JP2008122284A - Supercritical fluid chromatography device - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To maintain the constant concentration of solvent components in a moving phase based on the composition of a moving phase which is supplied to a column actually when the moving phase having a supercritical fluid and a solvent is supplied to the column. <P>SOLUTION: The composition of the moving phase having the supercritical fluid of carbon oxide and the solvent components containing a modifier and an additive, is detected by a near infrared spectroscopy sensor 10 located at an upstream side rather than the location of an injector 11 for injecting raw material liquid. Either of at least a metering pump 7 that quantitatively supplies the liquefied gas of carbon dioxide that becomes the liquefied gas of the carbon oxide to a heat exchanger 9 corresponding to the detection value of the near infrared spectroscopy sensor 10, and a metering pump 8 that quantitatively supplies the solvent components to the heat exchanger 9 is driven by the control of a moving phase controlling device. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a supercritical fluid chromatography apparatus, and more particularly to a supercritical fluid chromatography apparatus capable of detecting a composition of a mobile phase using a mixed fluid containing a supercritical fluid and a solvent component as a mobile phase.

  As a means for separating a specific component from a raw material liquid containing a plurality of components such as a mixture of isomers for industrial production, a chromatography apparatus is known. As a chromatography apparatus, a supercritical fluid chromatography apparatus using a mobile phase containing a supercritical fluid is known. A supercritical fluid is a fluid having a density close to a liquid and a viscosity close to a gas. A supercritical fluid chromatography apparatus using a mobile phase containing such a supercritical fluid is excellent from the viewpoint of separating a substance that is more difficult to separate from a raw material liquid.

  A supercritical fluid chromatography device uses a mixed fluid containing a supercritical fluid and a solvent component as a mobile phase from the viewpoint of adjusting the solubility of the mobile phase with respect to the components in the raw material liquid and the polarity of the mobile phase. A chromatography apparatus is known (for example, refer to Patent Document 1).

  In the supercritical fluid chromatography apparatus, a mobile phase containing a supercritical fluid and a raw material liquid are separately supplied to an endless flow channel in which a plurality of columns are connected in series, while in the raw material liquid A simulated moving bed supercritical fluid chromatography apparatus that discharges a mobile phase enriched with a predetermined component from the endless flow path is known (for example, see Patent Document 2).

  In the supercritical fluid chromatography apparatus, the mobile phase is a supercritical fluid that is sent by a metering pump at a predetermined flow rate, each of a supercritical fluid component and a solvent component that are substances constituting the supercritical fluid. It is produced by combining the component and the solvent component. The composition of the mobile phase can be obtained from, for example, the amount discharged from the metering pump, or can be inferred from the state of substance separation (the shape of the peak detected from the mobile phase that has passed through the column, the purity of the obtained product, etc.). In a supercritical fluid chromatography apparatus, it is difficult to collect a mobile phase and analyze the composition of the mobile phase because the sample of the collected mobile phase needs to be kept under the same high pressure as in the apparatus.

Therefore, when the composition of the mobile phase varies, the variation in the composition of the mobile phase may not be known until the actual separation state of the substance is known. For this reason, when the composition of the mobile phase deviates from the range of process control, it may not be possible to quickly respond. For this reason, a supercritical fluid chromatography apparatus capable of directly monitoring the composition of the mobile phase has been desired.
JP 2001-46804 A Japanese Patent No. 3306913

  In the present invention, when supplying a mobile phase containing a supercritical fluid and a solvent component to the column, the concentration of the solvent component in the mobile phase is kept constant based on the composition of the mobile phase actually supplied to the column. Is an issue.

The present invention relates to a supercritical fluid chromatography having means for directly detecting the concentration of a solvent component in a mobile phase supplied to a column and controlling the amount of the solvent component used for generating the mobile phase according to the detected value. Providing the device.

  That is, the present invention provides a mobile phase generation device for generating a mobile phase containing a supercritical fluid and a solvent component, a mobile phase generated by the mobile phase generation device, and a raw material liquid containing a target substance. A supercritical fluid chromatography apparatus having a column for separating the target substance, a mobile phase detector for detecting the composition of the mobile phase generated by the mobile phase generation apparatus, A mobile phase composition control device for controlling a relative amount of a solvent component used in the mobile phase generation device with respect to the supercritical fluid according to a detection value of the mobile phase detector; The phase detector is a supercritical fluid chromatography device, which is a near-infrared spectroscopic sensor.

  According to the said structure, the composition of the mobile phase supplied to a column is detected immediately by a mobile phase detector. In addition, when a change is detected in the composition of the mobile phase supplied to the column, the supercritical fluid or supercritical fluid component and solvent mixed in the mobile phase generation device according to the detection value of the mobile phase detector. The amount of at least one of the components is controlled, and the composition of the mobile phase supplied to the column is kept within a certain range.

  The present invention also provides an endless flow path having a plurality of columns and a plurality of connection flow paths for connecting the columns, and supplying the mobile phase to the endless flow path. A first channel, a second channel for supplying the raw material liquid to the endless channel, and a third for discharging the mobile phase that has passed through the column from the endless channel And a fourth channel, wherein the first to fourth channels are channels connected to any of the connection channels, and the first channel is the mobile phase. A simulated moving bed supercritical fluid chromatography apparatus, which is a flow path for supplying a mobile phase from the generation apparatus to the endless flow path, may be used.

  According to the above configuration, in the simulated moving bed supercritical fluid chromatography apparatus, the composition of the mobile phase supplied to the endless flow path is maintained in a certain range.

  The present invention also provides a supercritical fluid component separation device for separating a supercritical fluid component that is a substance constituting the supercritical fluid from a mobile phase that has passed through the column, and the supercritical fluid component is the mobile phase. A solvent component recovery device for recovering the solvent component from the liquid component separated from the solvent, a recovered solvent component detector for detecting the composition of the solvent component recovered by the solvent component recovery device, and the solvent component A solvent component reuse channel for supplying the solvent component recovered by the recovery device to the mobile phase generator, and the recovered solvent component detector is a near-infrared spectroscopic sensor. It may be a lithographic apparatus.

  According to the said structure, a solvent component is collect | recovered from the mobile phase which passed through the column, and is reused for the production | generation of a mobile phase. It is also possible to immediately detect the composition of the recovered solvent component and monitor the quality of the solvent component that is reused for the generation of the mobile phase.

  The present invention also provides a supercritical fluid component reuse channel for supplying the supercritical fluid component separated by the supercritical fluid component separation device to the mobile phase generating device, and the supercritical fluid component reuse. And a liquid component detector for detecting the liquid component in the supercritical fluid component of the flow path for use, wherein the liquid component detector is a supercritical fluid chromatography device that is a near-infrared spectroscopic sensor. Also good.

  According to the said structure, a supercritical fluid component is collect | recovered from the mobile phase which passed through the column, and is reused for the production | generation of a mobile phase. In addition, the liquid component in the recovered supercritical fluid component is detected immediately, and the quality of the supercritical fluid component reused for the generation of the mobile phase can be monitored.

  The present invention is also accommodated in the solvent component adjusting device for adjusting the solvent component of the solvent component reusing channel to the composition of the solvent component used for generating the mobile phase, and the solvent component adjusting device. And a solvent component adjustment detector for detecting the composition of the solvent component, and the solvent component adjustment detector may be a supercritical fluid chromatography device which is a near-infrared spectroscopic sensor.

  According to the said structure, the composition of the solvent component collect | recovered and reused for the production | generation of a mobile phase is detected immediately and adjusted. For this reason, the quality of the solvent component reused for the production | generation of a mobile phase is kept constant.

  Further, the present invention is a column in which the column includes a column tube and a separating agent for separating the target substance from the raw material liquid, and the target substance is optically isomerized. And a supercritical fluid chromatography apparatus in which the separating agent is a separating agent containing a polysaccharide or a polysaccharide derivative.

  According to the said structure, it is possible to manufacture the optical isomer used for a pharmaceutical etc. with high productivity also under the strict management standard regarding manufacture.

  The supercritical fluid chromatography device of the present invention includes a mobile phase generating device for generating a mobile phase, a column for separating a target substance, and a mobile for detecting the composition of the mobile phase supplied to the column. A phase detector and a mobile phase composition control device for controlling generation of a mobile phase based on a detection value of the mobile phase detector. A known supercritical fluid chromatography apparatus having a mobile phase generation apparatus and a column can be used.

