JP2005137958A - Method and apparatus for reacting two-phase solution changed in its phase state by temperature conversion - Google Patents
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本発明は、操作性及び生産効率が飛躍的に優れる温度変換により相状態が変化する二相溶液の反応方法及びこれを実施する装置に関するものである。 The present invention relates to a reaction method for a two-phase solution in which a phase state is changed by temperature conversion in which operability and production efficiency are remarkably improved, and an apparatus for carrying out the method.
化学プロセスにおいて、一連の混合および分離操作を簡便に行うことができれば、一連の作業効率や生産効率を飛躍的に向上することができる。これまでにパーフルオロアルキル基を有する溶媒と一般的な有機溶媒との組合せにより構成される溶媒混合物は、温度の変化により相溶・相分離を起こすことが知られている（I. T. Horvath, J. Rabai, Science, 1994, 266, 72 J.A.Gladysz, Science, 1994, 266, 55）。また、特開平１５−６２４４８号公報には、相溶・相分離を起こす溶媒混合物として、シクロアルカンおよび極性溶媒の組合せが例示されている。 If a series of mixing and separation operations can be easily performed in a chemical process, a series of work efficiency and production efficiency can be dramatically improved. It has been known that a solvent mixture composed of a combination of a solvent having a perfluoroalkyl group and a general organic solvent causes compatibility and phase separation due to a change in temperature (IT Horvath, J. Rabai, Science, 1994, 266, 72 JAGladysz, Science, 1994, 266, 55). Japanese Patent Application Laid-Open No. 15-62448 exemplifies a combination of cycloalkane and a polar solvent as a solvent mixture causing compatibility / phase separation.
このような溶媒混合物が相溶・相分離を起こす原理の概略図を図１に示す。図１（Ａ）は、単一有機溶媒又は混合有機溶媒に分離している状態を示す。例えば一の溶媒として反応原料を溶解するものを用い、他の溶媒として触媒、反応補助剤を溶解するものを用いる。（Ｂ）は、温度条件を均一相溶混合溶媒系の状態にして反応を進行させる工程である。（Ｃ）は、前記温度条件から、可逆的に溶媒システムを構成する溶媒を主成分とする各溶媒相に分離し、生成物を溶解する相と触媒、反応補助剤を溶解させた相に分離した分離溶媒系の状態を示す。そして、生成物を溶解する相（生成物溶液）を分離して取り出し、所望の用途に供すると共に、反応補助剤を溶解させた相（触媒反応補助剤溶液）を再利用に供する（（Ｄ））。 FIG. 1 shows a schematic diagram of the principle that such a solvent mixture causes compatibility / phase separation. FIG. 1A shows a state where a single organic solvent or a mixed organic solvent is separated. For example, a solvent that dissolves a reaction raw material is used as one solvent, and a solvent that dissolves a catalyst and a reaction aid is used as another solvent. (B) is a step in which the reaction is allowed to proceed with the temperature condition in a homogeneous compatible mixed solvent system. (C) is reversibly separated from the temperature conditions into each solvent phase mainly composed of the solvent constituting the solvent system, and separated into a phase dissolving the product, a catalyst, and a reaction auxiliary agent. The state of the separated solvent system is shown. And the phase (product solution) which melt | dissolves a product is isolate | separated and taken out, and while using for a desired use, the phase (catalyst reaction adjuvant solution) which melt | dissolved the reaction adjuvant is used for a reuse ((D)). ).
特開平１５−６２４４８号公報に記載のシクロアルカンを含む相溶性多相有機溶媒は僅かな温度変化で相溶、相分離を繰り返すことができるため、広範な化学プロセス等に利用可能である。
しかしながら、逐次相溶・相分離を繰り返すことにより多段階逐次反応プロセスなどを実施する場合、反応容器の温度を各段階で上昇または低下させ、これにより溶液温度を変化させることにより溶液の相構造を変化させなければならない。これは特に容量の大きなプラントスケールにおいてその制御が困難になるという問題がある。また、プラントスケールの反応容器の温度を各段階で上昇または低下させることは、電力や冷却水といったユーティリティーの使用が膨大となり、製造コストを上昇させるという問題がある。 However, when carrying out a multi-step sequential reaction process by repeating sequential solubilization and phase separation, the temperature of the reaction vessel is raised or lowered at each stage, thereby changing the solution temperature to change the phase structure of the solution. Must be changed. This has a problem that the control becomes difficult especially in a plant scale having a large capacity. Further, raising or lowering the temperature of the plant-scale reaction vessel at each stage has a problem that the use of utilities such as electric power and cooling water becomes enormous and the manufacturing cost increases.
従って、本発明の目的は、操作性と生産効率が飛躍的に優れる温度変換により相状態が変化する二相溶液の反応方法及びこれを実施する装置を提供することにある。 Accordingly, an object of the present invention is to provide a reaction method for a two-phase solution in which the phase state changes by temperature conversion, which is remarkably excellent in operability and production efficiency, and an apparatus for carrying out the method.
