JP2019032284A - Chromatographic separation method and chromatographic separation system - Google Patents

Abstract

To provide a simulated moving bed type chromatographic separation method capable of reducing the amount of use of eluate and separating and purifying a constituent to be purified with high recovery and high purity.SOLUTION: A simulated moving bed type chromatography separation method repeats steps (a1)-(b1) in the order, where the step (a1) is executed under a specific condition: (a1) a step for executing sub-steps (a-i)-(a-v) in this order: (a-i) a sub-step for circulating fluid within a circulation system; (a-ii) a sub-step for supplying eluate from an eluate supply port D and extracting a low adsorptive fraction from a low adsorptive fraction extraction hole A; (a-iii) a sub-step for supplying liquid concentrate from a liquid concentrate supply hole F and extracting a low adsorptive fraction from A, (a-iv) a sub-step for circulating fluid within a circulation system; and (a-v) a sub-step for supplying eluate from D and extracting a high adsorptive fraction from a high adsorptive fraction extraction hole C; and (b1) a step for shifting F, A, D, and C toward a distribution direction of fluid while maintaining their relative positional relationship.SELECTED DRAWING: None

Description

  The present invention relates to a chromatographic separation method and a chromatographic separation system. More specifically, the present invention relates to a chromatographic separation method and chromatographic separation system using a pseudo moving bed system.

  The chromatographic separation methods are roughly classified into a fixed bed method and a moving bed method. In the fixed bed system, a multi-component sample (hereinafter also referred to as “stock solution”) is injected into a column filled with an adsorbent, and the eluent is circulated in one direction in the column, thereby allowing the adsorbent. The target component in the stock solution is separated and purified from other components based on the difference in adsorption power. In this fixed bed system, the target component can be separated and purified simply by circulating the eluent while fixing the adsorbent. However, if there is no significant difference in the adsorptive power with respect to the adsorbent between the target component to be purified (hereinafter, also simply referred to as “component to be purified”) and other components, the fixed layer method is good. Separation and purification cannot be realized. Furthermore, in the fixed layer method, the target component cannot be separated while continuously injecting the sample, and there are limitations in industrial application.

On the other hand, in the moving bed method, the adsorbent is moved in the opposite direction to the flow direction of the eluent while flowing the eluent in one direction in the column. In the moving bed method, by adjusting the flow rate of the eluent and the moving speed of the adsorbent, the component to be purified in the stock solution is moved in the direction opposite to the direction of other components, based on the stock solution inlet. Can be made. Therefore, for example, when the component to be purified in the stock solution is a strongly adsorbing component compared to other components, the component to be purified is upstream with respect to the inlet of the stock solution (the direction opposite to the fluid flow direction). Therefore, it is possible to construct a system in which other components move downstream (fluid flow direction). By extracting the component to be purified on the upstream side and extracting other components on the downstream side, the component to be purified can be separated and purified continuously and with higher purity while continuously injecting the stock solution.
However, industrial application of the moving bed method is not easy. In a chromatographic separation system using a large column used industrially, it is technically difficult to move the adsorbent uniformly. Even if the adsorbent can be moved uniformly, a large load is applied to the adsorbent during this movement. As a result, the adsorbent easily breaks (crushes), and the constructed chromatographic separation system tends to be inferior in practicality in terms of durability.

  In order to solve the problems of the moving bed system, a chromatographic separation technique using a pseudo moving bed system has been proposed (for example, Patent Documents 1 and 2). The chromatographic separation by the simulated moving bed system is performed using a circulation system in which a plurality of unit packed columns (columns) packed with an adsorbent are connected in series and endlessly through a pipe. In this circulation system, the pipe has a stock solution supply port for supplying a stock solution containing a component to be purified, a weakly adsorbable fraction outlet, an eluent supply port, and a strong adsorptive fraction outlet. Are provided in this order in the flow direction, and between the stock solution supply port and the weakly adsorptive fraction extraction outlet, between the weakly adsorptive fraction extraction outlet and the eluent supply port, and between the eluent supply port and the strong outlet. At least one of the unit packed towers is disposed between the adsorbing fraction extraction outlet and between the strong adsorptive fraction extraction outlet and the stock solution supply port. The stock solution supply port, the weakly adsorptive fraction extraction outlet, the eluent supply port and the strong adsorptive fraction extraction outlet are directed in the fluid flow direction while maintaining their relative positional relationship. By moving the adsorbent intermittently, it is possible to obtain the same effect as when the adsorbent is moved in the direction opposite to the fluid flow direction, although the adsorbent is fixed.

  The chromatographic separation technique using the simulated moving bed method was originally performed by a method called a so-called classical SMB (simulated moving bed chromatography). In this classical SMB, the stock solution and the eluent are always supplied during the operation, and the weakly adsorbable fraction and the strongly adsorbable fraction are always extracted. In classical SMB, the supply flow rates of the stock solution and the eluent, and the extraction flow rates of the weakly adsorbable fraction and the strongly adsorbable fraction are constant (for example, Patent Document 2).

  Then, for the purpose of improving the separation performance of classical SMB, the operations of supplying the stock solution, supplying the eluent, extracting the weakly adsorbing fraction, and extracting the strongly adsorbing fraction are performed in one step. A method of dividing (substep method) has been studied. Here, “step” refers to the flow direction of the fluid while maintaining the relative positional relationship between the stock solution supply port, the weakly adsorbable fraction extraction outlet, the eluent supply port, and the strong adsorptive fraction extraction outlet. It means the time delimited by moving intermittently toward. That is, after moving the stock solution supply port, the weakly adsorptive fraction extraction outlet, the eluent supply port and the strong adsorptive fraction extraction outlet in the flow direction, the period from the next movement to the next movement is defined as one step. During the step, close any of the supply ports, close any of the outlets, or close all of the supply ports and outlets to circulate the liquid to further improve the purity, concentration, etc. of the target substance. Increased has been considered.

As an example of this sub-step method, for example, Example 3 of Patent Document 1 describes that the following sub-steps 1 to 3 are sequentially performed in one step.
<Substep 1>
While supplying both the stock solution and the eluent, both the strongly adsorbable fraction and the weakly adsorbable fraction are extracted.
<Sub-step 2>
Only the weakly adsorbable fraction is extracted while supplying only the eluent.
<Sub-step 3>
The liquid is circulated without any supply or withdrawal.

Also, in Example 1 of Patent Document 3, it is described that the following sub-steps 1 to 5 are performed in one step.
<Substep 1>
Only the weakly adsorbable fraction is extracted while supplying only the eluent.
<Sub-step 2>
Extract only the weakly adsorbable fraction while supplying only the stock solution.
<Sub-step 3>
The liquid is circulated without any supply or withdrawal.
<Sub-step 4>
While supplying only the eluent, only the strong adsorptive fraction is extracted.
<Sub-step 5>
The liquid is circulated without any supply or withdrawal.

  Here, in the chromatographic separation by the simulated moving bed system, the conditions for supplying or extracting the liquid necessary for realizing good separation and purification will be described with reference to the conceptual diagram of the simulated moving bed system shown in FIG. To do. FIG. 2 shows section 1 between the eluent supply port D and the strong adsorptive fraction extraction outlet C, section 2 between the strong adsorptive fraction extraction outlet C and the stock solution supply port F, and the stock solution supply port F. The section between the weakly adsorptive fraction extraction outlet A is shown as section 3, and the section between the weak adsorptive fraction extraction outlet A and the eluent supply port D is shown as section 4. V1 to V4 mean the integrated flow rates of sections 1 to 4 per step, respectively. The arrows in FIG. 2 indicate the direction of fluid flow. In the following description, the same column is used for each section.

Focusing on sections 2 and 3 in FIG. 2, in order to realize the pseudo moving bed system, the weakly adsorbing component moves beyond the length of section 2 at the integrated flow rate V2, and the movement of the strongly adsorbing component is It is necessary to keep the distance less than the distance of section 2, and at the integrated flow rate V3, the weakly adsorptive component moves beyond the length of section 3, and the strongly adsorbable component moves less than the distance of section 3. There is a need. In this way, when these are moved downstream with respect to the positions of the respective ports D, C, F, A, the weakly adsorbing components are further moved downstream, and the strong adsorbing components are upstream. Can be moved relatively (pseudo). That is, the weakly adsorbable component can be extracted from the outlet A, and the strong adsorptive component can be extracted from the outlet C.
That is, the integrated flow rate of section j (where j = 1 to 4) is V _j ^acc , the strongly adsorbing component is S, and the elution volume of S (the amount of liquid necessary to pass through the length of one section) ) as the _V ^{S elution,} the weakly adsorbable component W, when the elution volume of the W and _V ^{W elution,} the following equation (1) to (4) is satisfied.