  The mobile phase generation device is not particularly limited as long as it is a device capable of generating a mobile phase containing a supercritical fluid and a solvent component. The mobile phase generation device may be a device that mixes a supercritical fluid and a solvent component, or a supercritical fluid component in a mixture of a supercritical fluid component and a solvent component that is a substance constituting the supercritical fluid. May be a device for making a supercritical fluid. The mobile phase generator includes a temperature adjusting device such as a heat exchanger for adjusting the temperature of the supercritical fluid component, a pressure adjusting device such as a back pressure valve that can adjust the supercritical fluid component to a predetermined pressure, a solvent It can be configured by a known device such as a metering pump for quantitatively sending the component or supercritical fluid or supercritical fluid component.

  The supercritical fluid is 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). 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.

  The supercritical fluid component is a substance constituting the supercritical fluid, and is a substance in a state other than the supercritical state, such as gas, liquid, or liquefied gas.

The solvent component is one kind of solvent or a mixture of two or more kinds of solvents. Here, the solvent means a solvent different from the supercritical fluid. Various known solvents can be used as the solvent. Examples of the solvent include methanol, ethanol, 2-propanol, acetic acid, propionic acid, diethylamine, monoethanolamine, triethylamine, methyl acetate, ethyl acetate, tetrahydrofuran, ethyl ether, tert-butyl methyl ether (MTBE), 1, 4 -Dioxane, chloroform, methylene chloride, n-hexane, heptane, acetamide, N, N-dimethylacetamide (DMAc), toluene, acetone,
Examples include acetonitrile, dimethyl sulfoxide, dimethylformamide, and water.

  Among the solvents, acids and bases may be added in a small amount to the entire mobile phase from the viewpoint of stabilizing the target substance. The amount of the solvent added as such an additive may be 0.01 to 0.5% by volume with respect to the mobile phase from the viewpoint of stabilizing the target substance and preventing adverse effects on the separating agent. Preferably, it is 0.01-0.2 volume%.

  Examples of the solvent component that is a mixture of the solvent include two-component mixed solvents such as a methanol-ethanol mixed solvent, a 2-propanol-n-hexane mixed solvent, an ethanol-n-hexane mixed solvent, and a methanol-acetonitrile mixed solvent; And methanol-acetonitrile-acetic acid mixed solvent, methanol-acetonitrile-diethylamine mixed solvent, 2-propanol-n-hexane-diethylamine mixed solvent, ethanol-n-hexane-diethylamine mixed solvent and the like. .

  The mixing ratio of the solvent in the mixed solvent is appropriately determined according to the type of the solvent. For example, if it is a mixed solvent containing a first solvent selected from methanol, ethanol, and 2-propanol and a second solvent selected from n-hexane and acetonitrile, the first solvent and the second solvent The volume ratio to the solvent (first solvent: second solvent) is preferably 10:90 to 50:50 from the viewpoint of adjusting the separation state and elution time of the target substance.

  The mixing ratio of the supercritical fluid and the solvent component in the mobile phase is not particularly limited. From the viewpoint of quickly and clearly separating the target substance, the relative amount of the solvent component with respect to the supercritical fluid in the mobile phase is preferably 1 to 40% by volume. Similarly, the relative amount of the solvent component with respect to the supercritical fluid component in the mixture is preferably 1 to 40% by volume.

  The column is not particularly limited as long as it can separate a target substance. As the column, a normal column having a column tube and a separating agent that is contained in the column tube and separates the target substance from the raw material liquid can be used. The separating agent can be determined according to the target substance.

  For example, when the target substance is an optical isomer, the separating agent is preferably a separating agent containing a polysaccharide or a polysaccharide derivative.

  The polysaccharide is not particularly limited as long as it is an optically active polysaccharide. Various polysaccharides such as synthetic polysaccharides, natural polysaccharides, and natural product-modified polysaccharides can be used as the polysaccharide. The polysaccharide is preferably a polysaccharide with a high regularity of the binding mode, and is preferably a chain polysaccharide.

  The polysaccharide derivative is not particularly limited as long as it is a polysaccharide derivative containing the polysaccharide as a skeleton. Examples of such polysaccharide derivatives include polysaccharide derivatives in which at least a part of hydroxyl groups and amino groups of the polysaccharide are substituted with functional groups that act on optical isomers in the raw material liquid.

  As the polysaccharide and polysaccharide derivative, polysaccharides and derivatives thereof described in Japanese Patent No. 3306913 can be used. As the polysaccharide, cellulose and amylose are particularly preferable. The polysaccharide derivative is particularly preferably at least one selected from an ester derivative of cellulose, a carbamate derivative of cellulose, an ester derivative of amylose, and a carbamate derivative of amylose.

  The form of the separating agent is not particularly limited as long as it is a form accommodated in the column tube so that the target substance can be separated. Examples of the form of the separating agent include a particulate form filled in the column tube and a porous monolithic molded product accommodated in the column tube.

  As the separating agent in the particulate form, for example, particles of polysaccharides or polysaccharide derivatives, or particles composed of a particulate carrier and polysaccharides or polysaccharide derivatives carried on the carrier can be used. As the separating agent in the form of an integrally molded product, for example, an integrally molded product of a polysaccharide or a polysaccharide derivative, or an integrally molded product comprising a carrier in the shape of an integrally molded product and a polysaccharide or a polysaccharide derivative supported on the carrier is used. Can do.

  These forms of separating agents can be obtained using known techniques. For example, the polysaccharide or polysaccharide derivative particles may be prepared by dissolving the polysaccharide or polysaccharide derivative in an appropriate solvent as described in, for example, Japanese Patent No. 2,783,819. It can be obtained by adding the insoluble solvent dropwise with stirring to an insoluble solvent in which the separating agent does not dissolve, preferably a dispersant such as an anionic surfactant.

  Furthermore, bubbles or polygen are dispersed in the solution of the separating agent, the dispersed solution is dispersed in the insoluble solvent, and the solvent is distilled off or substituted from the dispersed separating agent solution to form particles. Porous particles of polysaccharide or polysaccharide derivative can be obtained by washing the obtained separating agent particles with a washing solvent that dissolves polygen as necessary. As the polygen, known particles such as a resin and a salt, which are more soluble in the washing solvent than the separating agent particles to be produced, are used.

  The separating agent in a form in which a polysaccharide or polysaccharide derivative is supported on a particulate or monolithic carrier can be obtained by, for example, supporting a polysaccharide or polysaccharide derivative on a carrier by physical adsorption or chemical bonding. The support of the polysaccharide or polysaccharide derivative on the carrier can be obtained by immersing the carrier in a solution of the polysaccharide or polysaccharide derivative and distilling off the solvent from the immersed carrier or replacing it with another solvent.

  Furthermore, a carrier or another compound for chemically bonding polysaccharides or polysaccharide derivatives to each other is added to the polysaccharide or polysaccharide derivative solution, and the other compound is reacted while the carrier is immersed in or after being immersed in this solution. By doing so, a chemically stronger separating agent can be obtained.

  Examples of the carrier include porous organic carriers such as polystyrene, polyacrylamide, polyacrylate, and derivatives thereof; silica, alumina, magnesia, glass, kaolin, titanium oxide, silicate, diatomaceous earth, hydroxyapatite, and the like. Porous inorganic carrier; and the like.

  The separating agent in the form of a monolithic molded article is obtained, for example, by storing a solution of polysaccharide or polysaccharide derivative in a container having an appropriate shape such as the column tube and distilling off the solvent in the solution or replacing it with another solvent. be able to.

  The carrier in the form of the integral molding is described in, for example, US Pat. No. 6,207,098, US Pat. No. 5,624,875, and JP-A-7-41374. In addition, a metal alkoxide is used as a starting material, and an appropriate coexisting substance such as a polymer soluble in a solvent such as polyoxyethylene or a nonionic surfactant is added to the raw material in the presence of an acid, It can be obtained by a sol-gel method that produces a structure having a solvent-rich phase.

  Further, examples of the carrier in the form of an integrally molded product include a porous shaped body described in JP-T-2000-515627, an integrated adsorbent described in JP-A-2002-505005, An inorganic porous column described in JP-A-6-265534 can be used.

  As the raw material liquid, a mixture containing a target substance is usually used. The raw material liquid may be a liquid mixture, or a solution of the mixture. The solvent of the solution of the mixture may be the aforementioned known solvent or the mobile phase.

  The mobile phase detector is a device that can quantitatively detect the composition of the mobile phase generated by the mobile phase generation device. In the present invention, a near-infrared spectroscopic sensor is used for the mobile phase detector. The number and positions of the mobile phase detectors installed are not particularly limited as long as the mobile phase detector can detect the composition of the mobile phase generated by the mobile phase generator and supplied to the column. The mobile phase detector is preferably provided between the mobile phase generation device and the injection device for injecting the raw material liquid into the mobile phase from the viewpoint of detecting the composition of the mobile phase with high accuracy.

