JP2006133159A - Simulated moving bed type chromatographic apparatus - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a simulated moving bed type chromatographic apparatus suitable for industrial production of products requiring a high degree of quality management. <P>SOLUTION: The simulated moving bed type chromatographic apparatus is constituted by connecting eight columns 1a-1h by fluid passages 2a-2h respectively to form an endless passage, providing the fluid passages 2a-2h with check valves 3a-3h respectively to make the flow direction of a fluid flowing in the endless passage, unidirectional, connecting mobile phase supply branch pipes 4a-4h, sample solution supply branch pipes 5a-5h, raffinate ejection branch pipes 6a-6h and extract ejection branch pipes 7a-7h to respective fluid passages downstream of the check valves 3a-3h, and providing these passages excluding the fluid passages 2a-2h, with opening/closing valves 8a-8h, 9a-9h, 10a-10h and 11a-11h for opening/closing the respective passages to the fluid passages 2a-2h. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a simulated moving bed chromatography apparatus that uses a mixed solvent containing two or more kinds of solvents as a mobile phase and that can recover and reuse the mobile phase.

  The simulated moving bed chromatography apparatus has an endless channel formed by connecting a plurality of columns in series. In the simulated moving bed chromatography apparatus, a sample solution containing a target substance and a mobile phase are supplied to any part of the endless channel, and the mobile phase is supplied from any two parts of the endless channel. Is discharged. When the supply of the sample solution and the discharge of the mobile phase are continuously performed, the target substance is contained in at least one of the discharged mobile phases and is taken out from the endless channel.

  The supply, discharge and circulation of the mobile phase in the simulated moving bed chromatography apparatus are controlled by the operation of a valve. Various proposals have been made regarding the use and arrangement of various valves in the simulated moving bed chromatography apparatus.

  For example, the simulated moving bed chromatography apparatus has an endless flow path formed by connecting four or more columns in series and an endless shape alternately along the flow direction of the circulating fluid. A fluid inlet and a fluid outlet disposed in the flow path, and intermittently moving the positions of the inlet and outlet in the flow direction of the fluid circulating in the endless flow path; In the simulated moving bed chromatography apparatus configured as described above, a single circulation pump and this circulation pump are connected from a non-sorbent rich fluid (raffinate) outlet to a desorbent fluid (eluent) inlet. For switching the flow path so that it always comes between the primary purification zone that occupies the area and the desorption zone that occupies the area from the desorbent fluid inlet to the sorbent rich fluid (extract) outlet Further arranged with a valve Location is known (e.g., see Patent Document 1.).

  The simulated moving bed chromatography apparatus has an endless flow path formed by connecting a plurality of columns in series, and the endless flow path includes a sample solution containing a target substance and In a simulated moving bed chromatography apparatus that supplies a mobile phase to separate a target substance from a sample solution, when the endless flow path is divided into first to fourth compartments, An on-off valve that shuts off the piping between the third compartments, an on-off valve that is interposed in a branch pipe that joins the liquid flowing out from the end of the second compartment with the stock solution, and an end of the second compartment A first pump means for joining the liquid flowing out to the stock solution and supplying it to the top of the third compartment; an on-off valve for shutting off the piping between the fourth compartment and the first compartment; It was installed in a branch pipe that merges the liquid flowing out from the end of the compartment with the eluent There is known an apparatus further comprising a valve closing and a second pump means for supplying the liquid flowing out from the end of the fourth compartment to the top of the first compartment after joining the eluent ( For example, see Patent Document 2.)

The simulated moving bed chromatography apparatus has an endless flow path formed by connecting a plurality of columns in series, and the endless flow path includes a sample solution containing a target substance and In a simulated moving bed chromatography apparatus that supplies a mobile phase and separates a target substance from a sample solution, an arbitrary fluid passage is selected from among the fluid passages connecting the columns, and the sample is placed in the selected fluid passage. A raffinate containing a substance that is difficult to adsorb is extracted from a first rotary valve that supplies a solution and a unit packed bed that is located downstream of the unit packed bed that is connected downstream of the fluid passage to which the sample solution is supplied. Two rotary valves, a third rotary valve for extracting fluid from the unit packed bed located downstream of the unit packed bed from which raffinate has been extracted, and the third rotor A fourth rotary valve that selects and supplies a fluid passage connected to the downstream side of the unit packed bed from which the fluid has been extracted through a circulation pump and a fluid discharged from the valve and a mobile phase; A fifth rotary valve for selecting a unit packed bed downstream of the unit packed bed connected to the downstream side of the fluid passage to which the phase is supplied and extracting an extract containing a substance easily adsorbed from the unit packed bed And upstream of the point where the sample solution is supplied by the first rotary valve and the point where the fluid and the mobile phase are supplied by the fourth rotary valve in each of the fluid passages, and in the direction of the third rotary valve A check valve is provided in the fluid passage on the downstream side of the point where the circulating fluid is withdrawn and allows a flow in the downstream direction but prevents a flow in the upstream direction. Apparatus is known which has (for example, see Patent Document 3.).

  The simulated moving bed chromatography apparatus is a useful means for producing a target substance by separating and taking out the target substance from a mixture containing the target substance such as an optical isomer. It is used in the field of manufacturing. In such a field, when industrially producing the target substance using a simulated moving bed chromatography apparatus, in addition to simplification of the configuration and control of the apparatus, there is an apparatus capable of advanced quality control. It is requested.

The simulated moving bed chromatography apparatus described above is excellent in terms of simplification of configuration and ease of control when applied to industrial production, but from the viewpoint of application to industrial production of products that require advanced quality control. There is still room for consideration.
Japanese Patent Publication No. 6-95090 Japanese Patent No. 29602590 Japanese Patent No. 3315149

  An object of the present invention is to provide a simulated moving bed chromatography apparatus suitable for industrially producing a product requiring high quality control.

  In the simulated moving bed chromatography apparatus, the flow direction of the fluid in the endless channel is controlled by a check valve, and the supply channel connected to the endless channel and the discharge channel are connected. Each flow path is opened and closed with an open / close valve.

