JP4430977B2 - Process for producing optical isomers by supercritical fluid chromatography - Google Patents

Description

  The present invention relates to a method for producing optical isomers by supercritical fluid chromatography, and in particular, a gas component that forms a supercritical fluid is recovered from a mobile phase containing a supercritical fluid and a solvent, and is contained in the mobile phase. The present invention relates to a method for producing optical isomers by supercritical fluid chromatography that is reused in supercritical fluids.

  Various methods are known for the production of optical isomers. As a method for producing such an optical isomer, for example, a method for producing a desired optical isomer by separating it from a mixture of optical isomers such as a racemate is known. In the case of producing a desired optical isomer by separating it from the mixture, high resolution is desired from the viewpoint of effectiveness and safety to living bodies, although it depends on the use of the optical isomer.

  The supercritical fluid is considered as a fluid having both characteristics of gas and liquid, and its application to various separation techniques is being studied. As one of such separation techniques, supercritical fluid chromatography using a supercritical fluid as a mobile phase is known. Supercritical fluids have excellent solubility and transport properties, but these excellent properties are likely to vary depending on conditions. Therefore, it is important to perform supercritical fluid chromatography under stable conditions, and in the case of performing optical resolution with supercritical fluid chromatography, optimization and stabilization of conditions are even more important.

  As the supercritical fluid, a supercritical fluid of carbon dioxide is usually used from the viewpoints of ease of handling, cost, safety to the environment, and the like. In the case of using a supercritical fluid of carbon dioxide, a small amount of an organic solvent such as alcohol or ketone may be added as a modifier to the supercritical fluid of carbon dioxide depending on the type of solute in order to increase the solubility of the supercritical fluid. is there.

  Carbon dioxide is a raw material for supercritical fluids, which is easy to handle, inexpensive, and safe for the environment. However, when optical isomers are industrially produced by supercritical fluid chromatography, carbon dioxide It is hoped that these will be recovered and reused.

  Therefore, when producing optical isomers by supercritical fluid chromatography, when recovering and reusing the gas components that form the supercritical fluid, it is sufficiently high that it does not affect the optical resolution when reused. It is important to recycle the purity gas component.

  On the other hand, as a technique including supercritical fluid chromatography and reuse of supercritical fluid, a supercritical fluid supplied from a cylinder is pumped, a sample is injected into the supercritical fluid, and a sample is injected. Pass the supercritical fluid through the column, reduce the pressure of the supercritical fluid passed through the column to precipitate the solute, separate the precipitated solute and supercritical fluid, and send the separated supercritical fluid to the pump. A technique for reusing the information is known (for example, see Patent Document 1).

However, the technique described above does not show the use of a mobile phase containing the modifier. For example, reusing a supercritical fluid when using a mobile phase containing a modifier, There remains room for study on ensuring the purity of the supercritical fluid component to be reused when it is used, application to the production of optical isomers, and the like.
Japanese Patent Laid-Open No. 5-3007026

  The present invention can recycle a gas forming a supercritical fluid when producing an optical isomer by supercritical fluid chromatography using a mobile phase containing a supercritical fluid and a solvent, and the optical isomer. It is an object of the present invention to provide a method capable of stably producing the above.

  As a means for solving the above problems, the present invention separates a gas that forms a supercritical fluid from a mobile phase that has passed through a column, and generates a liquefied gas from the separated gas having a purity of a predetermined level or higher. And a method for reusing the liquefied gas as a supercritical fluid in the mobile phase.

  That is, the present invention injects a sample containing a mixture of optical isomers into a mobile phase containing a supercritical fluid, and passes the mobile phase into which the sample has been injected through a column having a packing for identifying the optical isomers. , A method for producing a desired optical isomer in a sample by separating it from a mixture, the step of generating a mobile phase containing a supercritical fluid generated from a liquefied gas and a solvent, and movement through a column The phase is separated into the solvent and the gas that has formed the liquefied gas, and the separated gas, and the gas in which the concentration of the solvent in the gas is equal to or lower than the predetermined concentration, is liquefied and contained in the mobile phase A method for producing an optical isomer by supercritical fluid chromatography.

  According to such a method, the gas forming the supercritical fluid can be separated from the mobile phase and used again for the mobile phase. In addition, since a gas having a solvent concentration equal to or lower than a predetermined concentration is reused in the mobile phase, a change in the composition of the mobile phase accompanying the reuse of the supercritical fluid is suppressed. Therefore, since the influence on the optical resolution in supercritical fluid chromatography accompanying such a change in the composition of the mobile phase is suppressed, the optical isomer can be stably produced.

  In the present invention, the predetermined concentration is preferably 1% by volume. According to such a method, the composition ratio between the supercritical fluid and the solvent is kept substantially constant. Therefore, there is almost no influence on the optical resolution in supercritical fluid chromatography accompanying the change in the composition of the mobile phase, and the stability in the production of optical isomers is further enhanced.

  Further, the present invention is a recycling step, wherein the pressure of the separated gas having a solvent concentration equal to or lower than a predetermined concentration is higher than the pressure of a gas newly supplied to generate a liquefied gas. It is preferable to liquefy the separated gas. According to such a method, when the supercritical fluid contained in the mobile phase is formed, the separated gas is used with priority over the newly supplied gas. Therefore, in generating the supercritical fluid, most of the gas separated from the mobile phase can be reused as the supercritical fluid contained in the mobile phase, and the amount of new gas used is suppressed.

  The present invention further includes a step of lowering the pressure of the solvent separated in the step of separating and a step of recovering the gas separated from the solvent by decompression, wherein the concentration of the solvent in the recovered gas is a gas. A gas having a predetermined concentration or less is preferably used as a liquefied gas and reused as a supercritical fluid contained in the mobile phase. According to such a method, the gas contained in the solvent separated from the mobile phase is further recovered, and the gas recovery rate is further enhanced.

  The present invention preferably further includes a step of compressing the recovered gas to a pressure higher than the pressure of the separated gas. According to such a method, it becomes possible to easily join the recovered gas to the separated gas by using the pressure difference between these gases, and perform subsequent processing such as gas liquefaction all at once. Can be performed.

Moreover, it is preferable that this invention further includes the process of performing the process which removes the solvent which remains in either or both of the said isolate | separated gas and the collect | recovered gas. According to such a method, the concentration of the solvent in the gas separated from the solvent can be further reduced.

Moreover, in this invention, it is preferable to use the filler containing the polysaccharide derivative which is the polysaccharide which identifies an optical isomer, or its derivative (s) as a filler. According to such a method, productivity of various optical isomers can be enhanced. From this viewpoint, in the present invention, it is more preferable that the polysaccharide is cellulose scan or amylose.

  In the present invention, a sample containing a mixture of optical isomers is injected into a mobile phase containing a supercritical fluid, and the mobile phase into which the sample has been injected is passed through a column having a packing for identifying the optical isomers. A method for producing a desired optical isomer in a sample by separating the mixture from a mixture, the step of generating a mobile phase containing a supercritical fluid and a solvent generated from a liquefied gas, and a mobile phase passing through a column Is separated into a solvent and a gas that has formed a liquefied gas, and a gas that is the separated gas and the concentration of the solvent in the gas is equal to or lower than a predetermined concentration is defined as a liquefied gas and contained in the mobile phase. A gas that forms a supercritical fluid in the production of optical isomers by supercritical fluid chromatography using a mobile phase containing a supercritical fluid and a solvent. Can be reused Can be can be, and to stably manufacture the optical isomers

  In the present invention, if the predetermined concentration is 1% by volume, it is more effective from the viewpoint of stably producing optical isomers.

  In the present invention, in the step of reusing, when the pressure of the separated gas having a solvent concentration equal to or lower than a predetermined concentration is higher than the pressure of a gas newly supplied to generate a liquefied gas, When the separated gas is liquefied, it is more effective from the viewpoint of increasing the reuse rate of the gas forming the supercritical fluid with a simple configuration.