_{^V 2} ^acc> V ^W elution formula (1)
_{^V 2} ^acc <V ^S elution formula (2)
_{^V 3} ^acc> V ^W elution formula (3)
_{^V 3} ^acc <V ^S elution formula (4)

On the other hand, focusing on section 1, if the moving distance of the strong adsorptive component is less than the length of section 1 at integrated flow rate V1, the strong adsorptive component (passes upstream without being extracted from outlet C). The strongly adsorbing component that has been removed) cannot be extracted from the outlet C. Therefore, in section 1, it is said that the moving distance of the strongly adsorbing component needs to move beyond the length of section 1 at integrated flow rate V1.
That is, the following formula (5) is established.

_{^V 1} ^acc> V ^S elution formula (5)

Further, when attention is paid to section 4, when the moving distance of the weakly adsorbing component exceeds the length of section 4 at the integrated flow rate V4, the weakly adsorbing component (the weakly passing through the outlet A without being extracted). The adsorbing component) cannot be extracted from the outlet A. Therefore, in section 4, it is said that the moving distance of the weakly adsorptive component needs to be less than the length of section 4 at integrated flow rate V4.
That is, the following formula (6) is established.

_{^V 4} ^acc <V ^W elution formula (6)

  The relationship satisfying each of the above expressions is called a triangle theory. For example, Journal of Chromatography A, 1216 (2009) p. 709-738 etc. are also reported.

Subsequently, the above-described triangle theory is established when there are a plurality of components having different adsorptive properties as the weakly adsorbing component W in the sample and / or a plurality of components having different adsorptive properties as the strongly adsorbing component S. Consider the conditions. In this case, since the elution volume increases as the adsorptivity increases, the following formulas (7) to (10) are necessarily satisfied.

V _SF ^elution <V _NSF ^elution expression (7)
V _SL ^elimination > V _NSL ^elimination formula (8)
V _WF ^elution <V _NWF ^elution expression (9)
V _WL ^elimination > V _NWL ^elimination formula (10)
(Explanation of symbols)
SF: The component having the lowest adsorptivity among the strong adsorptive components NSF: The component other than SF among the strong adsorptive components SL: The component having the highest adsorptivity among the strong adsorptive components NSL: The component other than SL among the strong adsorptive components WF: The component with the lowest adsorptivity among the weak adsorptive components NWF: The component other than WF among the weak adsorptive components WL: The component with the highest adsorptivity among the weak adsorptive components NWL: Of the weak adsorptive components Ingredients other than WL

In addition to the above formulas (7) to (10), the following formula (11) is also established in the pseudo moving layer system. This is because V ₃ ^acc is larger than V ₂ ^acc by the amount of the stock solution supplied.

_{V 3} ^acc> V ^{2 acc} formula (11)

Considering satisfying the above formula (11), it can be seen that satisfying the above formulas (1) to (4) of the triangle theory is synonymous with satisfying the above formulas (1) and (4). Further, considering the above formulas (7) to (10), it is understood that the following formulas (1 ′), (4 ′), (5 ′) and (6 ′) may be satisfied in order to establish the triangle theory. . (Formulas (1 ′), (4 ′), (5 ′) and (6 ′) correspond to formulas (1), (4), (5) and (6), respectively.)

V ₁ ^acc > V _SL ^elimination expression (5 ′)
V ₂ ^acc > V _WL ^elimination expression (1 ′)
V ₃ ^acc <V _SF ^elution expression (4 ′)
_{^V 4} ^acc <V ^WF elution formula (6 ')

  The above is the description of the conditions for establishing the triangle theory. In the simulated moving bed system, the target object is separated and refined under the operating conditions that satisfy this triangle theory. The triangle theory can also be applied to a case where each section has two or more columns. In this case, the “section length” in the above description may be read as “the length of one column”.

Japanese Patent Publication No. 60-55162 JP 2009-36536 A Japanese Patent No. 4771460

In chromatographic separation, in addition to the stock solution containing the component to be purified, an eluent that pushes the stock solution is supplied. Therefore, the target fraction containing the component to be purified (hereinafter also referred to as “fraction to be purified”) is in a state in which the component to be purified is diluted to some extent with the eluent. Therefore, although the fraction to be purified obtained by chromatographic separation is usually shipped through a concentration operation, this concentration operation contributes to increase the purification cost. On the other hand, fractions other than the fraction to be purified are to be discarded. In order to reduce the amount of waste, it is desirable to reduce the amount of eluent in the waste fraction.
In order to cope with the above problem, it is required to increase the concentration of the purification target component in the purification target fraction or the concentration of the disposal target component in the waste fraction. However, in the triangle theory, there is a lower limit for the ratio of the amount of the eluent to the amount of the stock solution, and the amount of eluent used cannot be reduced below this lower limit. This will be described below with reference to FIG.

Since the eluent is supplied from between section 1 and section 4 and the stock solution is supplied from between section 3 and section 2, the integrated flow rate V _D ^acc of the eluate and the integrated flow rate V _F ^acc of the stock solution are expressed by the following equations. (12) and (13).

V _D ^acc = V ₁ ^acc −V ₄ ^acc formula (12)
^{_{V F acc = V 3 acc -V}} 2 acc formula (13)

Therefore, the ratio of the accumulated flow rate of the eluent to the accumulated flow rate of the stock solution is expressed by the following equation (14).

^{_{V D acc / V F acc =}} (V 1 acc -V 4 acc) / (V 3 acc -V 2 acc) formula (14)

On the other hand, the following formulas (15) and (16) are derived from the relationships shown in the above formulas (5 ′), (1 ′), (4 ′) and (6 ′).

V ₁ ^acc −V ₄ ^acc > V _SL ^elution −V _WF ^elution expression (15)
V ₃ ^acc −V ₂ ^acc <V _SF ^elimination −V _WL ^elimination equation (16)

When the relationship shown in the above equations (15) and (16) is applied to the above equation (14), the following equation (17) is derived.

V _D ^acc / V _F ^acc > (V _SL ^elimination −V _WF ^elimination ) / (V _SF ^elimination −V _WL ^elimination ) Expression (17)

From the above formula (17), in the triangle theory, it can be understood that there is a lower limit in the ratio “V _D ^acc / V _F ^acc ” of the eluent integrated flow rate to the stock solution integrated flow rate, and the eluent below this lower limit value. It is said that good separation and purification cannot be realized with the amount used.
The right side of the expression (17) is {(V _SL ^elimination −V _SF ^elimination ) + (V _SF ^elimination −V _WL ^elimination ) + (V _WL ^elimination −V _WF ^elimination )} / (V _SF ^elimination −V _WL ^elimination )
Therefore, when the distribution of the retention times of the components to be recovered in the strong adsorptive fraction is wide (that is, when the V _SL ^elimination -V _SF ^elution is large) and / or the components to be recovered in the weak adsorptive fraction When the distribution of the retention times is wide (that is, when V _WL ^elimination −V _WF ^elimination is large), the lower limit value of “V _D ^acc / V _F ^acc ” becomes a large value, which is a severe limitation.

Therefore, the present invention is a chromatographic separation method using a simulated moving bed method, which can effectively reduce the amount of eluent used, and separate and purify the components to be purified in the stock solution with high recovery and high purity. It is an object to provide a chromatographic separation method capable of performing
Moreover, this invention makes it a subject to provide the chromatographic separation system suitable for implementation of the said chromatographic separation method.

  As a result of intensive studies in view of the above problems, the inventors of the present invention, in a chromatographic separation method using a simulated moving bed system, with a small amount of eluent used, which is further lower than the lower limit of the amount of eluent used in the triangle theory. Even if it is present (that is, even if the ratio of the amount of the eluent used to the amount of the stock solution is reduced), a specific combination is adopted as a combination of sub-steps executed within one step, and the sub-step is executed under specific conditions. Thus, it has been found that the component to be purified can be obtained with a sufficiently high purity at an excellent recovery rate. The present invention has been further studied based on these findings and has been completed.

