JP2008155173A - Solvent substitution apparatus - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a technique capable of automatically and immediately observing a composition of a solution in a substitution of a solvent using an azeotrope, and further automatically performing an operation of the substitution of the solvent using the azeotope. <P>SOLUTION: A solvent substitution apparatus includes: a concentration tank 3; a means for supplying an ethanolic solution and an n-hexane containing a target substance into the concentration tank 3; a heating device 4 for heating a liquid in the concentration tank 3; a condenser 5 for cooling steam in the liquid in the concentration tank 3 for condensation; a distillation tank 6 for storing a condensate generated in the condenser 5; a detector for detecting the concentration of ethanol or n-hexane in the condensate or the liquid in the concentration tank 3; and a controlling device 8 for controlling the supply of n-hexane to the concentration tank 3 and the heating of the liquid in the concentration tank 3 by the heating device 4 according to the detected value of the detector, wherein an near-infrared spectroscopic sensor 7 is used for the detector. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an apparatus for replacing a solvent by azeotropy.

  As a method for crystallizing a target substance in a solution, after dissolving the target substance in a good solvent excellent in solubility of the target substance, a poor solvent which is azeotroped with the good solvent and has a lower solubility of the target substance is described above. A method of supplying a solution, concentrating a liquid containing a target substance, a good solvent, and a poor solvent to azeotrope the good solvent and the poor solvent, substituting the good solvent with the poor solvent, and then crystallizing the target substance. Are known.

  In such a method, as a device for replacing the good solvent in the solution with the poor solvent, for example, the solution of the good solvent as the target substance and the poor solvent are contained, and a concentration tank for concentrating the contained liquid And a device for supplying the poor solvent to the concentration tank, a heating device for heating the liquid in the concentration tank, a condenser for cooling the vapor of the liquid in the concentration tank, and the condenser There is a solvent displacement device having a distillation tank for containing condensate.

  The end point of the solvent replacement operation in the solvent replacement apparatus can be confirmed by the concentration of the good solvent or the poor solvent in the liquid in the concentration tank, which is directly or indirectly measured. The end point is confirmed by, for example, collecting a part of the liquid or condensate in the concentrating tank and detecting the concentration of the good solvent in the collected liquid by an appropriate known detector such as gas chromatography (GC). can do.

  For example, in crystallization using an optical isomer as a pharmaceutical or its intermediate as a target substance in a solution, a solution in which the target substance is dissolved in a first solvent that dissolves the target substance is charged into a concentration tank, while the first A predetermined amount of a second solvent which is azeotroped with the solvent and has a lower solubility of the target substance than the first solvent is charged into the concentration tank, and then the first and second are reduced by pressure reduction and heating in the concentration tank. The solvent may be azeotroped and the first solvent in the concentration tank may be replaced with the second solvent. This operation is a batch operation. The operation from charging of the second solvent into the concentration tank to azeotropy is usually performed a plurality of times, for example, about three times, depending on the amount of the target substance in the first solvent. Then, a part of the condensate is collected on site by the operator, the concentration of the first solvent in the collected condensate is detected by GC, and it is confirmed that the concentration of the first solvent is below a certain value. Then, the end point of the substitution from the first solvent to the second solvent is confirmed.

  However, in the confirmation method as described above, in order to confirm the end point of the operation, the manufacturing process (azeotropic process) is temporarily interrupted, and the operator confirms the sampling operation on the spot, the sample analysis operation, and the analysis result. The operation is performed. For this reason, the confirmation method described above requires time for confirmation and a work load. Further, when the amount of the first solvent initially charged in the concentration tank is changed, the number of batch operations described above may be changed. For this reason, the above-described confirmation method may require sampling, analysis, and confirmation each time the charge amount of the first solvent changes.

On the other hand, as a technique using the analysis of the liquid in the process without sampling, for example, in the operation control of the distillation column, the composition of one or both of the top liquid and the bottom liquid is analyzed with a near infrared spectrum, A method of making the composition of one or both of the tower top liquid and the tower bottom liquid constant using the measured values (see, for example, Patent Document 1), or the light in the near infrared region of the effluent during liquid separation A method of measuring the absorption rate and switching the flow path of the effluent based on the measured change in the absorption rate (see, for example, Patent Document 2) is known.
JP-A-8-266802 JP-A-11-314209

The present invention provides a technique capable of automatically and immediately observing the composition of a solution in solvent replacement using azeotropy.
The present invention also provides a technique capable of automatically performing an operation of replacing a solvent using azeotropy.

  In the solvent replacement using azeotropy, the present invention attaches a near-infrared spectroscopic sensor to the process line and measures the concentration of the target component (solvent) in the solution with this sensor, thereby ending the solvent replacement operation. Confirm. Further, the present invention is based on the measurement data of the near-infrared spectroscopic sensor, determines the amount of the solvent charged, determines the number of operations, decompresses the tank, starts and stops adjusting the temperature in the tank by the jacket, Each operation in the batch-type solvent replacement operation, such as opening and closing of a valve related to the charging and discharging of the solution, is automated by being controlled by a control device.

  That is, the present invention relates to a solution containing a target substance and a first solvent that dissolves the target substance, and azeotropic with the first solvent and has a lower solubility of the target substance than the first solvent. A second tank containing a second solvent, a second tank supply device for supplying the second solvent to the second tank, and a second liquid supply device for supplying the second solvent to the second tank. A heating device for heating, a condenser for cooling the vapor of the liquid in the concentrated layer generated in the concentration tank, a distilling tank for containing the condensate generated in the condenser, and the condensation A detector for detecting the concentration of the first or second solvent in the liquid or the liquid in the concentration tank, and supply of at least the second solvent to the concentration tank and the liquid in the concentration tank by the heating device Control device for controlling heating of the detector according to the detection value of the detector Have, the detector provides a solvent replacement unit is a near-infrared spectroscopic sensor.

  According to the apparatus, it is possible to automatically and immediately detect the composition of the condensate or the liquid in the concentrating tank during the solvent replacement operation, and in the solvent replacement using azeotrope, the solvent replacement It is possible to confirm the end point of the solvent replacement operation without stopping the operation and without collecting the solvent.

  Moreover, according to the said apparatus, it becomes possible to implement each operation in solvent substitution by a control apparatus based on the measurement data of the composition of the condensate in solvent replacement operation, or the liquid in a concentration tank.

  In the present invention, the solvent replacement device includes a reflux pipe for supplying the condensate to the concentration tank, and the condensate from the condenser to one or both of the distillation tank and the reflux pipe. A flow path forming device for forming a flow path, and the detector is a device for detecting the concentration of the first or second solvent in the condensate in the reflux pipe. The end point of the solvent replacement operation can be confirmed by detecting the composition.

  The present invention also provides a sample solution containing a target substance and a mobile phase in an endless channel formed by connecting a plurality of columns when the target substance is a medicine or an intermediate thereof. When obtained by simulated moving bed chromatography that supplies and discharges a mobile phase from an endless channel, or a fluid in which the target substance is a supercritical fluid and two or more solvents is used as the mobile phase It is also suitable when obtained by supercritical fluid chromatography.

  The solvent replacement device of the present invention includes the concentration tank, the second solvent supply device, the heating device, the condenser, the distilling tank, the detector, and the control device, and the detector is close. Since it is an infrared spectroscopic sensor, it is possible to automatically and immediately observe the composition of the solution in the solvent replacement using azeotropy. In addition, the solvent replacement apparatus of the present invention can automatically perform an operation of replacing a solvent using azeotropic distillation.

  The solvent replacement device of the present invention further includes the reflux pipe and the flow path forming device, and the detector is a device for detecting the concentration of the first or second solvent in the condensed liquid of the reflux pipe. If so, the end point of the solvent replacement operation can be confirmed from the composition of the reflux liquid. Further, the condensate can be refluxed, and a highly volatile component can be preferentially removed from the solution.

