JP7345296B2 - Chemical liquid synthesis equipment - Google Patents

Description

The present invention relates to a chemical solution synthesis device that is less likely to cause problems due to mechanical damage and can be used for single use when improving the synthesis efficiency by circulating the drug solution when synthesizing the drug solution.

In a chemical synthesis device that chemically synthesizes proteins, peptides, polymers, nucleic acids, etc., chemical synthesis is performed by supplying a plurality of chemical solutions (reagents) to a reaction container. For example, when synthesizing nucleic acids, a large number of carriers (porous beads, hereinafter referred to as beads) are provided in a reaction container, and while a chemical solution is sequentially supplied to the reaction container, detritylation, coupling, oxidation, Processes such as capping are repeated to bond bases to the beads one after another.

For example, as shown in FIG. 10, a general chemical liquid synthesis apparatus includes a reaction vessel 100 to which a chemical liquid is supplied, a chemical liquid tank 101 that stores the chemical liquid to be supplied to the reaction vessel 100, and a chemical liquid tank 101 that stores the chemical liquid to be supplied to the reaction vessel 100. The chemical solution tank 101 and the reaction container 100 are connected by supply pipes 103a and 103b, respectively, and the drain tank 102 and the reaction container 100 are connected by a drainage pipe 105a, 105b. In such a chemical liquid synthesis apparatus, the chemical liquid in the chemical liquid tank 101 is communicated with the reaction container 100 by connecting the supply pipe 103a and the supply pipe 103b through the valve 106. In this state, by operating the pump 104, the chemical solution is sent to the reaction container 100 through the supply line 103, and the beads in the reaction container 100 and the drug solution are chemically synthesized. After being synthesized in the reaction container 100, the chemical solution after the synthesis reaction is drained. Specifically, by connecting the drain pipe 105a and the drain pipe 105b with the valve 108, the reaction vessel 100 and the drain tank 102 are communicated with each other, and by operating the pump 109 in this state, the chemical solution is drained. The liquid is sent to the tank 102. By repeating such a synthesis reaction, a predetermined base can be bound to a bead and a predetermined nucleic acid can be obtained.

Further, a circulation line 110 is provided in the chemical liquid synthesis device. That is, when the chemical solution is supplied once, the chemical solution may not be able to fully react with all the beads in the reaction container 100, and some chemical solutions require a long time to react with the beads. Because of this presence, the chemical solution may be drained into the drain tank 102 without being sufficiently chemically synthesized. In order to avoid this problem, the same chemical solution is again supplied to the reaction vessel 100 through the circulation line 110 for chemical synthesis. In the example of FIG. 10, the circulation line 110 is formed by a drain pipe 105a, a bypass pipe 106, and a supply pipe 103b. Then, by operating the pump 109 with the supply pipe 103b and the bypass pipe 106 connected by the valve 106 and the bypass pipe 106 and the drain pipe 105a connected by the valve 108, the chemical solution in the reaction vessel 100 is circulated. By circulating through the line 110 and being supplied to the reaction vessel 100 again, the same chemical solution can be chemically synthesized in the reaction vessel 100 multiple times to improve the synthesis efficiency of the chemical solution (for example, as described below). (See Patent Document 1).

WO2010/038613 publication

However, in the chemical liquid synthesis apparatus described above, since the pump 109 is used as a driving source for feeding the liquid in the circulation line 110, the sliding part of the pump 109, which is the part that comes into contact with the chemical liquid, is easily damaged. There was a problem with leakage. Furthermore, since the sliding portion comes into contact with the liquid, there is also a problem that particles generated from the sliding portion may be mixed into the chemical solution.

Furthermore, in recent years, from the viewpoint of infection prevention and hygiene, not only medical equipment but also chemical synthesis equipment has been required to be disposable, so-called single-use. In the case of the above-mentioned chemical liquid synthesis apparatus, the piping system parts such as the supply piping 103a, 103b, the drain line 105a, 105b, the bypass piping 106, the valve 106, the valve 108, etc., which are the liquid contact parts, and the pump 109 are compatible with single use. Although the pump 109 needs to be replaced with a new one, the cost of the pump 109 is much higher than that of piping, valves, etc., and there is a problem in that the running cost increases if it is used for single use.

The present invention has been made in view of the above-mentioned problems, and aims to provide a chemical liquid synthesis device that is inexpensive and suitable for single use, and is less likely to cause problems due to mechanical damage by circulating the chemical liquid. There is.