かかる実情において、本発明者らは鋭意検討を行った結果、温度により相溶化、相分離を可逆的に繰り返す溶媒混合物において、相分離は温度を下げることにより自然に起こる一方で、相溶化は一定の物理的刺激を与えない限り温度を上げても起こらないこと、このため反応させるため一旦加温した反応容器を冷却することなく、反応容器内の均一溶液を冷却し二相溶液を得た後、該加温状態にある反応容器内に存在させても、二相溶液を維持したままであり、従って二相溶液の生成物溶液を抜き取った後も反応容器の温度を維持したまま多段階逐次反応プロセスを行うことができ、その結果、優れた操作性と生産効率が得られること等を見出し、本発明を完成するに至った。 In this situation, the present inventors have conducted intensive studies. As a result, in a solvent mixture in which compatibilization and phase separation are reversibly repeated depending on temperature, phase separation occurs spontaneously by lowering the temperature, while compatibilization is constant. It does not happen even if the temperature is raised unless physical stimulation is applied. For this reason, after cooling the homogeneous solution in the reaction vessel to obtain a two-phase solution without cooling the reaction vessel once heated for reaction. Even if the two-phase solution is present in the warmed reaction vessel, the two-phase solution is maintained, and therefore, after the product solution of the two-phase solution is withdrawn, the reaction vessel is maintained at the same temperature in a multi-step sequential manner. The reaction process can be performed, and as a result, it has been found that excellent operability and production efficiency can be obtained, and the present invention has been completed.
すなわち、本発明は、一定の温度を境に二相溶液状態及び均一溶液状態の相状態を可逆的に変化させる溶液を反応溶媒とする原料溶液を反応容器内において所定の温度下、攪拌して均一溶液を得ることで反応させる反応工程と、当該反応容器を冷却することなく、当該均一溶液を冷却して該反応容器内に二相溶液を得る冷却工程を有することを特徴とする温度変換により相状態が変化する二相溶液の反応方法を提供するものである。 That is, the present invention stirs a raw material solution using a solution that reversibly changes the phase state of a two-phase solution state and a homogeneous solution state at a predetermined temperature in a reaction vessel at a predetermined temperature. By a temperature conversion characterized by having a reaction step of reacting by obtaining a homogeneous solution and a cooling step of cooling the homogeneous solution to obtain a two-phase solution in the reaction vessel without cooling the reaction vessel A method for reacting a two-phase solution in which the phase state changes is provided.
また、本発明は、反応容器を加熱する加熱手段及び反応容器内の原料溶液に物理的刺激を与えて均一溶液とする刺激手段が付設された反応容器と、該反応容器を冷却することなく反応容器内の均一溶液を冷却する冷却手段と、を備えることを特徴とする温度変換により相状態が変化する二相溶液の反応装置を提供するものである。 The present invention also provides a reaction vessel provided with a heating means for heating the reaction vessel and a stimulating means for giving a physical stimulus to the raw material solution in the reaction vessel to make a uniform solution, and a reaction without cooling the reaction vessel. And a cooling means for cooling the uniform solution in the container. A reactor for a two-phase solution in which the phase state changes by temperature conversion is provided.
本発明の温度変換により相状態が変化する二相溶液の反応方法によれば、一つの反応容器の冷却及び再加熱が不要で温度を一定に保つことができるため、生産効率が大幅に向上する。また、一つのプロセス反応終了後、次ぎのプロセス反応に供される反応溶液の温度は速やかに一定温度（加温状態）になるため、多段階逐次プロセスなどにおいて、温度の変化時間を大幅に短縮することができる。 According to the reaction method of a two-phase solution in which the phase state is changed by the temperature conversion of the present invention, it is not necessary to cool and reheat one reaction vessel, and the temperature can be kept constant, so that the production efficiency is greatly improved. . In addition, after the completion of one process reaction, the temperature of the reaction solution used for the next process reaction quickly becomes constant (warmed), greatly reducing the temperature change time in multistage sequential processes. can do.
本発明の温度変換により相状態が変化する二相溶液の反応方法において、反応工程は、原料溶液を反応容器内において所定の温度下、攪拌して均一溶液を得ることで反応させる工程である。原料溶液は、一定の温度を境に二相溶液状態及び均一溶液状態の相状態を可逆的に変化させる溶液（以下、「溶媒混合物」とも言う。）を反応溶媒とするものである。当該溶媒混合物としては、特に制限されないが、例えば低極性有機溶媒と高極性有機溶媒の溶媒混合物が挙げられる。 In the reaction method of a two-phase solution in which the phase state changes by temperature conversion of the present invention, the reaction step is a step of reacting the raw material solution by stirring it at a predetermined temperature in a reaction vessel to obtain a uniform solution. The raw material solution uses a solution (hereinafter also referred to as “solvent mixture”) that reversibly changes the phase state between the two-phase solution state and the homogeneous solution state at a certain temperature as a reaction solvent. Although it does not restrict | limit especially as the said solvent mixture, For example, the solvent mixture of a low polar organic solvent and a highly polar organic solvent is mentioned.
