JP4771460B2 - Chromatographic separation method - Google Patents

Description

  The present invention relates to a chromatographic separation method that uses an optical resolution adsorbent to separate and purify an optically active substance simply and with high purity.

  The simulated moving bed type chromatographic separation apparatus is composed of a large number of unit packed towers (hereinafter simply referred to as packed towers) packed with an adsorbent having a selective adsorption ability with respect to a specific component of two or more components contained in the stock solution. In addition, the stock solution and the eluent are supplied to the endless packed bed by connecting the unit packed column at the most downstream part and the unit packed column at the most upstream part in series. , A position where the fraction moving in the packed bed (first fraction: A fraction) and the fraction moving in the packed bed (second fraction: C fraction) are different. The stock solution is supplied by sequentially moving the stock solution supply position, the eluent supply position, the A fraction extraction position, and the C fraction extraction position to the downstream side in the fluid circulation direction of the packed bed while maintaining a fixed positional relationship. Can be performed continuously It is well known that the processing operations is an apparatus for artificial manner (for example, Patent Document 1).

  The simulated moving bed type chromatographic separation apparatus is used for various separations, but in the separation of optical isomers, a column packed with an adsorbent for optical resolution is used, and a known pseudo moving bed type chromatographic separation method is used. Has proposed a method for separating optical isomers (Patent Document 2).

In addition, as an operation method that is not a general pseudo moving bed type chromatographic separation in which the liquid to be treated circulates through the packed bed while always supplying the stock solution and the eluent and extracting the A fraction and the C fraction. The operation methods described in Patent Document 3 and Patent Document 4 have been proposed. These operation methods are used in an operation method using a column packed with a solid adsorbent having an ion exchange resin as a filler and having a molecular sieve action.
Japanese Patent No. 2962589 Japanese Patent No.2925753 JP 2001-334103 A Japanese Patent Publication No. 60-55162

  When performing chromatographic separation and purification on an optical isomer using an optical resolution adsorbent, an apparatus of a pseudo moving bed system as in Patent Document 1 is used. Separation has been achieved by the interaction between the adsorbent for optical resolution and the object to be separated, but the interaction here is not a physical action like the action of a molecular sieve, but the action of intermolecular force and the adsorbent. It has an affinity between.

  When chromatographic separation and purification is performed using an adsorbent having such an action, the amount adsorbed on the adsorbent is often not proportional to the concentration (that is, it becomes a non-linear adsorption isotherm). Therefore, the elution curve tends to tail. Moreover, the moving speed of the elution curve is likely to change depending on the concentration. For this reason, when separating in the general simulated moving bed system, the concentration distributions of the components to be separated are easily overlapped, and when high separation performance is required in the general simulated moving bed system, the unit It is necessary to reduce the stock solution supply per adsorbent, reduce the product category recovery rate, or increase the number of columns. As a result, it is necessary to increase the amount of the adsorbent or increase the consumption of the eluent, and the processing apparatus and running cost tend to be expensive.

  As a result of intensive studies by the present inventors, the simulated moving bed system continuously supplies the stock solution and the eluent, and extracts the fraction in which the target component is purified, and the extraction position moves downstream. As a result of collecting the liquid that passes through the extraction position during the period from the start to the second transfer, it was found that the separation performance deteriorates because the concentration distribution tends to overlap due to tailing.

  Accordingly, the object of the present invention is to pay attention to various problems in the conventional method as described above, and in a chromatographic separation method using an adsorbent for optical resolution as an adsorbent, a pseudo-moving that provides a simple and high separation performance. The object is to provide a layered chromatographic separation method.

  Moreover, the subject of this invention is providing the method of isolate | separating an optical isomer with said chromatographic separation method.

In order to solve the above-mentioned problems, a chromatographic separation method according to the present invention has a plurality of unit packed towers packed with an optical resolution adsorbent, and these unit packed towers are connected in series with a pipe and at the most downstream portion. By connecting the unit packed column and the unit packed column in the uppermost stream portion to the packed bed constituting the endless circulation system, the stock fluid containing two or more components is allowed to flow, so that the affinity for the adsorbent is increased. For the circulation system in which adsorption zones are formed in order,
First, at least one of the stock solution and the eluent is supplied into the circulation system, and a total amount equal to the amount of the liquid supplied into the circulation system is extracted from a location corresponding to the packed tower enriched with a certain component in the circulation system. Combining the step with the second step of circulating the liquid in the circulation system without supplying any undiluted solution and eluent, and removing the separated components, and
In the first step, the eluent supplied to the circulation system by stock or eluant feed pump is fed into the circulation system by the supply position or the eluent supply pump stock supplied to the circulatory system by the starting solution feed pump Separation is performed by sequentially moving the supply position and the extraction position of each component to the downstream side of the circulation system in accordance with the movement of the adsorption zone in the circulation system,
In the second step, the total amount of circulating fluid extracted outside the circulatory system from one location or two locations in the circulatory system, by supplying again the circulating system using an eluent supply pump and / or the starting solution feed pump It consists of a method characterized by using a chromatographic separation device that circulates in the circulation system.