In order to solve the above problems, the chemical solution synthesis apparatus of the present invention includes: a reaction container in which a chemical solution is reacted; a primary pipe connected to the reaction container and mainly for supplying the chemical solution to the reaction container; and a circulation line connected to the primary pipe and the secondary pipe. The liquid feeding is carried out by supplying gas into a circulation line, and the circulation line is characterized by being provided with a circulator having a capacity greater than that of the reaction vessel .

According to the above-mentioned chemical liquid synthesis apparatus, the liquid is fed through the circulation line connected to the primary piping and the secondary piping by supplying gas into the circulation line. Since there are no moving parts, it is possible to eliminate problems caused by damage to sliding parts as in the conventional case. In addition, since there is no liquid supply drive source in the wetted parts, parts such as primary piping, secondary piping, circulation lines, valves, etc. must be replaced with new ones for single-use applications. There is no need to replace it, and it can be used for single use at low cost. Since all of the chemical solution supplied to the reaction container can be sent to the circulatory system and stored, all the chemical solution sent to the circulation line can be returned to the reaction container without any chemical solution remaining in the piping etc. The total amount can be recycled to improve synthesis efficiency.

Further, the circulation line includes a connector part that connects the circulation pipe through which the chemical solution is sent and the circulator, and the connector part connects the circulation pipe formed to have a smaller diameter than the circulator. It has a sealing part that seals the insertion part that is inserted into the circulator, and a liquid feeding gas pipe that supplies gas for feeding the chemical solution in the circulation line is connected to this sealing part, and gas from the liquid feeding gas piping is connected to the sealing part. When the medical fluid is supplied, the chemical solution in the circulatory system may be pressed through a difference in diameter between the circulation pipe and the circulatory system.

According to this configuration, the circulatory system, circulation piping, and liquid gas piping can be connected while being sealed with one connector portion, and the configuration of the connecting portion can be constructed at low cost.

Further, the circulator may be configured to be a pipe formed to have a larger diameter than the circulation pipe.

According to this configuration, since versatile piping can be used for both the circulator and the circulation piping, the circulation line can be configured at low cost and can be configured to be suitable for single use.

According to the chemical solution synthesis device of the present invention, problems due to mechanical damage are less likely to occur by circulating the chemical solution, and the device can be configured to be inexpensive and suitable for single use.

1 is a schematic piping route diagram of the chemical liquid synthesis apparatus of the present invention. It is an enlarged view of the reaction container vicinity of the said chemical|medical solution synthesis apparatus. It is a figure which shows the connector part of the said chemical|medical solution synthesis apparatus. It is a sectional view of the above-mentioned connector part. FIG. 3 is an enlarged cross-sectional view showing a main part of the connector section. FIG. 3 is a diagram showing the liquid level position of the chemical liquid and the opening/closing state of the valve; (a) is a diagram showing the state in which the chemical liquid is supplied from the chemical liquid tank to the reaction container; and (b) is a diagram showing the state in which the chemical liquid is supplied from the reaction container to the circulatory system. It is a figure showing the state where liquid was sent. FIG. 3 is a diagram showing the liquid level position of the chemical solution and the open/closed state of the valve; (a) is a diagram showing the state where the chemical solution is being sent from the circulatory system to the reaction container; and (b) is a diagram showing the state where the chemical solution is being sent from the circulatory system to the reaction container. FIG. 3 is a diagram showing a state in which liquid feeding has been completed. It is a figure which shows the state which drains the chemical|medical solution of a reaction container from a bypass line. It is a figure which shows the liquid level position of a chemical|medical solution, and the opening/closing state of a valve, (a) is a figure which shows a forward flow process, (b) is a figure which shows a reverse flow process. FIG. 1 is a diagram showing a conventional chemical liquid synthesis device.

Embodiments of a chemical liquid synthesis apparatus and a chemical liquid synthesis method of the present invention will be described with reference to the drawings.

FIG. 1 is a piping route diagram showing a chemical liquid synthesis apparatus in an embodiment of the present invention. Note that in this embodiment, an example in which a chemical solution (reagent) is used as the fluid will be described, but the present invention is not limited to chemical solutions, and is also applicable to cases where liquids other than chemical solutions are chemically synthesized, mixed, etc. be able to.