  That is, the present invention has an endless channel formed by connecting a plurality of columns in series, and a sample solution containing the target substance and a mobile phase are supplied to the endless channel. In the simulated moving bed chromatography apparatus that separates the target substance from the sample solution, the endless flow path includes a plurality of columns, a fluid flow path connecting the columns, and a fluid flowing through the fluid flow paths. A check valve provided in each fluid channel for flowing the fluid in one direction, each fluid channel including a mobile phase channel for supplying a mobile phase to the fluid channel, and a sample solution A sample solution channel for supplying the fluid channel to the fluid channel, a first discharge channel for discharging the fluid flowing through the fluid channel from the fluid channel, and a fluid flowing through the fluid channel from the fluid channel And a second discharge channel for connecting, a mobile phase channel and The material solution channel is connected to the fluid channel downstream of the check valve when the fluid flows through the fluid channel, and the mobile phase channel, the sample solution channel, the first discharge channel, Each of the second discharge channels is provided with an on-off valve that opens and closes each channel with respect to the fluid channel.

  According to the configuration, it is possible to control the flow direction of the fluid in the endless channel without operating the valve, which is excellent from the viewpoint of ease of operation in manufacturing the target substance. .

  Moreover, according to the said structure, since the opening and closing of the various flow paths connected to the endless flow path is performed by the on-off valve, the internal pressure of the flow path is made higher than that of the device using the rotary valve. This makes it possible to reduce the diameter of the particulate separation agent packed in the column and increase the flow rate of the mobile phase, which is excellent from the viewpoint of enhancing the productivity of the target substance and applying it to industrial production.

  In addition, according to the above-described configuration, since various types of flow paths connected to the endless flow paths are opened and closed by the open / close valves, the flow paths are opened and closed as compared with an apparatus using a rotary valve. It is possible to reduce the generation of fluid (so-called dead volume) that stays facing the endless flow path, and to obtain a solution of the target substance with high purity from the endless flow path. It is excellent from the viewpoint of manufacturing products that require high quality control.

  In the present invention, the first discharge channel and the second discharge channel are connected to the fluid channel on the downstream side of the check valve, and the fluid flow on the upstream side of the check valve. The channel is further connected with a third discharge channel for discharging the fluid flowing through the fluid channel from the fluid channel, and the third discharge channel is connected to the third discharge channel. An on-off valve that opens and closes the flow path is provided, and when the third discharge flow path is connected to the mobile phase flow path, the mobile phase that has flowed through the endless flow path is changed to an endless flow path. This is preferable because it can be supplied again to the road and reused as a mobile phase. Further, according to the above configuration, since the mobile phase upstream of the check valve is used for reuse, the sample solution is prevented from diffusing into the reused mobile phase in the endless channel. This is preferable from the viewpoint of increasing the purity of the mobile phase to be reused.

  In the present invention, the column is a column containing a separating agent containing an optically active polysaccharide or polysaccharide derivative. When the target substance is an optical isomer, the optical isomer as the target substance is separated. From the viewpoint, the polysaccharide is cellulose or amylose, and the polysaccharide derivative is more preferably selected from at least an ester derivative of cellulose, a carbamate derivative of cellulose, an ester derivative of amylose, and a carbamate derivative of amylose.

  In the present invention, when a fluid having a purity of 97% or more of the target substance is discharged from at least one of the first and second discharge channels, the medicine, food, or their This is preferable from the viewpoint of industrially producing products that require high quality control such as raw materials.

  According to the present invention, in the simulated moving bed chromatography apparatus, the check valve for controlling the flow direction of the fluid in the endless channel, the mobile phase channel connected to the endless channel, the sample solution flow Since it has an on-off valve that opens and closes each of the passage and the first and second discharge passages, it can be suitably used for industrial production of products that require high quality control.

  In the present invention, the third discharge flow path connecting the endless flow path and the mobile phase flow path is connected to the upstream side of the check valve in each fluid flow path, and this third discharge flow path is Providing an open / close valve that opens and closes is even more effective from the viewpoint of reusing a high-purity mobile phase.

  In the present invention, the column is a column containing a separating agent containing an optically active polysaccharide or polysaccharide derivative, and the target substance is an optical isomer from the viewpoint of efficiently separating the optical isomer. The polysaccharide is cellulose or amylose, and the polysaccharide derivative is more effective when selected at least from an ester derivative of cellulose, a carbamate derivative of cellulose, an ester derivative of amylose, and a carbamate derivative of amylose. is there.

  In the present invention, when a fluid having a purity of a target substance of 97% or more is discharged from at least one of the first and second discharge channels, a pharmaceutical, a food, a raw material thereof, or the like It is even more effective from the viewpoint of manufacturing products that require advanced quality control.

  The simulated moving bed chromatography apparatus of the present invention has an endless flow path formed by connecting a plurality of columns in series, and the endless flow path includes a sample solution containing a target substance and A mobile phase is supplied to separate the target substance from the sample solution.

  The endless flow path is a check provided in each of the plurality of columns, a fluid flow path connecting the columns, and a fluid flow path for flowing the fluid flowing through the fluid flow paths in one direction. And a valve.

  The column is not particularly limited as long as it has a separating agent capable of separating a target substance. The separating agent may be a particulate separating agent filled in the column tube, or may be a porous separating agent accommodated in the column tube. The separating agent may be composed of the separating agent itself, or may be composed of a carrier such as silica and a separating agent supported on the carrier. The number of columns is not particularly limited, but is preferably 4-24. The column preferably has an inner diameter of 30 cm to 100 cm from the viewpoint of increasing product productivity.

  The fluid channel can be a tube such as a stainless steel tube that is usually used to flow a pressurized liquid or fluid. As the check valve, a check valve usually used in a high performance liquid chromatography apparatus or a supercritical fluid chromatography apparatus can be used.

  Each of the fluid channels includes a mobile phase channel for supplying the mobile phase to the fluid channel, a sample solution channel for supplying the sample solution to the fluid channel, and the fluid flow. A first discharge channel for discharging the fluid flowing through the channel from the fluid channel and a second discharge channel for discharging the fluid flowing through the fluid channel from the fluid channel are connected. Similarly to the fluid flow path, these flow paths can be made of a pipe such as a stainless steel pipe that is usually used to flow a pressurized liquid or fluid.