The above-described problems of the present invention have been solved by the following means.
[1]
A chromatographic separation method for separating and purifying components in a stock solution by a simulated moving bed method using a circulation system in which a plurality of unit packed towers packed with an adsorbent are connected in series and endlessly through a pipe,
The circulation system has a stock solution supply port F, a weakly adsorptive fraction extraction outlet A, an eluent supply port D, and a strong adsorptive fraction extraction outlet C in this order in the fluid flow direction. And between the stock solution supply port F and the weakly adsorbable fraction outlet A, between the weakly adsorbable fraction outlet A and the eluent supply port D, and the eluent supply port D. Between the strong adsorptive fraction extraction outlet C and between the strong adsorptive fraction extraction outlet C and the stock solution supply port F, at least one unit packed tower is disposed,
The chromatographic separation method includes sequentially repeating the following steps (a1) and (b1), and the step (a1) is performed under conditions satisfying the following formulas (c1) and (d1):
(A1) A step of performing the following sub-steps (ai) to (av) in this order;
(Ai) a sub-step of circulating the fluid in the circulation system without supplying the stock solution and the eluent and without extracting the strongly adsorbable fraction and the weakly adsorbable fraction;
(A-ii) a sub-step of supplying an eluent from the eluent supply port D and extracting a weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(A-iii) a sub-step of supplying the stock solution from the stock solution supply port F and extracting the weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(A-iv) a sub-step of circulating the fluid in the circulation system without supplying the stock solution and the eluent and without extracting the strong and weakly adsorbable fractions;
(Av) a sub-step of supplying an eluent from the eluent supply port D and extracting a strongly adsorbable fraction from the strong adsorbent fraction outlet C;
(B1) After completion of the step (a1), the stock solution supply port F, the weakly adsorptive fraction extraction outlet A, the eluent supply port D, and the strong adsorptive fraction extraction port C are set to their relative positions. The step of moving toward the flow direction of the fluid while maintaining the positional relationship.
(C1) Elution volume of component X> Integrated flow rate of section 1 Here, component X is a component that is recovered in the strongly adsorbing fraction and satisfies the following formula (d1).
(D1) [2 × (the integrated flow rate in the sub-step (ai)) + the integrated flow rate in the sub-step (a-ii) + the integrated flow rate in the sub-step (a-iii) + the sub-step (a− iv) integrated flow rate] <[elution volume of component X] <[2 × (integrated flow rate of substep (ai)) + integrated flow rate of substep (a-iv) + substep (a -V) Integrated flow rate]

[2]
In the step (a1), the following substep (a-vi) is performed between the substep (av) and the step (b1), and the step (a1) is changed to the formula (d1). The chromatographic separation method according to [1], which is carried out under conditions satisfying the following formula (d1 ′) instead of:
(A-vi) a sub-step in which the fluid in the circulation system is circulated without supplying the stock solution and the eluent and without extracting the strong and weakly adsorbable fractions.
(D1 ′) [2 × (integrated flow rate in the sub-step (ai)) + integrated flow rate in the sub-step (a-ii) + integrated flow rate in the sub-step (a-iii) + sub-step (a -Iv) integrated flow rate + 2 × (the integrated flow rate of the substep (a-vi))] <[elution volume of the component X] <[2 × (the integrated flow rate of the substep (ai)) + the above Integrated flow rate of sub-step (a-iv) + integrated flow rate of sub-step (av) + 2 × (integrated flow rate of sub-step (a-vi))]

[3]
The chromatographic separation method according to [1] or [2], wherein the circulation system has at least four unit packed columns.

[4]
A chromatographic separation system that separates and purifies components in a stock solution by a simulated moving bed system using a circulation system in which a plurality of unit packed towers packed with an adsorbent are connected in series and endlessly via a pipe,
The circulation system has a stock solution supply port F, a weakly adsorptive fraction extraction outlet A, an eluent supply port D, and a strong adsorptive fraction extraction outlet C in this order in the fluid flow direction. And between the stock solution supply port F and the weakly adsorbable fraction outlet A, between the weakly adsorbable fraction outlet A and the eluent supply port D, and the eluent supply port D. Between the strong adsorptive fraction extraction outlet C and between the strong adsorptive fraction extraction outlet C and the stock solution supply port F, at least one unit packed tower is disposed,
A chromatographic separation system comprising means for sequentially repeating the following steps (a1) and (b1), and means for carrying out the step (a1) under conditions satisfying the following formulas (c1) and (d1):
(A1) A step of performing the following sub-steps (ai) to (av) in this order;
(Ai) a sub-step of circulating the fluid in the circulation system without supplying the stock solution and the eluent and without extracting the strongly adsorbable fraction and the weakly adsorbable fraction;
(A-ii) a sub-step of supplying an eluent from the eluent supply port D and extracting a weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(A-iii) a sub-step of supplying the stock solution from the stock solution supply port F and extracting the weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(A-iv) a sub-step of circulating the fluid in the circulation system without supplying the stock solution and the eluent and without extracting the strong and weakly adsorbable fractions;
(Av) A sub-step of supplying an eluent from the eluent supply port D and extracting a strongly adsorbable fraction from the strong adsorbent fraction outlet C.
(B1) After completion of the step (a1), the stock solution supply port F, the weakly adsorptive fraction extraction outlet A, the eluent supply port D, and the strong adsorptive fraction extraction port C are set to their relative positions. The step of moving toward the flow direction of the fluid while maintaining the positional relationship.
(C1) Elution volume of component X> Integrated flow rate of section 1 Here, component X is a component that is recovered in the strongly adsorbing fraction and satisfies the following formula (d1).
(D1) [2 × (the integrated flow rate in the sub-step (ai)) + the integrated flow rate in the sub-step (a-ii) + the integrated flow rate in the sub-step (a-iii) + the sub-step (a− iv) integrated flow rate] <[elution volume of component X] <[2 × (integrated flow rate of substep (ai)) + integrated flow rate of substep (a-iv) + substep (a -V) Integrated flow rate]

[5]
The step (a1) performs the following substep (a-vi) between the substep (av) and the step (b1), and the step (a1) The chromatographic separation system according to [4], which is carried out under conditions satisfying the following formula (d1 ′) instead of the formula (d1):
(A-vi) a sub-step in which the fluid in the circulation system is circulated without supplying the stock solution and the eluent and without extracting the strong and weakly adsorbable fractions.
(D1 ′) [2 × (integrated flow rate in the sub-step (ai)) + integrated flow rate in the sub-step (a-ii) + integrated flow rate in the sub-step (a-iii) + sub-step (a -Iv) integrated flow rate + 2 × (the integrated flow rate of the substep (a-vi))] <[elution volume of the component X] <[2 × (the integrated flow rate of the substep (ai)) + the above Integrated flow rate of sub-step (a-iv) + integrated flow rate of sub-step (av) + 2 × (integrated flow rate of sub-step (a-vi))]

In this specification, the terms “upstream” and “downstream” are used with respect to the flow direction of the fluid in the circulation system. That is, the “upstream side” with respect to a certain part of the circulatory system means the side where the fluid flows toward the part, and the “downstream side” means the side where the fluid flows out from the part. means.
In the present specification, “strongly adsorbing component” means a component having a strong adsorptive power to the adsorbent among a plurality of components contained in the stock solution, and “weakly adsorbing component” means the above strongly adsorbing component. Means a component having a lower adsorptivity to the adsorbent. In other words, the terms “strongly adsorbing” and “weakly adsorbing” represent the degree of strength of the adsorbing force when the adsorbing force relative to the adsorbent is relatively compared for each component contained in the stock solution. Is.
Further, the “strongly adsorbing component” and the “weakly adsorbing component” may each consist of a single component or a plurality of components. The plurality of components may have the same or different adsorptive power. Since the component to be purified is often a single component, when the strongly adsorbing component is the component to be purified, the strongly adsorbing component is usually the component having the strongest adsorption power to the adsorbent in the stock solution. However, the present invention is not limited to this embodiment. The weakly adsorptive component is one or more components that are less adsorbable to the adsorbent than the strong adsorbent component. Similarly, when the weakly adsorptive component is a component to be purified, the weakly adsorbable component is usually the component having the weakest adsorption power to the adsorbent in the stock solution, but the present invention is limited to this embodiment. It is not a thing. The strong adsorptive component is one or more components having a higher adsorptivity to the adsorbent than the weak adsorptive component.

  According to the chromatographic separation method of the present invention, the component to be purified in the stock solution can be separated and purified in high purity with an excellent recovery rate while reducing the use amount of the eluent relative to the stock solution use amount. Further, the chromatographic separation system of the present invention can be suitably used for carrying out the chromatographic separation method of the present invention.

FIG. 1 is a system diagram showing an embodiment of the chromatographic separation system of the present invention. FIG. 2 is an explanatory diagram for explaining the basic concept of chromatographic separation by the pseudo moving bed method. FIG. 3 is a flowchart of substeps performed in an embodiment of the chromatographic separation method of the present invention. Numbers 1 to 4 in FIG. 3 indicate section numbers.

  A preferred embodiment of the chromatographic separation method of the present invention (hereinafter also simply referred to as “the method of the present invention”) will be described.

The method of the present invention is carried out using a circulation system in which a plurality of unit packed towers filled with an adsorbent are connected in series and endlessly through a pipe. The circulation system itself used in the simulated moving bed system is known, and for example, JP 2009-36536 A and JP 7-46097 A can be referred to.
The circulatory system will be described below with reference to the drawings, but the present invention is not limited to these embodiments.
The drawings referred to below are explanatory diagrams for facilitating the understanding of the present invention, and the size and relative size relationship of each component may be changed for convenience of explanation, and the actual relationship may be changed. It is not shown as it is. Further, the present invention is not limited to the shapes and relative positional relationships shown in these drawings except for the matters defined in the present invention.

