, pump B The speed is: 15.7 g/min.
  • Pump A system is malononitrile (100g, 1.51mol) + acetic anhydride (325g, 3.18mol) + ethanol (100ml), pump B is triethyl orthoformate (247g, 1.67mol) + ethanol (100ml), pump A The speed is: 24.8g/min, the speed of pump B is: 15.7g/min, and pump A and pump B are turned on at the same time to pump the two raw materials into the continuous reactor (volume 5L), the temperature is controlled at 120°C, the continuous reactor The outlet pressure is 0.3-0.5MPa, the residence time is 100min, and the outlet sampling GC analysis shows that the remaining raw material is 0.0-0.5%. The outflow system is concentrated and concentrated to 6V. 4V n-heptane is added dropwise for crystallization and filtration to obtain the product Ethoxymethylene malononitrile 175.0g, GC purity: 75.3%, yield 66.15%.
  • Pump A system is malononitrile (100g, 1.51mol) + acetic anhydride (618.14g, 6.05mol), pump B is triethyl orthoformate (201.9g, 1.36mol), pump A speed is: 24.8g/min, The speed of pump B is: 15.7g/min, and pump A and pump B are turned on at the same time to pump the two raw materials into the continuous reactor (volume is 5L), the temperature is controlled at 120°C, and the outlet pressure of the continuous reactor is 0.3 ⁇ 0.5MPa. The residence time is 100min, and the outlet sampling GC analysis shows that the remaining raw material is 1.6-2.5%. The outflowing system is concentrated and concentrated to 6V. 4V n-heptane is added dropwise for crystallization and filtration to obtain the product ethoxymethylene propylene. Nitrile 173.0g, gas phase purity: 91.1%, yield 83.7%.
  • Pump A system is malononitrile (100g, 1.51mol) + acetic anhydride (386.3g, 3.78mol), pump B is triethyl orthoformate (336.5g, 2.27mol), pump A speed is: 24.8g/min, The speed of pump B is: 15.7 g/min.
  • Pump A system is malononitrile (100g, 1.51mol) + acetic anhydride (3091g, 3.03mol), pump B is triethyl orthoformate (1350g, 9.08mol), pump A speed is: 24.8g/min, pump B The speed is: 15.7 g/min. Turn on pump A and pump B at the same time to pump the two raw materials into the continuous reactor (volume 5L), control the temperature at 120°C, prepare the pressure at the outlet of the continuous reactor from 0.3 to 0.5 MPa, the residence time is 100 min, and sample the GC at the outlet for analysis.
  • Pump A system is malononitrile (100g, 1.51mol) + acetic anhydride (3091g, 3.03mol), pump B is triethyl orthoformate (1350g, 9.08mol), pump A speed is: 24.8g/min, pump B The speed is: 15.7 g/min. Turn on pump A and pump B at the same time to pump the two raw materials into the continuous reactor (volume 5L), control the temperature at 120°C, prepare the pressure at the outlet of the continuous reactor from 0.3 to 0.5 MPa, the residence time is 100 min, and sample the GC at the outlet for analysis.
  • Pump A system is malononitrile (100g, 1.51mol) + acetic anhydride (325g, 3.18mol), pump B is triethyl orthoformate (247g, 1.67mol), pump A speed is: 24.8g/min, pump B The speed is: 15.7g/min, and pump A and pump B are turned on at the same time to pump the two raw materials into the continuous reactor (volume 2.5L), the temperature is controlled at 120°C, the outlet of the continuous reactor is prepared for pressure 0.3 ⁇ 0.5MPa, and it stays The time is 45min, the outlet sampling GC analysis, the remaining raw material is 16-17%, the outflow system is concentrated, concentrated to 6V, 4V n-heptane is added dropwise for crystallization, filtered, and the product ethoxymethylenemalononitrile is obtained 143.1g, gas phase purity: 72.3%, yield 67.96%.
  • Pump A system is malononitrile (100g, 1.51mol) + acetic anhydride (325g, 3.18mol), pump B is triethyl orthoformate (247g, 1.67mol), pump A speed is: 24.8g/min, pump B The speed is: 15.7g/min, start pump A and pump B at the same time to pump the two raw materials into the continuous reactor (volume 5L), control the temperature at 120°C, prepare the pressure at the outlet of the continuous reactor from 0.3 to 0.5MPa, and the residence time It is 90min, the outlet sampling GC analysis, the remaining raw material is 0.0-0.5%, the outflow system is concentrated, concentrated to 6V, 4V n-heptane is added dropwise for crystallization, filtered, and the solid is dried to obtain the product ethoxymethylene propyl Dinitrile 182.3g, GC purity: 99.5%, yield 98.12%.