  The mobile phase flow path and the sample solution flow path are connected to the fluid flow path on the downstream side of the check valve when a fluid flows through the fluid flow path. The positional relationship of the above-mentioned flow paths connected to the fluid flow path is not particularly limited as long as the mobile phase flow path, the sample solution flow path, and the check valve are in the above-described positional relation. It is preferable that it is connected to the upstream side of the solution channel from the viewpoint of preventing the occurrence of contamination. In the case where the target substance is taken out from only one of the first and second discharge passages, the discharge passage for taking out the target substance is located upstream of the other discharge passage. The connection is preferable from the viewpoint of preventing the occurrence of contamination.

  Each of the mobile phase flow path, the sample solution flow path, the first discharge flow path, and the second discharge flow path has an open / close valve that opens and closes each flow path with respect to the fluid flow path. Provided. The on-off valve is not particularly limited as long as it is a valve that can open and close the flow path described above. As the on-off valve, a valve usually used for opening and closing a tube in a high performance liquid chromatography apparatus or a supercritical fluid chromatography apparatus can be used.

There are no particular restrictions on the installation position of the on-off valve in the various flow paths connected to the fluid flow path, but the end of the dead volume may be the end of the various flow paths connected to the fluid flow path. This is preferable from the viewpoint of preventing occurrence of contamination and accompanying contamination.

  The third discharge channel is a channel for discharging the fluid flowing through the fluid channel from the fluid channel, and one end is connected to the fluid channel upstream of the check valve, The other end is connected to the mobile phase flow path. For the third discharge channel, a tube such as a stainless steel tube that is normally used for flowing pressurized liquid or fluid is used, as is the case with the fluid channel and the various channels connected thereto. Can do.

  The positional relationship between the aforementioned various flow paths connected to the fluid flow path and the third discharge flow path is not particularly limited, but the third discharge flow path is a fluid flow path upstream of the check valve. From the viewpoint of recovering and reusing a high-purity mobile phase that does not contain a solvent other than that constituting the target substance or mobile phase, among the mobile phases that flow through the endless flow path. To preferred.

  The third discharge channel is provided with an open / close valve that opens and closes the third discharge channel with respect to the fluid channel. As this on-off valve, a valve usually used for opening and closing a tube in a high-performance liquid chromatography apparatus or a supercritical fluid chromatography apparatus can be used as in the above-described various channels.

  In the present invention, the separation agent can be accommodated in a column according to the type of the target substance to be separated, and can be used for separation of various target substances. For example, when the target substance is an optical isomer, the column is preferably a column containing a separating agent containing an optically active polysaccharide or polysaccharide derivative from the viewpoint of separating optical isomers with high separation efficiency. .

  The polysaccharide may be any of a synthetic polysaccharide, a natural polysaccharide, and a natural product-modified polysaccharide as long as it is an optically active polysaccharide. The polysaccharide is preferably a polysaccharide with a high regularity of the binding mode, and is preferably a chain polysaccharide. Examples of the polysaccharide include various polysaccharides, and cellulose and amylose are particularly preferable.

  The polysaccharide derivative is not particularly limited as long as it is a polysaccharide derivative that can be used for separation of optical isomers. As such a polysaccharide derivative, for example, a polysaccharide derivative containing the polysaccharide as a skeleton, wherein at least a part of the hydroxyl group and amino group of the polysaccharide is substituted with a functional group that acts on an optical isomer in a sample. Can be mentioned. Examples of the polysaccharide derivative include various polysaccharide derivatives, and 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 is particularly preferable. Specific examples of the polysaccharide derivative include various polysaccharide derivatives described in International Publication No. 95/23125 pamphlet.

  The separating agent may be in the form of particles, or in the form of particles such as the form supported on a particulate carrier, or supported on an integral carrier accommodated in a column. It may be in the form of a molded product that is integrally accommodated in a column, such as a molded product or a molded product of a separating agent. In particular, the form of the molded product housed in the column is preferable from the viewpoint of suppressing pressure loss in simulated moving bed chromatography.

  Among the separating agents in the particulate form, the separating agent in the form of particles is, for example, as described in Japanese Patent No. 2783819, using the polysaccharide or polysaccharide derivative as the separating agent as a solvent. Dissolve the resulting solution dropwise into an insoluble solvent that does not dissolve the separating agent such as water, preferably an insoluble solvent containing a dispersing agent such as an anionic surfactant, with stirring. It is possible to manufacture by.

  Further, the separating agent in the form of the particles can form a porous body. Such a separating agent, for example, disperses bubbles or polygen in the solution of the separating agent, disperses the dispersed solution in the insoluble solvent, distills or replaces the solvent from the dispersed separating agent solution, A method of washing the resulting separating agent particles with a washing solvent that dissolves polygen, if necessary, may be mentioned. As the polygen, known particles such as a resin and a salt, which are more soluble in the washing solvent than the particles of the separating agent to be produced, are used.

  Of the particulate separation agents, a separation agent in a form supported on a particulate carrier can be produced, for example, by supporting the separation agent on a carrier by physical adsorption or chemical adsorption. The separation agent is supported on the carrier by immersing the carrier in a solution containing the separation agent and, if necessary, another compound, reacting with the other compound as necessary, and distilling off the solvent in the solution, It can be carried out by a method of replacing the solvent in the solution with another solvent.

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

  Among the forms of molded products that are integrally accommodated in the column, the separation agent in the form of being supported on the integral carrier accommodated in the column is, for example, the method described above with the separation agent on the integral carrier. It is possible to manufacture by carrying it.

  In addition, the separating agent in the form of an integral molded article made of the separating agent is, for example, supplying the separating agent solution in the production of the particulate separating agent described above to a container of an appropriate shape, or supplying the separating agent solution. It can be produced by feeding directly to the column tube and then distilling or replacing the solvent.