  According to Development of chiral stationary phases consisting of polysaccharide derivatives (Kazuma Ogumi, Hirofumi Oda, Akito Ichida, Journal of Chromatography A, 694, 91-100, 1995) It can be classified into an optical resolution adsorbent used and an optical resolution adsorbent using a low molecular weight compound having optical resolution. Examples of the optically active polymer compound include, for example, polysaccharide derivatives (such as cellulose and amylose esters or carbamates), polyacrylate derivatives, or adsorbents obtained by chemically modifying polyamide derivatives on silica gel, or the polymer without using silica gel. Examples thereof include a bead-type adsorbent obtained by granulating itself and a cross-linked adsorbent obtained by further crosslinking a polymer. Examples of the low molecular weight compound having optical resolution include amino acids or derivatives thereof, crown ethers or derivatives thereof, cyclodextrins or derivatives thereof, and the like. These low molecular compounds are usually used after chemically modifying an inorganic carrier such as silica gel, alumina, zirconia, titanium oxide, silicate, diatomaceous earth, or an organic carrier such as polyurethane, polystyrene, or polyacrylic acid derivative.

  Commercially available products of these adsorbents can also be used. For example, Daicel Chemical Industries, Ltd. CHIRALCEL OB (registered trademark, the same applies hereinafter), CHIRALCEL OD, CROWNPAK CR (+), CHIRALCEL CA-1, CHIRALCEL OA, CHIRALCEL OK, CHIRALCEL OJ, CHIRALCEL OC, CHIRALCEL OF, CHIRALCEL OG, CHIRALPAK WH, CHIRALPAK WM, CHIRALPAK WE, CHIRALPAK OT (+), CHIRALPAK AD (+), IR

  First, at least one of the stock solution and the eluent is supplied into the circulation system, and a total amount equal to the amount of the liquid supplied into the circulation system is extracted from a location corresponding to the packed tower enriched with a certain component in the circulation system. The process specifically refers to the following FA, DA, FC, DC, FD-A, and FD-C processes.

  That is, in the chromatographic separation method according to the present invention, the operation process can be an operation process that is repeated in the following process order, for example. For example, as an operation process, (1) a D-A process for supplying the eluent and extracting the entire amount of the extracted liquid from the first fraction extraction position; (2) supplying the stock solution or the stock solution and the eluent and extracting the amount of the liquid The FA process or the FD-A process in which the total amount of the first fraction is extracted from the first fraction extraction position, (3) supply of any undiluted solution and eluent, and removal of the liquid in the circulation system without extracting the separated components R step to circulate, (4) DC step for supplying the eluent and extracting the entire amount of the extracted liquid from the second fraction extracting position, (5) Supplying all undiluted solution and eluent, separated components The process can be repeated in the order of the R process in which the liquid in the circulation system is circulated without removing the liquid.

  Further, in the chromatographic separation method according to the present invention, as an operation step, (1) an FA process or FD in which the stock solution or the stock solution and the eluent are supplied and the entire amount of the withdrawn liquid is withdrawn from the first fraction extraction position. -A step, (2) D-A step of supplying the eluent and extracting the entire amount of the extracted liquid from the first fraction extracting position, (3) Supplying all the stock solution and eluent, R step for circulating the liquid in the circulation system without performing extraction, (4) DC step for supplying the eluent and extracting the entire amount of the extracted liquid from the second fraction extraction position, (5) The process may be repeated in the order of the R process in which the liquid in the circulation system is circulated without supplying the stock solution and the eluent and extracting the separated components.

  Further, in the chromatographic separation method according to the present invention, as an operation step, (1) a D-A step of supplying an eluent and extracting the total amount of the extracted liquid from the first fraction extraction position, (2) R step of circulating the liquid in the circulation system without supplying the stock solution and the eluent, and extracting the separated components, (3) The second fraction extraction position for supplying the eluent and for the total amount of the extracted liquid (4) Extraction process from the second fraction extraction position while supplying the stock solution or the stock solution and the eluent and extracting the total amount of the extraction solution from the second fraction extraction position, (5) The process may be repeated in the order of the R process in which the liquid in the circulation system is circulated without supplying the stock solution and the eluent and extracting the separated components.

  Further, in the chromatographic separation method according to the present invention, as an operation step, (1) a D-A step of supplying an eluent and extracting the total amount of the extracted liquid from the first fraction extraction position, (2) R step of circulating the liquid in the circulation system without supplying the undiluted solution and the eluent, and (3) supplying the undiluted solution or the undiluted solution and the eluent, FC process or FD-C process for extracting from the fraction extraction position, (4) DC process for supplying the eluent and extracting the entire amount of the extracted liquid from the second fraction extraction position, (5) The process may be repeated in the order of the R process in which the liquid in the circulation system is circulated without supplying the stock solution and the eluent and extracting the separated components.