  The near-infrared spectroscopic sensor is preferably a device capable of detecting diffused light by irradiating a substance with light having a wavelength in the range of about 0.8 to 2.5 μm. As the near-infrared spectroscopic sensor, for example, MATRIX series manufactured by Bruker Optics can be used.

  The mobile phase composition control device is not particularly limited as long as it can control the relative amount of the solvent component mixed in the mobile phase generation device in the mobile phase according to the detection value of the mobile phase detector. The mobile phase composition control device is a device for controlling the operation of a flow rate adjusting device such as a valve or a pump for quantitatively supplying a solvent component, a supercritical fluid or a supercritical fluid component to the mobile phase generating device. It is possible to use a known control device capable of outputting a command for causing the flow rate adjusting device to execute a numerical value obtained by calculating the amount to be supplied of the solvent component, the supercritical fluid, or the supercritical fluid component. .

  Control of the relative amount of the solvent component used in the mobile phase generator with respect to the supercritical fluid may be performed by controlling the supply amount of the solvent component to the mobile phase generator, or to the mobile phase generator. The supercritical fluid or supercritical fluid component may be supplied by controlling the supply amount thereof, or both of these supply amounts may be controlled.

  The present invention can be applied to a simulated moving bed supercritical fluid chromatography apparatus. The simulated moving bed supercritical fluid chromatography apparatus of the present invention further includes an endless flow path and first to fourth flow paths.

  The endless flow path can be constituted by a plurality of the columns and a plurality of connection flow paths for connecting the columns. The number of columns in the endless flow path is not particularly limited as long as it is plural, but is preferably 4 to 12.

  The first flow path is a flow path for supplying a mobile phase to the endless flow path, and is a flow path connecting the endless flow path and the mobile phase generating device. The second channel is a channel for supplying the raw material liquid to the endless channel. The third and fourth channels are channels for discharging a mobile phase from the endless channel.

The first to fourth channels are connected to any of the connection channels. Connection between the first to fourth flow paths and any of the connection flow paths is performed by connecting all of the first to fourth flow paths via a flow path opening / closing device for opening and closing the arbitrary flow paths. This can be done by connecting to the connection channel. For example, a two-way valve provided in each of the first to fourth flow paths and all of the first to fourth flow paths are connected to the flow path opening and closing device, and the first to fourth connection flow paths are connected to the first flow path opening / closing device. A rotary valve that opens and closes any one of the fourth flow paths can be used.

  The simulated moving bed chromatography device may have a further flow path. As such a further flow path, for example, a fifth flow for connecting the endless flow path and the first flow path and supplying the mobile phase discharged from the endless flow path to the first flow path is provided. A flow path is mentioned. When the fifth channel is provided, a part of the mobile phase supplied to the endless channel can be reused as it is for the mobile phase newly supplied to the endless channel.

  The supercritical fluid chromatography apparatus of the present invention may have additional components. Such components include, for example, a supercritical fluid component separation device, a solvent component recovery device, a recovered solvent component detector, a solvent component reuse channel, a supercritical fluid component reuse channel, a liquid component detector, Examples include a solvent component adjusting device and a solvent component adjusting detector.

  The supercritical fluid component separation device is not particularly limited as long as it is a device that can separate the supercritical fluid component from the mobile phase that has passed through the column. The supercritical fluid component separation device includes, for example, a pressure regulating device such as a back pressure valve that can release the supercritical state of the supercritical fluid in the mobile phase by decompressing the mobile phase, and the supercritical state of the supercritical fluid is The released mobile phase can be composed of a supercritical fluid component as a gas and a gas-liquid separation device such as a cyclone for separating the supercritical fluid component into a liquid component obtained by separating the supercritical fluid component from the mobile phase. .

  The solvent component recovery device is not particularly limited as long as it can recover the solvent component from the liquid component. The recovery of the solvent component is preferably performed by concentration under reduced pressure from the viewpoint of preventing denaturation of the target substance that can be contained in the liquid component. The said solvent component collection | recovery apparatus can be comprised by the concentration apparatus for concentrating a liquid component, for example under pressure reduction.

  The recovered solvent component detector is a detector for quantitatively detecting the composition of the solvent component recovered by the solvent component recovery device, and the near infrared spectroscopic sensor described above is used. The number and position of the recovered solvent component detector are not particularly limited as long as the recovered solvent component detector can detect the composition of the recovered solvent component.

  The solvent component reuse flow path is not particularly limited as long as it is a flow path capable of supplying the solvent component recovered by the solvent component recovery apparatus to the mobile phase generation apparatus. The flow path for solvent component reuse may be a flow path that directly connects the solvent component recovery device and the mobile phase generation device, or the solvent component recovery device and the movement through other components. It may be a flow path connecting the phase generating device.

  The flow path for reusing the supercritical fluid component is not particularly limited as long as the flow path can supply the supercritical fluid component separated by the supercritical fluid component separation apparatus to the mobile phase generation apparatus. The flow path for reusing the supercritical fluid component may be a flow path that directly connects the supercritical fluid component separation device and the mobile phase generation device, or the supercritical fluid via another component. A flow path connecting the component separation device and the mobile phase generation device may be used.

  The liquid component detector is a detector for quantitatively detecting the liquid component present in a minute amount in the supercritical fluid component of the supercritical fluid component reuse channel, and the near-infrared ray described above. A spectroscopic sensor is used. As long as the liquid component detector can detect the liquid component present in the recovered supercritical fluid component, the number and position of the liquid component detector are not particularly limited.

The said solvent component adjustment apparatus will not be specifically limited if it is an apparatus which can adjust the solvent component of the said flow path for solvent component reuse to the composition of the solvent component used for the production | generation of a mobile phase. In the solvent component adjusting device, as described in US Pat. No. 6,325,898, an adjusting tank for storing the recovered solvent component, and a composition of the solvent component supplied to the adjusting tank A detector for adjusting the solvent component, a tank for supplying the solvent to be supplied to the solvent component supplied to the adjusting tank, and the tank for supplying according to the detection result of the detector for adjusting the solvent component And a control device for controlling the replenishment of the solvent. In the present invention, the above-described apparatus can be used other than the solvent component adjustment detector.

  The solvent component adjusting detector is a detector for quantitatively detecting the composition of the solvent component adjusted by the solvent component adjusting device, and the above-described near-infrared spectroscopic sensor is used. The number, position, and form of the solvent component adjustment detector are not particularly limited as long as the composition of the solvent component whose composition is adjusted can be detected.

  For example, the solvent component adjustment detector may be provided at a position for detecting the composition of the solvent component in the adjustment tank. In the case where the solvent component adjustment device further has a circulation channel for circulating the solvent component inside and outside the adjustment tank, the solvent component adjustment detector detects the composition of the solvent component in the circulation channel. In order to do so, it may be provided in the circulation channel.

  The supercritical fluid chromatography apparatus of the present invention may have further known components. Examples of such known components include an injection device for injecting the raw material liquid into the mobile phase supplied to the column, a detector for detecting components in the mobile phase that has passed through the column, The pressure adjusting device such as a back pressure valve for adjusting the pressure of the mobile phase flow path from the mobile phase generating device to the detector to a predetermined pressure, and contaminants such as the liquid component from the recovered supercritical fluid component A purification apparatus for supercritical fluid components for removing water, a purification apparatus for solvent components for removing contaminants such as by-products of the target substance and trace components mixed in the solvent component from the recovered solvent component, Examples include a cylinder for storing a gas as a supercritical fluid component, the raw material liquid, a liquefied gas as a supercritical fluid component, a solvent component, a separated liquid component, a tank for storing a recovered solvent component, and the like. .

  Examples of the purification device include an adsorption device that contains an adsorbent that adsorbs a predetermined component in the supercritical fluid component or the solvent component, a distillation device, and a gas-liquid separation device. Examples of the adsorbent include active substances and solvents. Moreover, each flow path in this invention can be comprised by well-known members, such as a pipe | tube, a valve, and a pump.

  The supercritical fluid chromatography device of the present invention can be suitably used in the field of producing a target substance by separating the target substance from a mixture containing the target substance. In particular, the supercritical fluid chromatography apparatus of the present invention can be suitably used for the production of pharmaceutical optical isomers that have strict standards for product quality control and manufacturing process control.

  Since the supercritical fluid chromatography device of the present invention includes the mobile phase generation device, the column, the mobile phase detector, and the mobile phase composition control device, it contains a supercritical fluid and a solvent component. In supplying the mobile phase to the column, the concentration of the solvent component in the mobile phase can be kept constant based on the composition of the mobile phase actually supplied to the column.