  The mobile phase is appropriately selected according to various conditions such as the type of the separating agent and the type of the target substance. As the mobile phase, there can be used a solvent usually used as a mobile phase in a high performance liquid chromatography apparatus or a supercritical fluid chromatography apparatus, and a mixture thereof. Examples of the solvent include water, acid, alkali, and organic solvent.

  Examples of the organic solvent include lower alcohols such as ethanolamine, methanol, ethanol, and isopropyl alcohol, low polarity solvents such as normal hexane, polar solvents such as acetonitrile and ethyl acetate, and mixed solvents obtained by mixing these, acetic acid, and the like. And basic solvents such as diethylamine.

  The mixing ratio of the mixed solvent is not particularly limited, but from the viewpoint of optimizing the elution time of the target substance and achieving good separation, the volume ratio of the first solvent to the second solvent (first solvent : Second solvent) is preferably 10:90 to 50:50. The acidic solvent or basic solvent is preferably 0.01 to 0.5% by volume based on the entire mobile phase from the viewpoint of stabilizing the target substance and suppressing adverse effects on the separating agent. More preferably, it is 0.01-0.2 volume%.

  In the present invention, a fluid in which the purity of the target substance in the fluid to be discharged is 97% or more is discharged from at least one of the first and second discharge channels. From the viewpoint of producing a product that requires a higher level of quality control by separating the target substance from the sample solution using a simulated moving bed chromatography apparatus, the purity of the target substance is more than 98%. preferable.

  The simulated moving bed chromatography apparatus of the present invention may have a configuration other than the configuration described above. Such other configurations include, for example, a control device for controlling circulation of a fluid in an endless flow path and a pump used for transferring the fluid discharged from the various flow paths described above, opening and closing of a valve, and operation of the pump. A purity detector for detecting the purity of the target substance in the fluid discharged from the endless flow path; and removing the mobile phase from the fluid containing the target substance discharged from the endless flow path A collection unit for collecting substances, a mobile unit removed by the collection unit, and an adjustment unit for adjusting the composition of the collected mobile phase to the composition of the mobile phase that can be supplied to an endless flow path. Examples include a purification apparatus for purifying the phase.

  As the pump, a metering pump usually used for fluid transfer in a high performance liquid chromatography apparatus or a supercritical fluid chromatography apparatus can be used. In addition, the control device may be a device that is normally used to control the opening / closing of a valve or the operation of a pump in a simulated moving bed chromatography device.

  The purity detector is not particularly limited as long as it can quantitate the target substance in the fluid discharged from the endless flow channel, and preferably can further quantitate impurities. As such a purity detector, for example, various analytical instruments such as a gas chromatography apparatus, a high performance liquid chromatography apparatus, a near infrared spectroscopic analysis apparatus, a mass analysis apparatus, and a GC-MS apparatus can be used.

  The collecting unit can adopt a known configuration as disclosed in, for example, Japanese Patent Laid-Open No. 6-239767, and is configured by a concentrating device that concentrates a mobile phase discharged from an endless flow path, for example. be able to. A single collection unit may be provided, or a plurality of collection units may be provided in accordance with the number of types of target substances contained in the sample solution. Moreover, well-known means, such as a vacuum concentration device, can be used for the concentration device. A single concentration device may be provided, or a plurality of concentration devices may be provided so as to concentrate the mobile phase stepwise.

  The adjustment unit includes, for example, an adjustment tank containing a mobile phase whose composition is to be adjusted as shown in US Pat. No. 6,325,898 as a regulating device, and a mobile phase supplied to the adjustment tank. A detector for detecting the composition of the liquid, a tank for supplying a solvent to be supplied to the mobile phase supplied to the adjustment tank, and a replenishment for controlling the replenishment of the solvent from the tank for replenishment according to the detection result of the detector. It is possible to employ a known configuration having a control device for a vehicle. Detection of the composition of the mobile phase in the adjustment unit can be performed using a calibration curve prepared in advance according to the element detected by the detector.

  The said refiner | purifier will not be specifically limited if it is an apparatus which raises the purity of the collect | recovered mobile phases. Examples of the purification apparatus include a distillation apparatus as disclosed in JP-A-6-239767, an adsorption tower containing an adsorbent such as activated carbon, and the like.

Hereinafter, an embodiment of the present invention will be described more specifically.
As shown in FIGS. 1 and 2, the simulated moving bed chromatography apparatus of the present embodiment has an endless channel formed by connecting eight columns 1 a to 1 h in series. The endless flow paths are configured to flow eight columns 1a to 1h, fluid flow paths 2a to 2h connecting the respective columns, and fluid flowing through the fluid flow paths 2a to 2h in one direction, respectively. Check valves 3a to 3h provided in the fluid flow paths 2a to 2h. The check valves 3a to 3h are provided so that the fluid flows in the direction indicated by the arrow in the drawing, that is, in the endless flow path, counterclockwise with respect to the paper surface.

The fluid flow paths 2a to 2h include a mobile phase supply branch 4a to 4h, a sample solution supply branch 5a to 5h, a raffinate discharge branch 6a to 6h, and an extract discharge branch 7 respectively.
a to 7h are connected to each other. The mobile phase supply branch pipes 4a to 4h and the sample solution supply branch pipes 5a to 5h are provided on the downstream side of the fluid flow paths 2a to 3h rather than the check valves 3a to 3h when the fluid flows to the fluid flow paths 2a to 2h. Connected to 2h. The raffinate discharge branch pipes 6a to 6h and the extract discharge branch pipes 7a to 7h are connected to the fluid flow paths 2a to 2h on the downstream side of the check valves 3a to 3h. The raffinate discharge branch pipes 6a to 6h and the extract discharge branch pipes 7a to 7h are provided on the downstream side of the mobile phase supply branch pipes 4a to 4h and the sample solution supply branch pipes 5a to 5h. Connected to ~ 2h.