In the chromatographic separation method according to the present invention, high separation performance satisfying all the conditions that the particle size of the adsorbent is 150 μm or less, the theoretical plate number is 200 plates / m or more, and the purity of the target product is 95% or more. The effect is remarkable in the condition where is required. Here, the number of theoretical plate (N) is one of the indicators for judging the performance and efficiency of the column. There are various calculation methods, but the 14th revised Japanese Pharmacopeia (JP = Japanese Pharmacopeia) ) Uses the following formula (1), and this calculation formula is also used in the present invention to convert the column length per 1 m. In the present invention, the sample is, for example, an optical isomer to be separated, and the solvent is the same as the eluent used for separation. When determining the number of stages, the injection amount is set to such an amount that the theoretical stage number does not change when the injection amount is halved or doubled.
N = 5.55 (Tr / W _0.5 ) ² (1)
here,
Tr: Retention time of substance W _0.5 : Peak width at the midpoint of the peak height. However, Tr and W _0.5 uses the same unit.

Furthermore, in the chromatographic separation method according to the present invention, in the second step, the entire amount of the circulating fluid extracted from one or two locations in the circulation system to the outside of the circulation system is used as an eluent supply pump and / or a stock solution supply pump. A chromatographic separation device is used which performs circulation in the circulation system by supplying it again into the circulation system. Thereby, the mixing of the separation object in the circulation pump when the circulation pump is provided in the circulation system can be avoided, and higher separation performance can be obtained.

  The present invention also provides a chromatographic separation method characterized by separating optical isomers by the method as described above.

  Here, the optical isomer refers to the following. In other words, it has a symmetrical chemical structure, and when polarized light, which is a wave that vibrates in only one direction through a Nicol prism, is applied, one rotates the plane of polarization to the right and the other rotates to the left. When both sex and levorotality are expressed, they are said to be optical isomers. For example, when the structural formula of lactic acid is written two-dimensionally, two structures can be considered: those having —OH groups on the left side of the asymmetric carbon are L-type (or L-form), and those having —OH groups on the right side. Although it is called D-type (or D-form), when polarized light is applied to such a substance as described above, it exhibits dextrorotatory and levorotatory properties, and becomes an optical isomer.

  According to the chromatographic separation method of the present invention, in the chromatographic separation step using the column packed with the optical resolution adsorbent, it is possible to obtain a simpler and higher separation performance than the conventional method. In particular, optical isomers can be separated with high separation performance.

  Hereinafter, preferred embodiments of a chromatographic separation method according to the present invention will be described with reference to the drawings. However, the present invention is not limited to the following embodiments without departing from the gist thereof.

  FIG. 1 shows a chromatographic separation apparatus suitable for carrying out a chromatographic separation method according to an embodiment of the present invention. The chromatographic separation apparatus 1 includes four unit packed columns 4 (No. 1 to No. 4 packed columns), and each packed column 4 is contained in a stock solution 3 supplied from a stock solution tank 2. An adsorbent 5 (adsorbent for optical resolution) having a selective adsorption ability with respect to a specific component in two or more components is packed. Each packed column 4 is connected by piping 6 from the outlet of each packed column 4 to the inlet of the adjacent packed column 4 and connected in series as a whole, and the last unit packed column 4 (for example, FIG. 1 is connected to the inlet of the foremost unit packed column 4 (for example, No. 1 packed column 4 in FIG. 1) by a pipe 6, so that all the unit packed columns 4 are connected. Are connected endlessly. Therefore, the packed bed in which all the unit packed columns 4 are connected endlessly is formed as a system 7 in which the fluid can circulate in the direction of the arrow.

  Between each adjacent packed tower 4 in the circulation system 7, shut-off valves R1, R2, R3, R4 capable of blocking the packed towers are provided. Between each shut-off valve R1 to R4 and the outlet of each packed tower 4 located on the upstream side thereof, a fraction having a high moving speed in the packed bed (Fraction A: low adsorption capacity for the adsorbent) A fraction extraction valves A1, A2, A3, and A4 are provided for the purpose of extracting the first fraction containing a large amount of non-adsorbing substances. Each A fraction extraction line 8 is merged into a single A fraction merging pipe 9. Similarly, extraction of the C fraction for the purpose of extracting a fraction having a low moving speed in the packed bed (C fraction: a second fraction containing a large amount of an adsorbent having a high adsorption capacity with respect to the adsorbent). Valves C1, C2, C3, C4 are provided. Each C fraction extraction line 10 is merged and grouped into one C fraction merge pipe 11. In addition, two-way valves Z1, Z2, Z3, and Z4 are provided for the purpose of extracting the entire amount in the circulation process. Each circulation extraction line 12 is merged and collected in a circulation extraction / merging pipe 13 and merged with the eluent supply line 20 upstream of the eluent supply pump PD.

  The circulation system 7 can be supplied with the stock solution 3 contained in the stock solution tank 2 and the eluent 16 contained in the eluent tank 15. In this embodiment, the stock solution 3 is supplied via the stock solution supply line 17 by a stock solution supply pump PF capable of controlling the supply flow rate. The stock solution supply line 17 is branched to each stock solution branch supply line 18, and the stock solution can be supplied to the inlet side of each unit packed tower 4 via each stock solution branch supply line 18. Each stock solution branch supply line 18 is provided with open and close stock solution supply valves F1, F2, F3, and F4, and the stock solution is supplied to the corresponding unit packed tower via the opened stock solution supply valve line. The In addition, when it is desired to operate the raw solution supply pump PF even in a process in which the raw solution is not supplied for stable operation of the raw solution supply pump PF, a valve F0 and a raw solution circulation line 19 are provided in front of the raw solution supply valve to provide a solution tank 2 You may make it return to.