  • Pump A system is malononitrile (100g, 1.51mol) + acetic anhydride (325g, 3.18mol), pump B is triethyl orthoformate (247g, 1.67mol), pump A speed is: 24.8g/min, pump B The speed is: 15.7g/min, start pump A and pump B at the same time to pump the two raw materials into the continuous reactor (volume 5L), control the temperature at 120°C, prepare the pressure at the outlet of the continuous reactor from 0.3 to 0.5MPa, and the residence time It is 120min, the outlet sampling GC analysis, the remaining raw material is 0.0-0.5%, the outflow system is concentrated, concentrated to 6V, 4V n-heptane is added dropwise for crystallization, filtered, and the solid is dried to obtain the product ethoxymethylene propyl Dinitrile 182.7g, GC purity: 99.5%, yield 98.33%.
  • Pump A system is malononitrile (100g, 1.51mol) + acetic anhydride (325g, 3.18mol), pump B is triethyl orthoformate (247g, 1.67mol), pump A speed is: 24.8g/min, pump B The speed is: 15.7g/min, and pump A and pump B are turned on at the same time to pump the two raw materials into the continuous reactor (volume 2.5L), the temperature is controlled at 120°C, the outlet of the continuous reactor is prepared for pressure 0.3 ⁇ 0.5MPa, and it stays The time is 30min, the outlet sampling GC analysis, the remaining raw material is 19-22%, the effluent system is concentrated, concentrated to 6V, 4V n-heptane is added dropwise for crystallization, filtered, and the product ethoxymethylenemalononitrile is obtained 139.4g, gas phase purity: 70.8%, yield 53.39%.
  • Pump A system is malononitrile (100g, 1.51mol) + acetic anhydride (325g, 3.18mol), pump B is triethyl orthoformate (247g, 1.67mol), pump A speed is: 24.8g/min, pump B The speed is: 15.7g/min, start pump A and pump B at the same time to pump the two raw materials into the continuous reactor (volume 5L), control the temperature at 120°C, prepare the pressure at the outlet of the continuous reactor from 0.3 to 0.5MPa, and the residence time It is 400min, the outlet sampling GC analysis, the remaining raw material is 0-0.5%, the outflow system is concentrated, concentrated to 6V, 4V n-heptane is added dropwise for crystallization, filtered, and the product ethoxymethylene malononitrile 180.0 is obtained. g, gas phase purity: 61.2%, yield 59.59%.
  • Pump A system is malononitrile (100g, 1.51mol) + acetic anhydride (325g, 3.18mol), pump B is triethyl orthoformate (247g, 1.67mol), pump A speed is: 24.8g/min, pump B The speed is: 15.7g/min, and pump A and pump B are turned on at the same time to pump the two raw materials into the continuous reactor (volume is 5L), the temperature is controlled at 110°C, the continuous reactor outlet pressure is 10MPa, and the residence time is 100min. Outlet sampling and GC analysis showed that the remaining raw material was 0.0-0.5%.
  • Example 1 The difference from Example 1: The reaction temperature is 110° C., and the pressure is 10 MPa.
  • Pump A system is malononitrile (100g, 1.51mol) + acetic anhydride (325g, 3.18mol), pump B is triethyl orthoformate (247g, 1.67mol), pump A speed is: 24.8g/min, pump B The speed is: 15.7g/min, and pump A and pump B are turned on at the same time to pump the two raw materials into the continuous reactor (volume is 5L), the temperature is controlled at 150°C, the pressure at the outlet of the continuous reactor is 0.9MPa, and the residence time is 100min , Outlet sampling GC analysis, the remaining raw material is 0.0-0.5%, the outflowing system is concentrated, concentrated to 6V, 4V n-heptane is added dropwise to crystallize, filtered to obtain 185.6g of product ethoxymethylene malononitrile, Gas phase purity: 59.4%, yield 59.64%.
  • Example 2 The difference from Example 1: The reaction temperature is 150° C., and the pressure is 0.9 MPa.
  • the continuous reaction equipment runs continuously for 24x7 hours, and the reaction column is equipped with corresponding spare equipment and parts, which can realize the online replacement of equipment without stopping the machine, so as to achieve a full continuous reaction without interruption in the whole process.