低極性有機溶媒としては、例えばアルカン、シクロアルカン、アルケン、アルキン、芳香族化合物などが挙げられる。このうち、シクロアルカン化合物が好ましい。シクロアルカン化合物としては、例えばシクロヘキサン、メチルシクロヘキサン、デカリンなどが挙げられ、このうち、シクロヘキサンは、融点が６．５℃と比較的高く、反応後の生成物等を固化して分離できる点で好ましい。 Examples of the low polar organic solvent include alkanes, cycloalkanes, alkenes, alkynes, aromatic compounds and the like. Of these, cycloalkane compounds are preferred. Examples of the cycloalkane compound include cyclohexane, methylcyclohexane, decalin, etc. Among them, cyclohexane is preferable in that the melting point is relatively high at 6.5 ° C., and the product after the reaction can be solidified and separated. .
高極性有機溶媒としては、例えばニトロアルカン、ニトリル、アルコール、ハロゲン化アルキル、カーボネート、イミダゾリジノン、カルボジイミド、エステル、カルボン酸、アルデヒド、ケトン、エーテル、ウレア、アミド化合物及びスルフォキサイドが挙げられ、これらは一種単独又は二種以上を組み合わせて用いることができる。 Examples of the highly polar organic solvent include nitroalkane, nitrile, alcohol, alkyl halide, carbonate, imidazolidinone, carbodiimide, ester, carboxylic acid, aldehyde, ketone, ether, urea, amide compound, and sulfoxide. One kind can be used alone, or two or more kinds can be used in combination.
本発明において用いる原料溶液は、当該溶媒混合物の他、溶質、触媒、基質及び反応補助剤等、種々の反応に関与する物質を含有する。原料溶液の具体的としては、シクロヘキサン、ジメチルホルムアミド、オクタデシルアミン及びベンゾイルクロライドの混合溶液、シクロヘキサン、ジメチルホルムアミド、オクタデシルアミン及び無水酢酸の混合溶液及びシクロヘキサン、N,N’-ジメチイミダゾリジノン、オクタデシルアルコール及び安息香酸の混合溶液、デカリン、N,N’-ジメチイミダゾリジノン、ヘキサデカンチオール及びアクリル酸メチルの混合溶液が挙げられる。上記、オクタデシルアミン、オクタデシルアルコール、ヘキサデカンチオールはシクロヘキサン、またはデカリンなどに溶解し、上記ベンゾイルクロライド、無水酢酸、及びアクリル酸メチルはジメチルホルムアミド、N,N’-ジメチイミダゾリジノンなどに溶解する。 The raw material solution used in the present invention contains substances involved in various reactions such as a solute, a catalyst, a substrate, and a reaction aid in addition to the solvent mixture. Specific examples of the raw material solution include a mixed solution of cyclohexane, dimethylformamide, octadecylamine and benzoyl chloride, a mixed solution of cyclohexane, dimethylformamide, octadecylamine and acetic anhydride, and cyclohexane, N, N'-dimethylimidazolidinone, octadecyl alcohol. And a mixed solution of benzoic acid, decalin, N, N′-dimethylimidazolidinone, hexadecanethiol and methyl acrylate. The above-mentioned octadecylamine, octadecyl alcohol, and hexadecanethiol are dissolved in cyclohexane or decalin, and the above benzoyl chloride, acetic anhydride, and methyl acrylate are dissolved in dimethylformamide, N, N′-dimethylimidazolidinone, and the like.
反応容器内において原料溶液を所定の温度にする方法としては、特に制限されず、例えば予め所定温度に加熱された原料溶液を反応容器に導入する方法、常温の原料溶液を反応容器に導入し、その後反応容器加熱用ヒーターをＯＮ状態として原料溶液を所定温度に維持する方法及び反応容器加熱用ヒーターをＯＮ状態として反応容器を所定温度を越える温度とし、該反応容器内に常温の原料溶液を導入し、原料溶液を所定温度に維持する方法が挙げられる。このうち、反応容器加熱用ヒーターを用いる方法が、別途の原料溶液加熱用の容器を必要としない点で好適である。所定の温度は反応温度であり、原料溶液や反応の種類により適宜決定される。
反応工程において、所定温度に加温された試料を攪拌する方法としては、特に制限されず、例えば先端部分に攪拌羽根を備えた攪拌棒の攪拌による機械的攪拌方法、試料中に窒素ガスを吹き込み気泡を導入するバブリング方法、試料容器又は試料に振動を与える振動攪拌方法などが挙げられる。このうち、先端部分に攪拌羽根を備えた攪拌棒の攪拌による機械的攪拌方法又は試料中に窒素ガスを吹き込み気泡を導入するバブリング方法が、簡易な装置でしかも攪拌効率が高い点で好ましい。本発明で用いる溶媒混合物は、所定温度に加温されただけでは均一溶液とはならず、一定の物理的刺激を与えることで相溶化がおきる。従って、反応工程における攪拌条件は、均一溶液が得られる条件で適宜選択される。均一溶液を得た後は、当該所定の温度で所定時間保持することもある。所定時間は、反応時間であり使用する溶媒や反応の種類、反応の目的などにより適宜決定される。本発明で用いる溶媒混合物において、相分離は温度を下げることにより自然に起こるため、当該均一溶液は、当該所定時間中、当該相分離が生じる温度以上に保持される。
The method of bringing the raw material solution to a predetermined temperature in the reaction vessel is not particularly limited, for example, a method of introducing a raw material solution heated to a predetermined temperature in advance into the reaction vessel, introducing a normal temperature raw material solution into the reaction vessel, Thereafter, the reaction vessel heating heater is turned on to maintain the raw material solution at a predetermined temperature, and the reaction vessel heating heater is turned on to bring the reaction vessel to a temperature exceeding the predetermined temperature, and the room temperature raw material solution is introduced into the reaction vessel. And a method of maintaining the raw material solution at a predetermined temperature. Among these, the method using the heater for heating the reaction vessel is preferable in that a separate vessel for heating the raw material solution is not required. The predetermined temperature is a reaction temperature and is appropriately determined depending on the raw material solution and the type of reaction.