  When the supercritical fluid chromatography apparatus of the present invention further includes the endless flow path and the first to fourth flow paths, in the simulated moving bed supercritical fluid chromatography apparatus, In supplying the mobile phase containing the solvent to the column, the concentration of the solvent component in the mobile phase supplied to the column can be kept constant.

  The supercritical fluid chromatography device of the present invention further includes the supercritical fluid component separation device, the solvent component recovery device, the recovered solvent component detector, and the solvent component reuse channel. Further, it is more effective from the viewpoint of reducing the raw material cost of the solvent component and preventing the fluctuation of the composition of the mobile phase due to the reused solvent component.

  Further, the supercritical fluid chromatography device of the present invention further includes a flow path for reusing the supercritical fluid component and the liquid component detector, thereby reducing the raw material cost of the supercritical fluid component and reusing it. This is even more effective from the viewpoint of preventing fluctuations in the composition of the mobile phase due to the supercritical fluid component.

  Further, the supercritical fluid chromatography apparatus of the present invention can efficiently reuse and reuse the recovered solvent component when it further includes the solvent component adjusting device and the solvent component adjusting detector. This is even more effective from the viewpoint of preventing fluctuations in the composition of the mobile phase due to the solvent component.

  Further, the supercritical fluid chromatography device of the present invention is a column in which the column has a column tube and a separating agent that is contained in the column tube and separates the target substance from the raw material liquid. When the target substance is an optical isomer, and the separating agent is a separating agent containing a polysaccharide or a polysaccharide derivative, it is even more preferable from the viewpoint of producing a high-quality optical isomer that can be used in medicine with high productivity. It is effective.

<First embodiment>
As shown in FIG. 1, the supercritical fluid chromatography apparatus of the present embodiment adjusts the pressure of a cylinder 1 for containing carbon dioxide and the gas of carbon dioxide supplied from the cylinder 1 to a predetermined pressure. A regulator 2 for cooling, a heat exchanger 3 for cooling and liquefying the carbon dioxide gas adjusted to a predetermined pressure, and a reverse for preventing a backflow of gas from the heat exchanger 3 to the regulator 2 The stop valve 4, the liquefied gas tank 5 for containing the gas liquefied by the heat exchanger 3, the solvent component tank 6 for containing the solvent component, and the liquefied gas contained in the liquefied gas tank 5 are quantitatively analyzed. A metering pump 7 for sending from the liquefied gas tank 5 and a metering port for sending the solvent component contained in the solvent component tank 6 quantitatively to the liquefied gas sent quantitatively by the metering pump 7. A heat exchanger 9 for heating the mixture of the liquefied gas and the solvent component to make the liquefied gas in the mixture a supercritical fluid, and a mixed fluid containing the supercritical fluid and the solvent component A near-infrared spectroscopic sensor 10 for detecting the composition of a certain mobile phase.

  Furthermore, the supercritical fluid chromatography apparatus of this embodiment includes an injector 11 for injecting a raw material liquid containing a target substance into the mobile phase, and a column 12 to which the mobile phase into which the raw material liquid has been injected is supplied. A detector 13 for detecting a component in the mobile phase passing through the column 12, a recovery device 14 for recovering carbon dioxide and a solvent component from the mobile phase detected by the detector 13, and a recovery device 14 for supplying the carbon dioxide gas recovered in 14 to the heat exchanger 3, and a near-infrared spectroscopic sensor for detecting the composition of the gas flowing in the gas reuse channel 15. 16, the solvent component reuse flow path 17 for supplying the solvent component recovered by the recovery device 14 to the solvent component tank 6, and the composition of the recovered solvent component flowing through the solvent component reuse flow path 17. To detect Near-infrared spectroscopic sensor 18, modifier supply channel 19 for newly supplying a modifier to solvent component tank 6, and additive supply channel 20 for supplying additive to solvent component tank 6 And a near-infrared spectroscopic sensor 21 for detecting the composition of the solvent component stored in the solvent component tank 6.

  As shown in FIG. 2, the recovery device 14 releases the mobile phase in accordance with the change in the pressure of the mobile phase on the detector 13 side and maintains the pressure of the mobile phase on the detector 13 side at a predetermined pressure. The back pressure valve 22 and the back pressure valve 22 and the gas reuse flow path 15 are connected in parallel to each other, and the mobile phase released from the back pressure valve 22 and released from the supercritical state of the supercritical fluid in the mobile phase is treated with carbon dioxide. Two gas-liquid separators 23 and 24 for gas-liquid separation into carbon gas and other liquid components are provided.

  Further, the recovery device 14 corresponds to the gas-liquid separation device 23 from a two-way valve 25 for opening and closing a flow path connecting the back pressure valve 22 and the gas-liquid separation device 23, and a gas reuse flow path 15. A check valve 26 for preventing the backflow of carbon dioxide gas to the gas-liquid separator 23, a liquid component storage tank 27 for storing the liquid component separated by the gas-liquid separator 23, and liquid component storage Three units of evaporators 28 to 30 that are connected in series to the tank 27 and evaporate the solvent component in the liquid component stored in the liquid component storage tank 27, the liquid component storage tank 27, and the evaporator 28 The two-way valve 31 for opening and closing the flow path connecting the two and the product storage tank 32 for storing the bottoms of the evaporator 30 that may contain the target substance.

  Corresponding to the gas-liquid separation device 24, the recovery device 14 includes a two-way valve 33 for opening and closing a flow path connecting the back pressure valve 22 and the gas-liquid separation device 24, and a gas reuse flow path 15. A check valve 34 for preventing the backflow of carbon dioxide gas to the gas-liquid separator 24, a liquid component storage tank 35 for storing the liquid component separated by the gas-liquid separator 24, and liquid component storage Three evaporators 36 to 38 that are connected in series to the tank 35 and evaporate the solvent component in the liquid component stored in the liquid component storage tank 35, the liquid component storage tank 35, and the evaporator 36 A two-way valve 39 for opening and closing a flow path connecting the two, and a product storage tank 40 for storing the bottoms of the evaporator 38 that may contain the target substance.

  Further, the recovery device 14 is not shown in the drawing to depressurize the inside of the recovery solvent component storage tank 41 for storing the respective distillates of the evaporators 28 to 30 and 36 to 38 and the evaporators 28 to 30 and 36 to 38. Vacuum pump. The recovered solvent component storage tank 41 is connected to the solvent component reuse channel 17.

  The near infrared spectroscopic sensors 10 and 16 are connected to a mobile phase composition control device (not shown). This mobile phase composition control device is connected to the metering pumps 7 and 8 and is a device for controlling the operation of the metering pumps 7 and 8 according to the detection values of the near-infrared spectroscopic sensors 10 and 16.

  The near infrared spectroscopic sensors 18 and 21 are connected to a solvent component composition control device (not shown). This solvent component composition control device is connected to a flow rate adjusting device such as a flow rate adjusting valve or a metering pump (not shown) in the modifier supply channel 19 and the additive supply channel 20, and the near infrared spectroscopic sensor 18. , 21 for controlling the operation of the flow rate adjusting device in each flow path according to the detected value of 21.

  The column 12 is a column composed of a column tube and a separating agent accommodated in the column tube. The separating agent is a particle made of a carbamate derivative of cellulose, for example, produced by a method described in Japanese Patent No. 2783819.

  The solvent component includes a modifier and an additive. The modifier is the main component of the solvent component, for example, an equivalent mixture based on the volume of methanol and acetonitrile. The additive is a minor component of the solvent component, for example, diethylamine, and is added in a total amount of 0.01% by volume with respect to the modifier.

Carbon dioxide gas and liquefied gas correspond to the supercritical fluid component. The metering pumps 7 and 8, the heat exchanger 9 and the back pressure valve 22 constitute the mobile phase generating device. The near-infrared spectroscopic sensor 10 corresponds to the mobile phase composition detector. The gas-liquid separators 23 and 24 are, for example, cyclones and correspond to the supercritical fluid component separator. The evaporators 28 to 30 and 36 to 38 correspond to the solvent component recovery device, respectively. The near infrared spectroscopic sensor 18 corresponds to the recovered solvent component detector. The near-infrared spectroscopic sensor 16 corresponds to the liquid component detector. The solvent component tank 6 and the additive supply flow path 20 constitute the solvent component adjusting device. The near infrared spectroscopic sensor 21 corresponds to the solvent component adjusting detector.

  In the present embodiment, the raw material liquid is a racemic solution, and the target substance is an optical isomer. Further, the pressure on the primary side of the back pressure valve 22 is set to a pressure equal to or higher than the critical pressure of carbon dioxide, for example.