  The present invention further includes a step of lowering the pressure of the solvent separated in the step of separating and a step of recovering the gas separated from the solvent by decompression, wherein the concentration of the solvent in the recovered gas is a gas. When a gas having a predetermined concentration or less is used as a liquefied gas and reused in the supercritical fluid contained in the mobile phase, it is more effective from the viewpoint of increasing the recovery rate of the gas reused in the formation of the supercritical fluid. is there.

  Further, in the present invention, when the recovered gas further includes a step of compressing the recovered gas to a pressure higher than the pressure of the separated gas, the gas reused for forming the supercritical fluid with a simple configuration and operation. Is more effective from the viewpoint of increasing the recovery rate.

  Further, in the present invention, when one or both of the separated gas and the recovered gas is further subjected to a treatment for removing the solvent remaining in the gas, the optical isomer can be stabilized. More effective from the viewpoint of manufacturing.

Further, in the present invention, when a filler containing a polysaccharide for identifying optical isomers or a polysaccharide derivative that is a derivative thereof is used as the filler, it is more effective from the viewpoint of increasing the productivity of the optical isomer. There, wherein the polysaccharide is even more effective when is cellulose scan or amylose.

In the method for producing an optical isomer of the present invention, a sample containing a mixture of optical isomers is injected into a mobile phase containing a supercritical fluid, and the mobile phase into which the sample is injected is packed to identify the optical isomers. The desired optical isomers in the sample are separated from the mixture and produced through a column having an agent.

  In the present invention, the basic operations for supercritical fluid chromatography such as injection of the sample into the mobile phase, detection of the sample in the mobile phase after passing through the column, preparation of the sample, etc. And can be carried out in the same manner as that usually carried out in high performance liquid chromatography, and can be carried out using known techniques. For example, for the injection of the sample into the mobile phase, it is possible to separate the optical isomers in the column by adopting an injection method that does not cause a pressure fluctuation during the injection as described in Patent Document 1 described above. It is preferable from the viewpoint of increasing the efficiency and increasing the productivity of the optical isomer.

  The optical isomer of the present invention comprises a mobile phase generation step for generating a mobile phase containing a supercritical fluid generated from a liquefied gas and a solvent, and a mobile phase that has passed through the column as a solvent and a liquefied gas. A gas-liquid separation step for separating the gas into a supercritical fluid contained in the mobile phase as a liquefied gas, wherein the separated gas and the concentration of the solvent in the gas is equal to or lower than a predetermined concentration. Gas recycling process to be used.

  In the mobile phase generation step, a mobile phase containing a supercritical fluid and a solvent is generated. A supercritical fluid is generated from a liquefied gas. In the present invention, the “supercritical fluid” is a substance that is in a state exceeding one or both of a critical temperature and a critical pressure. In the present invention, the supercritical fluid can be generated, for example, by one or both of pressurization and heating of a liquefied gas.

  As the supercritical fluid, for example, a known substance used for supercritical fluid extraction can be used. Examples of such substances include carbon dioxide, ammonia, sulfur dioxide, hydrogen halide, nitrous oxide, hydrogen sulfide, methane, ethane, propane, butane, ethylene, propylene, halogenated hydrocarbon, and water. The substance is preferably carbon dioxide from the viewpoints of flammability, explosiveness, harmfulness to the human body, ease of handling and economy.

  As the solvent, a solvent selected from known solvents according to the type of optical isomer or filler can be used. Examples of such a solvent include lower alcohols such as ethanol and 2-propanol, ketones such as acetone, acetonitrile, ethyl acetate, and water.

  The mixing ratio of the solvent in the mobile phase varies depending on conditions such as the type of optical isomer to be separated and the type of filler, but it is about 5 to 30% by mass with respect to the total amount of the mobile phase. This is preferable from the viewpoint of increasing productivity in the production of isomers.

  The production method of the mobile phase is not particularly limited. For example, the mobile phase may be produced by mixing a supercritical fluid and a solvent, or after mixing the liquefied gas and the solvent, Then, either or both of pressurization and heating may be performed, and the liquefied gas in the mixed solution may be generated as a supercritical fluid. The mixing of the liquefied gas or supercritical fluid and the solvent is carried out by feeding each fluid at a predetermined flow rate by a metering pump, for example, as in high performance liquid chromatography. This can be done by joining the fluid.

  The liquefied gas may be a liquefied gas accommodated in a cylinder, or is generated from the gas by adjusting the pressure and temperature of the gas, for example, the gas is compressed and liquefied by a compressor. It may be a thing. Pressure adjustment means such as a compressor and a back pressure valve can be used for adjusting the gas pressure, and temperature adjustment means such as a heat exchanger can be used for adjusting the gas temperature.

  In the gas-liquid separation step, the mobile phase that has passed through the column is separated into a solvent and a gas constituting the liquefied gas. The gas-liquid separation of the solvent and gas from the mobile phase can be performed, for example, by reducing the pressure of the mobile phase using a pressure regulating valve such as a back pressure valve, but it is preferable to further use a gas-liquid separation device. Such a gas-liquid separator includes, for example, an outer cylinder that is open at both ends, a flange portion that closes an opening at one end of the outer cylinder, and the mobile phase in the circumferential direction along the inner peripheral wall surface of the outer cylinder. A gas-liquid separation device having an introduction part for introducing the gas into the outer cylinder, and an inner cylinder that is open at both ends and extends to the other end side of the outer cylinder through the flange part. It is preferable to use it.

  According to the gas-liquid separation device, since the inner cylinder extends to the other end side of the outer cylinder from the introduction part, the droplets of the mobile phase introduced from the introduction part are separated from the inner cylinder. It is difficult to be contained in the exhausted gas, and it is possible to reduce the concentration of the solvent and optical isomers in the gas. Further, since the outer cylinder is cylindrical, pressure is evenly applied to the inner peripheral wall surface, so that the durability of the gas-liquid separator is enhanced. As described above, the gas-liquid separation device can recover a high-purity gas under high-pressure conditions. Therefore, in separation of optical isomers that require more precise separation in supercritical fluid chromatography, It is suitably used in a technique for reusing a gas separated from a mobile phase as a mobile phase.

  A jacket for covering the outer peripheral wall surface of the outer cylinder and adjusting the temperature of the outer cylinder; and a mobile phase supply for supplying the mobile phase to the introduction section, connected to the introduction section through the jacket It is preferable to further include a tube in order to further increase the separation efficiency of gas-liquid separation in the outer cylinder. Further, the temperature of the mobile phase is adjusted to the temperature of the outer cylinder before being introduced into the outer cylinder, which is preferable for further improving the separation efficiency of gas-liquid separation in the outer cylinder.

  The outer cylinder is not particularly limited as long as the mobile phase introduced from the introduction part can flow spirally along the inner peripheral wall surface from one end side to the other end side. The outer cylinder is generally cylindrical, but the shape of the inner peripheral wall surface in the cross section is for the purpose of causing a bias in the flow velocity of the mobile phase introduced into the outer cylinder, or for giving an appropriate impact. It may be a cylinder having a substantially circular shape such as an ellipse or a polygon.

  The flange portion is not particularly limited as long as it closes the opening at one end of the outer cylinder. For such a flange portion, for example, a non-diameter union for installing the inner cylinder and closing the outer cylinder can be suitably used.

  The introduction portion can be formed by a nozzle or a tube that introduces the mobile phase into the outer cylinder along a tangent line of the inner peripheral wall surface in the cross-sectional shape of the outer cylinder. The mobile phase is usually introduced in a direction parallel to the transverse direction of the outer cylinder. The present invention is not limited to this, and the introduction portion may be provided in parallel to the transverse direction of the outer cylinder, or may be provided obliquely.