As shown in FIG. 1, the chemical liquid synthesis apparatus includes a chemical liquid tank 1 in which a chemical liquid is stored, a reaction vessel 2 containing carriers (porous beads; hereinafter also referred to as beads), and a liquid discharged from the reaction vessel 2. and a drain tank 11 for storing the drained liquid, which are connected to each other by piping 4. When the chemical solution is supplied from the chemical solution tank 1 to the reaction container 2, the beads and the drug solution come into contact with each other in the reaction container 2 to be chemically synthesized, and the chemical solution after chemical synthesis is discharged to the drain tank 11. For example, when synthesizing nucleic acids, a large number of porous beads are contained in the reaction container 2, and while a chemical solution is sequentially supplied to the reaction container 2, detritylation, coupling, oxidation, capping, etc. The process is repeated to attach bases to the beads one after another.

The chemical solution tank 1 is for storing reagents used in chemical synthesis. In the example of FIG. 1, three chemical liquid tanks 1 are illustrated, but in reality, a plurality of chemical liquid tanks 1 are provided, and each chemical liquid tank 1 is connected to the reaction container 2 through the primary pipe 44. There is. In the example shown in FIG. 1, each chemical tank 1 is connected to a primary pipe 44 that mainly supplies the chemical to the reaction container 2, and these are gathered together in the middle to form one primary pipe 44. It is connected to reaction vessel 2.

A pressure regulating means 10 is connected to the chemical liquid tank 1, and the pressure regulating means 10 is configured to feed the chemical liquid in the chemical liquid tank 1. The pressure regulating means 10 includes a gas tank 10a filled with gas, and a gas pipe 41 that connects the gas tank 10a and the chemical tank 1. The gas in the gas tank 10a is transferred to the chemical tank 1 through the gas pipe 41. can be supplied to That is, by supplying the gas from the gas tank 10a, the pressure of the chemical liquid tank 1 is adjusted to the pressure of the gas tank 10a, and the chemical liquid in the chemical liquid tank 1 is sent to the reaction container 2. By adjusting the pressure of the gas tank 10a, the flow rate of the chemical liquid sent from the chemical liquid tank 1 can be adjusted. In other words, when the pressure difference between the chemical tank 1 and the reaction container 2 is increased, the speed of the chemical sent from the chemical tank 1 increases, the amount of the chemical can be increased, and the pressure in the chemical tank 1 increases. When the differential pressure between the chemical liquid tank 1 and the reaction container 2 is reduced, the liquid feeding speed of the chemical liquid fed from the chemical liquid tank 1 becomes small, and the amount of the chemical liquid can be suppressed.

Further, a valve 51 is provided in the primary pipe 44 and the gas pipe 41. That is, the primary piping 44 connected to each chemical tank 1 and the gas piping 41 are each provided with a valve 51, and the unified primary piping 44 has a supply side valve 52 and a valve 52 close to the reaction vessel 2. , and an upstream supply side valve 53 close to the chemical liquid tank 1 are provided. That is, with the valve 51, supply side valve 52, and upstream supply side valve 53 of the chemical liquid tank 1 selected as the supply target being opened, gas is supplied from the gas tank 10a of the pressure adjustment means 10 to the chemical liquid tank. By pressurizing the chemical liquid tank 1 , the pressure in the chemical liquid tank 1 is controlled to be higher than the pressure in the reaction vessel 2 , and the chemical liquid in the selected chemical liquid tank 1 is sent to the reaction vessel 2 through the primary pipe 44 . Note that when a predetermined amount of chemical liquid is sent from the chemical liquid tank 1, the pressure is adjusted in the primary piping 44 without passing through the chemical liquid tank 1 by closing the valves 51a and 51b of the chemical liquid tank 1. Only gas can be supplied from the means 10. Thereby, only a predetermined amount of the chemical solution can be sent into the primary pipe 44, and after being supplied to the reaction container 2, it can also be sent from the reaction container 2 into the secondary pipe 45, which will be described later.

In addition, as will be described later, when backflowing from the reaction container 2 to the chemical tank 1 side, the pressure in the reaction container 2 is controlled to be higher than that in the chemical tank 1, and the chemical solution supplied to the reaction container 2 is returned. be able to. In this way, the pressure adjusting means 10 can adjust the differential pressure between the chemical solution tank 1 and the reaction container 2, and can control the direction of feeding the chemical solution.