Abstract

本发明提供了一种乙氧基亚甲基丙二腈的连续合成方法。该方法包括以下步骤：将丙二腈、原甲酸三乙酯和乙酸酐连续地通入连续反应设备中进行取代反应，得到乙氧基亚甲基丙二腈，且在取代反应的过程中，生成的乙氧基亚甲基丙二腈连续地排出；其中，丙二腈、原甲酸三乙酯和乙酸酐的摩尔比为1:(0.9～6.0):(2.0～6.0)。本发明通过采用连续反应设备，由于单位时间内参与反应的物料量大大减少，高温危险区域减小，安全风险得到极大地降低。且通过连续反应器可将原料瞬间加热到反应温度，避免长时间升温过程造成原料分解，收率得到显著提高。而且，本发明反应过程中无需甲苯这样的二类毒性溶剂。

Description

乙氧基亚甲基丙二腈的连续合成方法 技术领域
本发明涉及有机合成技术领域，具体而言，涉及一种乙氧基亚甲基丙二腈的连续合成方法。
背景技术
乙氧基亚甲基丙二腈呈白色至类白色结晶性粉末，不溶于水，溶于甲醇、乙醇等有机溶剂，熔点65～67℃，沸点160℃(12mmHg)，常用于制备工业化学品、医药化学品的中间体，如用作制备米利农的中间体。因此，乙氧基亚甲基丙二腈具有极其广阔的领域和非常广阔的开发前景，开发一种高效益、低成本的乙氧基亚甲基丙二腈合成工艺具有重要意义。
目前，乙氧基亚甲基丙二腈的制备方法包括如下步骤：原甲酸三乙酯与丙二腈在有机溶剂和催化剂存在的条件下，回流至反应完全，其中，所述的有机溶剂通常为甲苯等高沸点有毒溶剂。根据国际人用药品协调会(ICH)的规定，甲苯属于限制使用的二类溶剂。
刘启明等(刘启明，苏玉永，陈邦银，张汉萍.磷酸二酯酶抑制剂米利农的合成和结构鉴定[J].华中科技大学学报(医学版)，2005，34(1)：74-75)公开了一种乙氧基亚甲基丙二腈的制备方法，该方法大量使用有毒的甲苯作溶剂，所用催化剂氯化锌不溶于有机溶剂(甲苯)而难与反应物质进行充分接触，导致催化效果不理想，影响反应速度和反应效果，收率仅为79％(以丙二腈计)，故存在不利于环保、生产成本高、溶剂回收困难、收率低等缺陷。
中国专利(CN102584626)提供了一种制备乙氧基亚甲基丙二腈的方法，该方法以丙二腈和原甲酸三乙酯为初始原料，氯化锌为催化剂，所用催化剂氯化锌不溶于有机溶剂，而难与反应物质进行充分接触，导致催化效果不理想，影响反应速度和反应效果，原料算三乙酯用量较大，收率仅为85％(以丙二腈计)，该方法仍然存在收率较低、成本高、反应速度慢、生产效率低的问题。
另外，国外专利(WO2014/2111，2014)提供了一种制备乙氧基亚甲基丙二腈的新方法，使用乙酸酐为试剂进行反应，反应温度为110～140℃，但工艺建议的安全操作温度为T<107℃(Td24)，该反应的Stoessel等级为5，危险等级较高，使用传统釜式反应器进行放大生产，具有很高的安全风险，无法进行规模化生产。
基于以上原因，有必要提供一种操作更安全、污染少、收率高的乙氧基亚甲基丙二腈生产工艺。
发明内容
本发明的主要目的在于提供一种乙氧基亚甲基丙二腈的连续合成方法，以解决现有技术中制备乙氧基亚甲基丙二腈时收率低、有毒溶剂污染环境及安全性差的问题。
为了实现上述目的，根据本发明的一个方面，提供了一种乙氧基亚甲基丙二腈的连续合成方法，其包括以下步骤：将丙二腈、原甲酸三乙酯和乙酸酐连续地通入连续反应设备中进行取代反应，得到乙氧基亚甲基丙二腈，且在取代反应的过程中，生成的乙氧基亚甲基丙二腈连续地排出；其中，丙二腈、原甲酸三乙酯和乙酸酐的摩尔比为1:(0.9～6.0):(2.0～6.0)。
进一步地，丙二腈、原甲酸三乙酯和乙酸酐的摩尔比为1:(1.1～1.5):(2.1～2.5)。
进一步地，取代反应的反应温度为110～150℃，反应压力为0.3～10MPa。
进一步地，取代反应的反应温度为110～120℃，反应压力为0.3～10MPa。
进一步地，取代反应在无溶剂或有溶剂的条件下进行。
进一步地，且当采用溶剂时，溶剂选自乙酸乙酯、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、丙酮、乙腈、甲醇、乙醇、异丙醇、乙二醇的一种或多种。