In the reaction step, the method of stirring the sample heated to a predetermined temperature is not particularly limited. For example, a mechanical stirring method by stirring with a stirring rod having a stirring blade at the tip, nitrogen gas is blown into the sample. Examples include a bubbling method for introducing bubbles, a vibration stirring method for applying vibration to a sample container or a sample, and the like. Among these, a mechanical stirring method by stirring with a stirring rod provided with a stirring blade at the tip portion or a bubbling method in which nitrogen gas is blown into a sample and bubbles are introduced is preferable in terms of simple stirring and high stirring efficiency. The solvent mixture used in the present invention does not become a homogeneous solution only by being heated to a predetermined temperature, but compatibilization occurs by applying a certain physical stimulus. Therefore, the stirring conditions in the reaction step are appropriately selected under the conditions that a uniform solution can be obtained. After obtaining a uniform solution, it may be held at the predetermined temperature for a predetermined time. The predetermined time is a reaction time and is appropriately determined depending on the solvent used, the type of reaction, the purpose of the reaction, and the like. In the solvent mixture used in the present invention, since phase separation occurs naturally by lowering the temperature, the homogeneous solution is maintained at a temperature equal to or higher than the temperature at which the phase separation occurs during the predetermined time.
冷却工程は、当該反応容器を冷却することなく当該均一溶液を冷却して該反応容器内に二相溶液を得る工程である。反応容器を冷却することなく均一溶液を冷却する方法としては、特に制限されないが、反応容器から当該均一溶液の一部又は全部を抜き出し、該抜き出された均一溶液を冷却器で冷却し、該冷却により得られた二相溶液を当該反応容器内に戻す方法、該反応容器の温度よりも低温の固体を該反応容器内の均一溶液に挿入する方法、又は低沸点化合物を直接、該反応容器内の均一溶液に混合する方法が挙げられる。「反応容器を冷却することなく」とは、反応容器を冷却することで、反応容器内の試料を冷却することを除外する意味であり、反応容器内の試料を冷却することに伴って反応容器が冷却されることは許容される。 The cooling step is a step of cooling the homogeneous solution without cooling the reaction vessel to obtain a two-phase solution in the reaction vessel. The method for cooling the homogeneous solution without cooling the reaction vessel is not particularly limited, but a part or all of the homogeneous solution is extracted from the reaction vessel, the extracted homogeneous solution is cooled with a cooler, and the A method of returning the two-phase solution obtained by cooling into the reaction vessel, a method of inserting a solid having a temperature lower than the temperature of the reaction vessel into the homogeneous solution in the reaction vessel, or a low boiling point compound directly in the reaction vessel The method of mixing in the uniform solution is mentioned. “Without cooling the reaction container” means that the reaction container is cooled to exclude the cooling of the sample in the reaction container, and the reaction container is cooled along with the cooling of the sample in the reaction container. Is allowed to cool.
反応容器から当該均一溶液の一部又は全部を抜き出し、該抜き出された均一溶液を冷却器で冷却し、該冷却により得られた二相溶液を当該反応容器内に戻す方法において、該方法に用いる装置としては、小規模反応装置の場合、例えば冷却装置を備えた抽出器が使用できる。当該抽出器は注射器と同様の機構のものであり、冷却装置としては、例えば抽出器のシリンダー周りに形成されたジャケットに水を通水する装置を用いることができる。また、大規模反応装置の場合、外部冷却器、ポンプ及び循環系を形成するように連結する配管類で構成された外部冷却ユニット装置を用いることができる。 In the method of extracting a part or all of the homogeneous solution from the reaction vessel, cooling the extracted homogeneous solution with a cooler, and returning the two-phase solution obtained by the cooling into the reaction vessel, In the case of a small-scale reaction apparatus, for example, an extractor equipped with a cooling device can be used. The extractor has a mechanism similar to that of a syringe, and as the cooling device, for example, a device for passing water through a jacket formed around the cylinder of the extractor can be used. Further, in the case of a large-scale reaction apparatus, an external cooling unit apparatus composed of piping connected to form an external cooler, a pump and a circulation system can be used.