In this embodiment, the pressure regulating means 10 regulates the differential pressure by regulating the pressure of the gas tank 10a, and pressure regulators such as valves are installed in piping connected to the gas tank 10a, the reaction container 2, and the chemical tank 1, respectively. By providing means, the pressure of the chemical solution tank 1 and the reaction container 2 may be controlled, and the pressure difference between the chemical solution tank 1 and the reaction container 2 may be adjusted. Note that the gas in this gas tank 10a is a gas (for example, argon gas, etc.) that does not react with the chemical liquid in the chemical liquid tank 1.

Further, the reaction container 2 provides a reaction field where the beads contained in the reaction container 2 and the supplied chemical solution are brought into contact to perform chemical synthesis. The reaction container 2 is a glass cylindrical tube extending in one direction, and beads are accommodated in the reaction container 2. Moreover, ports 21 to which piping 4 can be connected are provided at both ends of the reaction vessel 2, and a primary piping 44 and a secondary piping 45 are connected to each port 21. In this embodiment, a primary pipe 44 is connected to the lower part of the reaction vessel 2, and a secondary pipe 45 is connected to the upper part. That is, a liquid feeding path is formed by the primary piping 44, the reaction container 2, and the secondary piping 45, and when the selected chemical liquid tank 1 is pressurized by the pressure adjustment means 10, the chemical liquid is sent from the chemical liquid tank 1. The chemical solution is introduced into the reaction container 2 through the primary pipe 44 and the port 21. Then, the chemical solution and the beads are chemically synthesized in the reaction container 2, and the chemical solution after the reaction is drained into the drain tank 11 through a secondary pipe 45 disposed on the downstream side in the liquid feeding direction. In this embodiment, the direction in which the liquid is fed from the chemical solution tank 1 to the reaction container 2 and eventually to the drain tank 11 is referred to as the forward liquid feeding direction.

By adopting a method in which the chemical solution is introduced from the lower side of the reaction container 2 as in this embodiment, the chemical solution can be distributed throughout the reaction container 2, and the chemical solution can be mixed with the beads in the reaction container 2. It can be chemically synthesized without waste. That is, the chemical solution introduced into the reaction container 2 from the lower primary pipe 44 is influenced by gravity, so it spreads in the radial direction and is stored in the reaction container 2, and the chemical liquid is mixed with the entire beads contained in the reaction container 2. Synthesis begins. If the drug solution were introduced from above, the drug solution immediately after the port 21 would proceed directly to the port 21 below due to the influence of gravity, making it difficult to spread in the radial direction. Therefore, although the chemical solution introduced from above is chemically synthesized with the beads located in the axial direction directly under the port 21, it is difficult to react with the beads located radially apart, and locally unreacted beads may remain. Therefore, the method of introducing the chemical liquid from below as in this embodiment allows the beads in the reaction container 2 to react with the chemical liquid without waste.

Further, on the downstream side (outflow side) of the reaction container 2, a drain tank 11 is provided to store the chemical liquid etc. drained after the reaction in the reaction container 2 is completed. The drain tank 11 is formed to have a larger capacity than the reaction vessel 2, and has a capacity that can store the liquid even if the liquid is drained from the reaction vessel 2 multiple times.

Further, the drain tank 11 is connected to the reaction container 2 by a secondary pipe 45, and the drain liquid discharged from the reaction container 2 is sent to the drain tank 11 through the secondary pipe 45 connected from above. It has become so. Specifically, the secondary pipe 45 is provided with a first drain side valve 55 and a second drain side valve 59. The chemical solution can be drained into the drain tank 11 through the secondary pipe 45 by supplying gas from the gas tank 10a of the pressure adjusting means 10 and pressurizing it in the open state. That is, the pressure regulating means 10 causes the chemical solution in the reaction container 2 to be fed in the sequential liquid feeding direction and drained.

Further, as described above, the secondary pipe 45 is mainly used as a pipe for transporting the chemical solution after reaction in the reaction vessel 2, but is also used as a pipe for supplying gas to the reaction vessel 2. That is, the secondary pipe 45 is connected to the gas tank 10a of the pressure regulating means 10 and the first gas supply pipe 47a, and the first gas supply pipe 47a is provided with a gas valve 57. Then, by operating the pressure regulating means 10 by closing the second drain valve 59 and opening the first drain valve 55, the reaction vessel 2 gas can be supplied to