进一步地，取代反应的过程中，丙二腈、原甲酸三乙酯和乙酸酐在连续反应设备中的停留时间为30～400min。
进一步地，取代反应的过程中，丙二腈、原甲酸三乙酯和乙酸酐在连续反应设备中的停留时间为90～120min。
进一步地，连续反应设备为管式连续反应器或柱状连续反应器。
进一步地，取代反应的过程中，通过泵将丙二腈、原甲酸三乙酯、乙酸酐和可选地溶剂泵入连续反应设备，且总的泵入速度为20ml/min～5L/min。
本发明通过采用连续反应设备，以丙二腈、原甲酸三乙酯和乙酸酐的连续化取代反应实现了乙氧基亚甲基丙二腈的连续化生产。相比于传统釜式反应，由于单位时间内参与反应的物料量大大减少，高温危险区域减小，安全风险得到极大地降低。且通过连续反应器可将原料瞬间加热到反应温度，避免长时间升温过程造成原料分解，收率得到显著提高。而且，本发明反应过程中无需甲苯这样的二类毒性溶剂。此外，因采用连续性工艺和连续性反应设备可显著降低该工艺的安全风险，可实现放大生产。
具体实施方式
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。
正如背景技术部分所描述的，现有技术中制备乙氧基亚甲基丙二腈时存在收率低、有毒溶剂污染环境及安全性差的问题。
为了解决上述问题，本发明提供了一种乙氧基亚甲基丙二腈的连续合成方法，其包括以下步骤：将丙二腈、原甲酸三乙酯和乙酸酐连续地通入连续反应设备中进行取代反应，得到乙氧基亚甲基丙二腈，且在取代反应的过程中，生成的乙氧基亚甲基丙二腈连续地排出；其中，丙二腈、原甲酸三乙酯和乙酸酐的摩尔比为1:(0.9～6.0):(2.0～6.0)。
本发明通过采用连续反应设备，以丙二腈、原甲酸三乙酯和乙酸酐的连续化取代反应实现了乙氧基亚甲基丙二腈的连续化生产。相比于传统釜式反应，由于单位时间内参与反应的物料量大大减少，高温危险区域减小，安全风险得到极大地降低。且通过连续反应器可将原料瞬间加热到反应温度，避免长时间升温过程造成原料分解，收率得到显著提高(最高能够达到98.5％以上)。而且，本发明反应过程中无需甲苯这样的二类毒性溶剂。此外，因采用连续性工艺和连续性反应设备可显著降低该工艺的安全风险，可实现放大生产。
除了上述有益效果，本发明相比于传统的釜式生产工艺，还具有成本低和三废量小等优点，且因连续化反应大大缩短了反应时间，从而显著提高了生产效率高。同时，后处理简单，产品纯度较高，甚至能够达到99.5％以上。
为了进一步提高反应效率，提高产物收率，在一种优选的实施方式中，丙二腈、原甲酸三乙酯和乙酸酐的摩尔比为1:(1.1～1.5):(2.1～2.5)。
如前文所述，通过连续反应器可将原料瞬间加热到反应温度，避免长时间升温过程造成原料分解，收率得到显著提高。为了进一步提高反应效率和产物收率，同时避免过高温度造成原料，在一种优选的实施方式中，取代反应的反应温度为110～150℃，反应压力为0.3～10MPa。更优选地，取代反应的反应温度为110～120℃，反应压力为0.3～10MPa。
因连续化取代反应的安全性较高，上述丙二腈、原甲酸三乙酯和乙酸酐可以在无溶剂中的状态下直接进行反应。当然，也可以在有溶剂的条件下反应，这些溶剂为非二类毒性溶剂。优选且当采用溶剂时，溶剂选自乙酸乙酯、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、丙酮、乙腈、甲醇、乙醇、异丙醇、乙二醇的一种或多种。优选地，溶剂相对于丙二腈的用量为1～50mg/g。
在一种优选的实施方式中，取代反应的过程中，丙二腈、原甲酸三乙酯和乙酸酐在连续反应设备中的停留时间为30～400min，更优选为90～120min。该停留时间下，取代反应更为充分，有利于进一步提高反应收率。
在一种优选的实施方式中，取代反应的过程中，通过泵将丙二腈、原甲酸三乙酯、乙酸酐和可选地溶剂泵入连续反应设备，且总的泵入速度为20ml/min～5L/min，优选为100～300mL/min。需说明的是，上述泵入速度是指所有原料的总的泵入速度，本领域技术人员可以根据所需各原料的用量比换算各原料的进料速度，在此不再赘述。