  The mobile phase supply branch pipes 4a to 4h are connected to the mobile phase supply main pipe 4, respectively, and the mobile phase supply branch pipes 4a to 4h and the mobile phase supply main pipe 4 serve as mobile channels for the fluid flow paths 2a to 2h. The mobile phase flow path for supplying to is comprised. The sample solution supply branch pipes 5a to 5h are respectively connected to the sample solution supply main pipe 5. The sample solution supply branch pipes 5a to 5h and the sample solution supply main pipe 5 pass the sample solution to the fluid flow path 2a. The sample solution flow path for supplying to -2h is comprised.

  The raffinate discharge branch pipes 6a to 6h are respectively connected to the raffinate discharge main pipe 6. The raffinate discharge branch pipes 6a to 6h and the raffinate discharge main pipe 6 are fluids that flow through the fluid flow paths 2a to 2h. The 1st discharge flow path for discharging from flow paths 2a-2h is constituted. The extract discharge branch pipes 7a to 7h are respectively connected to the extract discharge main pipe 7. The extract discharge branch pipes 7a to 7h and the extract discharge main pipe 7 are connected to the fluid flow paths 2a to 2h. A second discharge channel for discharging the flowing fluid from the fluid channels 2a to 2h is configured.

  The mobile phase supply branch pipes 4a to 4h are provided with on-off valves 8a to 8h for opening and closing the mobile phase supply branch pipes 4a to 4h with respect to the fluid flow paths 2a to 2h. 5a to 5h are provided with on-off valves 9a to 9h for opening and closing the sample solution supply branch pipes 5a to 5h with respect to the fluid flow paths 2a to 2h. The raffinate discharge branch pipes 6a to 6h are provided with raffinate. On-off valves 10a to 10h that open and close the discharge branch pipes 6a to 6h with respect to the fluid flow paths 2a to 2h are provided, and the extract discharge branch pipes 7a to 7h include the extract discharge branch pipes 7a to 7h. Open / close valves 11a to 11h for opening and closing 7h with respect to the fluid flow paths 2a to 2h are provided.

  Furthermore, mobile phase discharge branch pipes 12a to 12h are respectively connected to the fluid flow paths 2a to 2h upstream of the check valves 3a to 3h. The mobile phase discharge branch pipes 12a to 12h are respectively connected to the mobile phase discharge main pipe 12, and a third discharge flow for discharging the fluid flowing through the fluid flow paths 2a to 2h from the fluid flow paths 2a to 2h. Constitutes the road. The mobile phase discharge branch pipes 12a to 12h are provided with on-off valves 13a to 13h for opening and closing the mobile phase discharge branch pipes 12a to 12h with respect to the fluid flow paths 2a to 2h, respectively.

  The mobile phase supply main pipe 4 is connected to a mobile phase tank (not shown) that houses the mobile phase. The mobile phase supply main pipe 4 includes a mobile phase supply pump 14 for sending a mobile phase from the mobile phase tank to the mobile phase supply branch pipes 4a to 4h, a mobile phase supply pump 14, and a mobile phase supply branch. An open / close valve 15 for opening and closing the mobile phase supply main pipe 4 is provided between the pipes 4a to 4h.

  The sample solution supply main pipe 5 is connected to a sample solution supply source (not shown) such as a sample solution tank for storing the sample solution and an injector for injecting the sample solution into the sample solution supply main pipe 5. The sample solution supply main pipe 5 includes a sample solution supply pump 16 for sending the sample solution from the sample solution supply source to the sample solution supply branch pipes 5a to 5h, a sample solution supply pump 16, and a sample solution supply. An open / close valve 17 for opening and closing the sample solution supply main pipe 5 is provided between the branch pipes 5a to 5h.

The raffinate discharge main pipe 6 is connected to a raffinate collecting device described later. The raffinate discharge main pipe 6 includes a raffinate discharge pump 18 for sending the fluid of the raffinate discharge main pipe 6 to the raffinate collecting device, and an on-off valve for opening and closing the raffinate discharge main pipe 6 on the downstream side of the raffinate discharge pump 18. 19 is provided.

  Further, the extract discharge main pipe 7 is connected to an extract collection device described later. The extract discharge main pipe 7 includes an extract discharge pump 20 for sending the fluid of the extract discharge main pipe 7 to the extract collecting device, and an extract discharge main pipe downstream of the extract discharge pump 20. 7 is provided.

  The mobile phase discharge main pipe 12 is connected to the mobile phase supply main pipe 4 between the mobile phase supply pump 14 and the on-off valve 15. The mobile phase discharge main pipe 12 is provided with a mobile phase discharge pump 22 for sending the fluid of the mobile phase discharge main pipe 12 to the mobile phase supply main pipe 4.

  The raffinate collecting apparatus includes three evaporators 30 to 32, a bottom discharge pipe 33 for discharging the bottoms of the evaporator 30 from the evaporator 30 and supplying the bottoms to the evaporator 31, and the evaporator 31. From the evaporator 31 and supply to the evaporator 32. A bottom discharge pipe 35 for discharging the bottom liquid from the evaporator 32 from the evaporator 32. And a raffinate storage tank 36 for storing the bottoms discharged from the bottoms discharge pipe 35.

  Similarly, the extract collecting apparatus includes three evaporators 40 to 42, a bottom discharge pipe 43 for discharging the bottoms of the evaporator 40 from the evaporator 40 and supplying the bottoms to the evaporator 41, A bottoms discharge pipe 44 for discharging the bottoms of the evaporator 41 from the evaporator 41 and supplying them to the evaporator 42, and a bottoms for discharging the bottoms of the evaporator 42 from the evaporator 42. It has a discharge pipe 45 and an extract storage tank 46 for storing the bottoms discharged from the bottoms discharge pipe 45.

  The evaporators 30 to 32 are connected in parallel by a mobile phase distillation pipe 37 for discharging the vapor of the mobile phase of the evaporators 30 to 32 from the evaporators 30 to 32. The evaporators 40 to 42 are also connected in parallel by a mobile phase distillation pipe 47 for discharging the vapor of the mobile phase of the evaporators 40 to 42 from the evaporators 40 to 42. The mobile phase distillation pipes 37 and 47 are connected to an adjustment tank 50 that accommodates the distilled mobile phase.