On the other hand, the primary pipe 44 is connected to the drain tank 11 by a bypass line 48, and the bypass line 48 is provided with a first bypass valve 58 and a second bypass valve 60. Thereby, the chemical solution in the reaction container 2 can be drained into the drain tank 11 through the bypass line 48. That is, when gas is supplied from the gas tank 10a of the pressure regulating means 10 with the upstream supply side valve 53 in the closed state and the supply side valve 52, the first bypass valve 58, and the second bypass valve 60 in the open state, the first gas supply pipe 47a and the secondary pipe 45 into the reaction container 2, the chemical liquid in the reaction container 2 is pushed back toward the primary pipe 44, and is discharged from the primary pipe 44 through the bypass line 48 to the drain tank 11. In this way, by introducing the gas from the upper side of the reaction container 2 in the direction of gravity, the chemical solution is pushed out of the reaction container 2 by its own weight and the increased pressure, and the drug solution in the reaction container 2 is efficiently drained. It is now possible. In this manner, in the present embodiment, the pressure adjustment means 10 also functions as a gas supply means for returning the chemical liquid from the reaction container 2 to the primary pipe 44 side.

The reaction vessel 2 and the primary piping 44 and secondary piping 45 in its vicinity are provided with a sensor P that detects passage of the chemical solution. As shown in FIG. 2, the primary pipe 44, the reaction vessel 2, and the secondary pipe 45 are provided with a sensor P1, a sensor P2, and a sensor P3, respectively. In this embodiment, a gas-liquid sensor is used, and reacts when the state of the sensor region changes, such as from gas to liquid or from liquid to gas. Therefore, when the chemical solution is sent from the chemical tank 1, the sensor P1 provided in the primary piping 44 on the upstream side of the reaction container 2 detects that when the chemical solution passes through the sensor area of the primary piping 44, A reaction occurs when the interior changes from an empty state (gas) to a liquid, and it is detected that the supply of the chemical solution to the reaction container 2 has started. In addition, when the chemical solution in the reaction container 2 is drained through the bypass line 48, when the drained chemical solution changes from gas to liquid as it passes through, and when the draining is completed, the sensor area changes from liquid to liquid. It reacts when it changes to gas, making it possible to detect the start and completion of drainage. Similarly, the sensor P3 provided in the secondary pipe 45 on the downstream side of the reaction vessel 2 is configured to detect when the chemical liquid drained from the reaction vessel 2 passes and when the passage of the drained liquid is completed. It has become. Note that the sensors P1 to P3 are simply referred to as sensors P unless there is a need to distinguish them.

In addition, in the example of FIG. 2, six sensors P2 are provided in the reaction vessel 2, and two sensors with a small interval are placed on the upstream side (sensor P21, sensor P22) and near the center (sensor P23, sensor P24). ), and are arranged on the downstream side (sensor P25, sensor P26). These sensors P2 also react when the inside of the reaction container 2 changes from gas to liquid or from liquid to gas, and the liquid level of the chemical solution in the reaction container 2 is adjusted to each sensor position. It is possible to detect whether it is located or not.

Furthermore, the chemical liquid synthesis apparatus of this embodiment includes a circulation line 7 (see FIG. 1). This circulation line 7 is for returning the chemical liquid discharged from the reaction vessel 2 to the reaction vessel 2 without discharging it into the drain tank 11, and causing the chemical liquid to react in the reaction vessel 2 again. The circulation line 7 is connected to the primary pipe 44 through a first bypass valve 58 and to the secondary pipe 45 through a first circulation valve 61, and the chemical liquid discharged from the reaction vessel 2 is passed through the circulation line 7. It is designed to return to the reaction vessel 2 through.

Specifically, the circulation line 7 includes a circulation pipe 71, a circulator 72 connected to the circulation pipe 71, a first circulation valve 61, a second circulation valve 62, and a first drainage valve 55. When the first circulation valve 61 is open and the second drain valve 59 is closed, the chemical liquid discharged from the reaction vessel 2 is sent to the circulator 72 through the secondary pipe and the circulation pipe 71. In addition, when the second bypass valve 60 is closed and the second circulation valve 62, first bypass valve 58, and supply side valve 52 are open, the chemical solution in the circulator 72 passes through the circulation pipe 71 and the primary pipe 44 to the reaction vessel 2. It is now back to .