  If the inner cylinder is a pipe having a smaller diameter than the outer cylinder, the cross-sectional shape is not particularly limited. The inner cylinder is configured to sufficiently extend to the other end side of the outer cylinder from the introduction portion, from the viewpoint of preventing the mobile phase droplets from being mixed into the gas in the outer cylinder. Such an extension length of the inner cylinder varies depending on various conditions such as the introduction condition of the mobile phase to the outer cylinder, the diameter of the outer cylinder, and the diameter of the inner cylinder. The inner cylinder is extended to a position where the flow of the mobile phase introduced into the outer cylinder loses momentum and the mobile phase is transmitted along the inner peripheral wall surface of the outer cylinder, that is, no splashing from the inner peripheral wall surface occurs. good.

  As the jacket, a normal jacket in which a heat medium is circulated outside the outer cylinder can be used. If the heating medium supplied to the jacket is a heating medium, it is effective in increasing the gas separation efficiency. If the heating medium supplied to the jacket is a refrigerant, the solubility of the optical isomer in the solvent is lowered. Effective above.

  The mobile phase supply pipe is preferably provided long in the jacket from the viewpoint of preliminarily adjusting the temperature of the mobile phase before gas-liquid separation to the temperature in the outer cylinder. For example, the mobile phase supply pipe is preferably provided in a meandering shape in the jacket, or provided in a spiral shape on the outer peripheral wall surface of the outer cylinder. Such a mobile phase supply pipe is preferable in order to suppress splashing due to a temperature change of the mobile phase when introduced into the outer cylinder, particularly when the heating medium is a heating medium.

  The solvent separated in the gas-liquid separation step contains an optical isomer. This optical isomer can be obtained from the solvent by reducing the pressure of the separated solvent under high pressure conditions and, if necessary, using a known method such as concentration under reduced pressure.

  In the gas recycling step, the primary recovery gas, which is the gas separated in the gas-liquid separation step (hereinafter also referred to as “primary recovery gas”) and the concentration of the solvent in the gas is equal to or lower than a predetermined concentration, is converted into liquefied gas. And reused in the supercritical fluid contained in the mobile phase. The primary recovery gas in which the concentration of the solvent in the gas is less than or equal to the predetermined concentration is the first method for measuring the concentration of the solvent in the primary recovery gas and confirming that it is below the predetermined concentration, or in the primary recovery gas It is obtained by a second method of gas-liquid separation by a gas-liquid separation means so that the concentration of the solvent becomes a predetermined concentration or less.

  As the first method, for example, a tank for storing the primary recovery gas is provided in the flow path of the primary recovery gas, the concentration of the solvent in the primary recovery gas stored in the tank is measured, and the concentration of the solvent is If it is confirmed that the concentration is lower than the predetermined concentration, a method of using the primary recovery gas stored in the tank for generating liquefied gas can be mentioned. The tank is preferably a plurality of tanks provided in parallel with the flow path of the primary recovery gas, from the viewpoint of continuously measuring the concentration of the solvent in the primary recovery gas and reusing the primary recovery gas. .

  The second method includes, for example, a means for detecting the concentration of the solvent in the primary recovery gas in the primary recovery gas flow path, a primary recovery gas bypass flow path that bypasses the detection means, and the bypass flow path. The concentration of the solvent in the primary recovery gas is continuously measured by using the gas-liquid separation means provided therein and the fluid distribution means for distributing the primary recovery gas to the detection means and the bypass flow path in a desired ratio. In addition, a method of performing gas-liquid separation of a part or all of the primary recovery gas according to the concentration of the solvent in the primary recovery gas can be mentioned.

  Further, as the second method, for example, there is a method in which a gas-liquid separation means is provided in the flow path of the primary recovery gas so that the concentration of the solvent in the primary recovery gas is not more than the predetermined concentration. . In such a method, it is necessary to provide a plurality of gas-liquid separation means depending on the case, and the configuration of the apparatus becomes complicated. However, the concentration of the solvent in the primary recovery gas need not be measured. The number of gas-liquid separation means installed in this method can be obtained, for example, based on the measured value of the actual number of installed units and the concentration of the solvent in the primary recovery gas at that time.

  In the first method and the second method, when the concentration of the solvent in the primary recovery gas is detected, as a method for detecting the concentration of the solvent in the primary recovery gas, the concentration of the solvent in the gas can be detected. If it is a method, it will not specifically limit. As such a detection method, for example, the solvent contained in the gas in the tank is quantified by gas chromatography to determine the concentration of the solvent in the primary recovery gas, or the primary in the tank or the flow path. A method using a gas sensor for detecting a solvent in the recovered gas is mentioned. In the present invention, the measurement of the concentration of the solvent in the primary recovery gas may be performed constantly or at an appropriate frequency.

In the first method and the second method, known means and the like can be used. For example, as the gas-liquid separation means, the gas-liquid separation device described above, an adsorption device having a liquid or solid adsorbent that adsorbs the solvent from the primary recovery gas in the gas flow path, or the like is used. For example, an automatic valve or a butterfly valve is used as the fluid distributing means. In the first method and the second method, the pressure of the recovered gas is controlled using a known means such as a compressor, a back pressure valve, a pressure regulating valve, an automatic valve, and the flow path of the recovered gas is set. By appropriately opening and closing, the flow of the recovered gas can be controlled.

  The primary recovery gas in which the concentration of the solvent in the gas is equal to or lower than a predetermined concentration is liquefied gas. As described above, the primary recovery gas can be liquefied by using a compressor, a pressure adjusting unit, a temperature adjusting unit, and the like. The obtained liquefied gas is reused in the production method of the present invention as the liquefied gas in the mobile phase generation step described above.

  The predetermined concentration is the concentration of the solvent in the recovered gas. The predetermined concentration may be a concentration that does not significantly reduce the productivity of optical isomers when the recovered gas is used as a liquefied gas and the liquefied gas is reused as a mobile phase.

  The predetermined concentration varies depending on various conditions such as the type and use of the optical isomer, the type of solvent and the content in the mobile phase, and the type of gas, but the concentration of the solvent in the recovered gas is 1% by volume or less, Further, it is preferably 0.5% by volume or less from the viewpoint of suppressing the change in the resolution of the optical isomer due to the change in the composition of the mobile phase and stably producing the optical isomer by supercritical fluid chromatography. . The predetermined concentration can be obtained, for example, by determining the concentration of the solvent in the primary recovery gas. The concentration of the solvent in the recovered gas can be adjusted by, for example, further gas-liquid separation operation or dilution with a new gas.

  In the gas recycling step, when the liquefied gas is generated, the pressure of the primary recovery gas having a solvent concentration equal to or lower than a predetermined concentration is higher than the pressure of the gas newly supplied to generate the liquefied gas. In addition, it is preferable to liquefy the primary recovery gas from the viewpoint of sufficiently reusing the gas. Such gas pressure control is achieved, for example, by connecting the primary recovery gas flow path and the new gas flow path to the above-described means for generating liquefied gas through a pressure adjusting means such as a back pressure valve. However, it can be performed by increasing the set value of the pressure of the primary recovery gas compared to the set value of the pressure of the new gas.

  In this case, the set value of the pressure of the primary recovery gas is not particularly limited as long as it is higher than the set value of the pressure of the new gas, but the pressure between the pressure of the primary recovery gas and the pressure of the new gas is not particularly limited. The differential pressure is preferably 0.1 MPa or more, for example.

  In addition, if the set value of the pressure of the primary recovery gas is too high, gas-liquid separation in the gas-liquid separation step may not be performed sufficiently, or the gas may be redissolved in the separated solvent. Therefore, the set value of the pressure of the primary recovery gas is set according to the solubility of the gas in the solvent from the viewpoint of suppressing re-dissolution of the primary recovery gas in the solvent. For example, when a supercritical fluid of carbon dioxide is used and a normal organic solvent is used as the solvent, the pressure of the primary recovery gas is set to about 1 to 10 MPa. It is preferable from the viewpoint of suppressing dissolution and increasing the reuse rate of the primary recovery gas.