  The solvent displacement apparatus according to the present invention can be used when the target substance is a medicine or an intermediate thereof, or when the target substance moves with a sample solution containing the target substance in an endless channel formed by connecting a plurality of columns. The target substance moves through a fluid consisting of a supercritical fluid and two or more solvents when obtained by simulated moving bed chromatography that supplies a phase and discharges the mobile phase from an endless channel. When high-level removal of impurities from the target substance is desired, as in the case obtained by supercritical fluid chromatography used as a phase, or when a target substance that is easily mixed with impurities as a mobile phase solvent is used. This is even more effective from the viewpoint of obtaining a highly purified target substance.

  The solvent replacement apparatus of the present invention comprises a solution containing a target substance and a first solvent that dissolves the target substance, and is azeotropic with the first solvent and has a solubility in the target substance as compared with the first solvent. A second tank having a low concentration, a concentration tank for concentrating the stored liquid, a second solvent supply device for supplying the second solvent to the concentration tank, and the concentration tank A heating device for heating the liquid in the generated concentrated layer, a condenser for cooling the vapor of the liquid in the concentration tank, and a distilling tank for containing the condensate generated in the condenser A detector for detecting the concentration of the first or second solvent in the condensate or the liquid in the concentration tank, and supply of at least the second solvent to the concentration tank and a concentration tank by the heating device Control for controlling the heating of the liquid in accordance with the detection value of the detector. And a device. In the present invention, the detector is a near-infrared spectroscopic sensor that can detect the intensity of each reflected light (or transmitted light) in the near-infrared region (for example, 0.8 to 2.5 μm). It is done.

  The concentration tank is not particularly limited as long as it contains a solution containing a target substance and a first solvent that dissolves the target substance and the second solvent, and can azeotrope these liquids. . Since the azeotropic distillation of the liquid is generally performed under reduced pressure, a known tank capable of reducing the pressure in the tank can be used as the concentration tank.

  The second solvent supply device is not particularly limited as long as it is a device that can supply the second solvent to the concentration tank. A 2nd solvent supply apparatus can be comprised using a well-known various member and apparatus. For example, the second solvent supply device includes a second solvent tank for containing the second solvent, a second solvent supply pipe connecting the second solvent tank and the concentration tank, and a second solvent. It can comprise from the pump for supplying the solvent of a supply pipe | tube toward a concentration tank, and the valve for opening and closing a 2nd solvent supply pipe | tube.

  The said heating apparatus will not be specifically limited if it is an apparatus which can heat the liquid in a concentration tank. As the heating device, a known device capable of heating the liquid in the tank, such as a jacket or a coil that forms a flow path of the heat medium in the outer peripheral portion of the concentration tank, or an electric heater provided in the concentration tank can be used. . The heating device is preferably a jacket or a coil from the viewpoint of realizing temperature adjustment including cooling of the liquid in the concentration tank.

  The condenser is not particularly limited as long as it is a device capable of cooling and condensing liquid vapor heated in the concentration tank. A known apparatus used for concentrating the solvent can be used for the condenser.

  The said distillation tank will not be specifically limited if it is a container which can accommodate the condensate produced | generated with the condenser. When the azeotropic distillation of the solution is performed under reduced pressure, it is preferable to use a known tank capable of reducing the pressure inside the distillation tank.

  The detector is a near-infrared spectroscopic sensor that detects the concentration of the first or second solvent in the condensed liquid or the liquid in the concentrating tank. The detector is not particularly limited as long as it can detect at least the concentration of the first or second solvent. In addition to the concentration of the first or second solvent, other detectors such as impurities associated with other solvents and target substances can be used. You may further detect the density | concentration of another component.

  Further, an appropriate number of detectors can be provided at positions for measuring one or both of the condensate and the liquid in the concentrating tank. In the case of providing a plurality of detectors, a near-infrared spectroscopic sensor is used as at least one of the detectors for detecting the composition of the condensate and the liquid in the concentration tank, An external spectroscopic sensor or another sensor may be used.

  The near-infrared spectroscopic sensor for detecting the composition of the condensate is provided, for example, in a condensate flow path connecting the condenser and the distillation tank or in the distillation tank. Moreover, the near-infrared spectroscopic sensor which detects the composition of the liquid in a concentration tank is provided in a concentration tank, for example. As the near-infrared spectroscopic sensor, for example, a known near-infrared spectroscopic sensor such as MATRIX series manufactured by Bruker Optics can be used. The other sensor may be a sensor capable of directly or indirectly detecting at least a part of the condensate or the liquid in the concentrating tank. For example, the liquid or condensate in the concentrating tank may be used. Examples thereof include a dielectric constant measuring device for detecting the dielectric constant.

  The control device is particularly a device that can control at least the supply of the second solvent to the concentration tank and the heating of the liquid in the concentration tank by the heating device according to the detection value of the detector. It is not limited. The supply of the second solvent to the concentration tank can be controlled by a control device based on the concentration of the first or second solvent detected by the detector, and a liquid meter is further added to the concentration tank. And the control value can be further controlled using the detected value of the liquid meter.

  Regarding the supply of the second solvent to the concentration tank, the control based on the concentration of the first or second solvent detected by the detector may be performed by, for example, detecting the concentration of the first or second solvent by the detector. When the detected value deviates from the set value (for example, when it falls below the set value), the value is compared with the set value of the concentration of the first or second solvent stored in the control device in advance. For example, the control device may supply a predetermined amount of the second solvent to the concentration tank. Further, according to the liquid meter, when the control device deviates from the permissible value range (permissible capacity) of the concentration liquid in the concentration tank preset in the control device, The control device can perform control to supply the second solvent continuously within the allowable capacity of the concentration tank or intermittently up to the upper limit. The control device can perform the control based on the liquid amount according to the detection value of the detector.

Furthermore, for the supply of the second solvent to the concentration tank, the control device determines the amount of the second solvent charged and the number of times of the charging operation from the viewpoint of further reducing the burden on the worker in the solvent replacement operation. It is preferable that The amount of charge of the second solvent and the number of charge operations are, for example, the amount of the first solvent in the solution supplied to the concentration tank, the azeotropic mixture ratio of the first and second solvents, and the concentration after azeotropy. The controller determines the total supply amount of the second solvent from the amount of the second solvent that should be accommodated in the tank, and the determined total supply amount of the second solvent and the amount of the second solvent per time. The control device can determine the number of charging operations based on the amount charged to the concentration tank. Each charged amount when the second solvent is charged into the concentration tank a plurality of times may be a constant value, or the number of times is increased in anticipation of a decrease in the first solvent in the solution due to the progress of azeotropy. It may be a different value that is increased with time.

  The heating of the liquid in the concentration tank by the heating device can be controlled based on the concentration of the first or second solvent detected by the detector. For example, the heating of the liquid in the concentration tank by the heating device is performed by setting the first or second solvent concentration detected by the detector and the first or second solvent concentration stored in advance in the control device. A control for comparing the value and heating the liquid in the concentrating tank by the heating device when the detected value is within the set value range can be mentioned.

  The solvent replacement apparatus of the present invention may further include other means other than the above-described apparatuses and members. The other means is not particularly limited as long as it can be used for concentration of a solvent and crystallization of a target substance and can be used for automatically controlling various operations. The other means includes a reflux pipe for supplying the condensate to the concentration tank, and a flow path for forming a flow path for the condensate from the condenser to the distillation tank and the reflux pipe. Examples thereof include a forming apparatus.

  The reflux pipe is not particularly limited as long as it forms a flow path for the condensate to the concentration tank. As the reflux tube, an appropriate known tube can be used according to various conditions such as the degree of reduced pressure in vacuum concentration and the type of solvent. In the case where a reflux pipe is provided, a detector may be provided in the reflux pipe in order to detect the concentration of an arbitrary component of the condensate.