  In this embodiment, the total amount of the circulating fluid is extracted at any one of the extraction valves Z1 to Z4, and is passed through the circulation extraction confluence pipe 13 to the upstream portion of the eluent supply pump PD between the eluent tank 15 and the eluent supply pump PD. The effluent is supplied to the circulation system 7 again through the eluent supply line 20 by the eluent supply pump PD which can be joined and the supply flow rate can be controlled. The eluent supply line 20 is branched to each eluent branch supply line 21, and the eluent can be supplied to the inlet side of each unit packed column 4 via each eluent branch supply line 21. Each eluent branch supply line 21 is provided with eluent supply valves D1, D2, D3, and D4 that can be opened and closed, and connected to the corresponding unit packed tower 4 via the opened eluent supply valve line. Eluent is supplied. If the eluent supply pump PD is to be operated in steps other than the step of supplying the eluent and the circulation step for stable operation of the eluent supply pump PD, the eluent is provided before the eluent supply valve. A circulation line may be provided to return to the eluent tank 15.

  In the chromatographic separation apparatus 1 configured as described above, the separation process is performed as follows. That is, in the chromatographic separation apparatus 1, the step of supplying the stock solution and extracting the entire amount from the A fraction extraction position, the step of supplying the eluent and extracting the entire amount from the C fraction extraction position, supplying the eluent and supplying the total amount of A It is possible to operate in four steps: the step of extracting from the fraction extraction position, and the step of circulating the liquid in the circulation system without any supply, extraction, or shutoff. It can be performed.

  In the step of supplying the stock solution and extracting the entire amount from the A fraction extraction position (FA step), one of the stock solution supply valves is opened and the stock solution is supplied into the circulation system 7 from the inlet side of the corresponding unit packed column 4. Then, open the A fraction extraction valve A (any one of A1 to A4) corresponding to the extraction position of the A fraction, close the shutoff valve R (any one of R1 to R4) immediately downstream thereof, and The entire amount of the A fraction is extracted through the extraction line 8.

  In the step of supplying the eluent and extracting the entire amount from the C fraction extraction position (DC step), one of the eluent supply valves is opened, and the eluent is introduced into the circulation system 7 from the inlet side of the corresponding unit packed column 4. The C fraction extraction valve C (any one of C1 to C4) corresponding to the C fraction extraction position is opened, and the shutoff valve R (any one of R1 to R4) immediately downstream is closed. , C fraction is extracted through the C fraction extraction line 10.

  In the step of supplying the eluent and extracting the entire amount from the A fraction extraction position (D-A step), one of the eluent supply valves is opened, and the eluent is introduced into the circulation system 7 from the inlet side of the corresponding unit packed column 4. The A fraction extraction valve A (any one of A1 to A4) corresponding to the A fraction extraction position is opened, and the shutoff valve R (any one of R1 to R4) immediately downstream is closed. The entire amount of the A fraction is extracted through the A fraction extraction line 8.

  In the process of moving the liquid in the circulation system without performing any supply or extraction (circulation process: R process), one of the circulating fluid extraction valves Z (any one of Z1 to Z4) is opened and immediately downstream thereof. A certain shutoff valve R (any one of R1 to R4) is closed, and the entire amount is drawn out of the circulation system 7 from the circulation extraction line 12, and the eluent supply valve D corresponding to the eluent supply position via the eluent supply pump PD. Supply from (any of D1 to D4).

  Next, each valve opening / closing cycle will be described. An example of this operation is shown in Table 1. In Table 1, the open / close control states of the F and D valves are shown, and the numbers in the table indicate the numbers of the respective valves (for example, 1 in the F section indicates the F1 valve), and the numbers are entered. It means that the valve is opened. When the column is blank, the valve is closed. In addition, in the terms of the A and C valves and the circulating fluid extraction valve Z, the numbers of valves for extracting the entire amount are shown. If the field is blank, the valve is not extracted. The R valve indicates that the valve in which the number is written is closed. In the case of a blank, the valve open state is indicated. Further, in the terms of the stock solution supply pump PF and the eluent supply pump PD, a circle indicates an operating state, and a blank state indicates a stopped state. In Table 1, the process No. 1-1 to 1-5 to step No. 4-1. Up to 4-5 shows one cycle of the separation process in the present chromatographic apparatus 1.

(About step 1-1)
Step No. shown in Table 1 As for 1-1 to 1-5, in step 1-1, the eluent supply valve D3 is opened to supply the eluent into the circulation system 7, and the A fraction extraction valve A1 is opened, from which the A fraction is separated. Extract the entire amount of. Therefore, this step 1-1 corresponds to the D-A step of supplying the eluent as referred to in the present invention and extracting the entire amount from the A fraction extraction position. At this time, the stock solution is returned to the stock solution tank through the F0 valve.

(About step 1-2)
In step 1-2, the stock solution supply valve F1 is opened to supply the stock solution into the circulation system 7, and the A fraction extraction valve A1 is opened, from which the entire amount of the A fraction is extracted. Therefore, this step 1-2 corresponds to the FA step of supplying the stock solution in the present invention and extracting the whole amount from the A fraction extraction position.