  Carbon dioxide gas is released from the cylinder 1 at an appropriate initial pressure set by the regulator 2 and supplied to the heat exchanger 3. The carbon dioxide gas supplied to the heat exchanger 3 is cooled by the heat exchanger 3 to become a liquefied gas. The liquefied gas of carbon dioxide is stored in the liquefied gas tank 5 and supplied to the metering pump 7.

  The metering pump 7 sends the liquefied gas quantitatively toward the heat exchanger 9 against the set pressure of the back pressure valve 22. On the other hand, the solvent component is supplied from the solvent component tank 6 to the metering pump 8. The metering pump 8 sends the solvent component quantitatively toward the heat exchanger 9 against the set pressure of the back pressure valve 22. The liquefied gas sent by the metering pump 7 and the solvent component sent by the metering pump 8 merge and mix before being supplied to the heat exchanger 9. This mixture is supplied to the heat exchanger 9 in a state of being pressurized to the set pressure of the back pressure valve 22.

  The mixture supplied to the heat exchanger 9 is heated by the heat exchanger 9 to a predetermined temperature (for example, a critical temperature or a set temperature of the column 12). By this heating, the liquefied gas in the mixture becomes a supercritical fluid, and a mobile phase containing the supercritical fluid and a solvent is generated.

  The composition of the generated mobile phase is detected by the near infrared spectroscopic sensor 10. A raw material liquid, which is a racemic solution, is injected into the mobile phase whose composition is detected by the near-infrared spectroscopic sensor 10 from the injector 11. The mobile phase into which the raw material liquid has been injected is sent to the column 12. In the column 12, optical isomers in the raw material liquid are separated.

  Among the separated optical isomers, the component (raffinate) that is not easily adsorbed by the separating agent is detected by the detector 13 before the component (extract) that is easily adsorbed by the separating agent.

  When the raffinate is detected by the detector 13, the two-way valve 25 is opened and the two-way valve 33 is closed. The mobile phase containing the raffinate is sent to the back pressure valve 22. The mobile phase that has passed through the back pressure valve 22 is released from the pressure adjustment by the back pressure valve 22, decompressed, and supplied to the gas-liquid separator 23.

  The mobile phase supplied to the gas-liquid separator 23 is gas-liquid separated by the gas-liquid separator 23. The carbon dioxide that formed the supercritical fluid is separated as a gas phase. The liquid component containing the raffinate and the solvent component is separated as a liquid phase. The carbon dioxide gas separated as a gas phase by the gas-liquid separator 23 is supplied to the gas reuse flow path 15 through the check valve 26. The liquid component separated as a liquid phase by the gas-liquid separator 23 is stored in the liquid component storage tank 27.

When an extract is detected by the detector, the two-way valve 25 is closed and the two-way valve 33 is opened. The mobile phase containing the extract is sent to the back pressure valve 22, released from the pressure adjustment by the back pressure valve 22, decompressed, and supplied to the gas-liquid separator 24. When the detection of the extract is completed, a new raw material liquid is injected from the injector 11 into the mobile phase, and the separation of the optical isomers as described above is repeated.

  The mobile phase supplied to the gas-liquid separator 24 is gas-liquid separated by the gas-liquid separator 24 in the same manner as the mobile phase containing raffinate. The carbon dioxide forming the supercritical fluid is separated as a gas phase and supplied to the gas reuse flow path 15 through the check valve 34. The liquid component containing the raffinate and the solvent component is separated as a liquid phase and stored in the liquid component storage tank 35.

  The composition of the carbon dioxide gas supplied to the gas reuse flow path 15 is detected by the near-infrared spectroscopic sensor 16. The carbon dioxide gas whose composition is detected by the near-infrared spectroscopic sensor 16 is supplied to the heat exchanger 3 according to the pressure.

  That is, when the pressure of the carbon dioxide gas in the gas reuse flow path 15 is higher than the initial pressure set by the regulator 2, the carbon dioxide gas in the gas reuse flow path 15 is transferred to the heat exchanger 3. Supplied and reused as a supercritical fluid component of a new mobile phase. When the pressure of the carbon dioxide gas in the gas reuse channel 15 is lower than the initial pressure, a new carbon dioxide gas supplied from the cylinder 1 is supplied to the heat exchanger 3. The inflow of the recovered carbon dioxide gas from the gas reuse flow path 15 to the cylinder 1 is prevented by the check valve 4.

  On the other hand, the liquid component stored in the liquid component storage tank 27 is sent to the evaporator 28 at an appropriate flow rate such that the liquid component is stored in the liquid component storage tank 27, for example. The flow rate of the liquid component to the evaporator 28 is adjusted by the opening degree of the two-way valve 31.

  In the evaporators 28 to 30, the solvent component is evaporated stepwise from the liquid component containing raffinate, and the liquid component is concentrated stepwise. For example, the liquid component containing raffinate is concentrated to 30-50% by weight by the evaporator 28, then concentrated to 40-70% by weight by the evaporator 29, and then concentrated by the evaporator 30 to 60-99% by weight. . The distillate distilled from the evaporators 28 to 30 is stored in the recovered solvent component storage tank 41. The concentrated liquid containing raffinate is stored in the product storage tank 32 as the bottoms of the evaporator 30.

  Similarly to the liquid component containing raffinate, the liquid component stored in the liquid component storage tank 35 is supplied to the evaporator 36 at an appropriate flow rate, and is concentrated stepwise by the evaporators 36 to 38. The distillate distilled from the evaporators 36 to 38 is stored in the recovered solvent component storage tank 41. The concentrate containing the extract is stored in the product storage tank 40 as the bottoms of the evaporator 38.

  The distillate stored in the recovered solvent component storage tank 41 is supplied to the solvent component reuse flow path 17. The composition of the distillate supplied to the solvent component reuse channel 17 is detected by the near infrared spectroscopic sensor 18. The distillate whose composition is detected by the near infrared spectroscopic sensor 18 is stored in the solvent component tank 6.

  The composition of the distillate stored in the solvent component tank 6 is detected by the near infrared spectroscopic sensor 21. The composition of the distillate stored in the solvent component tank 6 is adjusted as necessary and reused as a new solvent component. The composition of the distillate stored in the solvent component tank 6 is adjusted by supplying the modifier from the modifier supply channel 19 and supplying the additive from the additive supply channel 20.

The near-infrared spectroscopic sensor 10 detects the composition of the mobile phase by quantitatively detecting the composition of the solvent component in the generated mobile phase. When the detection value detected by the near-infrared spectroscopic sensor 10 is within the set range, the mobile phase composition control device (not shown) operates the metering pumps 7 and 8 as they are.

  When the detection value of the near infrared spectroscopic sensor 10 exceeds the set range, the mobile phase composition control device (not shown) operates the metering pump 7 or 8 under different conditions according to the detection value of the near infrared spectroscopic sensor 10. .

  For example, when the detected value of the solvent component detected by the near-infrared spectroscopic sensor 10 is smaller than the set range, the mobile phase composition control device is configured such that the flow rate of the solvent component is relatively larger than the flow rate of the liquefied gas. The metering pumps 7 and 8 are operated under any of the following conditions: a condition for increasing the flow rate of the metering pump 8, a condition for decreasing the flow rate of the metering pump 7, and both of these conditions.

  When the detected value of the solvent component detected by the near-infrared spectroscopic sensor 10 is larger than the set range, the mobile phase composition control device is configured such that the flow rate of the solvent component is relatively smaller than the flow rate of the liquefied gas. The metering pumps 7 and 8 are operated under any one of the conditions, that is, the condition for decreasing the flow rate of the metering pump 8, the condition for increasing the flow rate of the metering pump 7, and both of these conditions.

  The near-infrared spectroscopic sensor 16 detects a liquid component contained in the carbon dioxide gas in the gas reuse flow path 15. When the detected value detected by the near-infrared spectroscopic sensor 16 exceeds the set value, the mobile phase composition control device (not shown) notifies the administrator of an increase in the concentration of the liquid component in the carbon dioxide gas, for example.

  The near-infrared spectroscopic sensor 18 detects the composition of the solvent contained in the distillate of the solvent component reuse channel 17. For example, when the concentration of diethylamine in the distillate detected by the near-infrared spectroscopic sensor 18 exceeds a set value, the solvent component composition control device (not shown) uses the flow rate adjustment device of the modifier supply flow path 19. The operation is controlled, and a new modifier is supplied to the solvent component reuse flow path 17 to lower the concentration of diethylamine in the distillate below a set value.