  Further, the flow path forming device can form a flow path for the condensate from the condenser to the distilling tank, and can form a flow path for the condensate from the condenser to the reflux pipe. The apparatus is not particularly limited as long as it is an apparatus that can form a flow path of condensate from the condenser to the distillation tank and the reflux pipe. The flow path forming device includes, for example, a three-way valve provided at a connection position between a condensate supply pipe connecting a condenser and a distillation tank and a reflux pipe connected to the pipe, and the condensate supply pipe and the reflux Two or more two-way valves provided in each of the tubes can be used.

  Furthermore, the other means includes a decompression device for decompressing the inside of the concentration tank, a solution supply device for supplying a solution containing the target substance and the first solvent to the concentration tank, and the like.

  The decompression device is not particularly limited as long as it can decompress the solvent concentration atmosphere in the concentration tank. As the decompression device, a known decompression device such as a vacuum pump can be used. The decompression device is preferably connected to the condenser or the condensate flow path downstream of the condenser.

  The said solution supply apparatus will not be specifically limited if it is an apparatus which can supply the said solution to a concentration tank. Similarly to the second solvent supply device, the solution supply device can be configured using various known members and devices. For example, a solution tank for storing the solution, a solution tank, and a concentration tank are provided. A solution supply pipe to be connected, a pump for supplying the solution in the solution supply pipe toward the concentration tank, and a valve for opening and closing the solution supply pipe can be used.

  Furthermore, from the viewpoint of the accuracy of detection of the solvent concentration by the near-infrared spectroscopic sensor, the other means includes a device for adjusting the temperature of the detected solvent such as a coil or a jacket, and the temperature of the detected solvent. In order to adsorb and remove the thermometer to be measured and components that interfere with the detection of the solvent to be detected (for example, water when the solvent to be detected is alcohol) from the solution, the liquid or the condensate before detection. And the like. Known means can be used for these other means.

  The control device is preferably a device that further controls the further operation by the other means from the viewpoint of further reducing the burden on the worker in the solvent replacement operation. Examples of the further operation include supply of the solution from the solution supply device to the concentration tank, pressure reduction in the concentration tank in the case of vacuum concentration, and discharge of the liquid in the concentration tank.

  The supply of the solution from the solution supply device to the concentration tank can be performed, for example, when the controller supplies the set amount of the solution to the concentration tank by the solution supply device when instructing the start of the solvent replacement operation. The amount of solution supplied can be controlled by operating a pump that supplies the solution from the solution tank to the concentration tank, or by opening and closing a valve interposed between the solution tank and the concentration tank. Detection of the amount of liquid may be used for the control.

  Further, in the case of vacuum concentration, the pressure in the concentration tank is determined by the operation of the vacuum pump or the opening / closing of a valve in the pipe connecting the vacuum pump and the concentration tank, depending on the amount of liquid in the concentration tank or the detection value of the detector. This control can be performed by the control device reducing the pressure in the concentration tank to a preset pressure.

  In addition, for example, after confirming the end point of the concentration operation (solvent replacement) or after controlling the crystallization operation, the controller opens the valve provided at the bottom of the concentration tank. Can be done.

  In addition, the control device can appropriately control various devices constituting the solvent replacement device in accordance with the configuration of the solvent replacement device. A known control device used for plant operation control can be used as the control device.

  The first solvent and the second solvent are solvents that are azeotropic with each other, and one or two or more kinds of solvents are selected from known solvents in which the solubility of the target substance is different. The first and second solvents are specific to the solvent, as detected by the near-infrared spectroscopic sensor, the boiling point and azeotropic point of each solvent, the solubility of the target substance in each solvent, the difference in solubility of the target substance in these solvents Depending on various conditions such as the wave number region, water and a known organic solvent can be selected as appropriate.

  Examples of the organic solvent include general alcohols such as methanol, ethanol, and isopropyl alcohol (IPA), highly polar solvents such as acetic acid, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, ethyl acetate, methyl acetate, and diethylamine, chloroform And various organic solvents generally used as a mobile phase in a chromatographic apparatus, such as a solvent with low polarity such as acetonitrile and a solvent with low polarity such as n-hexane and cyclohexane. Further, examples of the organic solvent include heptane, tert-butyl methyl ether (MTBE), acetone, toluene, methylene chloride, 1,4-dioxane, and N, N-dimethylacetamide (DMAc).

  As for conditions regarding the boiling point and solubility of the solvent, normal conditions for solvent replacement by azeotropic distillation can be employed. Regarding the wave number region detected by the near infrared spectroscopic sensor, the wave number of the first region peculiar to the first solvent that changes in accordance with the concentration change of the first solvent and the concentration change of the second solvent The first and second solvents can be selected from two or more kinds of solvents that can be distinguished from the wave number of the second region specific to the second solvent that changes in accordance with the second solvent.

Examples of the wave number peculiar to the solvent detected by the near-infrared spectroscopic sensor include 6873.3 to 7332.3 cm ⁻¹ for acetonitrile, and 6873.3 to 7332.3 cm ^{−1 for} methanol. 4713.4～5114.5Cm ^-1 can be mentioned, 6611.1~6919.6cm ^-1 can be mentioned if IPA, 8153.9~ if n- hexane
8377.6 cm < ^-1 > is mentioned, and it is 6449.06-6468.35 cm < ^-1 > if it is diethylamine. Examples of combinations of two or more solvents that can be detected with a near-infrared spectroscopic sensor in the solvent include all combinations other than the combination of acetonitrile and IPA. The wave number region peculiar to the solvent can be determined by analyzing the mixed solvent with a near-infrared spectroscopic sensor while changing the concentration of a predetermined solvent in a mixed solvent of two or more solvents, for example.

  The target substance is not particularly limited as long as it is a substance that is not denatured by concentration at the time of substitution of a solvent such as vacuum concentration and is soluble in the first solvent.

  The solution containing the first solvent and the target substance can be obtained by mixing the target substance and the first solvent, and the composition containing the target substance and the first solvent are mixed. It can also be obtained by mixing. Examples of the composition containing the target substance include a solution of the target substance obtained by a separation method such as column chromatography, a concentrated liquid thereof, a reaction product of a reaction for obtaining the target substance, and a purified product thereof. It is done.

  In the present invention, the removal of specific components contained in the liquid in the concentration tank other than the first and second solvents may be performed before or after the solvent replacement by azeotropy, or the solvent replacement by azeotrope. Is possible in parallel. Examples of the specific component include a component having a lower boiling point than the first and second solvents, a component having higher volatility than the first and second solvents, and the first solvent or the second solvent. Examples include azeotropic components.

  For example, the target substance can be produced by separating desired components from the mixture by column chromatography. In this case, the target substance is usually obtained in the form of a concentrated solution. In separation by column chromatography, it is known that an appropriate amount of an additive such as an organic acid or an organic base is added to the mobile phase in order to improve the stability of the target substance during the separation. Examples of the specific component include solvents and additives used in the mobile phase.

  Examples of the column chromatography include various known methods such as high performance liquid chromatography, simulated moving bed chromatography, supercritical fluid chromatography, and simulated moving bed supercritical fluid chromatography.

  In the column chromatography, various known solvents such as water, acids, alkalis, organic solvents, and mixed solvents containing two or more of these can be used as the mobile phase. Examples of such mobile phase solvents include highly polar solvents such as methanol, ethanol, isopropyl alcohol, acetic acid, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, ethyl acetate, methyl acetate and diethylamine, and less polar solvents such as chloroform and acetonitrile. Non-high solvent, low polarity solvent such as n-hexane, heptane, tert-butyl methyl ether, acetone, toluene, methylene chloride, 1,4-dioxane, N, N-dimethylacetamide and the like.