(About step 1-3)
In step 1-3, the circulating fluid extraction valve Z2 is opened, and the entire amount of circulating fluid is extracted from the circulating system 7 therefrom. The extracted circulating fluid is supplied again into the circulation system 7 from the eluent supply valve D3 by the eluent supply pump PD as a circulation pump. Therefore, this step 1-3 corresponds to the step of moving the liquid in the circulation system (second step: circulation step R) without performing any supply, extraction, or shutoff in the present invention. At this time, the stock solution is returned to the stock solution tank through the F0 valve.

(About step 1-4)
In step 1-4, the eluent supply valve D3 is opened to supply the eluent into the circulation system 7, and the C fraction extraction valve C3 is opened, from which the entire amount of the C fraction is extracted. Therefore, this step 1-4 corresponds to the DC step of supplying the eluent as used in the present invention and extracting the entire amount from the C fraction extraction position. At this time, the stock solution is returned to the stock solution tank through the F0 valve.

(About Step 1-5)
In step 1-5, the circulating fluid extraction valve Z2 is opened, and the entire amount of circulating fluid is extracted from the circulating system 7 therefrom. The extracted circulating fluid is supplied again into the circulation system 7 from the eluent supply valve D3 by the eluent supply pump PD as a circulation pump. Therefore, this step 1-5 corresponds to the step of moving the liquid in the circulation system (second step: circulation step R) without performing any supply, extraction, or shutoff in the present invention. At this time, the stock solution is returned to the stock solution tank through the F0 valve.

  In the series of steps 1-1 to 1-5 described above, the supply position of the stock solution and the eluent, the extraction position of the A fraction and the C fraction, and the position of the circulating fluid extraction valve in the circulation process are in a specific positional relationship. When the series of steps 1-1 to 1-5 is completed, the position of each control target valve is shifted to the downstream side while maintaining the specific positional relationship, and the next series of steps is performed. Steps 2-1 to 2-5 are executed. By performing this transition sequentially, a function equivalent to the operation operation of the known pseudo moving bed type chromatographic separation apparatus can be achieved.

  In steps 2-1 to 2-5, steps 3-1 to 3-5, and steps 4-1 to 4-5 following the series of steps 1-1 to 1-5, the position of each valve is set to one as described above. The operation | movement similar to the said process 1-1 to 1-5 is performed in the state which shifted to each. When steps 1-1 to 4-5 are executed, one cycle of the separation process is completed.

  In the above separation operation, the stock solution supply pump PF and the eluent supply pump PD may be set to a constant flow rate discharge setting or may perform flow rate control.

  In the chromatographic separation apparatus 1 described above, in the circulation step, the entire amount of the circulating fluid immediately before the eluent supply in the circulation system 7 is extracted from the circulating fluid extraction valve Z, and immediately after the valve Z extracted using the eluent supply pump PD. Supply from the downstream eluent supply valve D. In other words, by sharing the eluent supply pump PD in the step of supplying the eluent and the step of circulating in the circulation system 7, the number of pumps required in the separation operation can be reduced to a total of two. Thus, the entire chromatographic separation apparatus 1 can be simplified.

  Further, the circulating fluid extracted in the circulation step has the lowest concentration of the stock solution in the circulation system 7 and the physical properties such as specific gravity and viscosity are the closest to the eluent, so that the eluent flowing into the eluent supply pump PD The physical properties of the circulating fluid such as specific gravity and viscosity are always stable in the separation operation. This makes it possible to operate at a stable flow rate that is closer to the set value than the conventional method without a control device in the circulation process, or with only a cheap and simple control device, and can stabilize the separation performance.

  Further, each component can be extracted by a normal valve without using a back pressure valve on the extraction valve side, so that the pressure specification in the circulation system can be lowered. From this aspect, the chromatographic separation apparatus 1 can be simplified and the cost can be reduced.

FIG. 2 shows another chromatographic separation apparatus different from FIG. 1 suitable for carrying out the chromatographic separation method according to one reference embodiment of the present invention. That is, an embodiment in which a circulation pump PR is provided in the circulation system 7 is shown.

  2, the chromatographic separation apparatus 31 includes four unit packed columns 4 (No. 1 to No. 4 packed columns), and each packed column 4 includes two or more components contained in the stock solution 3. An adsorbent 5 (adsorbent for optical resolution) having a selective adsorption ability for a specific component in the components is packed. Each packed column 4 is connected by piping 6 from the outlet of each packed column 4 to the inlet of the adjacent packed column 4 and connected in series as a whole, and the last unit packed column 4 (for example, FIG. 1 is connected to the inlet of the foremost unit packed column 4 (for example, No. 1 packed column 4 in FIG. 1) by a pipe 6, so that all the unit packed columns 4 are connected. Are connected endlessly. Therefore, the packed bed in which all the unit packed columns 4 are connected endlessly is formed as a system 7 in which the fluid can circulate in the direction of the arrow. A circulation pump PR is disposed in the circulation system 7.