  In the adjustment tank 50, for example, a stirrer that stirs the mobile phase accommodated in the adjustment tank 50, a near-infrared spectroscopic sensor that detects the composition of the mobile phase accommodated in the adjustment tank 50, and the adjustment tank 50. A temperature sensor that detects the temperature of the mobile phase, a control device that receives signals from the near-infrared spectroscopic sensor and the temperature sensor, and a replenisher that contains a solvent to be replenished in the mobile phase contained in the adjustment tank 50 A tank, a supply channel connecting the supply tank and the adjustment tank 50, and a pump and an automatic valve interposed in each supply channel are provided. The adjustment tank 50 is connected to the mobile phase supply main pipe 4 upstream of the mobile phase supply pump 14 by a mobile phase reflux pipe 51.

  Hereinafter, an example of the separation and production operation of the target substance by the simulated moving bed chromatography apparatus of the present embodiment will be described.

  The columns 1a to 1h are columns filled with particles made of a carbamate derivative of cellulose produced by, for example, the method described in Japanese Patent No. 2783819. Further, the mobile phase supply pump 14, the sample solution supply pump 16, the raffinate discharge pump 18, the extract discharge pump 20, and the mobile phase discharge pump 22 are metering pumps. Further, the on-off valve and the pump described above are connected to the control device provided in the adjustment tank 50, for example, and the opening / closing of the on-off valve and the operation of the pump are controlled by the control device.

  For the mobile phase, for example, a mixed solvent obtained by mixing a total volume of 0.01 volume% diethylamine in a mixed solvent of 50 volume% methanol and 50 volume% acetonitrile is used. The sample solution is a solution of a mixture of optical isomers such as a racemate, and the target substance is, for example, L form of the optical isomers.

  First, the open / close valves 15 and 8a are opened, the other open / close valves are closed, and the mobile phase is supplied from the mobile phase supply branch pipe 4a to the endless flow path. The mobile phase supplied to the endless channel circulates through the endless channel, for example, by a pump.

  Next, for example, the on-off valve 13h is opened, the mobile phase discharge pump 22 is operated, and the mobile phase is discharged from the endless flow path to the mobile phase discharge branch pipe 12h at a predetermined flow rate A. The discharged mobile phase is supplied to the mobile phase supply main pipe 4 via the mobile phase discharge pump 22 and supplied to the endless flow path as a new mobile phase.

  Next, for example, the on-off valves 17 and 9d are opened, and the sample solution is supplied from the sample solution supply branch pipe 5d to the endless flow path. The sample solution supplied to the endless flow path is sent to the column 1e, and among the optical isomers in the sample solution, the L form, which is the target substance, is strongly adsorbed by the separating agent in the column (hereinafter referred to as L The body is also referred to as “raffinate”), and the R body is weakly adsorbed by the separating agent (hereinafter, the R body is also referred to as “extract”). The extract is easier to desorb from the separating agent than the raffinate, and is distributed downstream of the raffinate in the flow direction of the mobile phase. Both raffinate and extract move through column 1e by the mobile phase flow.

  When the raffinate and the extract flow out of the column 1e, the on-off valves 8a, 13h and 9d are closed and the on-off valves 8b, 13a and 9e are opened. By operating this on-off valve, the mobile phase is supplied from the mobile phase supply branch pipe 4b to the endless flow path, and is discharged from the endless flow path to the mobile phase discharge branch pipe 12a. The sample solution is supplied from the sample solution supply branch pipe 5e to the endless flow path. In this way, the sample solution is supplied to a position where the mixing ratio of raffinate and extract is high in the endless channel.

  When the time required for the raffinate and extract to pass through the column 1e is set to one period, the opening / closing operation of the on-off valve as described above is performed every one period downstream in the flow direction of the mobile phase in the endless flow path. .

  When the opening / closing operation of the on-off valve is performed for several periods, the bias between the extract distribution and the raffinate distribution due to the adsorptivity to the separating agent becomes more obvious. The extract is mainly distributed and concentrated on the upstream side of the flow direction of the mobile phase in the endless channel with respect to the supply position of the sample solution, and the raffinate is mainly distributed and concentrated on the downstream side. The

  When the distribution of the raffinate and the extract has spread to an appropriate distance, the raffinate discharge branch pipe and the extract discharge branch pipe are further opened to the endless flow path. For example, the mobile phase is supplied from the mobile phase supply branch 4a to the endless flow path, the mobile phase is discharged from the endless flow path to the mobile phase discharge branch 12h, and the sample solution is supplied to the sample solution supply branch. If the raffinate is supplied from the pipe 5d to the endless flow path (see FIG. 1), for example, the on / off valves 10b and 19 are opened and the raffinate discharge pump 18 is operated to move the raffinate. The phase is discharged from the endless flow path to the raffinate discharge branch pipe 6b. Regarding the extract, for example, the on-off valves 11f and 21 are opened and the extract discharge pump 20 is operated to move the mobile phase containing the extract. Is discharged from the endless flow path to the extract discharge branch pipe 7f.

  At this time, the sum of the mobile phases discharged from the endless flow path, that is, the mobile phases discharged from the raffinate discharge branch pipe 6b, the extract discharge branch pipe 7f, and the mobile phase discharge branch pipe 12h is the predetermined value described above. The discharge amount of the mobile phase is adjusted so that the flow rate A becomes the same. The adjustment of the mobile phase discharge amount is performed by the operation of the mobile phase discharge pump 22, the raffinate discharge pump 18, and the extract discharge pump 20, and the opening degree of the on-off valves 31h, 10b, and 11f.

  Further, the raffinate-containing mobile phase is detected for the purity of the raffinate, and is sent to the raffinate collecting device if it has a predetermined purity (for example, 97% or more). The purity of the raffinate is detected by, for example, detection by a near-infrared spectroscopic sensor provided in the raffinate discharge main pipe 6 or by measuring the mobile phase collected from the raffinate discharge main pipe 6 with a measuring device such as a gas chromatography apparatus. The

  Note that the mobile phase discharged from the raffinate discharge main pipe 6 may be stored in another tank and stored until the purity is determined. Further, for example, a detector or measuring device for detecting the purity of the raffinate in the mobile phase in the raffinate discharge main pipe 6 and the on-off valve 19 are electrically connected to open and close according to the detected value of the purity of the raffinate in the mobile phase. It is also possible to open and close the valve 19.