  The additive in these column chromatography is not particularly limited as long as it can stabilize the target substance during separation. The additive can be appropriately selected from the viewpoint of the physical properties of the mobile phase such as pH and the physical properties of the target substance. Examples of the additive include a carboxylic acid such as acetic acid and an amine such as diethylamine.

  The addition amount of the additive is not particularly limited as long as it stabilizes the target substance during separation and does not adversely affect the separation of the target substance, but is 0.01 to 0.5 volume with respect to the total amount of the mobile phase. % Is preferable, and 0.01 to 0.2% by volume is more preferable.

  As the column chromatography, simulated moving bed chromatography and supercritical fluid chromatography are known as methods with excellent productivity. These column chromatography can be carried out as usual, depending on the type of target substance and the type of separating agent.

  The simulated moving bed chromatography contains an endless channel in which a plurality of columns are connected in series, a first channel for supplying a mobile phase to the endless channel, and a target substance. Using an apparatus having a second flow path for supplying a mobile phase to an endless flow path, and first and second discharge flow paths for discharging the mobile phase from the endless flow path It can be carried out.

  In supercritical fluid chromatography, a fluid containing a supercritical fluid and the mobile phase solvent can be used as the mobile phase from the viewpoint of adjusting the polarity of the mobile phase and improving the solubility in the target substance. Supercritical fluid chromatography is a mobile phase generation device that generates a mobile phase that is a fluid in which a supercritical fluid and a solvent are mixed, an injector for injecting a sample containing a target substance into the generated mobile phase, The column for separating the target substance in the injected sample, the detector for detecting the substance in the mobile phase passing through the column, and the pressure in the system from the supercritical fluid generator to the detector are set to a predetermined pressure. It is possible to use a device having a back pressure valve for maintaining the pressure and a gas-liquid separation device for separating the supercritical fluid from the solvent from the mobile phase that has passed through the back pressure valve.

  As the supercritical fluid in the supercritical fluid chromatography, a substance that is in one or both of a state of a critical pressure or higher and a critical temperature or higher (that is, a supercritical state) is used. Examples of substances used as the supercritical fluid include carbon dioxide, ammonia, sulfur dioxide, hydrogen halide, nitrous oxide, hydrogen sulfide, methane, ethane, propane, butane, ethylene, propylene, halogenated hydrocarbons, water, and the like. Can be mentioned.

  In the column chromatography, the separation agent packed or contained in the column for separating the target substance from the mixture can be appropriately selected from various separation agents according to the type of the target substance. For example, when the target substance is an optical isomer, examples of the separating agent include cellulose, amylose, cellulose ester derivatives, cellulose carbamate derivatives, and amylose as described in WO95 / 23125 pamphlet. Separation agents containing polysaccharides or polysaccharide derivatives such as ester derivatives of amylose and carbamate derivatives of amylose can be suitably used.

  The form of these separating agents is not particularly limited. For example, the separating agent may be supported on a known carrier made of silica gel or alumina, or the separating agent itself is contained in a particulate column tube. The form shape | molded to the shape which may be sufficient. Such a form of the separating agent can be realized by a known method as described in, for example, Japanese Patent No. 2778419.

  In the supercritical fluid chromatography, the mixing ratio of the mobile phase solvent to the supercritical fluid in the mobile phase can be appropriately determined according to various conditions such as the type of the target substance and the separation ability of the separating agent.

In the column chromatography apparatus, the target substance is obtained in a state dissolved in the mobile phase. The column chromatography apparatus preferably further includes an apparatus for recovering only the mobile phase from the separated mobile phase from the viewpoint of reducing the amount of solvent used in the mobile phase and reducing the burden on the environment. Such a recovery device includes an evaporation device for evaporating and distilling at least a part of the mobile phase discharged from the column chromatography device, and a recovery tank for storing the distillate distilled from the evaporation device. And a storage tank that contains the concentrated liquid concentrated in the evaporator, and an adjustment apparatus for adjusting the composition of the distillate in the recovery tank.

  In addition, the supercritical fluid chromatography device further includes a device for recovering the gas separated by the gas-liquid separation device to regenerate the supercritical fluid, thereby reducing the amount of components constituting the supercritical fluid. This is preferable from the viewpoint of reducing the load on the environment. Such a gas recovery apparatus includes, for example, a gas recovery pipe connecting the gas-liquid contact apparatus and the supercritical fluid purification apparatus, and a gas-liquid separation apparatus for separating a liquid from a recovery gas flowing in the gas recovery pipe; The apparatus which has is mentioned.

  In the column chromatography apparatus using the recovery solvent, the concentration of the specific component such as the above-mentioned additive in the mobile phase may increase as the mobile phase is repeatedly recovered, and the specific component accompanying the target substance may be increased. The concentration of can be high. Therefore, applying the target substance obtained by column chromatography using the recovery apparatus to the solvent replacement apparatus of the present invention capable of performing the solvent replacement and the removal of a specific component in parallel is highly purified. More effective from the viewpoint of obtaining the target substance. Therefore, the solvent displacement device of the present invention is suitable when a drug or its intermediate is used as the target substance.

  Furthermore, when the target substance obtained by column chromatography is used, it is possible to construct a separation and purification system including the above-described apparatus capable of performing column chromatography and the solvent displacement apparatus of the present invention.

  Hereinafter, embodiments of the present invention will be described with reference to the drawings.

  As shown in FIG. 1, the solvent replacement device according to one embodiment of the present invention includes a solution tank 1 containing a solution containing a target substance and a first solvent that dissolves the target substance, A second solvent tank 2 containing a second solvent which is azeotropic with the first solvent and has a lower solubility of the target substance than the first solvent, and the solution in the solution tank 1 and the second solvent tank 2 The second tank is supplied with the concentration tank 3, the heating device 4 for heating the liquid in the concentration tank, the condenser 5 for cooling the liquid vapor in the concentration tank 3, and the condenser 5, a distilling tank 6 for containing the condensate produced in 5, a near-infrared spectroscopic sensor 7 for detecting the concentration of the first or second solvent in the condensate, and detection by the near-infrared spectroscopic sensor 7. And a control device 8 to which a signal is input.

  The solution tank 1 and the concentration tank 3 are connected by a solution supply pipe 9. The solution supply pipe 9 is provided with a pump 10 for sending the solution toward the concentration tank 3 and a valve 11 for opening and closing the solution supply pipe 9. The solution tank 1, the solution supply pipe 9, the pump 10 and the valve 11 constitute a solution supply apparatus.

  The second solvent tank 2 and the concentration tank 3 are connected by a second solvent supply pipe 12. The second solvent supply pipe 12 is provided with a pump 13 for sending the second solvent toward the concentration tank and a valve 14 for opening and closing the second solvent supply pipe 12. The second solvent tank 2, the second solvent supply pipe 12, the pump 13 and the valve 14 constitute a second solvent supply device.

  The concentration tank 3 and the condenser 5 are connected by a steam supply pipe 15. The condenser 5 and the distillation tank 6 are connected by a condensate supply pipe 16. The condensate supply pipe 16 is provided with a three-way valve 17 and a near-infrared spectroscopic sensor 7 (for example, MATRIX series manufactured by Bruker Optics).

  The concentration tank 3 further has a discharge pipe 18 for discharging the liquid in the concentration tank 3. The discharge pipe 18 is provided with a valve 19 for opening and closing the discharge pipe 18.

  The heating device 4 is a jacket that forms a flow path of the heat medium in the outer peripheral portion of the concentration tank 3. The heating device 4 is connected to a heat medium supply device (not shown), and a heat medium whose temperature is controlled is supplied from the heat medium supply device.

  An exhaust pipe 20 is connected to the condenser 5. The exhaust pipe 20 is provided with a valve 21 for opening and closing the exhaust pipe 20 and a vacuum pump 22 for sucking the atmosphere of the condenser 5.