In this embodiment, the pressure adjustment means 10 is the driving source for feeding the liquid to circulate through the circulation line 7 . That is, when the liquid is fed from the reaction container 2, the first bypass valve 58 and the second drain side valve 59 are closed, and the upstream supply side valve 53, the supply side valve 52, and the first drain side valve are closed. When the valve 55 and the first circulation valve 61 are open, gas is supplied from the pressure regulating means 10 through the primary pipe 44, so that the chemical liquid in the reaction container 2 is sent to the circulator 72. On the other hand, gas is directly supplied to the circulator 72 from the pressure regulating means 10, and in the example of FIG. 1, it is directly supplied from the second gas supply pipe 47b. Therefore, when the medical solution is sent from the circulator 72, the first circulation valve 61, the second bypass valve 60, and the upstream supply side valve 53 are closed, and the gas valve 63, the second circulation valve 62, and the first bypass valve are closed. 58, by supplying gas from the second gas supply pipe 47b with the supply side valve 52 open, the chemical solution returns from the circulator 72 to the reaction vessel 2 through the bypass line 48 and the primary pipe 44. There is.

Here, the circulation pipe 71 is for sending a chemical solution, and like the primary pipe 44 and the secondary pipe 45, a chemically resistant tube is used. Further, the circulator 72 temporarily stores the chemical solution discharged from the reaction container 2, and in this embodiment, like the circulation pipe 71, a cylindrical tube with chemical resistance is used. . The circulator 72 is formed to have a larger diameter than the circulation pipe 71. Specifically, the circulator 72 is connected in such a way that when the circulation pipe 71 is connected to the circulator 72, a gap is formed between the circulator 72 and the circulation pipe 71 due to the difference in diameter between the two. . The circulator 72 of this embodiment is formed so that its capacity is greater than or equal to the capacity of the reaction vessel 2. That is, the piping length of the circulator 72 is adjusted so that the capacity is greater than or equal to the capacity of the reaction container 2, and the entire amount of the chemical solution discharged from the reaction container 2 can be stored in the circulator 72. ing.

Further, the circulation line 7 is provided with a connector portion 8 (see FIG. 3), and this connector portion 8 connects the circulation pipe 71, the second gas supply pipe 47b (liquid feeding gas pipe of the present invention), A circulatory system 72 is connected thereto. In the examples shown in FIGS. 3 and 4, the circulation pipe 71 and the circulator 72 are connected so as to extend in one direction, and the circulation pipe 71 and the circulator 72 are connected in a direction substantially perpendicular to the direction in which the circulation pipe 71 and the circulator 72 are connected. A two-gas supply pipe 47b is connected thereto.

The connector part 8 has a connector body part 81 to which the circulator 72 and the second gas supply pipe 47b are connected, and a through joint part 82 to which the circulation pipe 71 is connected. The portion 82 is connected and integrally formed. The connector main body part 81 and the through joint part 82 each have through holes 81a and 81b (see FIG. 5) extending in one direction, and when the connector main body part 81 and the through joint part 82 are connected, , are connected so that the extending directions of the through holes 81a and 81b are the same.

The connector main body part 81 has a joint connection part 811 to which the through joint part 82 is connected, and a circulatory system connection part 812 to which the circulatory system 72 is connected, at the end of the through hole 81a. The circulatory system connecting part 812 is formed so that the circulatory system 72 can be inserted therethrough, and when the circulatory system 72 is inserted into the circulatory system connecting part 812 and is fastened and fixed with a nut N4, the circulatory system connecting part 812 By sealing the interface between the circulator 72 and the circulator 72, the connection can be made while suppressing leakage of the chemical solution and air.

Further, the joint connecting portion 811 is formed so that the through joint portion 82 can be inserted therethrough. Here, the through joint part 82 is a cylindrical joint member having a through hole 82a, and is for fixing and connecting the circulation pipe 71 to the connector main body part 81. That is, when the nut N1 is fastened with the circulation pipe 71 inserted into the through hole 82a of the through joint portion 82, the circulation pipe 71 is fixed within the through hole 82a. A male threaded portion (not shown) is formed on the outer diameter of the through joint portion 82, and a female threaded portion is formed on the inner diameter of the through hole 81a of the joint connection portion 811. Therefore, when the male screw part of the through joint part 82 and the female screw part of the joint connection part 811 are screwed together, the through joint part 82 and the joint connection part 811 The through joint part 82 is connected to the connector main body part 81 while being sealed. In a state where the through joint portion 82 is connected to the connector main body portion 81, the circulator 72 and the circulation pipe 71 are connected with a part of the circulation pipe 71 being inserted into the circulator 72. That is, the circulation pipe 71 and the circulator 72 are connected to each other with a gap (insertion portion 85) formed between the circulator 72 and the circulation pipe 71 due to the difference in diameter.