A preferred embodiment of the circulatory system used in the method of the present invention is shown in FIG. The circulation system 100 shown in FIG. 1 includes four unit packed columns (columns) packed with an adsorbent Ab (unit packed columns 10a, 10b, 10c, and 10d), and the outlets of the unit packed columns are adjacent to each other. The unit packed tower is connected to the inlet of the unit packed tower via the pipe 1, and the unit packed towers are connected in series as a whole.
The outlet of the last unit packed column (for example, the unit packed column 10d) is connected to the inlet of the frontmost unit packed column (for example, the unit packed column 10a) via the pipe 1, and all the unit packed columns are endless. Connected in a circular shape. With this configuration, the fluid can be circulated in the circulation system 100. It is preferable that the unit packed towers 10a to 10d have the same internal shape, size, and adsorbent filling amount (preferably the same).

  In the circulation system 100, a circulation pump P1 for circulating fluid in the direction of the arrow is disposed. The circulation pump P1 is preferably a metering pump. Further, in the circulation system 100, the piping 1 between two adjacent unit packed towers is provided with shutoff valves R1, R2, R3, and R4 that can block the flow of fluid to the downstream unit packed tower. It has been.

  Between each shutoff valve R1-R4 and the outlet of each unit packed tower 10a-10d located on the upstream side thereof, a fraction containing a large amount of weakly adsorptive components for the adsorbent Ab (in this specification, “ The weakly adsorbable fraction extraction lines 2a, 2b, 2c, and 2d for extracting the “weakly adsorbable fraction with respect to the adsorbent Ab” or simply “the weakly adsorbable fraction”) are branched. Each weakly adsorptive fraction extraction line 2a, 2b, 2c, 2d has a weakly adsorptive fraction extraction valve A1, A2, A3, A4 that can open and close each weakly adsorptive fraction extraction line. Is provided. Each weakly adsorptive fraction extraction line 2a, 2b, 2c, 2d is merged and combined into one weakly adsorptive fraction confluence tube 3.

  Similarly, a fraction containing a large amount of strongly adsorbing components for the adsorbent Ab between the shutoff valves R1 to R4 and the outlets of the unit packed towers 10a to 10d located on the upstream side thereof (this specification) In FIG. 4, the strong adsorptive fraction extraction lines 4a, 4b, 4c, and 4d for extracting “the strongly adsorbable fraction with respect to the adsorbent Ab” or simply “the strong adsorptive fraction”) are branched. The strong adsorptive fraction extraction lines 4a, 4b, 4c, and 4d have strong adsorptive fraction extraction valves C1, C2, C3, and C4 that can open and close the strong adsorptive fraction extraction lines, respectively. Is provided. The strong adsorptive fraction extraction lines 4 a, 4 b, 4 c, and 4 d are joined together and combined into one strong adsorptive fraction confluence pipe 5.

  In steps (a1) and (a2) to be described later, any one of the weakly adsorbing fraction extraction valves A1, A2, A3, A4 is opened. The weakly adsorptive fraction extraction line in which the opened extraction valve is installed and the connection part of the pipe 1 are the outlet A of the weakly adsorptive fraction in steps (a1) and (a2). Become. In steps (a1) and (a2), one of the strong adsorptive fraction extraction valves C1, C2, C3, and C4 is opened. The strongly adsorbable fraction extraction line where the opened extraction valve is installed and the connection portion of the pipe 1 serve as the outlet C for the strong adsorbent fraction in steps (a1) and (a2). .

  In order to prevent the pressure of the circulation system 100 from rising excessively, the circulation system 100 is preferably provided with a safety valve (or a relief valve) that is not shown in an appropriate portion. Further, check valves T1, T2, T3, and T4 for preventing backflow are provided between two adjacent unit packed columns.

As shown in FIG. 1, the circulation system 100 is configured to be able to supply the stock solution 7 stored in the stock solution tank 6 and the eluent 9 stored in the eluent tank 8. The stock solution 7 is supplied via the stock solution supply line 11 by a stock solution supply pump P2 capable of controlling the supply flow rate. The stock solution supply pump P2 is preferably a metering pump. The stock solution supply line 11 preferably includes a relief valve U that returns the stock solution to the stock solution tank 6 when the supply pressure exceeds a set pressure during the supply of the stock solution. As shown in FIG. 1, the stock solution supply line 11 is branched into four stock solution supply branch lines 11a, 11b, 11c, and 11d, and the stock solution is supplied through each of the stock solution supply branch lines 11a, 11b, 11c, and 11d. The unit can be supplied to the entrances of the unit packed towers 10a, 10b, 10c, and 10d. Each stock solution supply branch line 11a, 11b, 11c, 11d is provided with an openable / closable stock solution supply valve F1, F2, F3, F4, through the stock solution supply branch line having the opened stock solution supply valve, The stock solution is supplied to the unit packed tower connected downstream.
In steps (a1) and (a2) to be described later, any one of the stock solution supply valves F1, F2, F3, and F4 is opened. The connection site between the undiluted solution supply branch line where the unfolded undiluted solution supply valve is installed and the pipe 1 becomes the undiluted solution supply port F in steps (a1) and (a2).

The eluent 9 is supplied via an eluent supply line 12 by an eluent supply pump P3 capable of controlling the supply flow rate. The eluent supply pump P3 is preferably a metering pump. The eluent supply line 12 preferably includes a relief valve V that returns the eluent to the eluent tank 8 when the supply pressure exceeds a set pressure during the supply of the eluent. As shown in FIG. 1, the eluent supply line 12 is branched into four eluent supply branch lines 12a, 12b, 12c, and 12d, and the eluent supply line 12a, 12b, 12c, and 12d are eluted. The liquid can be supplied to the entrances of the unit packed towers 10a, 10b, 10c, and 10d. Each eluent supply branch line 12a, 12b, 12c, 12d is provided with an eluent supply valve D1, D2, D3, D4 that can be opened and closed, and an eluent supply branch line having an opened eluent supply valve. Then, the eluent is supplied to the unit packed column connected downstream thereof.
In steps (a1) and (a2) to be described later, one of the eluent supply valves D1, D2, D3, and D4 is opened. A connecting portion between the eluent supply branch line where the opened eluent supply valve is installed and the pipe 1 becomes the eluent supply port D in steps (a1) and (a2).

  Subsequently, the operation of the circulatory system when the method of the present invention is performed by the circulatory system will be described. However, the present invention is not limited to these embodiments except as defined in the present invention. Absent. In the method of the present invention, the following steps (a1) and (b1) are repeated in order using the circulation system.

(A1) A step of performing the following sub-steps (ai) to (av) in this order;
(Ai) a sub-step of circulating the fluid in the circulation system without supplying the stock solution and the eluent and without extracting the strongly adsorbable fraction and the weakly adsorbable fraction;
(A-ii) a sub-step of supplying an eluent from the eluent supply port D and extracting a weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(A-iii) a sub-step of supplying the stock solution from the stock solution supply port F and extracting the weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(A-iv) a sub-step of circulating the fluid in the circulation system without supplying the stock solution and the eluent and without extracting the strong and weakly adsorbable fractions;
(Av) a sub-step of supplying an eluent from the eluent supply port D and extracting a strongly adsorbable fraction from the strong adsorbent fraction outlet C;
(B1) After the step (a1) is completed (that is, after the sub-step (av) is completed), the stock solution supply port F, the weakly adsorbable fraction extraction port A, the eluent supply port D, and the strong adsorption Moving the sex fraction extraction outlet C in the fluid flow direction while maintaining the relative positional relationship thereof;

[Step (a1)]
The step (a1) is a step of sequentially executing the five sub-steps (ai) to (av). Each sub-step will be described with reference to the circulation system shown in FIG.

<Substep (ai)>
In the sub-step (ai), the supply of the stock solution and the eluent is not performed, and the strong and weakly adsorbable fractions are not extracted, and the circulation pump P1 is operated to Simply circulate the fluid. As long as the stock solution supply pump P2 and the eluent supply pump P3 are stopped, the stock solution supply valves F1 to F4 and the eluate supply valves D1 to D4 may be opened, but from the viewpoint of controlling the fluid with higher accuracy, The stock solution supply valves F1 to F4 and the eluent supply valves D1 to D4 are preferably closed. The extraction valves A1 to A4 and the extraction valves C1 to C4 are all closed, and the shutoff valves R1 to R4 are all open.

  In the substep (ai), the circulation flow rate of the fluid in the system is preferably 1 to 20 liters per liter of the adsorbent Ab packed in the unit packed column 10a per hour. More preferably 10 liters.

<Substep (a-ii)>
In substep (a-ii), the eluent is supplied from the eluent supply port D, and the weakly adsorbable fraction is extracted from the weakly adsorbable fraction outlet A. In this sub-step (a-ii), the eluent supply valve D3 is opened and the eluent supply pump P3 is operated to supply the eluent supply to the connecting portion between the eluent supply branch line 12c having the supply valve D3 and the pipe 1. In the case of the port D, the outlet A1 is opened, and the connection portion between the weakly adsorbable fraction extraction line 2a and the pipe 1 is set as the weakly adsorbable fraction outlet A.