また、該反応容器の温度よりも低温の固体を該反応容器内の均一溶液に挿入する方法において、該方法で用いる装置としては、例えば冷却装置付きガラス棒または金属棒などが挙げられる。また、反応容器内の均一溶液に混合する低沸点化合物としては、例えば沸点が２５℃のｎ−ヘプタンが挙げられる。低沸点化合物は反応容器内の均一溶液と直接接触して、該溶液から気化熱を奪い冷却する。気化した低沸点化合物は気体気化器で液化して再び反応容器内に投入される。これを繰り返すことで、均一溶液を冷却することができる。上記方法により冷却された均一溶液は、所定の温度以下になると自然に二相に分離する。冷却工程で得られる二相溶液は、一相が例えばシクロヘキサンのような低極性有機溶媒に反応生成物を溶解した生成物溶液であり、他の相が例えばジメチルホルムアミドのような高極性有機溶媒に触媒や反応補助剤を溶解した溶液である。 In addition, in the method of inserting a solid having a temperature lower than the temperature of the reaction vessel into the uniform solution in the reaction vessel, examples of the device used in the method include a glass rod with a cooling device or a metal rod. Moreover, as a low boiling-point compound mixed with the homogeneous solution in reaction container, n-heptane whose boiling point is 25 degreeC is mentioned, for example. The low boiling point compound comes into direct contact with the homogeneous solution in the reaction vessel, takes the heat of vaporization from the solution and cools it. The vaporized low boiling point compound is liquefied with a gas vaporizer and charged again into the reaction vessel. By repeating this, the uniform solution can be cooled. The homogeneous solution cooled by the above method spontaneously separates into two phases when the temperature falls below a predetermined temperature. The two-phase solution obtained in the cooling step is a product solution in which one phase is a reaction product dissolved in a low polarity organic solvent such as cyclohexane, and the other phase is a high polarity organic solvent such as dimethylformamide. It is a solution in which a catalyst and a reaction aid are dissolved.
冷却工程においては、冷却後、該反応容器内に二相溶液を得る。冷却方法が、低温の固体を使用する方法又は低沸点化合物を使用する方法の場合、反応容器内において相分離するため、特段の操作を採ることなくそのままでよい。一方、反応容器から当該均一溶液の一部又は全部を抜き出し、該抜き出された均一溶液を冷却器で冷却する方法の場合、冷却により得られた二相溶液は該反応容器内に戻される。冷却工程における冷却方法としては、反応容器から当該均一溶液の一部又は全部を抜き出し、該抜き出された均一溶液を冷却器で冷却する方法が好ましい。すなわち、低温の固体や低沸点化合物を用いるような反応容器内での冷却の場合、加温状態にある反応容器も冷却することになり、冷却効率が悪くなる。更に、反応容器が冷却されるため、生成物溶液を抽出した後、残部の溶媒を再使用する際、再度の加温が必要となり、反応コストが嵩む。これに対して、外部の冷却装置又は冷却器で冷却する方法では、反応溶液のみを冷却すればよいため、冷却効率が高い。しかも、加温状態にある反応容器内に戻された、該二相分離溶液は例え加温されたとしても物理的刺激は与えられないため、二相に分離した状態を維持できる。 In the cooling step, after cooling, a two-phase solution is obtained in the reaction vessel. In the case where the cooling method is a method using a low-temperature solid or a method using a low-boiling compound, the phase separation is performed in the reaction vessel, so that it is not necessary to take any special operation. On the other hand, in the case of a method of extracting a part or all of the homogeneous solution from the reaction vessel and cooling the extracted homogeneous solution with a cooler, the two-phase solution obtained by cooling is returned to the reaction vessel. As a cooling method in the cooling step, a method of extracting a part or all of the homogeneous solution from the reaction vessel and cooling the extracted homogeneous solution with a cooler is preferable. That is, in the case of cooling in a reaction vessel using a low-temperature solid or a low boiling point compound, the reaction vessel in a heated state is also cooled, resulting in poor cooling efficiency. Furthermore, since the reaction vessel is cooled, after the product solution is extracted, when the remaining solvent is reused, reheating is required, which increases the reaction cost. On the other hand, in the method of cooling with an external cooling device or cooler, only the reaction solution needs to be cooled, so that the cooling efficiency is high. In addition, even if the two-phase separation solution returned to the warmed reaction vessel is heated, no physical stimulation is given, so that the two-phase separation solution can be maintained.
冷却工程後、反応容器内に得られた二相溶液の内、生成物溶液相を抽出し、そのまま又は必要に応じて、溶媒を除去した後、目的の用途で使用される。また、多段階逐次反応プロセスを実施する場合、生成物溶液相の抽出により残置された溶媒相はそのまま加温状態にある反応容器内に置いておくことが、残置された溶媒相を再使用する際、反応容器を再度加温するための熱エネルギーを最小限にすることができ、反応コストを抑制することができる点で好ましい。 After the cooling step, the product solution phase is extracted from the two-phase solution obtained in the reaction vessel, and the solvent is removed as it is or if necessary, and then used for the intended use. In addition, when performing a multi-step sequential reaction process, the solvent phase left by the extraction of the product solution phase may be left in the reaction vessel in a warmed state to reuse the remaining solvent phase. At this time, it is preferable in that heat energy for reheating the reaction vessel can be minimized and reaction cost can be suppressed.