  The three-way valve 17 and the concentration tank 3 are connected by a reflux pipe 23. The three-way valve 17 is a flow path forming device, and forms either a flow path from the condenser 5 to the distillation tank 6 or a flow path from the condenser 5 to the concentration tank 3.

  Although not shown, the control device 8 is connected to each of the valves 11, 14, 18 and 21, the three-way valve 17, the pumps 10 and 13, the vacuum pump 22, and the heat medium supply device, and a near infrared spectroscopic sensor The operation amount of these devices is controlled in accordance with either one or both of the detected value 7 and the program inputted in advance. The solution tank 1, the second solvent tank 2, the concentration tank 3 and the distilling tank 6 are each provided with a liquid meter (not shown) for detecting the amount of liquid in the tank. A meter is also connected to the control device 8.

  The target substance is, for example, a pharmaceutical product or an optical isomer as an intermediate thereof. The target substance is separated by column chromatography and taken out from the concentrated liquid of the mobile phase, and the first solvent is ethanol. The second solvent is n-hexane.

  The target substance and ethanol are supplied to the solution tank 1, and the solution tank 1 stores an ethanol solution of the target substance. On the other hand, n-hexane is accommodated in the second solvent tank 2. The amount of ethanol supplied to the solution tank 1 is input to the control device 8. This input may be input by a worker. Alternatively, instead of the input, a detector such as a near-infrared spectroscopic sensor capable of detecting the concentration of ethanol in the solution is provided in the solution tank 1, and the control device 8 is installed in the solution from the detection value input from the detector. The amount of ethanol may be determined.

  The control device 8 opens the valve 11 and operates the pump 10 to supply the solution of the target substance in the solution tank 1 to the concentration tank 3 in a predetermined amount (for example, half of the capacity in which the liquid is allowed to be stored in the concentration tank 3). . When a predetermined amount of the target substance solution is supplied to the concentration tank 3, the control device 8 stops the operation of the pump 10 and closes the valve 11.

  The control device 8 is necessary for distilling ethanol in the solution of the target substance supplied to the concentration tank 3 based on, for example, the azeotropic mixture ratio of ethanol and n-hexane maximizing the distillate amount of ethanol. Determine the amount of n-hexane. And the control apparatus 8 calculates | requires the total supply amount of n-hexane by adding the amount of n-hexane which should be accommodated in the concentration tank 3 after ethanol distillation to the calculated | required amount of n-hexane. Further, the control device 8 divides the obtained total supply amount of n-hexane by half of the allowable capacity which is the remaining allowable capacity of the concentration tank 3, and the obtained numerical value includes a value after the decimal point. Then, the value of the one's place is moved up by one to obtain the number of times n-hexane is charged (number of batches) from the second solvent tank 2.

  The control device 8 opens the valve 14 and operates the pump 13 to supply n-hexane, which is half the allowable capacity of the concentration tank 3, from the second solvent tank 2 to the concentration tank 3. When n-hexane is supplied to the concentration tank 3, the control device 8 stops the operation of the pump 13 and closes the valve 14.

  Control of supply of the solution of the target substance or n-hexane to the concentration tank 3 is carried out by a detection value of a liquid meter provided in the solution tank 1, the second solvent tank 2, and the concentration tank 3, or a pump 10 , 13 may be performed while further confirming the operation amount.

  For example, the control device 8 uses a heat medium supply device to generate heat such as water based on a temperature within a range where the thermal stability of the target substance is obtained, or a temperature or pressure at which the ethanol distillation amount is maximized by azeotropy. The temperature of the medium is adjusted, the heat medium whose temperature is adjusted is circulated between the heat medium supply device and the jacket, the liquid in the concentration tank 3 is heated, the valve 21 is opened, and the vacuum pump 22 is operated. The system from the concentration tank 3 to the distillation tank 6 through the condenser 5 is depressurized. By such heating and system decompression, ethanol and n-hexane azeotrope in the concentration tank 3.

  Ethanol and n-hexane vapor generated in the concentration tank 3 is supplied to the condenser 5 through the vapor supply pipe 15. The solvent vapor supplied to the condenser 5 is cooled and condensed to form a condensate. The condensate is supplied to the distillation tank 6 through the condensate supply pipe 16, the three-way valve 17, and the near infrared spectroscopic sensor 7.

  The near-infrared spectroscopic sensor 7 detects the intensity | strength for every wavelength of the reflected light (or transmitted light) in the near-infrared area | region (for example, 0.8-2.5 micrometers) of the condensate in the condensate supply pipe 16, and the The signal is transmitted to the control device 8. The control device 8 corrects the intensity of the wavelength peculiar to the specific component as necessary from the detection value, and calculates the concentration of the specific component. The control device 8 calculates, for example, the concentrations of ethanol and n-hexane in the condensate from the detection values, and the ethanol detection values and the n-hexane concentration detection values obtained in advance are set in advance. It is determined whether or not it is within the range of the set value of the concentration of n and the set value of the concentration of n-hexane.

  For example, when the detected value of the n-hexane concentration is within the range of the set value of the n-hexane concentration, the control device 8 determines that the azeotrope for solvent replacement is normally performed, and Continue control of heating and decompression. When the detected value of the n-hexane concentration is lower than the set value of the n-hexane concentration, the control device 8 determines that the amount of n-hexane in the concentration tank 3 is insufficient, as described above. N-Hexane is supplied from the second solvent tank 2 to the concentration tank 3. In this way, the n-hexane is replenished for the number of times the n-hexane is charged from the second solvent tank 2 obtained previously.

  When the detected value of the concentration of n-hexane is within the range of the set value of the concentration of n-hexane and the detected value of the concentration of ethanol is lower than the set value of the concentration of ethanol, the control device 8 is azeotropic. It is determined that the solvent replacement is completed, the valve 21 is closed, the vacuum pump 22 is stopped, the temperature of the heat medium in the heat medium supply device is adjusted as necessary, and the vacuum concentration operation is stopped. Through the above-described operation, the solvent of the target substance solution supplied to the concentration tank 3 is replaced with n-hexane from ethanol.

  In addition, even if it carries out supply of n-hexane of the total supply amount calculated | required previously and vacuum concentration, the reduced value concentration is still needed, ie, the detected value of the concentration of n-hexane is the setting value of the concentration of n-hexane. When the detected value of the ethanol concentration falls below the set value of the ethanol concentration, the control device 8 supplies n-hexane one more time, and performs the vacuum concentration operation.

  On the other hand, the control device 8 closes the valve 21 when the detected value of the liquid meter in the distillation tank 6 exceeds the set value of the liquid volume in the distillation tank 6 (for example, the allowable capacity of the distillation tank 6), The three-way valve 17 is operated so as to connect the condenser 5 and the concentrating tank 3 to form a condensate flow path from the condenser 5 to the concentrating tank 3, and an instruction to discharge the condensate from the distilling tank 6 is given. Or implement. When the condensate is discharged from the distillation tank 6, the control device 8 operates the three-way valve 17 to re-form the flow path from the condenser 5 to the distillation tank 6, and opens the valve 21 to continue the vacuum concentration operation. .

When the solvent of the solution is replaced from ethanol to n-hexane, the control device 8 opens the valve 19 and discharges the liquid in the concentration tank 3 from the concentration tank 3 to the discharge pipe 18. From ethanol to n
When the detected value of the liquid amount in the concentration tank 3 is smaller than the set value or calculated value of the liquid amount in the concentration tank 3 after the replacement with hexane is confirmed, the control device 8 causes the second solvent tank 2 to The required amount of n-hexane is supplied to adjust the liquid amount in the concentration tank 3. The control device 8 may further adjust the temperature of the heat medium in the heat medium supply device to precipitate the target material, and then discharge the slurry of the target material to the discharge pipe 18.