  In the sub-step (a-ii), the eluent supply valves D1, D2 and D4, the weakly adsorptive fraction extraction valves A3 and A4, the strong adsorptive fraction extraction valves C1, C3 and C4, and the shutoff valve R1 Are both closed. The adsorptive fraction extraction valve A2 and the strong adsorptive fraction extraction valve C2 are preferably closed. The stock solution supply valves F1 to F4 may be opened as long as the stock solution supply pump P2 is stopped. However, in order to perform the supply and extraction of the solution with higher accuracy, the stock solution supply valves F1 to F4 are It is preferably closed. The shutoff valve R2 may be open or closed, and is preferably closed. The shutoff valves R3 and R4 are both open. Further, the circulation pump P1 may be operated or stopped.

In the sub-step (a-ii), the amount of the eluent supplied from the eluent supply port D is not particularly limited, but per hour, per liter of the adsorbent Ab packed in the unit packed column 10a. 1 to 20 liters, preferably 2 to 10 liters. The total supply amount of the eluent in the substep (a-ii) is substantially the same as the total amount of the weakly adsorbable fraction extracted from the weakly adsorbable fraction outlet A in the substep (a-ii). It becomes.
In addition, description of each following substep is description in the driving | running aspect which opens the eluent supply valve D3 as mentioned above in substep (a-ii).

<Substep (a-iii)>
In the sub-step (a-iii), the weakly adsorbable fraction is extracted from the weakly adsorbable fraction extraction outlet A while supplying the stock solution from the stock solution supply port F. That is, the eluent supply pump P3 operated in the sub-step (a-ii) is stopped, or the eluent supply valve D3 is further closed, and instead, the stock solution supply valve F1 is opened and the stock solution supply pump P2 is opened. Operate. Then, similarly to the substep (a-ii), the connection site between the weakly adsorptive fraction extraction line 2a having the weakly adsorptive fraction extraction valve A1 and the pipe 1 is used as the weakly adsorptive fraction extraction outlet A. A weakly adsorptive fraction is extracted from the outlet A.

  In sub-step (a-iii), the stock solution supply valves F2 to F4, the shutoff valve R1, and the strong adsorptive fraction extraction valve C1 are all closed. The weak adsorptive fraction extraction valves A2 to A4 and the strong adsorptive fraction extraction valves C2 to C4 are preferably closed. The eluent supply valves D1 to D4 may be opened as long as the eluent supply pump P3 is stopped. However, in order to perform liquid supply and extraction with higher accuracy, elution liquid supply valves D1 to D4 may be opened. The liquid supply valves D1 to D4 are preferably closed. The shutoff valves R2-4 may be open or closed. Further, the circulation pump P1 is stopped.

  In the sub-step (a-iii), the amount of the stock solution supplied from the stock solution supply port F is not particularly limited, but 1 to 1 per liter of the adsorbent Ab packed in the unit packed column 10a per hour. It is preferably 20 liters, more preferably 2 to 10 liters. The total supply amount of the stock solution in the substep (a-iii) is substantially the same as the total amount of the weakly adsorbable fraction extracted from the weakly adsorbable fraction outlet A in the substep (a-iii). Become.

<Substep (a-iv)>
In the substep (a-iv), as in the above-described substep (ai), the stock solution and the eluent are not supplied, and the strong and weakly adsorbable fractions are not extracted. Then, the circulation pump P1 is operated to simply circulate the fluid in the circulation system.

  In the sub-step (a-iv), the circulating flow rate of the fluid in the system is preferably 1 to 20 liters per liter of the adsorbent Ab packed in the unit packed column 10a per hour. More preferably 10 liters.

<Sub-step (av)>
In the sub-step (av), the eluent is supplied from the eluent supply port D and the strong adsorptive fraction is extracted from the strong adsorptive fraction outlet C. In this sub-step (av), the eluent supply valve D3 is opened and the eluent supply pump P3 is operated so that the eluent supply branch line 12c having the supply valve D3 and the pipe 1 are connected to the eluent. The eluent is supplied as the supply port D. Further, the strong adsorptive fraction extraction valve C3 is opened, and the connection portion between the strong adsorptive fraction extraction line 4c and the pipe 1 is set as the strong adsorptive fraction extraction outlet C.

  In the sub-step (av), the weakly adsorptive fraction extraction valve A3 is closed and the shutoff valve R3 is also closed. D1, D2, and D4 are closed. The stock solution supply valves F1 to F4 may be opened as long as the stock solution supply pump P2 is stopped. However, in order to perform the supply and extraction of the solution with higher accuracy, the stock solution supply valves F1 to F4 are It is preferably closed. The weak adsorptive fraction extraction valves A1, A2 and A4, the strong adsorptive fraction extraction valves C1, C2 and C4, and the shutoff valves R1, R2 and R4 are preferably all closed. Further, the circulation pump P1 is stopped.

  In the sub-step (av), the amount of the eluent supplied from the eluent supply port D is not particularly limited, but per hour, per liter of the adsorbent Ab packed in the unit packed column 10a. 1 to 20 liters, preferably 2 to 10 liters. The total supply amount of the eluent in the substep (av) is substantially the same as the total amount of the strong adsorptive fraction extracted from the strong adsorptive fraction outlet C in the substep (av). It becomes.

  After the sub-step (av) is performed in the step (a1), the following sub-step (a-vi) may be performed before the step (b1) described later is performed.

(A-vi) a sub-step in which the fluid in the circulation system is circulated without supplying the stock solution and the eluent and without extracting the strong and weakly adsorbable fractions.

  That is, the time of the substep (ai) can be shortened, and the substep (ai) can be carried out in a position that compensates for the shortened time of the substep (ai). Included in embodiments of the invention.

  Although the sequential implementation of each sub-step in step (a1) has been described, a simpler illustration of these is shown in FIG. FIG. 3 is an explanatory diagram when the sub-step (a-vi) is performed.

  The relationship between the supply amount of liquid and the circulation flow rate in each sub-step is appropriately adjusted according to the type of components in the stock solution and the like within a range that satisfies formulas (c1) and (d1) described later.

In the circulation system used in the present invention, the amount of adsorbent packed in one unit packed column is not particularly limited and may be appropriately selected according to the purpose, but is usually 10 mL to 150 m ³ , preferably Is 150 mL to ³⁰ m ³ , more preferably 300 mL to 15 m ³ .
In addition, the relationship between the total capacity of the adsorbent Ab filled in all the unit packed towers in the circulation system and the total volume of the pipe 1 (the total volume in the cavity of the pipe 1) is a volume ratio [pipe 1 Of the total volume] / [total capacity of the adsorbent Ab] = 0.01 to 0.2.
In the present invention, it is preferable that the unit packed columns used have the same column size and the same kind and size of the filler.

The temperature at which step (a1) is performed is not particularly limited as long as the fluid in the circulation system is liquid, and is appropriately selected according to the purpose. Usually, it is carried out at 40 to 80 ° C.
In the method of the present invention, the flow rate of the supplied liquid or the flow rate of the liquid circulating in the circulation system may be constant during each sub-step or may be varied, but is usually constant. . Further, between each sub-step, the flow rate of the supplied liquid or the flow rate of the liquid circulating in the circulation system may be constant or may be varied, but is usually constant.

[Step (b1)]
After step (a1) is completed (after completion of sub-step (av) or (a-vi)), step (b1) is performed. In the step (b1), the stock solution supply port F, the weakly adsorptive fraction extraction outlet A, the eluent supply port D, and the strong adsorptive fraction extraction outlet C are maintained in their relative positional relationship. This is a step of moving the fluid in the direction of fluid flow.
In this specification, “the flow direction of the fluid while maintaining the relative positional relationship between the stock solution supply port F, the weakly adsorbable fraction outlet A, the eluent supply port D, and the strong adsorptive fraction outlet C”. "Transfer toward the liquid" means that the stock solution supply port F, the weakly adsorbable fraction extraction port A, the eluent supply port D, and the strong adsorptive properties that were sequentially arranged in the fluid flow direction in the immediately preceding step (a1). This means that the order of the fraction extraction outlets C is switched between the strong adsorptive fraction extraction outlet C, the stock solution supply port F, the weak adsorptive fraction extraction port A, and the eluent supply port D, respectively.
In other words, with the positions of all the unit packed columns fixed, the positions of the stock solution supply port F, the weakly adsorbable fraction extraction outlet A, the eluent supply port D, and the strong adsorptive fraction extraction outlet C are set. By switching
1) A unit packed tower between the stock solution supply port F and the weakly adsorptive fraction extraction outlet A in the immediately preceding step (a1) is placed between the strong adsorptive fraction extraction port C and the stock solution supply port F.
2) A unit packed column between the weakly adsorbing fraction extraction outlet A and the eluent supply port D in the immediately preceding step (a1) is placed between the stock solution supply port F and the weakly adsorbing fraction extraction port A.
3) The unit packed tower between the eluent supply port D and the strong adsorptive fraction extraction outlet C in the immediately preceding step (a1) is placed between the weak adsorbent fraction extraction outlet A and the eluent supply port D. ,
4) The unit packed tower between the strong adsorptive fraction extraction outlet C and the stock solution supply port F in the immediately preceding step (a1) is arranged between the eluent supply port D and the strong adsorptive fraction extraction port C, respectively. It means to be placed.
In the form of the circulatory system in FIG. 1, this step (b1) is not a step of giving a physical change to the structure of the circulatory system, but a preparatory process for carrying out the step (a1) following this step (b1). It is.