また、本発明の温度変換により相状態が変化する二相溶液の反応装置は、反応容器を加熱する加熱手段及び反応容器内の原料溶液に物理的刺激を与えて均一溶液とする刺激手段が付設された反応容器と、該反応容器を冷却することなく反応容器内の均一溶液を冷却する冷却手段と、を備える。 In addition, the two-phase solution reactor in which the phase state is changed by temperature conversion of the present invention is provided with a heating means for heating the reaction vessel and a stimulating means for giving a physical stimulus to the raw material solution in the reaction vessel to make a uniform solution. And a cooling means for cooling the homogeneous solution in the reaction vessel without cooling the reaction vessel.
反応容器を加熱する加熱手段としては、特に制限されないが、例えば反応容器の壁内に付設される埋め込みヒーターが挙げられる。このヒーターは通常反応容器の温度を制御する温度制御機構に接続されている。 The heating means for heating the reaction vessel is not particularly limited, and examples thereof include an embedded heater provided in the reaction vessel wall. This heater is usually connected to a temperature control mechanism for controlling the temperature of the reaction vessel.
反応容器内の原料溶液に物理的刺激を与えて均一溶液とする刺激手段としては、例えば先端部分に攪拌羽根を備えた攪拌棒、原料溶液中に気泡を導入する気泡導入管と気泡発生器を備えるバブリング装置、反応容器又は原料溶液に振動を与える振動器などが挙げられる。 Examples of the stimulating means for applying a physical stimulus to the raw material solution in the reaction vessel to obtain a uniform solution include a stirring rod having a stirring blade at the tip, a bubble introduction tube for introducing bubbles into the raw material solution, and a bubble generator. Examples thereof include a bubbling device, a reaction vessel, or a vibrator that vibrates the raw material solution.
前記反応容器を冷却することなく該反応容器内の均一溶液を冷却する冷却手段としては、反応容器から当該均一溶液を抜き出し、該抜き出された均一溶液を冷却器で冷却し、該冷却により得られた二相溶液を当該反応容器内に戻す手段、該反応容器の温度よりも低温の固体を該反応容器内の均一溶液に挿入する挿入手段、又は低沸点化合物を直接、該反応容器内の均一溶液に混合する混合手段が挙げられる。 As a cooling means for cooling the homogeneous solution in the reaction vessel without cooling the reaction vessel, the homogeneous solution is extracted from the reaction vessel, the extracted uniform solution is cooled with a cooler, and obtained by the cooling. Means for returning the obtained two-phase solution into the reaction vessel, insertion means for inserting a solid having a temperature lower than the temperature of the reaction vessel into the uniform solution in the reaction vessel, or a low-boiling compound directly in the reaction vessel A mixing means for mixing in a uniform solution is mentioned.
次に、実施例を挙げて本発明を更に具体的に説明するが、これは単に例示であって、本発明を制限するものではない。 EXAMPLES Next, although an Example is given and this invention is demonstrated more concretely, this is only an illustration and does not restrict | limit this invention.
直径２０ｍｍ、高さ６０ｍｍの円筒系ガラス瓶を反応容器としてブロックヒーター内蔵の卓上装置を用い、下記反応条件に準拠して、プロセス化学反応を行った。容器温度２５℃の反応容器にオクタデシルアミン（５１ミリグラム）を溶解させたシクロヘキサン２ｍｌ、ベンゾイルクロライド（４９ミリグラム）溶解させたジメチルホルムアミド（ＤＭＦ）２ｍｌを添加して原料溶液を調製した。このとき液体は二相に分離した。 Using a cylindrical glass bottle having a diameter of 20 mm and a height of 60 mm as a reaction vessel and using a tabletop device with a built-in block heater, a process chemical reaction was performed in accordance with the following reaction conditions. A raw material solution was prepared by adding 2 ml of cyclohexane in which octadecylamine (51 mg) was dissolved and 2 ml of dimethylformamide (DMF) in which benzoyl chloride (49 mg) was dissolved in a reaction vessel having a vessel temperature of 25 ° C. At this time, the liquid separated into two phases.
次いで反応容器温度を６０℃に加温し、溶液温度が４８℃に達した段階で、窒素ガスを溶液内に直接吹き込み、物理的な攪拌を行うと、溶液は直ちに均一溶液となった。次に冷却装置を備えた注射器状の冷却器を用い、主プロセス容器から均一溶液３．６ｍｌを吸い上げ、該冷却容器内で静置したところ、溶液温度が約４０℃に降下すると二相に分離した。さらに２分間放置した後、該冷却器から漸次、６０℃に加温してある該主プロセス反応容器に液体を戻した。この溶液は放置すると再び４８℃以上になるが、窒素ガスの吹き込みなど、激しい物理的な攪拌を行わない限り、二相状態を保った。 Next, when the reaction vessel temperature was raised to 60 ° C. and the solution temperature reached 48 ° C., nitrogen gas was blown directly into the solution and physical stirring was performed, and the solution immediately became a homogeneous solution. Next, using a syringe-like cooler equipped with a cooling device, sucking up 3.6 ml of the uniform solution from the main process vessel and allowing it to stand in the cooling vessel. When the solution temperature drops to about 40 ° C., it separates into two phases. did. After standing for another 2 minutes, the liquid was gradually returned from the cooler to the main process reaction vessel heated to 60 ° C. When this solution was allowed to stand, the temperature again reached 48 ° C. or higher, but the two-phase state was maintained unless vigorous physical stirring such as blowing of nitrogen gas was performed.