  According to this embodiment, the ethanol concentration in the condensate can be continuously measured by the near-infrared spectroscopic sensor 7 without sampling the condensate, and the vacuum concentration operation for azeotropy can be performed by sampling. Therefore, the end point of the vacuum concentration operation can be confirmed without interruption.

  Further, according to the present embodiment, the control device 8 supplies at least n-hexane to the concentration tank 3 and heats the liquid in the concentration tank 3 by the heating device 4 according to the detection value of the near-infrared spectroscopic sensor 7. Since the control and the pressure reduction in the system are further controlled, a series of operations of the vacuum concentration operation can be automated.

  Moreover, in this Embodiment, since it further has the three-way valve 17 and the reflux pipe | tube 23, the condensate of the distillation tank 6 can be discharged | emitted from the distillation tank 6 without interrupting decompression concentration operation.

  Moreover, in this Embodiment, since the heating apparatus 4 is a jacket, since the temperature of the liquid in the concentration tank 3 can be adjusted with the temperature of a heat medium, it is also possible to cool the liquid in the concentration tank 3. It is. Therefore, the crystallization of the target substance can be performed in the concentration tank 3 following the above-described solvent replacement.

  In the present embodiment, replenishment of n-hexane is controlled based on the detected values of ethanol and n-hexane concentrations by the near infrared spectroscopic sensor 7, but the near infrared spectroscopic sensor 7 is a solvent to be replaced. Only the concentration of ethanol is detected, and replenishment of n-hexane is performed so that the amount of liquid in the concentration tank 3 is always within the allowable capacity range of the concentration tank 3 based on the detection value of the liquid meter in the concentration tank 3. It can also be carried out by supplying n-hexane from the second solvent tank 2 to the concentration tank 3 by the control prime minister 8.

  In the present embodiment, the near-infrared spectroscopic sensor 7 is provided in the condensate supply pipe 16, but the near-infrared spectroscopic sensor 7 may be provided in the reflux pipe 23 as shown in FIG. May be provided in the concentration tank 3 as shown in FIG.

  In the case where the near-infrared spectroscopic sensor 7 is provided in the reflux tube 23, the ethanol concentration in the condensate can be measured for each batch. Therefore, it is more effective from the viewpoint of further simplifying the vacuum concentration operation in which the conditions for vacuum concentration are already known.

  When the near-infrared spectroscopic sensor 7 is provided in the concentration tank 3, the concentration of liquid ethanol in the concentration tank 3 can be measured. As shown in FIGS. 1 and 2, when the concentration of ethanol in the condensate is measured by the near-infrared spectroscopic sensor 7, the controller 8 sets the ethanol concentration as a set value in the liquid in the concentration tank 3. The range of the ethanol concentration value in the condensate until the desired ethanol concentration is obtained is set. However, when the ethanol concentration of the liquid in the concentration tank 3 is measured by the near-infrared spectroscopic sensor 7, the desired ethanol concentration in the liquid in the concentration tank 3 can be directly set as the ethanol concentration set value. Further, it is more effective from the viewpoint of further simplifying the condition setting for the control of the vacuum concentration operation. Further, providing the near-infrared spectroscopic sensor 7 in the concentration tank 3 is suitable for studying the conditions for solvent replacement.

In the present embodiment, the three-way valve 17 is used in the flow path forming device. However, as shown in FIG. 4 instead of the three-way valve 17, the connection place between the condensate supply pipe 16 and the reflux pipe 23 and the near red Outside spectral sensor 1
7 is provided with a valve 24 for opening and closing the condensate supply pipe 16 between them and a valve 25 for opening and closing the reflux pipe 23, and these valves can be connected to the control device 8 and controlled by the control device 8. You may comprise as follows. When the flow path forming device is constituted by the two valves 24 and 25, the condensate can be distributed to both the distillation tank 6 and the reflux pipe 23 at an arbitrary ratio.

  In some cases, the target substance supplied to the solution tank 1 is accompanied by impurities such as solvents and additives used in the mobile phase of column chromatography. From the detected signal, it is possible to correct the intensity of light having a wavelength peculiar to the impurity as necessary, and obtain the impurity concentration. In this case, the control device 8 further confirms that the impurity concentration in the liquid in the concentration tank 3 is equal to or lower than a predetermined value by comparing the detected value of the impurity concentration with the set value of the impurity concentration. If necessary, the vacuum concentration operation may be further controlled.

  For example, when impurities are easily distilled components, the concentration of impurities in the condensate is obtained using the near-infrared spectroscopic sensor 7 and it is confirmed that the detected value of the impurity concentration is lower than the set value of the impurity concentration. By doing so, the end point of the removal of impurities from the liquid in the concentration tank 3 may be determined.

  In the case where the impurity is a component that is more easily distilled out by concentration under the condition of ethanol alone than in the presence of ethanol and n-hexane, the control device 8 can transfer the n-hexane from the second solvent tank 2 to the concentration tank 3. Before the supply, the vacuum concentration operation for removing impurities is performed. In the case where the impurity is a component that is more easily distilled out by concentration under the condition of n-hexane alone than in the presence of ethanol and n-hexane, the controller 8 performs the above-described vacuum concentration operation for solvent replacement, A vacuum concentration operation is further performed to remove impurities. In the vacuum concentration operation for removing these impurities, the end point can be determined by comparing the detection value by the near infrared spectroscopic sensor 7 with the set value, similarly to the vacuum concentration operation for solvent replacement described above.

  When the component separated from the mixture by column chromatography is used as the target substance, the impurities are easily accompanied. As such a column chromatography, the form which is excellent in the productivity of a target substance is shown below.

<Pseudo moving bed chromatography>
Simulated moving bed chromatography can be performed using the apparatus shown in FIG. The simulated moving bed chromatography apparatus includes an endless channel 31 in which 12 columns a to l are connected in series, and a first flow for supplying a mobile phase to the endless channel 31. A channel 32, a second channel 33 for supplying a mobile phase containing a target substance to the endless channel 31, and first and second for discharging the mobile phase from the endless channel 31 Discharge channels 34 and 35 and a circulation pump 36 for circulating the mobile phase in the endless channel 31.

  The simulated moving bed chromatography apparatus is further connected to the tops of three evaporators 37 to 39 connected in series to the first discharge flow path 33 and the evaporators 37 to 39, respectively. The first distillate flow path 40 through which the distillate distilled from the evaporators 37 to 39 flows and the first storage tank 41 for storing the bottoms of the evaporator 39 are provided.

  The simulated moving bed chromatography apparatus is further connected to the top of each of three evaporators 42 to 44 connected in series to the second discharge flow path 34 and the evaporators 42 to 44. The second distillate flow path 45 through which the distillate distilled from the evaporators 42 to 44 flows and the second storage tank 46 for storing the bottoms of the evaporator 44 are included.

The simulated moving bed chromatography apparatus further includes first and second distillate flow paths 40,
45 are connected to each other, a recovery tank 47 for storing the distillate in these distillate flow paths, a distillation device 48 for purifying the distillate recovered in the recovery tank 47, and a purified distillate. A solvent adjusting device 49 for adjusting the composition of the discharged liquid, and a reuse channel 50 that connects the solvent adjusting device 49 and the first channel 32 are provided.

  The endless flow channel 31 includes columns a to l and a plurality of connection channels that connect the columns a to l in series. The first and second flow paths 32 and 33 and the first and second discharge flow paths 34 and 35 are connected to the connection flow paths, respectively, for specific connection. It is comprised so that it may open and close with respect to a flow path.

  The evaporators 37 to 39 are connected such that the bottoms of the evaporator 37 are supplied to the evaporator 38 and the bottoms of the evaporator 38 are supplied to the evaporator 39. Similarly, the evaporators 42 to 44 are connected such that the bottoms of the evaporator 42 are supplied to the evaporator 43 and the bottoms of the evaporator 43 are supplied to the evaporator 44.