The step (b1) will be specifically described with reference to FIG.
Assume that in step (a1) immediately before step (b1), the supply valve F1 is opened and the stock solution is supplied. In this case, in the substep (a1), the stock solution supply port F is connected to the stock solution supply branch line 11a and the pipe 1,
The weakly adsorptive fraction extraction outlet A is a connection site between the weakly adsorptive fraction extraction line 2a and the pipe 1,
The eluent supply port D is connected to the eluent supply branch line 12c and the pipe 1;
The strong adsorptive fraction extraction outlet C is a connecting portion between the strong adsorptive fraction extraction line 4 c and the pipe 1.
The ports F, A, D, and C in step (a1) are switched as follows according to step (b1). That is,
The stock solution supply port F becomes a connection part between the stock solution supply branch line 11b and the pipe 1,
The weakly adsorptive fraction extraction outlet A is a connection site between the weakly adsorptive fraction extraction line 2b and the pipe 1,
The eluent supply port D becomes a connecting portion between the eluent supply branch line 12d and the pipe 1,
The strong adsorptive fraction extraction outlet C serves as a connection site between the strong adsorptive fraction extraction line 4 d and the pipe 1.
That is, in step (a1) immediately after step (b1), the supply of the stock solution in substep (a-iii) is performed through stock solution supply branch line 11b, and substeps (a-ii) and (a- The supply of the eluent in v) is performed through the eluent supply branch line 12d, and the strong adsorptive fraction is extracted in the sub-step (av) through the strong adsorbent fraction extraction line 4d. Extraction of the weakly adsorbable fraction in a-ii) and (a-iii) is performed through the weakly adsorbable fraction extraction line 2b.

  By repeating the steps (a1) and (b1) in order, the method of the present invention by the pseudo moving layer system is carried out. The step (a1) in the present invention includes the sub-steps (a-vi) described above. ) Is not carried out under the conditions satisfying the following formulas (c1) and (d1), and the following formulas (c1) and (d1 ′) are required when performing the above-mentioned substep (a-vi). It is necessary to carry out under conditions that satisfy

(C1) Elution volume of component X> Integrated flow rate of section 1 Here, component X is a component that is recovered in the strongly adsorbing fraction and satisfies the following formula (d1) or (d1 ′) .

In the present invention, section 1 means a unit packed column disposed between the eluent supply port D and the strong adsorptive fraction outlet C as shown in FIG. “Section 1 integrated flow rate” means each sub-step in which liquid flows through section 1 (ie, sub-steps (a-i), (a-ii), ( a-iv) and (av); when substep (a-vi) is performed, substeps (ai), (a-ii), (a-iv), (av) and (a) -The total amount of liquid flowing in vi)). The integrated flow rate in section 1 is, for example, 1 L when fluid is passed through section 1 and the pump set flow rate is 1 L / hour for 1 hour.
In the present invention, the “elution volume” of a component means the amount of liquid required for the component to pass through the unit packed column (column) (note that two or more unit packed columns are connected in series in one section). The amount of liquid required to pass through one unit packed column). The unit of elution volume and integrated flow rate are both liters (L).

Satisfying the formula (c1), that is the equation required for Triangle Theory ^₍₅₎ V ₁ ^acc> that do not meet the ^{V S Elution,} i.e., means that the beating triangle theory. As described above, in the technical common sense of those skilled in the art that the conditions necessary for the establishment of the triangle theory must be satisfied in order to achieve good separation in the pseudo moving layer system, the present inventors have used the triangle theory. Even when it is broken, it has been found that satisfactory separation and purification can be achieved when the following formula (d1) is satisfied, and the present invention has been completed.
As is clear from the comparison between the above formula (c1) and the above formula (5), when the formula (c1) is satisfied, the integrated flow rate in the section 1 is made smaller than when the above formula (5) is satisfied. Can do. As shown in FIG. 2, the integrated flow rate of the eluent is an amount obtained by subtracting (subtracting) the integrated flow rate of section 4 from the integrated flow rate of section 1. Therefore, the integrated flow rate of section 1 can be reduced. This makes it possible to effectively reduce the amount of eluent used.

(D1) [2 × (the integrated flow rate in the sub-step (ai)) + the integrated flow rate in the sub-step (a-ii) + the integrated flow rate in the sub-step (a-iii) + the sub-step (a− iv) integrated flow rate] <[elution volume of component X] <[2 × (integrated flow rate of substep (ai)) + integrated flow rate of substep (a-iv) + substep (a -V) Integrated flow rate]

(D1 ′) [2 × (integrated flow rate in the sub-step (ai)) + integrated flow rate in the sub-step (a-ii) + integrated flow rate in the sub-step (a-iii) + sub-step (a -Iv) integrated flow rate + 2 × (the integrated flow rate of the substep (a-vi))] <[elution volume of the component X] <[2 × (the integrated flow rate of the substep (ai)) + the above Integrated flow rate of sub-step (a-iv) + integrated flow rate of sub-step (av) + 2 × (integrated flow rate of sub-step (a-vi))]

  By making the said step (a1) into the driving | operation which satisfy | fills said Formula (c1) and (d1), or the driving | operation which satisfy | fills said Formula (c1) and (d1 '), the refinement | purification object component is excellent in the recovery rate. The fact that it can be obtained in a predetermined fraction with high purity is supported by the examples described later.

By repeating the steps (a1) and (b1) in order, the amount of the eluent used can be effectively reduced as compared with the chromatographic separation by the normal simulated moving bed system. That is, according to the method of the present invention, the target component to be purified can be obtained in high purity with a small amount of eluent used in the fraction selected from the strongly adsorbable fraction and the weakly adsorbable fraction.
In the method of the present invention, the component to be purified is preferably a weakly adsorptive component.

  The method of the present invention includes various modifications in addition to the embodiments specifically described above. For example, between the stock solution supply port F and the weakly adsorbable fraction outlet A, between the weakly adsorptive fraction outlet A and the eluent supply port D, eluent supply port D and the strong adsorptive fraction outlet One unit packed tower may be provided between C and the strongly adsorbing fraction outlet C and the stock solution supply port F, or two or more units may be provided. May be. However, the number of unit packed towers disposed between the weakly adsorbing fraction extraction outlet A and the eluent supply port D is one. That is, the circulation system preferably has at least 4 unit packed towers, and more preferably has 4 unit packed towers.

  In the method of the present invention, the adsorbent packed in the unit packed column is appropriately selected according to the component to be purified, and various adsorbents can be employed. For example, strong acid cation exchange resin, weak acid cation exchange resin, strong base anion exchange resin, weak base anion exchange resin, synthetic adsorbent, zeolite, silica gel, and functional group-modified silica gel (preferably Octadecylsilyl-modified silica gel) can be used as the adsorbent.

  The chromatographic separation system of the present invention is a system for carrying out the method of the present invention. That is, the chromatographic separation system of the present invention has the above-described circulation system configuration, and the circulation system sequentially performs the operation of step (a1) or (a2) and the operation of step (b1) or (b2). It is a system that can be repeated.

  EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited to the following Example.

[Preparation of stock solution]
Preparation of three component methanol solution of acetone (Ac), aniline (An) and ethylbenzene (EB) (Ac concentration: 4.0 g / L, An concentration: 3.0 g / L, EB concentration: 3.0 g / L) And used as a stock solution.

[Preparation of eluent]
Methanol was the eluent.

[Chromatograph separation system]
Using the circulation system shown in FIG. 1, the separation and purification of Ac was performed from the stock solution. As the unit packed towers 10a to 10d, cylindrical packed towers having an inner diameter of 2 cm and a height of 1 m were used. Further, the unit packed towers 10a to 10d were filled with 0.314L of a synthetic adsorbent Amberlite (registered trademark) XAD1200N (manufactured by Dow Chemical Co.) as an adsorbent (porosity: 0.360). The inside of each unit packed column was adjusted to 40 ° C.
The distribution coefficients and elution volumes of Ac, An, and EB in the stock solution are shown in Table 1 below.