６０℃の加温状態にある反応容器内の二相溶液の中、上部の相である生成物溶液部分を抽出し、溶媒を除去したところ反応生成物がN-オクダデシルベンズアミドであることを確認した（収率９６％）。また、反応容器内に残存する溶液は、ベンゾイルクロライドを溶解する４８℃以上に加温されたジメチルホルムアミド溶液であり、次段階における反応の原料溶液の一部として再使用状態にあった。 In the two-phase solution in the reaction vessel heated at 60 ° C, the product solution portion, which is the upper phase, was extracted, and the solvent was removed, confirming that the reaction product was N-octadecylbenzamide. (Yield 96%). The solution remaining in the reaction vessel was a dimethylformamide solution heated to 48 ° C. or higher in which benzoyl chloride was dissolved, and was in a reused state as part of the raw material solution for the next step.
直径２０ｍｍ、高さ６０ｍｍの円筒系ガラス瓶を反応容器としてブロックヒーター内蔵の卓上装置を用い、下記反応条件に準拠して、プロセス化学反応を行った。容器温度２５℃の反応容器に２−アミノブチリックアシッド３，４，５−トリスオクタデシロキシベンジルエステル（６０ミリグラム）を溶解させたシクロヘキサン２ｍｌ、９-フルオレニルメトキシカルボニルアミノアセティックアシッド（５７ミリグラム）、ジイソプロピルカルボジイミド（２５ミリグラム）、１−ヒドロキシベンゾトリアゾール（５５ミリグラム）を溶解して９０分攪拌させたジメチルホルムアミド（ＤＭＦ）２ｍｌを添加して原料溶液を調製した。このとき液体は二相に分離した。 Using a cylindrical glass bottle having a diameter of 20 mm and a height of 60 mm as a reaction vessel and using a tabletop device with a built-in block heater, a process chemical reaction was performed in accordance with the following reaction conditions. 2 ml of cyclohexane in which 2-aminobutyric acid 3,4,5-trisoctadecyloxybenzyl ester (60 mg) was dissolved in a reaction vessel having a vessel temperature of 25 ° C., 9-fluorenylmethoxycarbonylaminoacetic acid (57 Milligrams), diisopropylcarbodiimide (25 milligrams) and 1-hydroxybenzotriazole (55 milligrams) were dissolved and 2 ml of dimethylformamide (DMF) stirred for 90 minutes was added to prepare a raw material solution. At this time, the liquid separated into two phases.
次いで反応容器温度を６０℃に加温し、溶液温度が４８℃に達した段階で、先端に攪拌羽根の付いた攪拌棒で物理的な攪拌を行うと、溶液は直ちに均一溶液となった。次に５℃に冷却された冷却装置付き直径８ｍｍのガラス棒を該主プロセス溶液に挿入し、溶液温度を低下させることにより二相に分離させた。二相分離後、該冷却装置付きガラス棒を引き上げ、該溶液を放置した。溶液温度はその後上昇し４８℃以上になっても二相に分離した状態を維持した。 Next, when the reaction vessel temperature was heated to 60 ° C. and the solution temperature reached 48 ° C., physical stirring was performed with a stirring rod having a stirring blade at the tip, and the solution immediately became a homogeneous solution. Next, an 8 mm diameter glass rod with a cooling device cooled to 5 ° C. was inserted into the main process solution and separated into two phases by lowering the solution temperature. After the two-phase separation, the glass rod with a cooling device was pulled up and the solution was allowed to stand. The solution temperature then increased and maintained a state separated into two phases even when the temperature reached 48 ° C. or higher.
６０℃の加温状態にある反応容器内の二相溶液の中、上部の相である生成物溶液部分を抽出して溶媒を除去したところ、目的とする反応生成物が２―[２−（９Ｈ―フルオレ−９−イルメトキシカルボニル−アミノ）−アセチルアミノ]−３−メチル−ブチリックアシド３，４，５−トリスオクタデシロキシベンジルエステルが９５％の収率で得られた。 In the two-phase solution in the reaction vessel heated at 60 ° C., the product solution portion as the upper phase was extracted and the solvent was removed. As a result, the target reaction product was 2- [2- ( 9H-Fluoro-9-ylmethoxycarbonyl-amino) -acetylamino] -3-methyl-butyric acid 3,4,5-trisoctadecyloxybenzyl ester was obtained in 95% yield.