具体的进液方式可以有多种：方式一、无溶剂条件下，将丙二腈和乙酸酐混合形成原料A，将原甲酸三乙酯作为原料B，通过泵A和泵B分别将原料A和原料B同时泵入连续反应器中进行反应；方式二、有溶剂参与时，将丙二腈和乙酸酐化合物溶解在一部分溶剂中，形成原料A，将原甲酸三乙酯溶解在另一部分溶剂中，形成原料B；然后通过泵A和泵B分别将原料A和原料B同时泵入连续反应器中进行反应。
上述连续反应器可以优选为管式连续反应器或柱状连续反应器。更优选地，连续反应器为盘管式反应器，其内部的盘管特殊结构有助于增加反应效果。更优选地，连续反应器包括盘管、换热设备、温度检测设备、压力检测设备、液体流量控制器、在线PAT设备、自动化控制系统；盘管用于提供反应场所；换热设备用于调节盘管内部的温度；温度检测设备用于监测盘管中的反应温度；压力检测设备用于监测盘管中的反应压力；液体流量控制器连接在泵和盘管的进料口之间，用于调节控制进料量；在线PAT设备用于检测盘管内的产物组成；自动化控制系统与泵、液体流量控制器、换热设备、温度检测设备、压力检测设备和在线PAT设备电连接。采用自动化控制系统，可对反应的相关参数例如温度、压力、流速等进行精确的控制和实时的反馈。
生成的乙氧基亚甲基丙二腈连续地排出后，上述合成方法还包括对其进行提纯的步骤，优选地，提纯步骤包括：将排出的产物真空浓缩，然后向体系中滴加正庚烷以使乙氧基亚甲基丙二腈析出，过滤，得到乙氧基亚甲基丙二腈产物。
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。
实施例1
Figure PCTCN2019126378-appb-000001
投料量为1.0kg，室温下将丙二腈(1.0kg，15.14mol)和乙酸酐(3.25kg，31.79mol)混合均匀，记为物料A；原甲酸三乙酯(2.47kg，16.65mol)记为物料B。泵A速度为：248g/min，泵B速度为:157g/min，分别用泵将物料A和物料B泵入连续管道反应器(体积为50L)中，控温120℃，连续反应器出口备压0.3～0.5MPa，停留时间为100min，出口取样GC分析，原料剩余为0.0～0.5％。将从连续反应器中流出的体系于真空下浓缩至6V，控温20～30℃，向上述体系中滴加4V正庚烷，滴毕，体系析出大量固体。过滤，固体烘干得到产物乙氧基亚甲基丙二腈1.83kg，GC纯度：99.7％，收率98.69％。
实施例2
泵A体系为丙二腈(100g，1.51mol)+乙酸酐(325g，3.18mol)，泵B为原甲酸三乙酯(247g，1.67mol)，泵A速度为：24.8g/min，泵B速度为:15.7g/min。同时开启泵A和泵B将两股原料泵入到连续反应器(体积为5L)中，控温130℃，连续反应器出口备压0.3～0.5MPa，停留时间为100min，出口取样GC分析，原料剩余为0.0～0.5％，流出的体系进行浓缩，浓缩至6V，滴加4V正庚烷进行析晶，过滤，得到产物乙氧基亚甲基丙二腈165.0g，GC纯度：97.2％，收率79.8％。
与实施例1的区别：反应温度为130℃。
实施例3
泵A体系为丙二腈(100g，1.51mol)+乙酸酐(325g，3.18mol)+乙醇(100ml)，泵B为原甲酸三乙酯(247g，1.67mol)+乙醇(100ml)，泵A速度为：24.8g/min，泵B速度为:15.7g/min，同时开启泵A和泵B将两股原料泵入到连续反应器(体积为5L)中，控温120℃，连续反应器出口备压0.3～0.5MPa，停留时间为100min，出口取样GC分析，原料剩余为0.0～0.5％，流出的体系进行浓缩，浓缩至6V，滴加4V正庚烷进行析晶，过滤，得到产物乙氧基亚甲基丙二腈175.0g，GC纯度：75.3％，收率66.15％。
与实施例1的区别：使用乙醇作溶剂。
实施例4
泵A体系为丙二腈(100g，1.51mol)+乙酸酐(618.14g，6.05mol)，泵B为原甲酸三乙酯(201.9g，1.36mol)，泵A速度为：24.8g/min，泵B速度为:15.7g/min，同时开启泵A和泵B将两股原料泵入到连续反应器(体积为5L)中，控温120℃，连续反应器出口备压0.3～0.5MPa，停留时间为100min，出口取样GC分析，原料剩余为1.6～2.5％，流出的体系进行浓缩，浓缩至6V，滴加4V正庚烷进行析晶，过滤，得到产物乙氧基亚甲基丙二腈173.0g，气相纯度：91.1％，收率83.7％。