  The solvent adjustment device 49 is a device using the device disclosed in, for example, US Pat. No. 6,325,898, and instead of the dielectric constant measurement device, for example, near infrared such as MATRIX series manufactured by Bruker Optics. An apparatus provided with a spectroscopic sensor.

  The target substance is an optical isomer, the sample solution is a mixture of optical isomers, and the column contains particles made of a carbamate derivative of cellulose produced by the method described in, for example, Japanese Patent No. 2783819 as a separating agent. In the case of using as a mobile phase a mixed solvent prepared by mixing a total volume of 0.01% by volume of diethylamine with a mixed solvent of 50% by volume of methanol and 50% by volume of acetonitrile, the simulated moving bed by the above apparatus is used. Formula chromatography will be described.

  The first channel 32 supplies the mobile phase to the endless channel 31 from between the column 1 and the column a, for example. The second flow path 33 supplies the sample solution to the endless flow path 31 from between the column f and the column g, for example. The first discharge flow path 33 discharges the mobile phase of the endless flow path 31 from between the column c and the column d, for example. The second discharge channel 34 discharges the mobile phase of the endless channel 31 from between the column i and the column j, for example.

  The optical isomer in the sample solution supplied to the endless flow channel 31 is first adsorbed on the separation agent of the column g. Of the optical isomers in the sample solution, a component that is easily adsorbed to the separating agent (hereinafter, this component is also referred to as “extract”) is strongly adsorbed to the separating agent, and is difficult to adsorb to the separating agent (hereinafter, this component). (Also called “raffinate”) adsorbs weakly compared to the extract. Both the raffinate and the extract move in the column g by the flow of the mobile phase, but the raffinate is distributed downstream of the extract in the direction in which the mobile phase flows.

  When the raffinate and the extract flow out of the column g, the first and second flow paths 32 and 33 and the first and second discharge flow paths 34 and 35 are connected at positions downstream of one column. And switch the flow path. That is, in the endless flow channel 31, the first flow channel 32 is connected between the column a and the column b, and the second flow channel 33 is connected between the column g and the column h. The discharge flow path 34 is connected between the column d and the column e, and the second discharge flow path 35 is connected between the column j and the column k. When the time required for the raffinate and the extract to pass through the column g is 1 period, the flow path switching as described above is performed for each period.

If the above-described channel switching is continued for several periods, the bias between the extract distribution and the raffinate distribution due to the adsorptivity to the separating agent becomes more apparent. That is, the extract is mainly distributed and concentrated on the upstream side in the flow direction of the mobile phase in the endless channel 31 with respect to the supply position of the sample solution, and the raffinate is mainly distributed on the downstream side. Concentrated. The unevenly concentrated and concentrated extract is discharged from the endless flow path 31 through the first discharge flow path 34 together with the mobile phase, and the unevenly concentrated and concentrated raffinate is discharged from the endless flow path 31 to the mobile phase. At the same time, it is discharged through the second discharge channel 35.

  When the extract and the raffinate are discharged from the endless channel, the distribution of the extract and the raffinate in the endless channel becomes almost constant. Therefore, when the supply of the mobile phase and the sample solution to the endless flow path 31 and the discharge of the mobile phase from the endless flow path 31 are performed constantly, and the switching of the flow path described above is performed for each period, The supply of the sample solution and the discharge of the mobile phase containing the separated target substance are continuously performed.

  The mobile phase containing the extract discharged into the first discharge channel 34 is first 30 to 50% by mass, then 40 to 70% by mass, and further 60 to 99% by mass by the evaporators 37 to 39. Until it is concentrated step by step. The concentrated mobile phase containing the extract is stored in the first storage tank 41, and the distillate distilled from the evaporators 37 to 39 is transferred to the recovery tank 47 via the first distillate flow path 39. Be contained.

  Similarly, the mobile phase containing the raffinate discharged to the second discharge channel 35 is concentrated stepwise by the evaporators 42 to 44. The concentrated mobile phase containing raffinate is stored in the second storage tank 46, and the distillate distilled from the evaporators 42 to 44 is stored in the recovery tank 47 via the second distillate flow path 45. Is done.

  The liquid stored in the first storage tank 41 or the liquid stored in the second storage tank 46 is used as it is or in an appropriate operation such as washing, and used as a target substance in the solvent replacement device of the present invention.

  The distillate stored in the recovery tank 47 is supplied to the distillation device 48 for further purification, supplied to the solvent adjustment device 49, adjusted to the composition of the mobile phase, and passed through the reuse channel 50. It is supplied to the first flow path 32 and reused as a mobile phase.

<Supercritical fluid chromatography>
Supercritical fluid chromatography can be performed using the apparatus shown in FIG. This supercritical fluid chromatography device includes a cylinder 51 filled with carbon dioxide at a high pressure, a heat exchanger 52 for cooling the carbon dioxide supplied from the cylinder 51 into a liquefied gas, and a heat exchanger 52. The buffer tank 53 for storing the liquefied gas generated in step S3, the high-pressure pump 54 for quantitatively sending the liquefied gas stored in the buffer tank 53, the solvent tank 55 for storing the solvent, and the high-pressure pump 54 A high pressure pump 56 for quantitatively supplying the solvent to the liquefied gas from the solvent tank 55, and heating the mixed liquid of the liquefied gas and the solvent to make the liquefied gas in the mixed liquid a supercritical fluid, A heat exchanger 57 for generating a mobile phase which is a fluid mixture with a solvent.

  The supercritical fluid chromatography apparatus further includes an injector 58 for injecting a sample containing the target substance into the generated mobile phase, a column 59 for separating the target substance in the injected sample, It has a detector 60 that detects a substance in the mobile phase that has passed through 59, and a back pressure valve 61 that maintains the pressure in the system from the high-pressure pump 54 to the detector 60 at a predetermined pressure.

The supercritical fluid chromatography device further includes two gas-liquid separation devices 62 and 63 connected in parallel to the back pressure valve 61 for gas-liquid separation of the mobile phase that has passed through the back pressure valve 61, and a back pressure valve. 61 and valves 64 and 65 for opening and closing flow paths connecting the gas-liquid separators 62 and 63, and a first tank 66 for storing the liquid phase separated by the gas-liquid separators 62 and 63, 67, a valve 68 for opening and closing the first discharge flow path 34 connected to the first tank 66, and a second discharge flow path 35 connected to the first tank 67. And a valve 69 for The first and second discharge channels 34 and 35 to the solvent adjusting device 49 are configured in the same manner as the above-described simulated moving bed chromatography device.

  The supercritical fluid chromatography apparatus further includes a gas recovery pipe 70 for connecting the gas-liquid separators 62 and 63 and the heat exchanger 52, and a gas / liquid for separating the liquid from the recovered gas flowing through the gas recovery pipe 70. Separator 71, check valve 72 for preventing gas backflow from gas-liquid separator 71 to gas-liquid separator 62, and gas back-flow from gas-liquid separator 71 to gas-liquid separator 63 are prevented. A check valve 73, a second tank 74 containing the liquid phase separated by the gas-liquid separator 71, a third tank 75 connected to the second tank 74, and a second tank 74 A valve 76 for opening and closing a pipe connecting the tank 74 and the third tank 75, a regulator 77 for supplying carbon dioxide gas from the cylinder 51 at a predetermined pressure, and the heat exchanger 52 to the cylinder 51. A check valve 78 for preventing the backflow of gas, And a recycling passage 79 for connecting the adjusting device 49 and the solvent tank 55.

  Supercritical fluid chromatography using the above apparatus will be described by taking as an example a case where a target substance, a sample solution, a separating agent contained in a column, and a mobile phase in the simulated moving bed chromatography are used as a solvent.