  The near infrared spectroscopic sensor 21 detects the composition of the distillate stored in the solvent component tank 6. For example, when the concentration of diethylamine in the distillate detected by the near-infrared spectroscopic sensor 21 is smaller than the set range, the near-infrared spectroscopic sensor 21 has a solvent component composition control device (not shown) The operation of the flow rate adjusting device of the additive supply flow path 20 is controlled to supply the additive to the solvent component tank 6 and raise the diethylamine concentration in the distillate within the set range.

  The supercritical fluid chromatography apparatus of the present embodiment adds a metering pump 7 for quantitatively sending liquefied gas, a metering pump 8 for quantitatively sending solvent components, and a mixture of liquefied gas and solvent components. A heat exchanger 9 for heating, a back pressure valve 22 for adjusting the pressure of the mixture to a predetermined pressure, an infrared spectroscopic sensor 10 for detecting the composition of the generated mobile phase, and an infrared spectroscopic sensor 10 Since the mobile phase composition control device controls the relative amount of the solvent component sent to the liquefied gas by the metering pump 8 in accordance with the detected value, the concentration of modifiers and additives in the mobile phase can be determined in real time. The mobile phase composition can be kept constant based on the result of monitoring.

Further, the supercritical fluid chromatography device of the present embodiment includes gas-liquid separation devices 23 and 24 for separating carbon dioxide gas and liquid components from the mobile phase that has passed through the column 12, and solvent components from the liquid components. Evaporators 28 to 30 and 36 to 38 for recovering the solvent, a solvent component recycling channel 17 for supplying the recovered solvent component distillate to the solvent component tank 6, and solvent component recycling Since it further has a near-infrared spectroscopic sensor 18 for detecting the composition of the distillate in the working channel 17, the quality of the recovered solvent component can be monitored.

  The supercritical fluid chromatography apparatus of the present embodiment also includes a modifier supply channel 19 for supplying a new modifier to the solvent component tank via the solvent component reuse channel 17, and the solvent. Since it further includes a component composition control device, a new modifier is appropriately supplied according to the detection value of the near-infrared spectroscopic sensor 18, and the composition of the recovered solvent component can be used to generate a mobile phase. It can adjust to a composition suitable as a solvent component.

  In addition, the supercritical fluid chromatography device of the present embodiment includes a gas reuse flow path 15 for supplying the recovered carbon dioxide gas to the heat exchanger 3, and the gas reuse flow path 15. Since the apparatus further includes a near-infrared spectroscopic sensor 16 for detecting the liquid component in the carbon gas, the quality of the recovered carbon dioxide (supercritical fluid component) can be monitored.

  The supercritical fluid chromatography device of the present embodiment further includes a near-infrared spectroscopic sensor 21 for detecting the composition of the solvent component accommodated in the solvent component tank 6, so that the metering pump 8 The concentration of the solvent component additive being sent can be monitored.

  Further, the supercritical fluid chromatography apparatus of the present embodiment further includes an additive supply flow path 20 for supplying an additive to the solvent component tank 6 and the solvent component composition control device. The additive can be appropriately supplied according to the detection value of the near-infrared spectroscopic sensor 21, and the composition of the recovered solvent component can be adjusted to an appropriate composition as the solvent component used for generating the mobile phase.

  Further, since the supercritical fluid chromatography apparatus of the present embodiment further includes a column 12 filled with polysaccharide derivative particles, optical isomers can be quickly and clearly separated and collected from a racemic solution. Can do.

  In addition, the supercritical fluid chromatography apparatus of the present embodiment adjusts the liquid component storage tanks 27 and 35 for storing the separated liquid components and the outflow amount of the liquid components from the liquid component storage tanks 27 and 35. Since the two-way valves 31 and 39 that can be used are further provided, the liquid components are supplied to the evaporators 28 to 30 and 36 to 38 at a flow rate at which the liquid components are always kept in the liquid component storage tanks 27 and 35. Can do. Therefore, the evaporators 28 to 30 and 36 to 38 can be operated under certain conditions, and deterioration of product quality due to fluctuations in the operation of the evaporators 28 to 30 and 36 to 38 can be prevented.

<Second Embodiment>
The supercritical fluid chromatography apparatus according to the present embodiment replaces the injector 11, the column 12, the detector 13, and the recovery device 14 with an endless flow channel 51 and first to fourth flow channels 52 to 52. 55, the mobile phase branch channel 56, the raw material liquid tank 57, and the two recovery devices 58 and 59 are configured in the same manner as the supercritical fluid chromatography device of the first embodiment. . The supercritical fluid chromatography device of the present embodiment is a simulated moving bed supercritical fluid chromatography device.

  The endless flow channel 51 includes 12 columns 60 a to 60 l, 12 connection flow channels for connecting these columns in series and endlessly, and the endless flow channel 51 having an endless shape. And a metering pump 61 for sending the mobile phase of the flow channel 51 in a predetermined direction.

The first flow path 52 is a flow path that connects the endless flow path 51 and the near-infrared spectroscopic sensor 10, and the mobile phase whose composition is detected by the near-infrared spectroscopic sensor 10 is used as an endless flow path. 51 is a flow path for supplying to 51.

  The second flow path 53 is a flow path connecting the endless flow path 51 and the raw material liquid tank 57 for storing the raw material liquid, and the raw material liquid stored in the raw material liquid tank 57 is passed through the endless flow path. 51 is a flow path for supplying to 51.

  The third channel 54 is a channel that connects the endless channel 51 and the recovery device 58, and discharges the mobile phase flowing through the endless channel 51 from the endless channel 51 to the recovery device 58. It is a channel for doing. Similarly, the fourth flow channel 55 is a flow channel that connects the endless flow channel 51 and the recovery device 59, and the mobile phase flowing through the endless flow channel 51 is recovered from the endless flow channel 51. 59 is a flow path for discharging to 59.

  The first to fourth flow paths 52 to 55 are two-way valves for opening and closing each of the first to fourth flow paths 52 to 55, or the first to fourth flow paths 52 to 55. Are connected to each of the connection flow paths in the endless flow path 51 via a rotary valve for opening and closing the arbitrary flow path.

  The mobile phase branch channel 56 is a channel that connects the first channel 52 and the second channel 53. Each flow path at the connection portion between the mobile phase branch flow path 56 and the first flow path 52 and each flow path at the connection portion between the mobile phase branch flow path 56 and the second flow path 53 are shown in the figure. A two-way valve is provided, and each of these flow paths can be freely opened and closed at a desired opening degree.

  Each of the collection devices 58 and 59 is configured in the same manner as the collection device 14. Further, each of the columns 60a to 60l is configured in the same manner as the column 12 described above. The third and fourth flow paths 54 and 55 are each provided with a detector (not shown) that is the same as the detector 13. In addition, devices such as a metering pump and a two-way valve are provided in each channel as necessary.

  The first flow path 52 is opened with respect to the connection flow path that connects the column 60 l and the column 60 a in the endless flow path 51. A mobile phase is supplied from the first flow path 52 between the column 60 l and the column 60 a in the endless flow path 51.

  The second flow path 53 is opened with respect to the connection flow path that connects the column 60f and the column 60g in the endless flow path 51. The raw material liquid stored in the raw material liquid tank 57 is supplied from the second flow path 53 between the column 60 f and the column 60 g in the endless flow path 51.

  The third flow path 54 is opened with respect to the connection flow path that connects the column 60 c and the column 60 d in the endless flow path 51. The mobile phase is discharged to the third channel 54 from between the column 60c and the column 60d in the endless channel 51.

  The fourth flow path 55 is opened with respect to the connection flow path that connects the column 60 i and the column 60 j in the endless flow path 51. The mobile phase is discharged to the fourth channel 55 from between the column 60 i and the column 60 j in the endless channel 51.

  In the endless flow channel 51, the mobile phase flows counterclockwise with respect to the paper surface of FIG.

The raw material liquid supplied to the endless flow channel 51 gradually moves in the column 60g along the direction in which the mobile phase flows while repeating adsorption and desorption with respect to the separation agent of the column 60g. The extract moves slower in the column 60g and the raffinate moves faster in the column 60g.

  When the extract and the raffinate pass through the column 60g, the respective flow paths are connected to the column in the flow direction of the mobile phase in the endless flow path 51 while maintaining the relative positional relationship between the first to fourth flow paths. Switch downstream by one line.