  In the present invention, gas can be further recovered from the solvent separated in the gas-liquid separation step. The recovery of the gas from the solvent after the gas-liquid separation can be performed by a depressurization step for reducing the pressure of the solvent separated in the gas-liquid separation step and a recovery step for recovering the gas separated from the solvent by the depressurization.

The decompression step is not particularly limited as long as the solvent can be further decompressed in a sealed system. Such a process can be performed, for example, by storing the solvent in a sealable container and setting the pressure in the sealable container to a pressure lower than the pressure of the solvent before storage. The pressure in the container may be set in advance to a predetermined pressure before the solvent is accommodated, or may be adjusted by reducing the pressure continuously or stepwise after the solvent is accommodated.

  The recovery step is not particularly limited as long as it is a step of recovering a gas that is separated from the solvent in the decompression step (hereinafter also referred to as “secondary recovery gas”). Such a process can be performed, for example, by collecting gas in the container after pressure adjustment, collecting gas released from the solvent at the time of pressure adjustment, or the like.

  A single container may be used, but a plurality of containers are preferably used. For example, in the case where a plurality of the containers are connected in series to the gas-liquid separation device, a plurality of stages of solvent decompression and a plurality of stages of gas recovery can be performed continuously. For example, the recovery rate of the secondary recovery gas It is possible to increase. In the case where a plurality of the containers are connected in parallel to the gas-liquid separator, it is possible to continuously perform one-stage solvent decompression and one-stage gas recovery for one gas-liquid separator. The number of containers in the case of connecting in series is not particularly limited, but is preferably about 1 to 3 from the viewpoints of ease of equipment and operation and increasing the recovery rate of gas from the solvent.

  In the decompression step, when the solvent is fed to a low-pressure side container, the temperature of the solvent may be lowered by the heat of vaporization when the gas is released from the solvent. In such a case, having a means to adjust the temperature of the containers and the pipes connecting the containers suppresses the precipitation of optical isomers from the solvent during liquid feeding and the adhesion and residual of the optical isomers in the container. From the viewpoint of As such means, known means such as a jacket and a heating coil can be used.

  If the concentration of the solvent in the gas is equal to or lower than the predetermined concentration, the secondary recovery gas can be liquefied like the primary recovery gas and reused as a supercritical fluid contained in the mobile phase. In the present invention, the secondary recovery gas may be compressed to a higher pressure than the pressure of the primary recovery gas. By including such a step, the secondary recovery gas can be easily merged with the primary recovery gas. The secondary recovery gas is preferably joined to the primary recovery gas before the gas recycling step from the viewpoint of simplifying the apparatus and operation.

  The secondary recovery gas can be compressed using, for example, a compressor. In addition, the compressed secondary recovery gas may be merged into the primary recovery gas by, for example, connecting the flow path of the secondary recovery gas and the flow path of the primary recovery gas via a pressure adjusting means such as a back pressure valve. This can be done by setting the pressure of the secondary recovery gas higher than the pressure of the primary recovery gas.

  In the present invention, one or both of the primary recovery gas and the secondary recovery gas may be subjected to a treatment for removing the solvent remaining in the gas. Such treatment is preferably performed on the gas before the gas recycling step from the viewpoint of reducing the concentration of the solvent in the gas. Moreover, such a process can be performed by using the gas-liquid separation apparatus and adsorption apparatus mentioned above.

  The filler used in the present invention may be any filler that identifies optical isomers, but from the viewpoints of versatility and productivity, polysaccharides that identify optical isomers or polysaccharide derivatives that are derivatives thereof are used. The filler is preferably contained.

  Any of natural polysaccharides, synthetic polysaccharides, and natural product-modified polysaccharides can be used as the polysaccharide as long as it has chirality. Among them, those having a regular bonding mode are preferable because the ability to separate optical isomers can be further increased.

  Examples of such polysaccharides include cellulose, amylose, xylan, chitosan, chitin, mannan, inulin, curdlan, starch, dextran, amylopectin, bustulan, glucan, galactan, levan, bullulan, agarose, alginic acid, amylose. Examples include starch. Among these, cellulose, amylose, xylan, chitosan, chitin, mannan, inulin, curdlan and the like that can be easily obtained as high-purity polysaccharides are preferable, and cellulose and amylose are particularly preferable.

  The number average degree of polymerization (average number of pyranose rings or furanose rings contained in one molecule) of the polysaccharide is 5 or more, preferably 10 or more. 000 or less is desirable.

  Examples of the polysaccharide derivatives include ester derivatives and carbamate derivatives of the polysaccharides as preferable polysaccharide derivatives.

  As the filler, various types of known fillers can be used. As such a filler, for example, a filler made of a particulate or integrally-molded silica gel carrier and the polysaccharide or polysaccharide derivative carried on the carrier, or a filler made of a polysaccharide or polysaccharide derivative is used. Thus, the filler etc. which are comprised only from the optical identification part are mentioned.

  In the present invention, from the viewpoint of further improving the productivity of optical isomers, it is preferable to use a filler comprising a polysaccharide or a polysaccharide derivative. Such a filler is used to crosslink the hydroxyl groups of a polysaccharide derivative in a droplet formed of a polysaccharide derivative in a desired shape such as a particulate shape, or to have a desired shape such as a particulate shape. The filler matrix formed of saccharides can be obtained by esterification or carbamate formation as necessary.

  The present invention is particularly effective when a large amount of the solvent is separated in the gas-liquid separation step. Examples of such a case include a case where an optical isomer is separated from the mixture using a column having a large inner diameter, such as industrial production. In such a case, the inner diameter of the column is preferably 10 cm or more, and more preferably 20 cm or more.

  It should be noted that the present invention may further include other steps as long as the effects of the present invention are not impaired. For example, in the present invention, the gas that forms the supercritical fluid is repeatedly reused. Therefore, when the present invention is carried out over a long period of time, impurities dissolved in the liquefied gas and the supercritical fluid are generated along with the reuse of the gas. And can affect the production of optical isomers. The present invention may further include an impurity removal step for removing such accumulated impurities.

  In the impurity removal step, impurities may be removed from the recovered gas, or impurities may be removed from the mobile phase. As a method for removing impurities from the recovery gas, for example, an adsorption device having a liquid or solid adsorbent that adsorbs the impurities is provided in the flow path of the primary recovery gas and the secondary recovery gas, and the recovery gas is adsorbed. The method of passing through is mentioned. As a method for removing impurities from the mobile phase, for example, a method in which a guard column that adsorbs the impurities is provided in the flow path of the mobile phase upstream of the injector that injects the sample into the mobile phase, and the mobile phase is passed through the guard column. Is mentioned.

  The present invention is applied to industrial production of optical isomers with high optical purity, such as production of active ingredients in pharmaceuticals, where high optical separation accuracy and production of large amounts of optical isomers under stable conditions are desired. can do.

  Hereinafter, an embodiment of the present invention will be described with reference to the drawings. First, a supercritical fluid chromatographic fractionation apparatus used in the separation method of the present invention is shown in FIG.

  As shown in FIG. 1, the supercritical fluid chromatographic separation apparatus cools and liquefies a cylinder 1 serving as a gas supply unit, which is filled with high-pressure carbon dioxide, and carbon dioxide supplied from the cylinder 1. Heat exchanger 2, a pump 3 for sending a liquefied gas of carbon dioxide generated in heat exchanger 2, a solvent tank 4 for containing a solvent, and a solvent tank 4 for liquefied gas sent by pump 3. A pump 5 for supplying a solvent supplied from a heat exchanger 6, a heat exchanger 6 for heating the mixed solvent of the liquefied gas and the solvent to make the liquefied gas into a supercritical fluid, and the generated supercritical fluid An injector 7 for injecting a sample containing an optical isomer into a mobile phase which is a mixture of the solvent and the solvent, a column 8 for separating the optical isomer in the injected sample, and a column 8 Substances in the mobile phase It has a detector 9 which exits, and a first back-pressure valve 10 is a pressure regulator for keeping the pressure in the system from the pump 3 to the detector 9 at a predetermined pressure.