The connector main body 81 also has a gas pipe connection part 813 to which the second gas supply pipe 47b is connected, and is formed to protrude in a direction perpendicular to the through hole 81a of the connector main body 81. The gas pipe connection part 813 is formed so that the second gas supply pipe 47b can be inserted therethrough, and when the nut N2 is fastened with the second gas supply pipe 47b inserted into the gas pipe connection part 813, the gas pipe The second gas supply pipe 47b is fixed within the connection portion 813. This gas pipe connection part 813 is formed with a communication hole 81b (see FIG. 5) that communicates with the through hole, and the gas supplied from the second gas supply pipe 47b is supplied to the through hole 81a through the communication hole 81b. Ru. Then, by supplying gas to the through hole 81a, the medical solution in the circulator 72 is sent to the circulation line 7. Here, as shown in FIG. 5, the through hole 81a of the connector body 81 is sealed by the through joint part 82 at the joint connection part 811, and by the circulator 72 at the circulatory system connection part 812. As a result, the through hole 81a of the connector body 81, the through joint 82, and the circulator 72 form a closed space 81a'. Therefore, when gas is supplied from the second gas supply pipe 47b, the gas that has moved to the through hole 81a (sealed part 81a') of the connector main body part 81 is caused by the difference in diameter between the circulation pipe 71 and the circulator 72. By pressing the medicinal solution flowing into the circulator 72 and staying in the circulator 72 through the formed insertion portion 85, the medicinal solution in the circulator 72 is fed.

Further, as shown in FIGS. 3 and 4, a joint part 83 is provided on the downstream side of the connector part 8, and the circulator 72 and the circulation pipe 71 are connected by this joint part 83. That is, by tightening the circulator 72 and the circulation pipe 71 with the nuts N3 while the circulator 72 and the circulation pipe 71 are inserted into the joint part 83, the circulator 72 and the circulation pipe 71 are fixed within the joint part 83 and connected to each other. It looks like this.

The chemical liquid synthesis apparatus is also provided with a control device (not shown), which controls the pressure adjusting means 10, each valve 51 to 59, 60 to 63, etc. in order to execute a series of chemical liquid synthesis operations according to a pre-stored program. Each drive device can be controlled.

This control device has a function as a circulation control means for performing chemical synthesis multiple times in the reaction vessel 2 by circulating the chemical solution by controlling the pressure adjustment means 10 and the valves 51 to 59 and 60 to 63. are doing.

Specifically, first, a predetermined chemical solution is supplied from the chemical solution tank 1 to the reaction container 2, as shown in FIG. 6(a). When the first bypass valve 58 is closed and the upstream supply side valve 53 and the supply side valve 52 are open, the pressure regulating means 10 is operated to pressurize the chemical liquid tank 1, so that the chemical liquid is sent through the primary piping. , is supplied to the reaction vessel 2. Here, for the valves in the figure, white indicates an open state and black indicates a closed state, and colored piping and containers indicate a state in which a chemical solution is being supplied. In this manner, the pressure regulating means 10 continues to pressurize and feed the liquid until a predetermined amount of the predetermined chemical solution is supplied. Note that when a predetermined amount of the chemical liquid is supplied, the valves 51a and 51b (see FIG. 1) are closed, and the pressure is pressurized by the pressure adjustment means 10 without going through the chemical liquid tank 1, and the primary pipe to which the liquid has already been sent is The chemical solution inside is delivered. Then, in the reaction container 2, the supplied chemical solution and the beads in the reaction container 2 undergo a chemical synthesis reaction, and a base is bonded to the beads.

Next, the chemical solution is fed from the reaction container 2 to the circulation line 7. As shown in FIG. 6(b), the second drain side valve 59, the second bypass valve 60, and the second circulation valve 62 are in a closed state, and the first drain side valve 55 is in an open state, and the pressure regulating means 10 By activating , the chemical solution in the reaction container 2 is sent into the secondary pipe 45 . The fed chemical solution is then supplied to the circulator 72 through the circulation pipe 71. In this embodiment, since the capacity of the circulator 72 is set to be greater than or equal to the capacity of the reaction container 2, all of the chemical solution in the reaction container 2 is stored in the circulator 72.