  That is, the first flow path 52 in the connection flow path between the column 60l and the column 60a is closed, and the first flow path 52 in the connection flow path between the column 60a and the column 60b is opened. Further, the second flow path 53 in the connection flow path between the column 60f and the column 60g is closed, and the second flow path 53 in the connection flow path between the column 60g and the column 60h is opened. Further, the third flow path 54 in the connection flow path between the column 60c and the column 60d is closed, and the third flow path 54 in the connection flow path between the column 60d and the column 60e is opened. Further, the fourth flow path 55 in the connection flow path between the column 60i and the column 60j is closed, and the fourth flow path 55 in the connection flow path between the column 60j and the column 60h is opened.

  When the time for the extract and the raffinate to pass through the column 60 g is 1 period, the flow path is switched as described above for each period. The time for the extract and raffinate to pass through the column 60g may be obtained by collecting and analyzing the mobile phase in the flow path for connection between the column 60g and the column 60h, or calculated from a computer simulation. You may do it.

  After several periods, in the endless flow channel 51, the raffinate is unevenly distributed and concentrated in the endless flow channel 51 on the downstream side of the connection position of the second flow channel 53. In the endless flow channel 51 on the upstream side of the connection position of the flow channel 53, the extract is unevenly distributed and concentrated. And the mobile phase containing an extract begins to be discharged | emitted to the 3rd flow path 54, and the mobile phase containing a raffinate begins to be discharged | emitted to the 4th flow path 55. FIG.

  If the switching of each channel for each period in the endless channel 51 is further continued, the supply of the raw material liquid to the endless channel 51 and the discharge of the extract and raffinate from the endless channel 51 are performed. Is almost constant. The mobile phase containing extract is continuously discharged from the endless channel 51 to the third channel 54, and the mobile phase containing raffinate is passed from the endless channel 51 to the fourth channel 55. Are continuously discharged.

  The mobile phase discharged to the third flow path 54 is supplied to the recovery device 58. The mobile phase supplied to the recovery device 58 is supplied to the gas-liquid separators 23 and 24 according to the purity of the extract in the mobile phase discharged to the third flow path 54, for example. For example, a mobile phase having an extract purity of a predetermined value (for example, 97%) or more is supplied to the gas-liquid separator 23, and other mobile phases are supplied to the gas-liquid separator 24. The high purity extract is stored in the product storage tank 32.

  Similarly, the mobile phase discharged to the fourth channel 55 is supplied to the recovery device 59. The mobile phase supplied to the recovery device 59 is supplied to the gas-liquid separators 23 and 24 according to the purity of the raffinate in the mobile phase discharged to the fourth channel 55, for example. For example, a mobile phase having a raffinate purity of a predetermined value (for example, 97%) or more is supplied to the gas-liquid separator 23, and the other mobile phases are supplied to the gas-liquid separator 24. The high purity raffinate is stored in the product storage tank 32.

The components stored in the product storage tank 40 in the recovery devices 58 and 59 are the raw material liquid tank 5.
7 can be reused as a raw material.

  Generation of the mobile phase, separation and recovery of the mobile phase, and reuse of the recovered mobile phase are performed in the same manner as in the first embodiment described above.

  In the present embodiment, the mobile phase can be supplied from the first flow path 52 to the second flow path 53 via the mobile phase branch flow path 56 at an arbitrary flow rate. That is, the mobile phase can be supplied from both the first and second flow paths 52 and 53 to the endless flow path 51. Further, it is possible to stop the supply of the raw material liquid from the second flow path 53 to the endless flow path 51. Since the supply of the mobile phase via the mobile phase branch flow path 56 can supply the mobile phase instead of the raw material liquid, for example, the pseudo phase supply of the raw material liquid to the endless flow path 51 intermittently is possible. It is possible to perform moving bed chromatography.

  According to such simulated moving bed chromatography, for example, as described in JP-A-6-39205, it is possible to fractionate the three components contained in the raw material liquid. In this case, it is preferable to properly use the gas-liquid separator in the recovery device according to the components to be separated. For example, the mobile phase containing the component most easily adsorbed by the separating agent is supplied to the gas-liquid separation device 23 of the recovery device 58, and the mobile phase containing the component most difficult to be adsorbed by the separating agent is the gas-liquid of the recovery device 59. The mobile phase that is supplied to the separation device 23 or 24 and contains a component having a medium adsorptivity to the separation agent may be supplied to the gas-liquid separation device 24 of the recovery device 58 or 59.

  The simulated moving bed supercritical fluid chromatography apparatus of the present embodiment performs simulated moving bed chromatography in which the raw material liquid is continuously supplied to the column in addition to the effects of the first embodiment described above. Therefore, the product can be continuously produced by separating the components in the raw material liquid.

  Further, the simulated moving bed type supercritical fluid chromatography device of the present embodiment further includes a mobile phase branch channel 56, and therefore, the simulated moving bed type chromatography in which the raw material liquid is intermittently supplied to the column is also available. Since it can be performed, three or more components in the raw material liquid can be separated.

  Further, in the simulated moving bed supercritical fluid chromatography device of the present embodiment, each of the recovery devices 58 and 59 has two sets from the gas-liquid separation device to the product storage tank. Both of the two components can be produced at a high purity at once.

<Third embodiment>
As shown in FIG. 4, the supercritical fluid chromatography device of the present embodiment is a gas purification device for purifying the gas by removing the liquid component from the gas supplied to the gas reuse flow path 15. And a distillate refining device for purifying the distillate by distilling off low-boiling substances from the distillate supplied to the solvent component reuse flow path 17 and the solvent component tank 6. The configuration is the same as that of the supercritical fluid chromatography apparatus of the first embodiment except that it further includes a liquid level gauge (not shown) for detecting the amount of the solvent component (distillate).

The gas purifier includes a two-way valve 71 for opening and closing the gas reuse flow path 15, a check valve 72 for preventing a reverse flow of gas in the gas reuse flow path 15, and a two-way valve 71. And a gas bypass passage 73 for connecting the gas reuse passage 15 upstream of the check valve 72 and the gas reuse passage 15 downstream, and for opening and closing the gas bypass passage 73. The two-way valve 74 is connected to the gas bypass passage 73 so that the gas passing through the two-way valve 74 is gas-liquid separated and supplied to the gas reuse passage 15 downstream of the check valve 72. Gas-liquid separator 75, liquid component storage tank 76 for storing the liquid component separated by gas-liquid separator 75, and liquid component discharge for storing the liquid component discharged from liquid component storage tank 76 Tank 77, liquid component storage tank 76 and liquid component discharge It is constituted by a two-way valve 78 for opening and closing the flow path connecting the tank 77.

  The distillate purification apparatus includes a two-way valve 81 for opening and closing the solvent component reuse channel 17 and a check valve 82 for preventing a backflow of the distillate in the solvent component reuse channel 17. A solvent component reuse flow path 17 that connects the upstream solvent component reuse flow path 17 and the downstream solvent component reuse flow path 17 of the two-way valve 81 and the check valve 82; A two-way valve 84 for opening and closing the bypass flow path 83, and a solvent component reuse flow path downstream of the check valve 82 by distilling the distillate that has passed through the two-way valve 84 The distillation apparatus 85 is connected to the solvent component bypass flow path 83 so as to be supplied to the solvent 17, and the exhaust path 86 is used to discharge low-boiling substances in the distillate from the top of the distillation apparatus 85. Has been.

  The mobile phase composition control device (not shown) to which the near-infrared spectroscopic sensor 16 is connected is further connected to the two-way valves 71 and 74, and the two-way valve according to the detection value of the near-infrared spectroscopic sensor 16. It is comprised so that the opening degree of 71 and 74 may be controlled further.

  The solvent component composition control device (not shown) to which the near-infrared spectroscopic sensor 18 is connected is further connected to the two-way valves 81 and 84 and the liquid level gauge, and the detected value of the near-infrared spectroscopic sensor 18 and The two-way valves 81 and 84 are further controlled according to the detection value of the liquid level gauge.

  The process from the generation of the mobile phase to the recovery of the carbon dioxide gas and the solvent component (distillate) in the recovery device 14 is performed in the same manner as the supercritical fluid chromatography device of the first embodiment described above. As an initial state, the two-way valves 71 and 81 are opened, and the two-way valves 74 and 84 are closed.

  The carbon dioxide gas supplied to the gas reuse flow path 15 is sent to the near-infrared spectroscopic sensor 16 through the two-way valve 71 and the check valve 72. The composition of the gas of carbon dioxide sent to the near infrared spectroscopic sensor 16 is detected by the near infrared spectroscopic sensor 16.

  The mobile phase composition control device obtains the amount of the liquid component in the carbon dioxide gas based on the detection value of the near-infrared spectroscopic sensor 16, and determines the amount of the liquid component in the obtained carbon dioxide gas, It compares with the allowable content of the liquid component in the set gas. When the amount of the liquid component in the carbon dioxide gas is larger than the set value, the mobile phase composition control device partially or entirely closes the two-way valve 71 and partially or entirely opens the two-way valve 74. When the two-way valve 74 is opened, carbon dioxide gas is supplied to the gas bypass passage 73 from the gas reuse passage 15.