  Between each adjacent packed tower 4 in the circulation system 7, shut-off valves R1, R2, R3, R4 capable of blocking the packed towers are provided. Between the shutoff valves R1 to R4 and the outlet of each packed tower 4 located on the upstream side thereof, an A picture for the purpose of extracting a fraction (A fraction) that moves at a high speed in the packed bed. Extraction valves A1, A2, A3, A4 are provided. Each A fraction extraction line 8 is merged into a single A fraction merging pipe 9. Similarly, C fraction extraction valves C1, C2, C3, and C4 are provided for the purpose of extracting a fraction (C fraction) that moves at a low speed in the packed bed. Each C fraction extraction line 10 is merged and grouped into one C fraction merge pipe 11.

The circulation system 7 can be supplied with the stock solution 3 contained in the stock solution tank 2 and the eluent 16 contained in the eluent tank 15. Stock solution 3, in this reference embodiment, the starting solution feed pump PF capable of controlling the supply flow rate is supplied via the starting solution feed line 17. The stock solution supply line 17 is branched to each stock solution branch supply line 18, and the stock solution can be supplied to the inlet side of each unit packed tower 4 via each stock solution branch supply line 18. Each stock solution branch supply line 18 is provided with open and close stock solution supply valves F1, F2, F3, and F4, and the stock solution is supplied to the corresponding unit packed tower via the opened stock solution supply valve line. The

Eluent 16 is in this reference embodiment, the starting solution feed pump PD capable of controlling the supply flow rate, is supplied through an eluent supply line 20. The eluent supply line 20 is branched to each eluent branch supply line 21, and the eluent can be supplied to the inlet side of each unit packed column 4 via each eluent branch supply line 21. Each eluent branch supply line 21 is provided with eluent supply valves D1, D2, D3, and D4 that can be opened and closed. The eluent supply valves 21 are eluted to the corresponding unit packed tower through the opened eluent supply valve line. Liquid is supplied.

  A circulation line 32 from the stock solution supply line 17 to the stock solution tank 2, a circulation line 33 from the eluent supply line 20 to the eluent tank 15, and a discharge line 34 connected to any part of the circulation system 7, respectively, Safety valves 35, 36, and 37 are provided so that when an excessive pressure is applied, the apparatus can be prevented from being damaged by circulation to each tank or discharge outside the system.

  In the chromatographic separation apparatus 31 configured as described above, the separation process is performed as follows. That is, in the chromatographic separation apparatus 1, the step of supplying the stock solution and extracting the entire amount from the A fraction extraction position, the step of supplying the eluent and extracting the entire amount from the C fraction extraction position, supplying the eluent and supplying the entire amount to the A fraction It is possible to operate in four steps: a step of extracting from the parting position and a step of circulating the liquid in the system without performing any supply, extraction or shut-off, and separation is performed by combining these steps. be able to.

  In the step of supplying the stock solution and extracting the entire amount from the A fraction extraction position (FA step), one of the stock solution supply valves is opened and the stock solution is supplied into the system 7 from the inlet side of the corresponding unit packed column 4. The A fraction extraction valve A corresponding to the extraction position of the A fraction is opened, the shut-off valve immediately downstream thereof is closed, and the entire amount of the A fraction is extracted through the A fraction extraction line 8.

  In the process of supplying the eluent and extracting the entire amount from the C fraction extraction position (DC process), one of the eluent supply valves is opened, and the eluent is introduced into the system 7 from the inlet side of the corresponding unit packed column 4. The C fraction extraction valve C corresponding to the C fraction extraction position is opened, the shut-off valve immediately downstream thereof is closed, and the entire C fraction is extracted through the C fraction extraction line 10.

  In the step of supplying the eluent and extracting the entire amount from the A fraction extraction position (D-A step), one of the eluent supply valves is opened, and the eluent is introduced into the system 7 from the inlet side of the corresponding unit packed column 4. The A fraction extraction valve A corresponding to the extraction position of the A fraction is opened, the shut-off valve immediately downstream thereof is closed, and the entire amount of the A fraction is extracted through the A fraction extraction line 8.

  In the process of moving the liquid in the system without performing any supply or extraction (circulation process), all the stock solution supply valve, eluent supply valve, A fraction extraction valve A, and C fraction extraction valve C are closed, By starting the circulation pump PR with all the shut-off valves open, the liquid in the system is circulated.

  An example of operation using the chromatographic separation apparatus 31 is shown in Table 2. Table 2 shows the open / close control status of the F and D valves. The numbers in the table show the numbers of the respective valves (for example, 1 in the F section indicates 1 valve), and the numbers are entered. It means that the valve is opened. When the column is blank, the valve is closed. Further, in the terms of the A and C valves, the number of the valve from which the entire amount is extracted is shown. If the field is blank, the valve is not extracted. The R valve indicates that the valve in which the number is written is closed. In the case of a blank, the valve open state is indicated. Further, in the terms of the stock solution supply pump PF, the eluent supply pump PD, and the circulation pump PR, a circle indicates an operating state, and a blank state indicates a stopped state.

  In Table 2, the process No. 1-1 to 1-5 to step No. 4-1. Up to 4-5 shows one cycle of the separation process in the present chromatographic separation apparatus 31.