  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 substantially constant.

  Thereafter, similarly to the opening and closing of the open / close valve related to the supply and discharge of the mobile phase and the supply of the sample solution described above, the discharge of the mobile phase containing raffinate and the release of the mobile phase containing the extract Opening and closing is performed intermittently at each period. For example, in the case of the opening / closing operation of the on / off valve from the above-described case, the on / off valves 8a, 13h, 9d, 10b and 11f are closed and the on / off valves 8b, 13a, 9e, 10c and 11g are opened. Thus, the supply of the mobile phase, the supply of the sample solution, the discharge of the raffinate, the discharge of the extract, and the discharge of the mobile phase are continuously performed.

  The mobile phase containing raffinate of a predetermined purity or higher is concentrated stepwise by the evaporators 30 to 32, for example. For example, the mobile phase containing raffinate is concentrated by evaporator 30 to 30-50% by weight, then concentrated by evaporator 31 to 40-70% by weight, then evaporated by evaporator 32 to 60-99% by weight, It is accommodated in the storage tank 36. The mobile phase removed by each evaporator is supplied to the adjustment tank 50 by the mobile phase distillation pipe 37. The raffinate-containing composition stored in the storage tank 36 is purified by recrystallization, vacuum distillation, or the like as necessary.

  Similarly to the mobile phase containing raffinate, the mobile phase containing extract is concentrated stepwise by the evaporators 40 to 42 and accommodated in the storage tank 46. The mobile phase removed by each evaporator is supplied to the adjustment tank 50 by the mobile phase distillation pipe 47. The extract-containing composition accommodated in the storage tank 46 may be purified by recrystallization, vacuum distillation, or the like as necessary, or may be racemized by heating or the like and reused as a sample solution material.

The composition of the mobile phase supplied to the adjustment tank 50 is adjusted as necessary, and is sent to the mobile phase supply main pipe 4 via the mobile phase reflux pipe 51 to be returned to the mobile phase in the simulated moving bed chromatography apparatus. Used. The adjustment of the composition of the mobile phase in the adjustment tank 50 is, for example, uniformly stirred by the stirring device and reflected by the mobile phase in the near infrared region (for example, 0.8 to 2.5 μm) by the near infrared spectroscopic sensor ( Or the intensity of each wavelength of the transmitted light) is detected, the temperature of the mobile phase is detected by the temperature sensor, and the type and amount of the solvent to be replenished are determined by the control device that has received these detection values, This is done by operating the automatic valve and pump to replenish a predetermined solvent.

  The raffinate discharge main pipe 6 may be further provided with an adsorbing means such as an adsorber or a guard column for removing impurities in the mobile phase discharged from the endless flow path from the mobile phase. Similarly, the mobile phase discharge main pipe 12 and the mobile phase reflux pipe 51 may further be provided with the adsorption means for removing impurities in the mobile phase from the mobile phase.

  In this embodiment, the mobile phase is supplied, the sample solution is supplied, the raffinate is discharged, and the extract is discharged at equally spaced positions between two columns, and the mobile phase is discharged. Although explained as a form to be performed immediately before the supply, the present invention is not limited to this form, and the intervals between the supply of the mobile phase, the supply of the sample solution, the discharge of raffinate, the discharge of the extract, and the discharge of the mobile phase are separated. It is possible to set appropriately according to the type of the substance, the kind of the target substance, and the like.

  In the present embodiment, the mobile phase is discharged from the endless flow path to the mobile phase discharge branch pipe. However, the mobile phase is discharged from the endless flow path to the mobile phase discharge branch pipe. May not be performed after the mobile phase starts to be discharged from the endless channel to the raffinate discharge branch pipe and the extract discharge branch pipe.

  The simulated moving bed chromatography apparatus of the present embodiment includes an endless channel formed by columns 1a to 1h and fluid channels 2a to 2h, check valves 3a to 3h, and check valves 3a to 3h. Mobile phase supply branch pipes 4a to 4h, sample solution supply branch pipes 5a to 5h, raffinate discharge branch pipes 6a to 6h, and extract discharge branch connected to the fluid flow paths 2a to 2h on the downstream side of 3h Since it has the pipes 7a to 7h and the on-off valves 8a to 8h, 9a to 9h, 10a to 10h, and 11a to 11h provided in each of these branch pipes, the end of each branch pipe on the endless channel side It is possible to open and close each branch pipe in the section, reduce the dead volume leading to the mobile phase in the endless flow path, and can be suitably used for the manufacture of products that require high quality control .

  Further, the simulated moving bed chromatography apparatus of the present embodiment has endless valves 8a to 8h, 9a to 9h, 10a to 10h, and 11a to 11h as means for opening and closing each branch pipe. It is possible to further increase the internal pressure of the flow path, further increase the flow rate of the mobile phase, or further reduce the particle size of the separating agent, thereby increasing the productivity of the target substance. And can be suitably used for industrial production of such a target substance.

  In addition, the simulated moving bed chromatography apparatus of the present embodiment has mobile phase supply branch pipes 4a to 4h and sample solution supply branch pipe 5a in the fluid flow paths 2a to 2h on the downstream side of the check valves 3a to 3h. ~ 5h are connected, so that the mobile phase supplied to the endless flow channel and the backflow of the sample solution to the upstream side can be prevented, and the target substance can be efficiently separated. It is possible to prevent the occurrence of contamination due to the backflow of the sample solution and the sample solution, which is more effective from the viewpoint of manufacturing a product that requires high quality control.