直径２０ｍｍ、高さ６０ｍｍの円筒系ガラス瓶を反応容器としてブロックヒーター内蔵の卓上装置を用い、下記反応条件に準拠して、プロセス化学反応を行った。容器温度２５℃の反応容器にオクタデシルアミン（５１ｍｇ）を溶解させたシクロヘキサン２ｍｌ、無水酢酸（２０ｍｇ）を溶解させたジメチルイミダゾリジノン（ＤＭＩ）２ｍｌを添加して原料溶液を調製した。このとき液体は二相に分離した。 Using a cylindrical glass bottle having a diameter of 20 mm and a height of 60 mm as a reaction vessel and using a tabletop device with a built-in block heater, a process chemical reaction was performed in accordance with the following reaction conditions. A raw material solution was prepared by adding 2 ml of cyclohexane in which octadecylamine (51 mg) was dissolved and 2 ml of dimethylimidazolidinone (DMI) in which acetic anhydride (20 mg) was dissolved in a reaction vessel having a vessel temperature of 25 ° C. At this time, the liquid separated into two phases.
次いで反応容器温度を６０℃に加温し、溶液温度が４８℃に達した段階で、窒素ガスを溶液内に直接吹き込み、物理的な攪拌を行うと、溶液は直ちに均一溶液となった。次にこの均一溶液に２５℃のｎ-ペンタンを漸次注入した。ｎ-ペンタンは直ちに揮発し始め、溶液が二相に分離した段階でｎ-ペンタンの注入をやめた。約１０分間放置することにより、ｎ-ペンタンはほぼ完全に揮発し、溶液温度は４８℃以上になっても二相に分離した状態を維持した。 Next, when the reaction vessel temperature was raised to 60 ° C. and the solution temperature reached 48 ° C., nitrogen gas was blown directly into the solution and physical stirring was performed, and the solution immediately became a homogeneous solution. Next, n-pentane at 25 ° C. was gradually injected into the homogeneous solution. The n-pentane started to evaporate immediately, and the injection of n-pentane was stopped when the solution separated into two phases. By leaving for about 10 minutes, n-pentane was almost completely volatilized, and the two-phase separation was maintained even when the solution temperature reached 48 ° C. or higher.
６０℃の加温状態にある反応容器内の二相溶液の中、上部の相である生成物溶液部分を抽出して溶媒を除去したところ、N-オクタデシルアセトアミドが得られた（収率９７％）。 The product solution portion, which is the upper phase, was extracted from the two-phase solution in the reaction vessel heated at 60 ° C., and the solvent was removed to obtain N-octadecylacetamide (yield 97%). ).
本発明の温度変換により相状態が変化する二相溶液の反応方法及びこれに用いる装置は、卓上試験研究用化学プロセス装置、フロー系化学反応装置及び大型反応プラントに適用できる。 The reaction method of a two-phase solution whose phase state changes by temperature conversion of the present invention and the apparatus used therefor can be applied to a chemical process device for desktop test research, a flow chemical reaction device, and a large reaction plant.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6461497A (en) * | 1987-08-31 | 1989-03-08 | Central Glass Co Ltd | Mixed solvent |
| JPH07252680A (en) * | 1994-03-16 | 1995-10-03 | Tokuyama Corp | Cleaning method of article |
| JP2000218155A (en) * | 1999-01-28 | 2000-08-08 | Shimadzu Corp | Apparatus for automatic synthesis |
| JP2003062448A (en) * | 2001-08-24 | 2003-03-04 | Japan Science & Technology Corp | Compatible multiphase organic solvent system |
| WO2004024315A1 (en) * | 2002-08-29 | 2004-03-25 | Tokyo University Of Agriculture And Technology Tlo Co., Ltd. | Apparatus for carrying out chemical process using set of solvents undergoing reversible change between mutual dissolution and separation depending on temperature |
| WO2004073852A1 (en) * | 2003-02-24 | 2004-09-02 | Tokyo University Of Agriculture And Technology Tlo Co., Ltd. | Chemical processes by the use of combinations of solvents capable of taking reversibly homogeneously mixed state and separated state dependently on temperature |
| JP2005111367A (en) * | 2003-10-08 | 2005-04-28 | Japan Science & Technology Agency | Method for subjecting many processes to reaction by using two-phase solution to be made phase-transitional by temperature change and apparatus for executing the method |
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Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6461497A (en) * | 1987-08-31 | 1989-03-08 | Central Glass Co Ltd | Mixed solvent |
| JPH07252680A (en) * | 1994-03-16 | 1995-10-03 | Tokuyama Corp | Cleaning method of article |
| JP2000218155A (en) * | 1999-01-28 | 2000-08-08 | Shimadzu Corp | Apparatus for automatic synthesis |
| JP2003062448A (en) * | 2001-08-24 | 2003-03-04 | Japan Science & Technology Corp | Compatible multiphase organic solvent system |
| WO2004024315A1 (en) * | 2002-08-29 | 2004-03-25 | Tokyo University Of Agriculture And Technology Tlo Co., Ltd. | Apparatus for carrying out chemical process using set of solvents undergoing reversible change between mutual dissolution and separation depending on temperature |
| WO2004073852A1 (en) * | 2003-02-24 | 2004-09-02 | Tokyo University Of Agriculture And Technology Tlo Co., Ltd. | Chemical processes by the use of combinations of solvents capable of taking reversibly homogeneously mixed state and separated state dependently on temperature |
| JP2005111367A (en) * | 2003-10-08 | 2005-04-28 | Japan Science & Technology Agency | Method for subjecting many processes to reaction by using two-phase solution to be made phase-transitional by temperature change and apparatus for executing the method |
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