(About step 1-1)
Step No. As for 1-1 to 1-5, in step 1-1, the eluent supply valve D3 is opened to supply the eluent into the circulation system 7, and the A fraction extraction valve A1 is opened, from which the A fraction is separated. Extract the entire amount of. Therefore, this step 1-1 corresponds to the D-A step of supplying the eluent as referred to in the present invention and extracting the entire amount from the A fraction extraction position.

(About step 1-2)
In step 1-2, the stock solution supply valve F1 is opened to supply the stock solution into the circulation system 7, and the A fraction extraction valve A1 is opened, from which the entire amount of the A fraction is extracted. Therefore, this step 1-2 corresponds to the FA step of supplying the stock solution in the present invention and extracting the whole amount from the A fraction extraction position.

(About step 1-3)
In step 1-3, all the undiluted solution supply valves, the eluent supply valve, the A fraction extraction valve A, the C fraction extraction valve C are closed, and the circulation pump PR is started with all the shut-off valves open. To circulate the liquid in the circulation system. Therefore, this step 1-3 corresponds to the step (second step: circulation step R) of moving the liquid in the system without performing any supply, extraction, or shutoff referred to in the present invention.

(About step 1-4)
In step 1-4, the eluent supply valve D3 is opened to supply the eluent into the circulation system 7, and the C fraction extraction valve C3 is opened, from which the entire amount of the C fraction is extracted. Therefore, this step 1-4 corresponds to the DC step of supplying the eluent as used in the present invention and extracting the entire amount from the C fraction extraction position.

(About Step 1-5)
In step 1-5, all the undiluted solution supply valves, the eluent supply valve, the A fraction extraction valve A, the C fraction extraction valve C are closed, and the circulation pump PR is started with all the shut-off valves open. To circulate the liquid in the circulation system.
Therefore, this step 1-5 corresponds to the step (second step: circulation step R) in which the liquid in the system is moved without performing any supply, extraction, or shut-off in the present invention.

  In the series of steps 1-1 to 1-5 described above, the supply position of the stock solution and the eluent, the extraction position of the A fraction and the C fraction, and the position of the circulating fluid extraction valve in the circulation process are in a specific positional relationship. When the series of steps 1-1 to 1-5 is completed, the position of each control target valve is shifted to the downstream side while maintaining the specific positional relationship, and the next series of steps is performed. Steps 2-1 to 2-5 are executed. By performing this transition sequentially, a function equivalent to the operation operation of the known pseudo moving bed type chromatographic separation apparatus can be achieved.

  In steps 2-1 to 2-5, steps 3-1 to 3-5, and steps 4-1 to 4-5 following the series of steps 1-1 to 1-5, the position of each valve is set to one as described above. The operation | movement similar to the said process 1-1 to 1-5 is performed in the state which shifted to each. When steps 1-1 to 4-5 are executed, one cycle of the separation process is completed.

  In the above separation operation, the stock solution supply pump PF and the eluent supply pump PD may be set to a constant flow rate discharge setting or may perform flow rate control.

  Next, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples without departing from the gist thereof.

Example 1
Using a chromatographic separation apparatus as shown in FIG. 1 in which four packed towers having an inner diameter of 1.0 cm and a length of 20 cm are connected in an endless series, the adsorbent is CHIRALCEL OD (manufactured by Daicel Chemical) and the desorbing liquid is n-hexane. : Using a mixed solution of isopropanol = 8: 2 and keeping the packed bed temperature at 45 ° C., the stock solution supply amount Uf = 1.684 (kg / kg-CSP / day), the desorbed liquid use ratio D / F (desorption) Separation and purification were performed under the operating condition of (separated liquid supply amount / stock solution supply amount) = 25. The operation process was repeated by setting the operation in the order of DA, FA, circulation 1, DC, and circulation 2 as one step. Table 3 shows the stock solution composition of Phenyl Glycidyl Ether used in this test. In the present embodiment, two components having optical activity are separated, and each high-purity component is taken out from the raffinate component outlet and the extract component outlet. Table 4 shows the results (component composition) of operating the chromatographic separation apparatus under such conditions. The number of theoretical plates for four packed towers was measured using the separation object as a sample. The peak detected at the exit of the packed tower was taken on a recording paper, and the retention time Tr of the substance and the peak width W _0.5 at the midpoint of the peak height were read from the peak recorded on the recording paper as shown in Table 5. The theoretical plate number N was converted per 1 m.

Comparative Example 1
As shown in Table 6, using a chromatographic separation apparatus 51 as shown in FIG. 3, in which eight packed towers having an inner diameter of 1.0 cm and a length of 10 cm are connected in an endless series, as shown in JP-A-2001-354690. Table 7 shows the results of separation of phenyl glycidyl ether using the operation process table.

  As is apparent from Tables 4 and 7, according to the present invention, high separation efficiency and high recovery rate can be achieved while the number of unit packed columns is as small as four columns and the same adsorbent amount.

It is an equipment system diagram showing an example of a chromatographic separation device used for a chromatographic separation method according to the present invention. It is an equipment system diagram showing a reference example of a chromatographic separation apparatus used for a chromatographic separation method according to the present invention. It is an equipment system diagram of a chromatographic separation apparatus according to a conventional method (Japanese Patent Laid-Open No. 2001-354690).