与实施例1的区别：按摩尔比丙二腈：原甲酸三乙酯：乙酸酐＝1：0.9：4.0
实施例5
泵A体系为丙二腈(100g，1.51mol)+乙酸酐(386.3g，3.78mol)，泵B为原甲酸三乙酯(336.5g，2.27mol)，泵A速度为：24.8g/min，泵B速度为:15.7g/min。同时开启泵A和泵B将两股原料泵入到连续反应器(体积为5L)中，控温120℃，连续反应器出口备压0.3～0.5MPa，停留时间为100min，出口取样GC分析，原料剩余为0.0～0.5％，流出的体系进行浓缩，浓缩至6V，滴加4V正庚烷进行析晶，过滤，得到产物乙氧基亚甲基丙二腈181.0g，GC纯度：99.6％，收率98.52％。
与实施例1的区别：按摩尔比丙二腈：原甲酸三乙酯：乙酸酐＝1：1.5：2.5。
实施例6
泵A体系为丙二腈(100g，1.51mol)+乙酸酐(3091g，3.03mol)，泵B为原甲酸三乙酯(1350g，9.08mol)，泵A速度为：24.8g/min，泵B速度为:15.7g/min。同时开启泵A和泵B将两股原料泵入到连续反应器(体积为5L)中，控温120℃，连续反应器出口备压0.3～0.5MPa，停留时间为100min，出口取样GC分析，原料剩余为0.0～0.5％，流出的体系进行浓缩，浓缩至6V，滴加4V正庚烷进行析晶，过滤，得到产物乙氧基亚甲基丙二腈141.0g，GC纯度：91.2％，收率69.6％。
与实施例1的区别：按摩尔比丙二腈：原甲酸三乙酯：乙酸酐＝1：6.0：2.0。
实施例7
泵A体系为丙二腈(100g，1.51mol)+乙酸酐(3091g，3.03mol)，泵B为原甲酸三乙酯(1350g，9.08mol)，泵A速度为：24.8g/min，泵B速度为:15.7g/min。同时开启泵A和泵B将两股原料泵入到连续反应器(体积为5L)中，控温120℃，连续反应器出口备压0.3～0.5MPa，停留时间为100min，出口取样GC分析，原料剩余为0.0～0.5％，流出的体系进行浓缩，浓缩至6V，滴加4V正庚烷进行析晶，过滤，得到产物乙氧基亚甲基丙二腈140.1g，GC纯度：91.6％，收率68.7％。
与实施例1的区别：按摩尔比丙二腈：原甲酸三乙酯：乙酸酐＝1：0.9：6.0。
实施例8
泵A体系为丙二腈(100g，1.51mol)+乙酸酐(325g，3.18mol)，泵B为原甲酸三乙酯(247g，1.67mol)，泵A速度为：24.8g/min，泵B速度为:15.7g/min，同时开启泵A和泵B将两股原料泵入到连续反应器(体积为2.5L)中，控温120℃，连续反应器出口备压0.3～0.5MPa，停留时间为45min，出口取样GC分析，原料剩余为16～17％，流出的体系进行浓缩，浓缩至6V，滴加4V正庚烷进行析晶，过滤，得到产物乙氧基亚甲基丙二腈143.1g，气相纯度：72.3％，收率67.96％。
与实施例1的区别：保留时间为45min。
实施例9
泵A体系为丙二腈(100g，1.51mol)+乙酸酐(325g，3.18mol)，泵B为原甲酸三乙酯(247g，1.67mol)，泵A速度为：24.8g/min，泵B速度为:15.7g/min，同时开启泵A和泵B将两股原料泵入到连续反应器(体积为5L)中，控温120℃，连续反应器出口备压0.3～0.5MPa，停留时间为90min，出口取样GC分析，原料剩余为0.0～0.5％，流出的体系进行浓缩，浓缩至6V，滴加4V正庚烷进行析晶，过滤，固体烘干得到产物乙氧基亚甲基丙二腈182.3g，GC纯度：99.5％，收率98.12％。
与实施例1的区别：保留时间为90min。
实施例10