  Further, the supercritical fluid chromatographic separation device includes a plurality of gas-liquid separation devices 11 for gas-liquid separation of a mobile phase whose pressure is adjusted by passing through the first back pressure valve 10, and each gas-liquid separation device 11. And a plurality of first tanks 12 for storing the liquid separated by the gas-liquid separator 11 and the system from the first back pressure valve 10 to each gas-liquid separator 11 and the first tank 12 And a second back pressure valve 13 for maintaining the pressure at a predetermined pressure.

Further, the supercritical fluid chromatographic separation device includes a plurality of second tanks 14 provided corresponding to the respective first tanks 12 and supplied with the liquid stored in the first tank 12, and each of the second tanks 14. A compressor 15 for compressing the gas (secondary recovery gas) recovered from the tank 14 and a third back pressure valve 16 for maintaining the pressure of the secondary recovery gas compressed by the compressor 15 at a predetermined pressure. And have.

  Further, the supercritical fluid chromatographic separation device has a gas (primary recovered gas) separated by the gas-liquid separation device 11 adjusted to a predetermined pressure by the second back pressure valve 13 and a predetermined value by the third back pressure valve 16. The purifier 17 for removing the liquid in the secondary recovery gas adjusted to the pressure of the gas, the third tank 18 for storing the liquid removed by the purifier 17, and the gas purified by the purifier 17 And a gas storage tank 19 to be stored.

  The cylinder 1, the heat exchanger 2, the pump 3, the heat exchanger 6, the injector 7, the column 8, the detector 9, and the first back pressure valve 10 are connected in series by a pipe. The solvent tank 4 and the pump 5 are connected by a pipe, and the pump 5 is connected by a pipe to a pipe connecting the pump 3 and the heat exchanger 6.

  The gas-liquid separator 11 is connected to the first back pressure valve 10 and the second back pressure valve 13 in parallel by a pipe. Each gas-liquid separator 11, the 1st tank 12, and the 2nd tank 14 are connected with the pipe | tube in series.

  The second tank 14 is connected to the compressor 15 by a pipe in parallel. The compressor 15 and the third back pressure valve 16 are connected in series by a pipe. The second back pressure valve 13 and the third back pressure valve 16 are connected to the purifier 17 in parallel by a pipe.

  The purifier 17 and the third tank 18, and the purifier 17 and the gas storage tank 19 are connected in series by pipes. The gas storage tank 19 is connected to the heat exchanger 2 by a pipe.

Between the cylinder 1 and the heat exchanger 2, a pressure regulating valve 20 that releases carbon dioxide from the cylinder 1 at a predetermined pressure, and a check that prevents a backflow of gas from the heat exchanger 2 side to the pump 1 side. A valve 25 is provided. A buffer tank 22 that receives the liquefied gas generated by the heat exchanger 2 is provided between the heat exchanger 2 and the pump 3. Further, the column 8 is accommodated in a column oven 23 for adjusting the inside of the column 8 to a predetermined temperature.

  Between the first back pressure valve 10 and each gas-liquid separation device 11, a valve corresponding to each gas-liquid separation device 11 is selected so that a mobile phase supply destination from the first back pressure valve 10 can be selected. 24 is provided. Between each gas-liquid separation device 11 and the first back pressure valve 13, a check valve 25 for preventing a backflow of gas from the first back pressure valve 13 side to each gas-liquid separation device 11, respectively. The gas-liquid separator 11 is provided.

  Between the 1st tank 12 and the 2nd tank 14, the valve | bulb 26 which opens and closes the pipe | tube which connects the 1st tank 12 and the 2nd tank 14, and the heating coil 27 for heating the said pipe | tube Are provided. A check valve 28 is provided between the second tank 14 and the compressor 15 so as to prevent the backflow of the secondary recovery gas from the compressor 15 side corresponding to each second tank 14. It has been.

  Between the second back pressure valve 13 and the purifier 17, a check valve 29 for preventing a back flow of gas from the purifier 17 to the second back pressure valve 13 is provided. Between the pressure valve 16 and the purifier 17, a check valve 30 is provided for preventing a backflow of gas from the purifier 17 to the third back pressure valve 16.

  The pumps 3 and 5 are pumps that can send liquid quantitatively. The column 8 also has a filler containing a polysaccharide derivative such as cellulose 2,3-bis (3,5-dimethylphenylcarbamate). As the filler, a filler in which a polysaccharide derivative for identifying optical isomers is supported on a carrier such as silica, or a filler formed of the polysaccharide derivative without a carrier is used.

The first back pressure valve 10 gas-liquid separates the mobile phase when the pressure exceeds the predetermined pressure so as to maintain the pressure of the system on the column 8 side, that is, the primary side, at a predetermined pressure (P ₁ , for example, 20 MPa). It is a valve that opens and closes to escape to the device 11 side, that is, the secondary side.

Similarly, the second back pressure valve 13 maintains the pressure of the system on the gas-liquid separation device 11 side at a predetermined pressure P ₂ , and releases the primary recovery gas to the purification device 17 side when the pressure becomes P ₂ or higher. It is a valve that opens and closes like this. The third back pressure valve 16 maintains the pressure of the compressed secondary recovery gas at a predetermined pressure P ₃ , and opens and closes so that the secondary recovery gas is released to the purifier 17 side when the pressure becomes P ₃ or higher. It is a valve to do. The pressure regulating valve 20 is a valve that opens and closes so as to release carbon dioxide from the cylinder 1 at a predetermined pressure P ₀ .

P ₀ is set to a pressure sufficient to generate liquefied gas, and is determined by the type of liquefied gas. P ₁ is set to a pressure sufficient to elute the optical isomer by the mobile phase, and is determined by the type of supercritical fluid, the composition of the mobile phase, the solubility of the mobile phase, and the like. P ₂ and P ₃ are both set to a value slightly larger than P ₀ , and P ₂ is set to a value slightly smaller than P ₃ .

  The detector 9 is connected to a control device (not shown) that controls opening and closing of the predetermined valve 24 and the first tank 12 and the third tank 18 according to the detection result of the detector 9. .

As shown in FIGS. 2 and 3, the gas-liquid separation device 11 includes a cylindrical outer cylinder 31 that is open at both ends, a flange portion 32 that closes an opening at one end of the outer cylinder 31, and a crossing of the outer cylinder 31. An introduction portion 33 which is a pipe provided along the tangent line of the inner peripheral surface in the surface shape and opens into the outer cylinder 31, and both ends are open, and the outer cylinder 31 penetrates the flange portion 32 and is more than the introduction portion 33. An inner cylinder 34 that extends to the other end of the outer cylinder 31, a jacket 35 that covers the outer peripheral wall surface of the outer cylinder 31 and forms a circulation path for the heat medium, and a mobile phase supply pipe that is connected to the introduction portion 33 through the jacket 35. 36.

  The jacket 35 is provided with a heat medium supply port 37 on the other end side and a heat medium discharge port 38 on one end side. The mobile phase supply pipe 36 is passed through one end portion of the jacket 35 into the jacket 35, wound around the outer periphery of the outer cylinder 31 from one end side to the other end side of the jacket 35, and the other end of the jacket 35. It goes out from the side and is connected to the introduction part 33. The mobile phase supply pipe 36 is connected to the valve 24. The inner cylinder 34 is connected to the purification device 17. The other end of the outer cylinder 31 is connected to the first tank 12. The supply port 37 and the discharge port 38 are connected to a heat medium circulating means (not shown).