Explanation of symbols

1, 31 Chromatographic separation device 2 Stock solution tank 3 Stock solution 4 Unit packed bed 5 Adsorbent 6 Pipe 7 System 8 A fraction extraction line 9 A fraction confluence tube
10 C fraction extraction line
11 C fraction confluence pipe
12 Circulation extraction line (when using eluent supply pump as circulation pump)
13 Circulation extraction junction pipe (when using eluent supply pump as circulation pump)
14 Check valve
15 Eluent tank
16 Eluent
17 Stock solution supply line
18 Stock solution branch supply line
19 Stock solution return line
20 Eluent supply line
21 Eluent branch supply line
32, 33 Circulation line
34 Discharge line
35, 36, 37 Safety valve

Claims (7)

By having a plurality of unit packed towers packed with an adsorbent for optical resolution, and connecting these unit packed towers in series by piping and connecting the unit packed tower at the most downstream part and the unit packed tower at the most upstream part By passing a stock fluid containing two or more components through a packed bed that constitutes an endless circulation system, a circulation system in which an adsorption zone that is sequentially divided in order of affinity for the adsorbent is formed. A first step of supplying at least one of the eluent into the circulation system, and extracting all of the amount equal to the amount of liquid supplied into the circulation system from a location corresponding to the packed tower enriched with a certain component in the circulation system; , Combining the second step of circulating the liquid in the circulation system without supplying any undiluted solution and eluent, and extracting the separated components, and
In the first step, the supply position of the stock solution supplied into the circulation system by the stock solution supply pump or the supply position of the eluent supplied into the circulation system by the eluent supply pump and the extraction position of each component are set in the circulation system. Separation is carried out by performing an operation of sequentially moving to the downstream side of the circulation system in accordance with the movement of the adsorption zone of
In the second step, the total amount of circulating fluid extracted outside the circulatory system from one location or two locations in the circulatory system, by supplying again the circulating system using an eluent supply pump and / or the starting solution feed pump A chromatographic separation method characterized by using a chromatographic separation device that circulates in a circulation system.   Operation steps are as follows: (1) D-A step of supplying the eluent and extracting the entire amount of the extracted liquid from the first fraction extraction position; (2) Supplying the stock solution or the stock solution and the eluent and The FA process or FD-A process in which the entire amount is extracted from the first fraction extraction position, (3) Circulation of the liquid in the circulation system without supplying any undiluted solution and eluent, and extracting the separated components R step, (4) D-C step of supplying the eluent and extracting the entire amount of the extracted liquid from the second fraction extracting position, (5) Supplying all undiluted solution and eluent, The chromatographic separation method according to claim 1, wherein the method is repeated in the order of the R step in which the liquid in the circulation system is circulated without extraction.   As the operation process, (1) the stock solution or the stock solution and the eluent are supplied, and the entire amount of the extracted liquid is extracted from the first fraction extraction position, the FA process or the FD-A process, and (2) the eluent is supplied. At the same time, the D-A step of extracting the entire amount of the extracted liquid from the first fraction extracting position, (3) circulating the liquid in the circulation system without supplying any undiluted solution and eluent, and extracting the separated components. R step, (4) D-C step of supplying the eluent and extracting the entire amount of the extracted liquid from the second fraction extracting position, (5) Supplying all undiluted solution and eluent, The chromatographic separation method according to claim 1, wherein the method is repeated in the order of the R step in which the liquid in the circulation system is circulated without extraction.   Operational steps are as follows: (1) D-A step of supplying the eluent and extracting the entire amount of the extracted liquid from the first fraction extracting position; (2) Supplying all undiluted solutions and eluents, R step for circulating the liquid in the circulation system without extracting, (3) DC step for supplying the eluent and extracting the entire amount of the extracted liquid from the second fraction extracting position, (4) Stock solution or F-C process or FD-C process for supplying the stock solution and the eluent and extracting the total amount of the extracted solution from the second fraction extraction position, (5) Supplying all the undiluted solution and eluent, The chromatographic separation method according to claim 1, wherein the method is repeated in the order of the R step in which the liquid in the circulation system is circulated without extraction.   Operational steps are as follows: (1) D-A step of supplying the eluent and extracting the entire amount of the extracted liquid from the first fraction extracting position; (2) Supplying all undiluted solutions and eluents, R step for circulating the liquid in the circulation system without performing extraction, (3) F-C step or FD for supplying the stock solution or the stock solution and the eluent and extracting the entire amount of the extracted solution from the second fraction extraction position -C step, (4) Supplying the eluent and taking out the total amount of the extracted liquid from the second fraction extracting position, DC step, (5) Supplying all undiluted solution and eluent, The chromatographic separation method according to claim 1, wherein the method is repeated in the order of the R step in which the liquid in the circulation system is circulated without extraction.   The chromatographic separation method according to any one of claims 1 to 5, wherein the adsorbent has a particle size of 150 µm or less, a theoretical plate number of 200 plates / m or more, and a purity of a separation target component of 95% or more. .   A chromatographic separation method, wherein optical isomers are separated by the method according to claim 1.

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