  Further, the simulated moving bed chromatography apparatus of the present embodiment is downstream of the check valves 3a to 3h and includes the mobile phase supply branch pipes 4a to 4h and the sample solution supply branch pipes 5a to 5h. Since the raffinate discharge branch pipes 6a to 6h and the extract discharge branch pipes 7a to 7h are connected to the downstream fluid flow paths 2a to 2h, the reverse flow of the fluid adhering to these branch pipes to the upstream side It is possible to prevent the occurrence of contamination due to the backflow of raffinate, extract and impurities in the sample, which is more effective from the viewpoint of manufacturing a product that requires high quality control.

  Further, the simulated moving bed chromatography apparatus of the present embodiment includes mobile phase discharge branch pipes 12a to 12h connected to endless flow channels upstream of the check valves 3a to 3h, and open / close valves, respectively. Since the mobile phase discharge main pipe 12 connecting the mobile phase discharge branch pipes 12a to 12h and the mobile phase supply main pipe 4 is included in the endless flow path, the above-mentioned contamination is present. The prevented mobile phase is discharged, and the mobile phase discharged from the endless flow path can be reused as a new mobile phase as it is, and the amount of mobile phase required for separation and production of the target substance can be reduced. It can be reduced and is more effective from the viewpoint of industrially manufacturing a product that requires high quality control.

  Further, the simulated moving bed chromatography apparatus of the present embodiment includes the mobile phase discharge branch pipes 12a to 12h and the on-off valves 13a to 13h, so that the internal pressure of the endless flow path can be further increased. It is possible to recycle the mobile phase and improve the productivity of the target substance, which is more effective from the viewpoint of industrial production of the target substance.

  In addition, the simulated moving bed chromatography apparatus of the present embodiment collects raffinate having a predetermined quality or higher because the mobile phase containing raffinate having a predetermined purity is discharged from the endless flow path and collected. It is more effective from the viewpoint of industrially manufacturing a product that requires high quality control.

  In addition, the simulated moving bed chromatography device of the present embodiment includes the raffinate collection device and the extract collection device, and thus collects a desired substance from a mobile phase discharged from an endless flow path. The mobile phase can be recovered, the recovered mobile phase can be reused as a new mobile phase, and the amount of mobile phase required for separation and production of the target substance can be reduced. This is even more effective from the viewpoint of industrially producing this material.

  Moreover, since the simulated moving bed type chromatography apparatus of this embodiment has the adjustment tank 50, it is possible to adjust the composition of the mobile phase as necessary, and industrialize products that require high quality control. More effective from the viewpoint of production.

  In addition, the simulated moving bed chromatography apparatus of the present embodiment has a near-infrared spectroscopic sensor as a means for detecting the composition of the recovered mobile phase, so that the composition of the mobile phase can be detected quickly and accurately. This makes it possible to adjust the mobile phase quickly and precisely, and is even more effective from the viewpoint of industrially producing a product that requires high quality control.

It is a figure which shows roughly the structure of one Embodiment of the simulated moving bed type chromatography apparatus of this invention. It is a figure which shows schematically the structure of the principal part in the simulated moving bed type chromatography apparatus shown in FIG.

Explanation of symbols

1a to 1h Column 2a to 2h Fluid flow path 3a to 3h Check valve 4 Mobile phase supply main pipe 4a to 4h Mobile phase supply branch pipe 5 Sample solution supply main pipe 5a to 5h Sample solution supply branch pipe 6 For raffinate discharge Main pipe 6a-6h Branch pipe for raffinate discharge 7 Extract discharge main pipe 7a-7h Extract discharge branch pipe 8a-8h, 9a-9h, 10a-10h, 11a-11h, 13a-13h, 15, 17, 19, 21 On-off valve 12 Mobile phase discharge main pipe 12a to 12h Mobile phase discharge branch pipe 14 Mobile phase supply pump 16 Sample solution supply pump 18 Raffinate discharge pump 20 Extract discharge pump 22 Mobile phase discharge pump 30 to 32 , 40-42 Evaporator 33-35, 43-45 Drain discharge pipe 36 Raffinate storage tank 46 Extract Tomeso 37,47 mobile phase distillation pipe 50 adjusting tank 51 mobile phase reflux pipe

Claims (5)

It has an endless flow path formed by connecting a plurality of columns in series, and a sample solution containing a target substance and a mobile phase are supplied to the endless flow path from the sample solution. In a simulated moving bed chromatography apparatus that separates substances,
The endless flow path is a check provided in each of the plurality of columns, a fluid flow path connecting the columns, and a fluid flow path for flowing the fluid flowing through the fluid flow paths in one direction. And a valve
Each of the fluid channels includes a mobile phase channel for supplying the mobile phase to the fluid channel, a sample solution channel for supplying the sample solution to the fluid channel, and the fluid flow. A first discharge channel for discharging the fluid flowing through the channel from the fluid channel and a second discharge channel for discharging the fluid flowing through the fluid channel from the fluid channel;
The mobile phase flow path and the sample solution flow path are connected to the fluid flow path on the downstream side of the check valve when a fluid flows through the fluid flow path,
Each of the mobile phase flow path, the sample solution flow path, the first discharge flow path, and the second discharge flow path has an open / close valve that opens and closes each flow path with respect to the fluid flow path. A device characterized in that it is provided. The first discharge channel and the second discharge channel are connected to the fluid channel downstream of the check valve,
A third discharge channel for discharging the fluid flowing through the fluid channel from the fluid channel is further connected to the fluid channel upstream of the check valve,
The third discharge channel is provided with an open / close valve that opens and closes the third discharge channel with respect to the fluid channel,
The apparatus according to claim 1, wherein the third discharge channel is connected to the mobile phase channel.   The column contains a separating agent containing an optically active polysaccharide or polysaccharide derivative, the target substance is an optical isomer, and the sample solution contains a mixture of the optical isomers. Device according to claim 1 or 2, characterized.   4. The apparatus according to claim 3, wherein the polysaccharide is cellulose or amylose, and the polysaccharide derivative is at least selected from an ester derivative of cellulose, a carbamate derivative of cellulose, an ester derivative of amylose, and a carbamate derivative of amylose.   5. The fluid according to claim 1, wherein a fluid having a purity of 97% or more of the target substance is discharged from at least one of the first and second discharge channels. A device according to claim 1.

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