  The purifier 17 has the same configuration as the gas-liquid separator 11 shown in FIGS. In the purifier 17, the mobile phase supply pipe 36 is connected to the check valves 29 and 30. The inner cylinder 34 is connected to the gas storage tank 19. The other end of the outer cylinder 31 is connected to the third tank 18. Similarly to the gas-liquid separator 11, the supply port 37 and the discharge port 38 are connected to a heat medium circulating means (not shown).

  A heat medium circulates in the jacket 35 of the gas-liquid separator 11 and the purifier 17, and the temperature of the outer cylinder 31 is adjusted to a predetermined temperature.

  In addition, although not shown in the supercritical fluid chromatographic fractionation device, in addition to these, valves such as valves, check valves, safety valves, various detection means such as pressure gauges, thermometers, flow meters, heaters, Peripheral devices such as brachinlers and accumulators are in place.

In the present embodiment, the pressure regulating valve 20 is adjusted to supply carbon dioxide from the cylinder 1 to the heat exchanger 2 at a predetermined pressure P ₀ (for example, 4 to 5 MPa). Carbon dioxide is cooled and liquefied in the heat exchanger 2.

  The carbon dioxide liquefied gas generated in the heat exchanger 2 is accommodated in the buffer tank 22 and supplied to the heat exchanger 6 by the pump 3 at a predetermined flow rate. The liquefied gas supplied to the heat exchanger 6 includes an organic solvent such as lower alcohol and acetonitrile, a mixed solvent thereof, or a mixture of these organic solvents and water, which are sent from the solvent tank 4 by a pump 5 at a predetermined flow rate. The liquefied gas and the solvent are mixed at a predetermined ratio.

The mixed solvent composed of the liquefied gas and the solvent is pressurized in the course of liquid feeding by the pumps 3 and 5 up to a predetermined pressure P ₁ set by the first back pressure valve 10, and is supplied to the heat exchanger 6. Supplied. In the heat exchanger 6, the mixed solvent is heated so that the liquefied gas in the mixed solvent becomes a supercritical fluid, and the temperature of the mobile phase formed by mixing the supercritical fluid and the solvent is set to the column oven 23. The temperature is adjusted to the column 8 temperature set at (for example, 40 ° C.). In this way, a mobile phase containing a supercritical fluid generated from the liquefied gas and the solvent is generated. A solution of a mixture containing an optical isomer which is a separation target is injected from the injector 7 as a sample into the mobile phase whose temperature has been adjusted.

  The mobile phase into which the sample has been injected by the injector 7 is passed through the column 8, and one of the optical isomers in the sample is separated from the mixture.

The optical isomer in the mobile phase that has passed through the column 8 is detected by the detector 9. The control device (not shown) opens a predetermined valve 24 and closes the other valves 24 according to the detection result of the detector 9. The mobile phase that has passed through the detector 9 is sent to the first back pressure valve 10. With the passage through the first back pressure valve 10, the pressure of the mobile phase decreases from P ₁ to a predetermined pressure P ₂ set by the second back pressure valve 13, and a predetermined gas-liquid separation from the predetermined valve 24. It is supplied to the mobile phase supply pipe 36 of the apparatus 11.

  In the gas-liquid separator 11, the mobile phase supplied to the mobile phase supply pipe 36 is supplied to the introduction unit 33 after moving in a spiral along the outer peripheral surface of the outer cylinder 31 in the jacket 35. Thus, the mobile phase is preliminarily adjusted to the temperature of the outer cylinder 31 before being supplied to the introduction part 33. The mobile phase whose temperature has been adjusted is introduced into the outer cylinder 31 from the introduction portion 33. The mobile phase falls while making a circular motion along the circumferential direction of the inner peripheral wall surface of the outer cylinder 31. In this process, most of the carbon dioxide in the mobile phase is separated from the mobile phase as a gas. In this way, the mobile phase that has passed through the column is separated into the solvent and the gas that formed the liquefied gas.

  Here, the solvent separated by the gas-liquid separator 11 will be described first. The solvent separated by the gas-liquid separation device 1 contains the solvent, the predetermined optical isomer separated from the sample by the column 8, and the residue of the gas component that has formed the supercritical fluid. This solution falls along the inner peripheral wall surface of the outer cylinder 31 and is stored in the first tank 12.

The solution contained in the first tank 12 is depressurized from the pressure P ₁ to P ₂ when the optical isomer is eluted, and most of the gas components forming the supercritical fluid are removed. Therefore, the optical isomer is concentrated in the solution.

  When the predetermined valve 26 is opened here, the solution stored in the first tank 12 is stored in the predetermined second tank 14 through a tube heated by the heating coil 27. The pressure in the second tank 14 is almost atmospheric pressure, and further gas components are released from the solution stored in the second tank 14 and the optical isomers are further concentrated. In this way, the pressure of the solution separated from the mobile phase is further reduced. The valve 26 is opened and closed by the control device described above based on the detection result of the pressure in the second tank 14, for example.

  The optical isomer is extracted from the solution stored in the second tank 14. The optical isomer is taken out by adopting a known method such as concentration under reduced pressure as necessary, for example, by precipitating the optical isomer in the solution or volatilizing the solution. In this way, the desired optical isomer in the sample is separated from the mixture and produced.

Next, the gas separated by the gas-liquid separator 11 will be described. In the gas-liquid separator 11, in the outer cylinder 31, when the mobile phase is introduced into the outer cylinder 31 with a strong momentum, and while the mobile phase flows in the outer cylinder 31 as described above, splashes of the mobile phase are generated. However, the inner cylinder 34 extends from the introduction portion 33 to the other end side of the outer cylinder 31 (lower side in the gas-liquid separator 11 in FIG. 2). For this reason, the above-mentioned droplets are absorbed again by the solvent, or fall off the outer cylinder 31 as it is, and do not easily enter the inner cylinder 34. Therefore, from the inner cylinder 34, the above-described gas with less splashing is recovered. The primary recovery gas separated by the gas-liquid separator 11 passes through the check valve 25 and is maintained at a predetermined pressure P ₂ by the second back pressure valve 13.

Next, the gas separated in the second tank 14 will be described. The gas further released from the solution in the second tank 14 is supplied to the compressor 15 through the check valve 28. In this way, the gas separated from the solution by the reduced pressure in the second tank 14 is recovered. The secondary recovery gas supplied to the compressor 15 is compressed to a predetermined pressure P ₃ set by the third back pressure valve 16. In this way, the secondary recovery gas is compressed to a pressure higher than the pressure of the primary recovery gas.

  The primary recovery gas and the secondary recovery gas are recycled to the supercritical fluid. First, the reuse of the primary recovery gas will be described.

When the recovered amount of the secondary recovery gas is not sufficient to pressurize to the pressure P ₃ , the primary recovery gas is supplied to the purifier 17 through the second back pressure valve 13 and the check valve 29. The primary recovery gas supplied to the purifier 17 is introduced from the mobile phase supply pipe 34 through the introducing portion 33, introduced into the outer cylinder 31, and discharged from the purifier 17 through the inner cylinder. In the purifier 17, for example, a trace amount of solvent entrained by gas-liquid separation in the gas-liquid separator 11 is removed. In this way, a treatment for removing the solvent remaining in the primary recovery gas is performed on the primary recovery gas.

  The primary recovery gas discharged from the purifier 17 is stored in the gas storage tank 19. The primary recovery gas stored in the gas storage tank 19 is sampled, for example, and the concentration of the solvent in the gas is measured by gas chromatography using a thermal conductivity detector (TCD).

  If the concentration of the solvent in the primary recovery gas is a predetermined concentration (for example, 1% by volume) or less, the primary recovery gas stored in the gas storage tank 19 is supplied to the heat exchanger 2. The primary recovery gas supplied to the heat exchanger 2 is liquefied in the same manner as the gas from the cylinder 1. In this way, the primary recovery gas having a concentration of the solvent in the gas equal to or lower than the predetermined concentration is used as the liquefied gas and reused as the supercritical fluid contained in the mobile phase.