  The carbon dioxide gas supplied to the gas bypass passage 73 is supplied to the gas-liquid separator 75. The carbon dioxide gas supplied to the gas-liquid separator 75 is gas-liquid separated by the gas-liquid separator 75, and the liquid component in the carbon dioxide gas is stored in the liquid component storage tank 76. The carbon dioxide gas from which the liquid component has been further removed is supplied to the gas reuse flow path 15 via the gas bypass flow path 73. In this way, the content of the liquid component in the carbon dioxide gas in the gas reuse flow path 15 is reduced to a set value or less, and the quality of the recovered carbon dioxide gas is maintained at a predetermined quality.

On the other hand, the distillate supplied to the solvent component reuse flow path 17 is sent to the near-infrared spectroscopic sensor 18 through the two-way valve 81 and the check valve 82. The composition of the distillate sent to the near-infrared spectroscopic sensor 18 is detected by the near-infrared spectroscopic sensor 18, and a new modifier is supplied to the distillate as necessary and stored in the solvent component tank 6. Is done. The liquid level of the distillate stored in the solvent component tank 6 is detected by the liquid level gauge.

  The solvent component composition control device obtains the concentration of diethylamine in the distillate before being supplied to the solvent component tank 6 from the detection value of the near infrared spectroscopic sensor 18. The solvent component composition control device obtains the amount of distillate stored in the solvent component tank 6 from the detected value of the liquid level gauge.

  The solvent component composition control device compares the concentration of diethylamine in the distillate before being stored in the solvent component tank 6 with the preset allowable concentration of diethylamine in the distillate. The permissible concentration of diethylamine is, for example, a value of diethylamine concentration set according to the capacity of the solvent component tank 6, and a distillate containing a high concentration of diethylamine before being stored in the solvent component tank 6 is used. The value is set so that the amount of the solvent component stored in the solvent component tank 6 does not exceed the allowable amount stored in the solvent component tank 6 when diluted with a new modifier.

  When the concentration of diethylamine in the distillate before being stored in the solvent component tank 6 exceeds the allowable concentration of diethylamine in the storage capacity of the solvent component tank 6 at that time, the solvent component composition control device The valve 81 is partially or completely closed, and the two-way valve 84 is partially or fully opened. When the two-way valve 84 is opened, the distillate is supplied to the distillate bypass channel 83 from the solvent component reuse channel 17.

  The distillate supplied to the distillate bypass channel 83 is supplied to the distillation apparatus 85. The distillate supplied to the distillation apparatus 85 is distilled by the distillation apparatus 85, and diethylamine having the lowest boiling point among the components of the distillate is removed from the distillate, and an exhaust path is formed from the top of the distillation apparatus 85. 86 is discharged. The fraction or bottoms in the distillation apparatus 85 is supplied to the solvent component reuse passage 17 via the distillate bypass passage 83. In this way, the concentration of diethylamine in the distillate of the solvent component reuse flow path 17 is reduced below the permissible concentration of diethylamine, preventing overflow of the distillate (solvent component) from the solvent component tank 6. Is done.

  The exhaust passage 86 and the additive supply passage 20 may be connected via a capacitor. According to such a configuration, diethylamine removed by the distillation apparatus 85 can be reused as an additive, which is effective from the viewpoint of reducing the raw material cost of the solvent component and the emission amount of the solvent component.

  The supercritical fluid chromatography apparatus of the present embodiment can maintain the quality of the recovered carbon dioxide gas at a predetermined quality in addition to the effects of the first embodiment described above.

  Furthermore, the supercritical fluid chromatography apparatus of the present embodiment can prevent the overflow of the solvent component from the solvent component tank 6 due to the increase in the amount of the solvent component accompanying the adjustment of the composition of the recovered distillate. . It should be noted that the same effect can be obtained even if another detector for detecting an element capable of obtaining the amount of the solvent component tank 6 is provided in place of the liquid level gauge. Examples of such other detectors include a flow meter that detects the flow rate of the distillate in the solvent component reuse flow path 17 before being stored in the solvent component tank 6.

It is a figure which shows roughly the structure of the supercritical fluid chromatography apparatus in 1st embodiment of this invention. It is a figure which shows roughly the structure of the collection | recovery apparatus in embodiment of this invention. It is a figure which shows schematically the structure of the supercritical fluid chromatography apparatus in 2nd embodiment of this invention. It is a figure which shows schematically the structure of the supercritical fluid chromatography apparatus in 3rd embodiment of this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Cylinder 2 Regulator 3, 9 Heat exchanger 4, 26, 34, 72, 82 Check valve 5 Liquefied gas tank 6 Solvent component tank 7, 8, 61 Metering pump 10, 16, 18, 21 Near infrared spectroscopy sensor 11 Injector 12, 60a to 60 l Column 13 Detector 14, 58, 59 Recovery device 15 Gas recycling channel 17 Solvent component recycling channel 19 Modifier supply channel 20 Additive supply channel 22 Back pressure valve 23, 24, 75 Gas-liquid separator 25, 31, 33, 39, 71, 74, 78, 81, 84 Two-way valve 27, 35, 76 Liquid component storage tank 28-30, 36-38 Evaporator 32, 40 Product storage Tank 41 Recovery solvent component storage tank 51 Endless flow path 52 First flow path 53 Second flow path 54 Third flow path 55 Fourth flow path 56 Mobile phase branch flow For 57 raw material tank 73 gas bypass passage 77 the liquid component discharge tank 83 solvent component bypass channel 85 distillation apparatus 86 exhaust path

Claims (6)

A mobile phase generating device for generating a mobile phase containing a supercritical fluid and a solvent component, and a raw material liquid containing the mobile phase generated by the mobile phase generating device and a target substance are supplied. In a supercritical fluid chromatography apparatus having a column for separating a target substance,
A mobile phase detector for detecting the composition of the mobile phase generated by the mobile phase generation device, and the supercriticality of the solvent component used in the mobile phase generation device according to the detection value of the mobile phase detector A mobile phase composition control device for controlling a relative amount with respect to the fluid;
The supercritical fluid chromatography apparatus, wherein the mobile phase detector is a near-infrared spectroscopic sensor. An endless flow path having a plurality of columns and a plurality of connection flow paths for connecting the columns, and a first flow path for supplying the mobile phase to the endless flow path A second flow path for supplying the raw material liquid to the endless flow path, and third and fourth flow paths for discharging the mobile phase that has passed through the column from the endless flow path. And
The first to fourth channels are channels connected to any of the connection channels, and the first channel is a mobile phase from the mobile phase generator to the endless channel. The supercritical fluid chromatography apparatus according to claim 1, wherein the supercritical fluid chromatography apparatus is a simulated moving bed type supercritical fluid chromatography apparatus that is a flow path for supplying gas. A supercritical fluid component separation device for separating a supercritical fluid component that is a substance constituting the supercritical fluid from a mobile phase that has passed through the column; and a liquid in which the supercritical fluid component is separated from the mobile phase The solvent component recovery device for recovering the solvent component from the components, the recovered solvent component detector for detecting the composition of the solvent component recovered by the solvent component recovery device, and the solvent component recovery device recovered A solvent component reuse flow path for supplying the solvent component to the mobile phase generator,
The supercritical fluid chromatography apparatus according to claim 1, wherein the recovery solvent component detector is a near-infrared spectroscopic sensor. A supercritical fluid component reuse channel for supplying the supercritical fluid component separated by the supercritical fluid component separator to the mobile phase generating device, and a supercritical of the supercritical fluid component reuse channel A liquid component detector for detecting the liquid component in the fluid component;
The supercritical fluid chromatography apparatus according to claim 3, wherein the liquid component detector is a near-infrared spectroscopic sensor. A solvent component adjusting device for adjusting the solvent component of the solvent component reusing channel to the composition of the solvent component used for generating the mobile phase, and the composition of the solvent component accommodated in the solvent component adjusting device And a solvent component adjustment detector for detecting
The supercritical fluid chromatography apparatus according to claim 3, wherein the solvent component adjustment detector is a near-infrared spectroscopic sensor. The column is a column having a column tube and a separating agent that is contained in the column tube and separates the target substance from the raw material liquid.
The target substance is an optical isomer,
The supercritical fluid chromatography apparatus according to any one of claims 1 to 5, wherein the separating agent is a separating agent containing a polysaccharide or a polysaccharide derivative.

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