泵A体系为丙二腈(100g，1.51mol)+乙酸酐(325g，3.18mol)，泵B为原甲酸三乙酯(247g，1.67mol)，泵A速度为：24.8g/min，泵B速度为:15.7g/min，同时开启泵A和泵B将两股原料泵入到连续反应器(体积为5L)中，控温120℃，连续反应器出口备压0.3～0.5MPa，停留时间为120min，出口取样GC分析，原料剩余为0.0～0.5％，流出的体系进行浓缩，浓缩至6V，滴加4V正庚烷进行析晶，过滤，固体烘干得到产物乙氧基亚甲基丙二腈182.7g，GC纯度：99.5％，收率98.33％。
与实施例1的区别：保留时间为120min。
实施例11
泵A体系为丙二腈(100g，1.51mol)+乙酸酐(325g，3.18mol)，泵B为原甲酸三乙酯(247g，1.67mol)，泵A速度为：24.8g/min，泵B速度为:15.7g/min，同时开启泵A和泵B将两股原料泵入到连续反应器(体积为2.5L)中，控温120℃，连续反应器出口备压0.3～0.5MPa，停留时间为30min，出口取样GC分析，原料剩余为19～22％，流出的体系进行浓缩，浓缩至6V，滴加4V正庚烷进行析晶，过滤，得到产物乙氧基亚甲基丙二腈139.4g，气相纯度：70.8％，收率53.39％。
与实施例1的区别：保留时间为30min。
实施例12
泵A体系为丙二腈(100g，1.51mol)+乙酸酐(325g，3.18mol)，泵B为原甲酸三乙酯(247g，1.67mol)，泵A速度为：24.8g/min，泵B速度为:15.7g/min，同时开启泵A和泵B将两股原料泵入到连续反应器(体积为5L)中，控温120℃，连续反应器出口备压0.3～0.5MPa，停留时间为400min，出口取样GC分析，原料剩余为0～0.5％，流出的体系进行浓缩，浓缩至6V，滴加4V正庚烷进行析晶，过滤，得到产物乙氧基亚甲基丙二腈180.0g，气相纯度：61.2％，收率59.59％。
与实施例1的区别：保留时间为400min。
实施例13
泵A体系为丙二腈(100g，1.51mol)+乙酸酐(325g，3.18mol)，泵B为原甲酸三乙酯(247g，1.67mol)，泵A速度为：24.8g/min，泵B速度为:15.7g/min，同时开启泵A和泵B将两股原料泵入到连续反应器(体积为5L)中，控温110℃，连续反应器出口备压10MPa，停留时间为100min，出口取样GC分析，原料剩余为0.0～0.5％，流出的体系进行浓缩，浓缩至6V，滴加4V正庚烷进行析晶，过滤，固体烘干得到产物乙氧基亚甲基丙二腈180.4g，GC纯度：98.9％，收率96.51％。
与实施例1的区别：反应温度为110℃，压力为10MPa。
实施例14
泵A体系为丙二腈(100g，1.51mol)+乙酸酐(325g，3.18mol)，泵B为原甲酸三乙酯(247g，1.67mol)，泵A速度为：24.8g/min，泵B速度为:15.7g/min，同时开启泵A和泵B将两股原料泵入到连续反应器(体积为5L)中，控温150℃，连续反应器出口备压0.9MPa，停留时间为100min，出口取样GC分析，原料剩余为0.0～0.5％，流出的体系进行浓缩，浓缩至6V，滴加4V正庚烷进行析晶，过滤，得到产物乙氧基亚甲基丙二腈185.6g，气相纯度：59.4％，收率59.64％。
与实施例1的区别：反应温度为150℃，压力为0.9MPa。
需说明的是，上述实施例中，连续反应设备持续运行24x7h，反应柱等配备了相应的备用设备和零部件，可以实现不停机在线更换设备，做到全过程不中断的全连续反应。
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。

Claims (10)

  1. 一种乙氧基亚甲基丙二腈的连续合成方法，其特征在于，包括以下步骤：将丙二腈、原甲酸三乙酯和乙酸酐连续地通入连续反应设备中进行取代反应，得到所述乙氧基亚甲基丙二腈，且在所述取代反应的过程中，生成的所述乙氧基亚甲基丙二腈连续地排出；其中，所述丙二腈、所述原甲酸三乙酯和所述乙酸酐的摩尔比为1:(0.9～6.0):(2.0～6.0)。
  2. 根据权利要求1所述的乙氧基亚甲基丙二腈的连续合成方法，其特征在于，所述丙二腈、所述原甲酸三乙酯和所述乙酸酐的摩尔比为1:(1.1～1.5):(2.1～2.5)。