The pressure of the primary recovery gas supplied to the heat exchanger 2 is the pressure P ₂ set by the second back pressure valve 13, and P ₂ is slightly lower than the pressure P ₀ set by the pressure regulating valve 20. Therefore, the primary recovery gas is sent to the heat exchanger 2 with priority over the new gas from the cylinder 1. In this way, the primary recovery gas is liquefied when the pressure of the primary recovery gas is higher than the pressure of the new gas from the cylinder 1.

Next, the reuse of the secondary recovery gas will be described.
When the secondary recovery gas is pressurized to the pressure P ₃ , the secondary recovery gas is supplied to the purifier 17 through the third back pressure valve 16 and the check valve 30. From the secondary recovery gas supplied to the purifier 17, a trace amount of solvent entrained by, for example, decompression in the second tank 14 is removed in the same manner as the primary recovery gas. In this way, the secondary recovery gas is subjected to a treatment for removing the solvent remaining in the secondary recovery gas.

  The secondary recovery gas discharged from the purifier 17 is stored in the gas storage tank 19, and the concentration of the solvent in the gas is measured in the same manner as the primary recovery gas, and the concentration of the solvent in the gas is a predetermined concentration (for example, 1). If it is less than (volume%), it is supplied to the heat exchanger 2. The secondary recovery gas supplied to the heat exchanger 2 is liquefied similarly to the gas from the cylinder 1. In this way, the secondary recovery gas having a concentration of the solvent in the gas equal to or lower than the predetermined concentration is used as the liquefied gas and reused as the supercritical fluid contained in the mobile phase.

The pressure of the secondary recovery gas supplied to the heat exchanger 2 is the pressure P ₃ set by the third back pressure valve 16, and P ₃ is higher than the pressure P ₀ set by the pressure regulating valve 20. Since it is set to a slightly large value, the secondary recovery gas is sent to the heat exchanger 2 with priority over the new gas from the cylinder 1. In this way, when the pressure of the secondary recovery gas is higher than the pressure of the new gas from the cylinder 1, the secondary recovery gas is liquefied.

  In the gas storage tank 19, when the concentration of the solvent in the gas is higher than a predetermined concentration, the recovered gas in the gas storage tank 19 is discharged out of the system from the gas storage tank 19. The recovered gas that has been discharged may be discharged to the outside air, or may be returned to the second tank 14 and reused, for example, after being subjected to an appropriate solvent removal process, or compressed by a condenser or the like to be bombed. It may be housed and reused. Alternatively, when the concentration of the solvent in the gas is higher than the predetermined concentration, a new gas is introduced from the cylinder 1 into the gas storage tank 19 using, for example, a compressor, and the recovered gas in the gas storage tank 19 is sufficient. And may be supplied to the heat exchanger 2.

  In addition, the flow of the recovered gas supplied from the gas storage tank 19 to the heat exchanger 2 to the cylinder 1 is prevented by a check valve 21. Further, in the case where the pressure of the recovered gas is lower than the pressure set by the pressure regulating valve 20, carbon dioxide is supplied from the cylinder 1 toward the heat exchanger 2, but the backflow of gas from the cylinder 1 is It is prevented by the check valve 29 and the check valve 30.

  Thereafter, the valve 24 is appropriately opened and closed in accordance with the substance detected by the detector 9, and the desired optical isomer in the sample is separated.

  In the present embodiment, the recovery rate of carbon dioxide supplied for the supercritical fluid varies depending on the type of solvent, the composition of the mobile phase, and the like. For example, a primary phase when a mobile phase composed of carbon dioxide and methanol is used. The recovery rate is about 80% in theory, and the unrecovered 20% is considered to be a portion re-dissolved in the solvent mainly by the gas-liquid separator 11. Further, when a mobile phase composed of carbon dioxide and acrylonitrile (carbon dioxide / acrylonitrile: 60/40 (vol%)) is used, the loss during the primary recovery is about 30%.

  In this embodiment, by using a supercritical fluid of carbon dioxide, it is possible to separate an acidic substance such as an organic carboxylic acid as it is without adding an acid to the mobile phase and without performing esterification. It is. This is considered because the carbon dioxide in a mobile phase shows weak acidity. Since it is not necessary to add an acid to the mobile phase, the decomposition of the acidic substance as a desired substance can be suppressed, and since it is not necessary to esterify, compared to the case of separation after esterification Thus, the yield of the acidic substance from the sample can be increased.

  In the present embodiment, optical isomers can be separated with high purity. For example, in the optical resolution of a racemic guaifenesin, 99.0% R-isomer is obtained in a yield of 94.9%, and 98.8% S-isomer is 98.8% in optical purity. The yield is obtained.

  In this embodiment mode, a desired substance in a sample can be separated with high productivity by intermittently injecting the sample into the mobile phase. For example, in the above optical resolution, it is possible to produce 4.06 kg of an optical isomer per 1 kg of the column packing material per day.

  In this embodiment, after the solvent is mixed with the liquefied gas, the temperature of the mixed solvent is adjusted to use the liquefied gas in the mixed solvent as a supercritical fluid. For example, the liquefied gas before the solvent is mixed is used. A heat exchanger that heats the liquefied gas so that it exceeds the critical temperature, and after mixing the solvent with the supercritical fluid, the temperature of the mobile phase may be adjusted to a temperature suitable for separation in the column 8 good.

  In the present embodiment, the gas-liquid separation device 11 is provided so that the gas is separated upward and the solvent is separated downward. However, the present invention is not limited to such an installation, and the vertical direction is not limited. The gas-liquid separation device 11 and the purification device 17 may be provided obliquely or orthogonally.

  Moreover, in this Embodiment, you may provide the further means for removing a solvent from collection | recovery gas. Examples of such means include a buffer tank provided between the compressor 15 and the third back pressure valve 16.

Further, in the present embodiment, the configuration in which one gas storage tank 19 is provided is shown, but a plurality of gas storage tanks 19 may be provided in parallel to the purifier 17. According to such an embodiment, it is possible to apply a detection method that requires a long time in detecting the concentration of the solvent in the gas, and for example, it is possible to further improve the detection accuracy of the concentration of the solvent in the gas. Alternatively, a cheaper detection device can be used.

  Moreover, although the form which detects the density | concentration of the solvent in the gas accommodated in the gas storage tank 19 was shown in this Embodiment, you may connect a some refinement | purification apparatus in series instead of the gas storage tank 19. FIG. According to such a form, a recovered gas containing no solvent or containing only a solvent having a predetermined concentration or less is always obtained, and detection of the concentration of the solvent in the gas can be omitted. In such a form, it is necessary to provide a means for the recovered gas to flow through these purifiers sequentially. Examples of such means include a compressor and a back pressure valve that are appropriately installed to provide an appropriate pressure difference between the purification apparatuses.

  In the present embodiment, the gas is recovered in two stages of the gas-liquid separator 11 and the second tank 14, but a tank is further provided in series with the second tank 14, and these are provided. It is possible to collect the gas in three stages, four stages, or more stages by configuring the like as the second tank 14.

  In this embodiment, since the mobile phase containing the optical isomer in the sample is gas-liquid separated, the desired liquid isomer is contained in the separated liquid, and the desired pressure is obtained by decompressing the separated liquid. These optical isomers can be easily recovered in a concentrated state. In addition, since the desired optical isomer can be recovered in a concentrated state by simply decompressing it, it is advantageous for the separation of optically unstable optical isomers that are likely to change over time due to heat. .