  Carbon dioxide is supplied from the cylinder 51 to the heat exchanger 52 at an appropriate initial pressure. The supplied carbon dioxide is cooled by the heat exchanger 52 to become liquefied gas, and is stored in the buffer tank 53. The liquefied gas stored in the buffer tank 53 is quantitatively sent to the heat exchanger 57 by the high-pressure pump 54, and heat is exchanged while being pressurized to a predetermined pressure (for example, critical pressure) defined by the back pressure valve 61. To the device 57.

  On the other hand, the solvent is quantitatively sent from the solvent tank 55 toward the heat exchanger 57 by the high-pressure pump 56. The solvent joins and mixes with the liquefied gas before being supplied to the heat exchanger 57. The mixed liquid of the liquefied gas and the solvent is supplied to the heat exchanger 57 and heated to a predetermined temperature (for example, a critical temperature or a set temperature of the column 59). By this heating, the liquefied gas in the mixture becomes a supercritical fluid, and a mobile phase containing the supercritical fluid and the solvent is generated.

  A sample containing the target substance is injected from the injector 58 into the generated mobile phase. The mobile phase into which the sample has been injected is sent to the column 59. In the column 59, the target substance is separated from the sample. The target substance is detected by the detector 60. When the target substance is detected by the detector 60, for example, the valve 64 corresponding to the first discharge channel 16 is opened and the valve 65 is closed. The mobile phase containing the target substance is sent to the back pressure valve 61.

  The mobile phase that has passed through the back pressure valve 61 is released from the pressure adjustment by the back pressure valve 61, is decompressed, and is supplied to the gas-liquid separator 62. The mobile phase sent to the gas-liquid separator 62 is gas-liquid separated. The carbon dioxide forming the supercritical fluid is separated from the mobile phase as a gas phase, and the target substance and the solvent are separated from the mobile phase as a liquid phase. The carbon dioxide separated by the gas-liquid separator 62 is sent to the gas-liquid separator 71 through the check valve 72. The liquid phase separated by the gas-liquid separator 62 is accommodated in the first tank 66.

The liquid phase accommodated in the first tank 66 is a solution of a solvent containing the target substance. As described in the simulated moving bed chromatography, this solution passes through the first discharge channel 34, is concentrated, is stored in the first storage tank 41, and is subjected to an appropriate treatment as necessary. And used as a target substance in the solvent displacement apparatus of the present invention. Further, the liquid phase solvent is recovered, purified, adjusted in composition, supplied to the solvent tank 55 through the reuse channel 79, and recycled to the solvent constituting a part of the mobile phase. Used.

  On the other hand, the carbon dioxide gas (recovered gas) sent to the gas-liquid separator 71 is gas-liquid separated by the gas-liquid separator 71. A small amount of the liquid phase (solvent) contained in the recovered gas is stored in the second tank 74 and then stored in the third tank 75 and discarded.

  The recovered gas purified by the gas-liquid separator 71 is sent to the heat exchanger 52 through the gas recovery pipe 70. When the pressure of the recovered gas is higher than the initial pressure defined by the regulator 77, the recovered gas is supplied to the heat exchanger 52 and liquefied. The liquefied recovered gas is reused as a liquefied gas that becomes a supercritical fluid constituting a part of the mobile phase.

  When the pressure of the recovered gas is lower than the initial pressure defined by the regulator 77, new carbon dioxide gas from the cylinder 51 is supplied to the heat exchanger 52 and liquefied.

  When a substance other than the target substance is detected by the detector 60, the valve 64 corresponding to the gas-liquid separator 62 is closed and the valve 65 corresponding to the gas-liquid separator 63 is opened. In the gas-liquid separator 63, as in the gas-liquid separator 62 described above, carbon dioxide in the mobile phase is sent as a gas phase to the gas-liquid separator 71 through the check valve 73, and the solvent component in the mobile phase. Is stored in the first tank 67 as a liquid phase.

  The liquid phase stored in the first tank 67 is also concentrated as described above, the solution containing the other substance is stored in the second storage tank 46, and the distillate is reused as the solvent. . The recovered gas sent to the gas-liquid separator 71 is also reused as a liquefied gas in accordance with the pressure as described above. The solution stored in the second storage tank 46 may be racemized with the other substances by heating or the like and reused as a sample solution.

It is a figure which shows roughly the structure of the solvent replacement apparatus of one embodiment of this invention. It is a figure which shows schematically the structure of the solvent replacement apparatus of other embodiment of this invention. It is a figure which shows schematically the structure of the solvent replacement apparatus of other embodiment of this invention. It is a figure which shows schematically the structure of the solvent replacement apparatus of other embodiment of this invention. It is a figure which shows roughly the structure of an example of the simulated moving bed type chromatography apparatus which can obtain the target substance in this invention. It is a figure which shows roughly the structure of an example of the supercritical fluid chromatography apparatus which can obtain the target substance in this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Solution tank 2 Second solvent tank 3 Concentration tank 4 Heating device 5 Condenser 6 Distillation tank 7 Near-infrared spectroscopic sensor 8 Control device 9 Solution supply pipe 10, 13 Pump 11, 14, 19, 21, 64, 65 , 68, 69, 76 Valve 12 Second solvent supply pipe 15 Steam supply pipe 16 Condensate supply pipe 17 Three-way valve 18 Discharge pipe 20 Exhaust pipe 22 Vacuum pump 23 Reflux pipe 31 Endless flow path 32 First flow path 33 Second flow path 34 First discharge flow path 35 Second discharge flow path 36 Circulation pumps 37 to 39, 42 to 44 Evaporator 40 First distillate flow path 41 First storage tank 42 Second distillate flow channel 46 Second storage tank 47 Recovery tank 48 Distillation device 49 Solvent adjustment device 50, 79 Reuse channel 51 Cylinder 52, 57 Heat exchanger 53 Buffer tank 54, 56 High pressure pump 55 Solvent Tank 58 Injector 60 Detector 61 Back pressure 62,63,71 gas-liquid separation device 66, 67 first tank 70 the gas recovery pipe 72,73,78 check valve 74 second tank 75 third tank 77 the regulator to l, 59 column

Claims (5)

A solution containing a target substance and a first solvent that dissolves the target substance; and a second solvent that is azeotropic with the first solvent and has a lower solubility in the target substance than the first solvent. A concentration tank for concentrating the contained and contained liquid;
A second solvent supply device for supplying the second solvent to the concentration tank;
A heating device for heating the liquid in the concentration tank;
A condenser for cooling and condensing liquid vapor in the concentration tank generated in the concentration tank;
A distillation tank for containing the condensate produced in the condenser;
A detector for detecting the concentration of the first or second solvent in the condensate or the liquid in the concentration tank;
A controller for controlling at least the supply of the second solvent to the concentration tank and the heating of the liquid in the concentration tank by the heating device according to the detection value of the detector;
The detector is a near infrared spectroscopy sensor. A reflux pipe for supplying the condensate to the concentration tank, and a flow path formation for forming a flow path for the condensate from the condenser to one or both of the distillation tank and the reflux pipe And further comprising a device,
2. The solvent replacement device according to claim 1, wherein the detector is a device for detecting the concentration of the first or second solvent in the condensate in the reflux pipe.   3. The solvent replacement device according to claim 1, wherein the target substance is a medicine or an intermediate thereof.   The target substance is a simulated moving bed type in which a sample solution containing a target substance and a mobile phase are supplied to an endless channel formed by connecting a plurality of columns, and the mobile phase is discharged from the endless channel. The solvent replacement device according to any one of claims 1 to 3, wherein the solvent replacement device is obtained by chromatography.   The said target substance was obtained by the supercritical fluid chromatography using the fluid which consists of a supercritical fluid and 2 or more types of solvents as a mobile phase, The Claim 1 characterized by the above-mentioned. Solvent replacement device.

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