  3. 根据权利要求1所述的乙氧基亚甲基丙二腈的连续合成方法，其特征在于，所述取代反应的反应温度为110～150℃，反应压力为0.3～10MPa。
  4. 根据权利要求3所述的乙氧基亚甲基丙二腈的连续合成方法，其特征在于，所述取代反应的反应温度为110～120℃，反应压力为0.3～10MPa。
  5. 根据权利要求1至4中任一项所述的乙氧基亚甲基丙二腈的连续合成方法，其特征在于，所述取代反应在无溶剂或有溶剂的条件下进行。
  6. 根据权利要求5所述的乙氧基亚甲基丙二腈的连续合成方法，其特征在于，且当采用所述溶剂时，所述溶剂选自乙酸乙酯、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、丙酮、乙腈、甲醇、乙醇、异丙醇、乙二醇的一种或多种。
  7. 根据权利要求5所述的乙氧基亚甲基丙二腈的连续合成方法，其特征在于，所述取代反应的过程中，所述丙二腈、所述原甲酸三乙酯和所述乙酸酐在所述连续反应设备中的停留时间为30～400min。
  8. 根据权利要求7所述的乙氧基亚甲基丙二腈的连续合成方法，其特征在于，所述取代反应的过程中，所述丙二腈、所述原甲酸三乙酯和所述乙酸酐在所述连续反应设备中的停留时间为90～120min。
  9. 根据权利要求1至4中任一项所述的乙氧基亚甲基丙二腈的连续合成方法，其特征在于，所述连续反应设备为管式连续反应器或柱状连续反应器。
  10. 根据权利要求5所述的乙氧基亚甲基丙二腈的连续合成方法，其特征在于，所述取代反应的过程中，通过泵将所述丙二腈、原甲酸三乙酯、所述乙酸酐和可选地所述溶剂泵入所述连续反应设备，且总的泵入速度为20ml/min～5L/min。
PCT/CN2019/126378 2019-12-18 2019-12-18 乙氧基亚甲基丙二腈的连续合成方法 WO2021120064A1 (zh)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4468353A (en) * 1976-08-10 1984-08-28 Dynamit Nobel Ag Method of preparing alkoxymethylene compounds
WO2014002111A1 (en) * 2012-06-26 2014-01-03 Rallis India Limited Process of preparation of azimsulfuron
CN103626776A (zh) * 2013-12-05 2014-03-12 北京师范大学 吡唑并[1,5-a]嘧啶氮芥衍生物及其制备方法和肿瘤治疗应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4468353A (en) * 1976-08-10 1984-08-28 Dynamit Nobel Ag Method of preparing alkoxymethylene compounds
WO2014002111A1 (en) * 2012-06-26 2014-01-03 Rallis India Limited Process of preparation of azimsulfuron
CN103626776A (zh) * 2013-12-05 2014-03-12 北京师范大学 吡唑并[1,5-a]嘧啶氮芥衍生物及其制备方法和肿瘤治疗应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LONG ZHICHENG: "Study on the synthesis of ethoxymethylene malononitrile", CORROSION CONTROL IN SICHUAN CHEMICAL INDUSTRY, vol. 2, no. 4, 1 January 1999 (1999-01-01), pages 2 - 4, XP055821407, ISSN: 1672-4887 *

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