  In the present embodiment, in the production of optical isomers by supercritical fluid chromatography, a mobile phase containing a supercritical fluid generated from a liquefied gas and a solvent is generated, and the mobile phase that has passed through the column is converted into a solvent. The gas in which the concentration of the solvent in the separated gas is not more than a predetermined concentration (more preferably not more than 1% by volume) is liquefied and reused as a supercritical fluid. Thus, the gas forming the supercritical fluid can be reused. Thereby, the cost of carbon dioxide can be reduced. Moreover, the discharge | release to the environment of the carbon dioxide in a supercritical fluid chromatography can be suppressed.

  Further, in this embodiment, since the gas whose concentration in the separated gas is equal to or lower than the predetermined concentration is reused, the concentration of the solvent in the liquefied gas generated by gas reuse is always the above. It becomes below a predetermined density | concentration and the fluctuation | variation of the composition of the mobile phase containing the supercritical fluid produced | generated from such a liquefied gas can be prevented. Therefore, the optical isomer can be stably produced.

  Further, in the present embodiment, each recovered gas is liquefied when the pressure of each subsequent recovered gas is higher than the pressure of the new gas from the cylinder 1, so that the recovered gas can be reused more. It can be performed with a simple configuration and operation.

  Further, in the present embodiment, the pressure of the solution separated from the mobile phase is further reduced, and the secondary recovery gas separated from the solution is further recovered by reducing the pressure of the solution. Further, the concentration of the solvent in the gas is predetermined. Since the secondary recovery gas having a concentration equal to or less than the above is used as the liquefied gas and reused, the recovery rate of the gas from the mobile phase can be further increased.

  In the present embodiment, since the secondary recovery gas is compressed to a pressure higher than the pressure of the primary recovery gas, the secondary recovery gas can be joined to the pipe through which the primary recovery gas flows. Therefore, the secondary recovery gas can be reused with a simple configuration and operation.

  Further, in the present embodiment, since the process for removing the solvent remaining in each recovered gas is performed on each recovered gas, the concentration of the solvent in the recovered gas can be further reduced, and the optical isomerism can be reduced. The body can be manufactured more stably over a long period of time.

  In the present embodiment, since a filler containing a polysaccharide derivative that identifies optical isomers is used, it is possible to deal with separation of various optical isomers and is excellent in optical resolution. Further, productivity in the production of optical isomers by supercritical fluid chromatography can be further enhanced.

  In the present embodiment, since the gas-liquid separation device 11 including the inner cylinder 34 extending into the outer cylinder 31 to a position where the mobile phase does not splash in the outer cylinder 31 is used, the gas-liquid separation is performed. In addition, it is possible to reduce the mixing of the mobile phase droplets generated in the process, and it is possible to obtain a reusable high-purity gas by gas-liquid separation.

  In the present embodiment, since the mobile phase before being introduced into the outer cylinder 31 is passed through the jacket 35 for adjusting the temperature of the outer cylinder 31, the mobile phase before being introduced into the outer cylinder 31 is reduced. The temperature can be adjusted in advance to the temperature of the outer cylinder 31. Therefore, the efficiency of gas-liquid separation by adjusting the temperature of the outer cylinder 31 can be further enhanced.

  In the present embodiment, since the mobile phase supply pipe 36 is provided in a shape that wraps around the outer peripheral wall surface of the outer cylinder 31 in the jacket 35, the efficiency of gas-liquid separation by adjusting the temperature of the outer cylinder 31 can be reduced. Can be increased.

  Further, in the present embodiment, since the outer cylinder 31 is cylindrical, a uniform pressure is applied to the peripheral wall of the outer cylinder 31, so that gas-liquid in gas-liquid separation under high-pressure conditions such as supercritical fluid chromatography. The durability of the separation device 11 can be further enhanced.

  In the present embodiment, since the check valve 21 for preventing the gas flow from the heat exchanger 2 to the cylinder 1 is provided between the cylinder 1 and the heat exchanger 2, the refining apparatus It is possible to prevent the gas purified in 17 from flowing into the cylinder 1.

  Further, in the present embodiment, check valves are provided corresponding to the respective gas-liquid separation devices 11 and the respective second tanks 14, and the second back pressure valve 13 and the third back pressure valve 16 are provided. Since a check valve is also provided between the purifier 17 and the gas-liquid separator 11, gas mixing between the second tank 14, and the second and third back pressure valves, and As a result, contamination of the apparatus can be prevented.

  In the present embodiment, since the flow path of the solution connecting the first tank 12 and the second tank 14 is kept warm by, for example, the heating coil 27, the heat of vaporization is reduced by the reduced pressure during the solution feeding. It is possible to prevent a decrease in the temperature of the solution due to the occurrence, and it is possible to suppress adhesion and remaining of optical isomers in the flow path of the solution and the second tank 14.

It is the schematic which shows the structure of an example of the supercritical fluid chromatographic fractionation apparatus used for the separation method of this invention. It is sectional drawing which shows the longitudinal cross-section of the principal part of an example of the gas-liquid separator of this invention. It is sectional drawing which shows the cross section of the principal part when the gas-liquid separator shown in FIG. 2 is cut | disconnected by the AA line.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Cylinder 2, 6 Heat exchanger 3, 5 Pump 4 Solvent tank 7 Injector 8 Column 9 Detector 10 1st back pressure valve 11 Gas-liquid separation device 12 1st tank 13 2nd back pressure valve 14 2nd tank 15 Compressor 16 Third back pressure valve 17 Purification device 18 Third tank 19 Gas storage tank 20 Pressure regulating valve 21, 25, 28-30 Check valve 22 Buffer tank 23 Column oven 24, 26 Valve 27 Heating coil 31 Outer cylinder 32 Flange part 33 Introduction part 34 Inner cylinder 35 Jacket 36 Mobile phase supply pipe

Claims (7)

A sample containing a mixture of optical isomers is injected into a mobile phase containing a supercritical fluid, and the mobile phase into which the sample has been injected is passed through a column having a filler that identifies the optical isomer, A method for producing a desired optical isomer by separating it from the mixture,
Generating a mobile phase containing a supercritical fluid generated from a liquefied gas and a solvent;
Separating the mobile phase that has passed through the column into the solvent and the gas that formed the liquefied gas;
Gas the concentration of the solvent in a separate gas gas is equal to or less than a predetermined concentration, and liquefied gas, viewed including the steps, a to reuse the supercritical fluid contained in the mobile phase,
In the recycling step, when the pressure of the separated gas having a concentration of the solvent equal to or lower than a predetermined concentration is higher than the pressure of a gas newly supplied to generate the liquefied gas, the separation is performed. A method for producing an optical isomer by supercritical fluid chromatography, wherein the gas is liquefied .   The method for producing an optical isomer by supercritical fluid chromatography according to claim 1, wherein the predetermined concentration is 1% by volume. Further comprising a step of lowering the pressure of the solvent separated in the step of separating, and a step of recovering a gas separated from the solvent by reduced pressure,
The gas concentration of the solvent was by gas is recovered gas is equal to or less than a predetermined concentration, and liquefied gas, according to claim 1, characterized in that reuse the supercritical fluid contained in the mobile phase or 3. A method for producing an optical isomer by supercritical fluid chromatography according to 2 . The method for producing an optical isomer by supercritical fluid chromatography according to claim 3 , further comprising the step of compressing the recovered gas to a pressure higher than the pressure of the separated gas. The method according to any one of claims 1 to 4 , further comprising a step of subjecting either one or both of the separated gas and the recovered gas to a treatment for removing the solvent remaining in the gas. A method for producing an optical isomer by supercritical fluid chromatography as described in the above item. The supercritical fluid according to any one of claims 1 to 5 , wherein a filler containing a polysaccharide for identifying optical isomers or a polysaccharide derivative that is a derivative thereof is used as the filler. A method for producing optical isomers by chromatography. The polysaccharide production method of optical isomers by supercritical fluid chromatography according to claim 6, characterized in that a cellulose scan or amylose.

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