[Example 1]
The above circulatory system was operated under the conditions defined in the present invention (a mode including substep (av) between substep (av) and step (b1)). This operation can recover Ac in the weakly adsorbable fraction with a high purity of 95% or more (the ratio of Ac in the total mass of Ac, An and EB), and in the weakly adsorbable fraction, It was set as a condition for recovering 95% by mass or more of the contained Ac. In this embodiment, the composition (ratio of each component in the total mass of Ac, An and EB) in the weakly adsorbable fraction is as follows: Ac: 95.2%, An: 1.2%, EB: 3.6% Met. In this embodiment, the recovery rate in the weakly adsorptive fraction (for each component, the ratio of the mass recovered in the weakly adsorbed component to the total mass recovered in the strongly adsorbable fraction and the weakly adsorbable fraction) is Ac: 96.9%, An: 1.6%, EB: 4.9%. Table 2 below shows specific operating conditions, that is, sub-step execution conditions in step (a1).
In Example 1, 20 cycles of the step (a1) and the step (b1) including the sequential execution of the following substeps were performed. In each of the examples and comparative examples described in this [Example], the number of cycles was all set to 20 cycles. And the thing of the last cycle (20th cycle) was made into the performance in each Example and a comparative example.

Under the operating conditions in Table 2, the elution volume of EB (component X): 0.4474L is the integrated flow rate of section 1 (ie, the integrated flow rate of substep (ai) and the integrated flow of substep (a-ii). The sum of the flow rate, the integrated flow rate of sub-step (a-iv), the integrated flow rate of sub-step (av), and the integrated flow rate of sub-step (a-vi)): greater than 0.4147L, specified by the present invention. The expression (c1) is satisfied. That is, the driving conditions in Table 2 above break the triangle theory.
Further, regarding the triangle theory related to the other sections, in the separation target in this case, since WF = Ac, WL = Ac, SF = An, SL = EB, V _SL ^elimination = 0.4474L, V _WL ^elimination = 0.2599L, V _SF ^elimination = 0.3159L, and V _WF ^elimination = 0.2599L. Since the integrated flow rates of the sections 2, 3 and 4 are V ₂ ^acc = 0.2603L, V ₃ ^acc = 0.3149L and V ₄ ^acc = 0.2356L, respectively, The triangle theory formulas (1 ′), (4 ′), and (6 ′) are satisfied.
Further, since the left side of the formula (d1 ′) = 0.4163 and the right side of the formula (d1 ′) = 0.4913, the formula (d1 ′) defined in the present invention is satisfied.

Under the above operating conditions, the ratio of the eluent integrated flow rate (V _D ^acc ) to the stock solution integrated flow rate (V _F ^acc ) is V _D ^acc / V _F ^acc = 3.28.
The ^{_V D acc} _{/ V} ^F acc, from ^{_{V D acc / V F acc =}} (V EB elution -V Ac elution) / (V An elution -V Ac elution) = 3.35 derived from the formula (17) It can also be seen that the value is further lower than the lower limit of the amount of eluent used derived from the triangle theory.

[Comparative Example 1]
Comparative Example 1 is an operating condition in which the execution order of the substeps is the same as the order of the substeps defined in the present invention, and in accordance with the triangle theory.
Specifically, in Example 1, except that the operating conditions of step (a1) shown in Table 2 above were as shown in Table 3 below, the weakly adsorbable fraction was collected in the same manner as in Example 1. Was recovered. The operating conditions shown in Table 3 below are such that Ac can be recovered in the weakly adsorptive fraction with a high purity of 95% or more, and 95% by mass or more of Ac contained in the stock solution in the weakly adsorbable fraction. It is a condition that can be recovered.

In the operating conditions of Table 3 above, the elution volume of EB (component X): 0.4474L is the integrated flow rate of section 1 (that is, the integrated flow rate of substep (ai) and the integrated substep (a-ii). The sum of the flow rate, the integrated flow rate of sub-step (a-iv), the integrated flow rate of sub-step (av), and the integrated flow rate of sub-step (a-vi)): smaller than 0.4524L, specified by the present invention. The expression (c1) to be satisfied is not satisfied. That is, it is a condition that satisfies the triangle theory.
Further, since the left side of the formula (d1 ′) = 0.4163 and the right side of the formula (d1 ′) = 0.5290, the formula (d1 ′) defined in the present invention is satisfied.

In the above operation, the ratio of the integrated flow rate (V _D ^acc ) of the eluent to the integrated flow rate (V _F ^acc ) of the stock solution is V _D ^acc / V _F ^acc = 3.97.
The ^{_V D acc} _{/ V} ^F acc, from ^{_{V D acc / V F acc =}} (V EB elution -V Ac elution) / (V An elution -V Ac elution) = 3.35 derived from the formula (17) It can be seen that the amount of eluent used is larger than the lower limit of the amount of eluent used in accordance with the triangle theory.

[Comparative Example 2]
Comparative Example 2 is an operating condition in which the execution order of the sub-steps is the same as the order of the sub-steps defined in the present invention, and the condition of formula (d1 ′) is not satisfied after breaking the triangle theory. It is.
Specifically, in Example 1, except that the operating conditions of step (a1) shown in Table 2 above were as shown in Table 4 below, the weakly adsorbable fraction was collected in the same manner as in Example 1. Was recovered. In the implementation of Comparative Example 2, the aim was to recover Ac with a high purity of 95% or more in the weakly adsorptive fraction, but the purity of Ac in the weakly adsorbable fraction was 92.7. %. The recovery rate of Ac to the weakly adsorbable fraction was as good as 95% by mass or more.

In the operating conditions of Table 4 above, the elution volume of EB (component X): 0.4474L is the integrated flow rate of section 1 (that is, the integrated flow rate of sub-step (ai) and the integrated flow of sub-step (a-ii). The sum of the flow rate, the integrated flow rate of sub-step (a-iv), the integrated flow rate of sub-step (av), and the integrated flow rate of sub-step (a-vi)): greater than 0.4147L, specified by the present invention. The expression (c1) is satisfied. That is, the driving conditions in Table 4 above break the triangle theory.
On the other hand, since the left side of the formula (d1 ′) = 0.5388 and the right side of the formula (d1 ′) = 0.6139, the formula (d1 ′) defined in the present invention is not satisfied.

In the above operation, the ratio of the integrated flow rate (V _D ^acc ) of the eluent to the integrated flow rate (V _F ^acc ) of the stock solution is V _D ^acc / V _F ^acc = 3.28.
The ^{_V D acc} _{/ V} ^F acc, from ^{_{V D acc / V F acc =}} (V EB elution -V Ac elution) / (V An elution -V Ac elution) = 3.35 derived from the formula (17) However, as described above, the purity of Ac in the weakly adsorptive fraction is less than 95%, and the components to be purified are separated and purified with the desired purity. I can't.

[Comparative Example 3]
In Comparative Example 3, the order of execution of the sub-steps is the same as the order of the sub-steps defined in the present invention, and after breaking the triangle theory, the operating conditions are set so as not to satisfy the condition of the formula (d1 ′) It is.
Specifically, in Example 1, except that the operating conditions of step (a1) shown in Table 2 above were as shown in Table 5 below, the weakly adsorptive fraction was subjected to Ac as in Example 1. Was recovered. In carrying out this Comparative Example 3, the aim was to recover Ac in a weakly adsorbable fraction with a high purity of 95% or more, but the purity of Ac in the weakly adsorbable fraction was 90.7. %. The recovery rate of Ac in the weakly adsorbable fraction was as good as 95% by mass or more.

In the operating conditions of Table 5 above, the elution volume of EB (component X): 0.4474L is the integrated flow rate of section 1 (ie, the integrated flow rate of substep (ai) and the integrated flow of substep (a-ii)). The sum of the flow rate, the integrated flow rate of sub-step (a-iv), the integrated flow rate of sub-step (av), and the integrated flow rate of sub-step (a-vi)): greater than 0.4147L, specified by the present invention. The expression (c1) is satisfied. That is, the driving conditions in Table 5 above break the triangle theory.
On the other hand, since the left side of the formula (d1 ′) = 0.3456 and the right side of the formula (d1 ′) = 0.4207, the formula (d1 ′) defined in the present invention is not satisfied.

In the above operation, the ratio of the integrated flow rate (V _D ^acc ) of the eluent to the integrated flow rate (V _F ^acc ) of the stock solution is V _D ^acc / V _F ^acc = 3.28.
The ^{_V D acc} _{/ V} ^F acc, from ^{_{V D acc / V F acc =}} (V EB elution -V Ac elution) / (V An elution -V Ac elution) = 3.35 derived from the formula (17) However, as described above, the purity of Ac in the weakly adsorptive fraction is less than 95%, and the components to be purified are separated and purified with the desired purity. I can't.

In each of the above examples and comparative examples, in the sub-step corresponding to step (a1), the liquid circulation step (sub-step (a-vi)) is performed as a sub-step immediately before the subsequent step (b1) is performed. Has been implemented.
On the other hand, the present inventors do not carry out the liquid circulation step immediately before carrying out step (b1) (for example, the embodiment in which substep (a-vi) is not carried out in step (a1) in Example 1). Experiments were also conducted for these (these forms are the forms in which the liquid circulation step immediately before the execution of step (b1) is absorbed in the first sub-step (ai) in step (a1)). As a result, it was clarified that immediately before the step (b1) is performed, results equivalent to those of the above examples and comparative examples can be obtained even in the case where the liquid circulation step is not performed.
The operating conditions in these experiments are shown below.

  The operating conditions under which results equivalent to those of Example 1 were obtained are as follows.

  The operating conditions under which results equivalent to Comparative Example 1 were obtained are as follows.

  The operating conditions under which results equivalent to those of Comparative Example 2 were obtained are as follows.

  The operating conditions under which results equivalent to Comparative Example 3 were obtained are as follows.

100 Circulation system 10a, 10b, 10c, 10d Unit packed tower (column)
Ab adsorbent R1, R2, R3, R4 Shut-off valve 2a, 2b, 2c, 2d Weakly adsorbing fraction extraction line A1, A2, A3, A4 Weakly adsorbing fraction extraction valve 4a, 4b, 4c, 4d Strong Adsorption fraction extraction line C1, C2, C3, C4 Strong adsorption fraction extraction valve T1, T2, T3, T4 Check valve 1 Pipe 3 Weak adsorption fraction junction pipe 5 Strong adsorption fraction junction pipe 6 Stock solution tank 7 Stock solution 8 Eluent tank 9 Eluent 11 Stock solution supply line 11a, 11b, 11c, 11d Stock solution supply branch line F1, F2, F3, F4 Stock solution supply valve 12 Eluent supply line 12a, 12b, 12c, 12d Liquid supply branch line D1, D2, D3, D4 Eluent supply valve P1 Circulation pump P2 Stock solution supply pump P3 Eluent supply pump U, V Relief valve

Claims (5)

A chromatographic separation method for separating and purifying components in a stock solution by a simulated moving bed method using a circulation system in which a plurality of unit packed towers packed with an adsorbent are connected in series and endlessly through a pipe,
The circulation system has a stock solution supply port F, a weakly adsorptive fraction extraction outlet A, an eluent supply port D, and a strong adsorptive fraction extraction outlet C in this order in the fluid flow direction. And between the stock solution supply port F and the weakly adsorbable fraction outlet A, between the weakly adsorbable fraction outlet A and the eluent supply port D, and the eluent supply port D. Between the strong adsorptive fraction extraction outlet C and between the strong adsorptive fraction extraction outlet C and the stock solution supply port F, at least one unit packed tower is disposed,
The chromatographic separation method includes sequentially repeating the following steps (a1) and (b1), and the step (a1) is performed under conditions satisfying the following formulas (c1) and (d1):
(A1) A step of performing the following sub-steps (ai) to (av) in this order;
(Ai) a sub-step of circulating the fluid in the circulation system without supplying the stock solution and the eluent and without extracting the strongly adsorbable fraction and the weakly adsorbable fraction;
(A-ii) a sub-step of supplying an eluent from the eluent supply port D and extracting a weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(A-iii) a sub-step of supplying the stock solution from the stock solution supply port F and extracting the weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(A-iv) a sub-step of circulating the fluid in the circulation system without supplying the stock solution and the eluent and without extracting the strong and weakly adsorbable fractions;
(Av) a sub-step of supplying an eluent from the eluent supply port D and extracting a strongly adsorbable fraction from the strong adsorbent fraction outlet C;
(B1) After completion of the step (a1), the stock solution supply port F, the weakly adsorptive fraction extraction outlet A, the eluent supply port D, and the strong adsorptive fraction extraction port C are set to their relative positions. The step of moving toward the flow direction of the fluid while maintaining the positional relationship.
(C1) Elution volume of component X> Integrated flow rate of section 1 Here, component X is a component that is recovered in the strongly adsorbing fraction and satisfies the following formula (d1).
(D1) [2 × (the integrated flow rate in the sub-step (ai)) + the integrated flow rate in the sub-step (a-ii) + the integrated flow rate in the sub-step (a-iii) + the sub-step (a− iv) integrated flow rate] <[elution volume of component X] <[2 × (integrated flow rate of substep (ai)) + integrated flow rate of substep (a-iv) + substep (a -V) Integrated flow rate] In the step (a1), the following substep (a-vi) is performed between the substep (av) and the step (b1), and the step (a1) is changed to the formula (d1). The chromatographic separation method according to claim 1, which is carried out under conditions satisfying the following formula (d1 ′) instead of
(A-vi) a sub-step in which the fluid in the circulation system is circulated without supplying the stock solution and the eluent and without extracting the strong and weakly adsorbable fractions.
(D1 ′) [2 × (integrated flow rate in the sub-step (ai)) + integrated flow rate in the sub-step (a-ii) + integrated flow rate in the sub-step (a-iii) + sub-step (a -Iv) integrated flow rate + 2 × (the integrated flow rate of the substep (a-vi))] <[elution volume of the component X] <[2 × (the integrated flow rate of the substep (ai)) + the above Integrated flow rate of sub-step (a-iv) + integrated flow rate of sub-step (av) + 2 × (integrated flow rate of sub-step (a-vi))]   The chromatographic separation method according to claim 1, wherein the circulation system has at least four unit packed columns. A chromatographic separation system that separates and purifies components in a stock solution by a simulated moving bed system using a circulation system in which a plurality of unit packed towers packed with an adsorbent are connected in series and endlessly via a pipe,
The circulation system has a stock solution supply port F, a weakly adsorptive fraction extraction outlet A, an eluent supply port D, and a strong adsorptive fraction extraction outlet C in this order in the fluid flow direction. And between the stock solution supply port F and the weakly adsorbable fraction outlet A, between the weakly adsorbable fraction outlet A and the eluent supply port D, and the eluent supply port D. Between the strong adsorptive fraction extraction outlet C and between the strong adsorptive fraction extraction outlet C and the stock solution supply port F, at least one unit packed tower is disposed,
A chromatographic separation system comprising means for sequentially repeating the following steps (a1) and (b1), and means for carrying out the step (a1) under conditions satisfying the following formulas (c1) and (d1):
(A1) A step of performing the following sub-steps (ai) to (av) in this order;
(Ai) a sub-step of circulating the fluid in the circulation system without supplying the stock solution and the eluent and without extracting the strongly adsorbable fraction and the weakly adsorbable fraction;
(A-ii) a sub-step of supplying an eluent from the eluent supply port D and extracting a weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(A-iii) a sub-step of supplying the stock solution from the stock solution supply port F and extracting the weakly adsorbable fraction from the weakly adsorbable fraction outlet A;
(A-iv) a sub-step of circulating the fluid in the circulation system without supplying the stock solution and the eluent and without extracting the strong and weakly adsorbable fractions;
(Av) A sub-step of supplying an eluent from the eluent supply port D and extracting a strongly adsorbable fraction from the strong adsorbent fraction outlet C.
(B1) After completion of the step (a1), the stock solution supply port F, the weakly adsorptive fraction extraction outlet A, the eluent supply port D, and the strong adsorptive fraction extraction port C are set to their relative positions. The step of moving toward the flow direction of the fluid while maintaining the positional relationship.
(C1) Elution volume of component X> Integrated flow rate of section 1 Here, component X is a component that is recovered in the strongly adsorbing fraction and satisfies the following formula (d1).
(D1) [2 × (the integrated flow rate in the sub-step (ai)) + the integrated flow rate in the sub-step (a-ii) + the integrated flow rate in the sub-step (a-iii) + the sub-step (a− iv) integrated flow rate] <[elution volume of component X] <[2 × (integrated flow rate of substep (ai)) + integrated flow rate of substep (a-iv) + substep (a -V) Integrated flow rate] The step (a1) performs the following substep (a-vi) between the substep (av) and the step (b1), and the step (a1) The chromatographic separation system according to claim 4, which is carried out under conditions satisfying the following formula (d1 ') instead of the formula (d1):
(A-vi) a sub-step in which the fluid in the circulation system is circulated without supplying the stock solution and the eluent and without extracting the strong and weakly adsorbable fractions.
(D1 ′) [2 × (integrated flow rate in the sub-step (ai)) + integrated flow rate in the sub-step (a-ii) + integrated flow rate in the sub-step (a-iii) + sub-step (a -Iv) integrated flow rate + 2 × (the integrated flow rate of the substep (a-vi))] <[elution volume of the component X] <[2 × (the integrated flow rate of the substep (ai)) + the above Integrated flow rate of sub-step (a-iv) + integrated flow rate of sub-step (av) + 2 × (integrated flow rate of sub-step (a-vi))]

Images