Next, the chemical solution is fed from the circulator 72 to the reaction container 2. As shown in FIG. 7(a), the chemical solution is delivered with the first circulation valve 61 and the second bypass valve 60 in the closed state and the second circulation valve 62 and the first bypass valve 58 in the open state. Here, the chemical liquid was sent from the reaction container 2 to the circulator 72 through the primary pipe, but the liquid was sent from the circulator 72 to the reaction container 2 through the second gas supply pipe 47b. That is, by operating the pressure regulating means 10 with the valve 51 in the closed state and the gas valve 63 in the open state, gas is directly supplied to the circulator 72 through the second gas supply pipe 47b. As described above, the supplied gas presses the chemical solution in the circulator 72 through the insertion part 85, so that the drug solution in the circulator 72 is sent from the circulator 72 to the reaction container 2 through the circulation piping 71. Ru. In this way, even if the liquid feeding drive source for the chemical solution is common, liquid feeding from the reaction container 2 to the circulation line 7 and liquid feeding from the circulation line 7 to the reaction container 2 can be constructed using independent liquid feeding circuits. This makes it possible to realize a circulation circuit using gas pressure feeding (gas supply) to the reaction vessel 2. Thereby, the chemical synthesis reaction can be performed again within the reaction vessel 2. Thereafter, as described above, the same chemical solution is circulated through the reaction container 2 multiple times via the circulation line 7, such as by sending the drug solution from the reaction container 2 to the circulator 72 again. Chemical solutions can be subjected to chemical synthesis reactions multiple times.

Next, after the chemical solution and beads have sufficiently reacted, drainage treatment is performed. That is, as shown in FIG. 8, when the gas valve 63, the second drain side valve 59, and the second circulation valve 62 are in a closed state, and the supply side valve 52, the first bypass valve 58, and the second bypass valve 60 are in an open state, the pressure is By operating the adjustment means 10, the chemical solution is discharged into the drain tank 11 through the primary pipe 44 and the bypass line 48. That is, when the pressure adjustment means 10 is operated, pressure is increased through the first gas supply pipe 47a, and gas enters from the secondary pipe 45 side of the reaction vessel 2, so that the chemical solution in the reaction vessel 2 is caused to flow from the primary pipe 44 side. It is discharged. In this way, by supplying gas from the upper side of the reaction container 2 and discharging the liquid, it is possible to prevent the chemical solution in the reaction container 2 from remaining in the reaction container 2 and to efficiently discharge it.

Further, this control device has a function as a stirring control means. The stirring control means is formed by the pressure adjustment means 10, the valves 51 to 59, 60 to 63, and the sensor P in this embodiment. This stirring control means has a function of stirring the chemical liquid within the liquid feeding path, and stirs the chemical liquid in the reaction container 2 by displacing the liquid level of the chemical liquid supplied to the reaction container 2 within the liquid feeding path. It is something.

For example, after positioning the liquid level of the chemical liquid supplied to the reaction container 2 in the secondary pipe 45, the chemical liquid is pushed back in the reverse flow direction opposite to the forward liquid feeding direction, and the liquid level of the chemical liquid is placed in the primary pipe 44. position. By repeating this, the chemical solution can be stirred.

Specifically, as shown in FIG. 9(a), with the chemical liquid being supplied from the circulation line 7 to the reaction container 2, the control device closes the gas valve 57 and the upstream supply bubble 53, and closes the first exhaust gas valve 57. The liquid side valve 55 is opened, the pressure regulating means 10 is operated to pressurize through the second gas supply pipe 47b, and the chemical liquid is sent to the secondary pipe 45 (forward liquid feeding direction) (forward flow process). When the chemical liquid is sent to the secondary pipe 45, the sensor area of the sensor P3 changes from gas to liquid, thereby detecting that the liquid level of the chemical liquid has reached the position of the sensor P3. When the control device receives the signal from the sensor P3, the control device closes the gas valve 63 to stop feeding the chemical solution (forward flow stop step).

Next, as shown in FIG. 9(b), the control device causes the chemical solution to flow backward in a direction opposite to the forward liquid feeding direction (backflow step). Specifically, the second drain side valve 59 is closed, the gas valve 57 is opened, the pressure regulating means 10 is operated, gas is supplied from the first gas supply pipe 47a, and the liquid level reaches the sensor P3. Pushes the chemical solution back into the flow direction. Then, the chemical liquid is pushed back from the secondary pipe 45 to the reaction container 2 and further to the primary pipe 44, and the sensor area of sensor P1 finally changes from liquid to gas, so that the liquid level of the chemical liquid reaches the position of sensor P1. The arrival is detected.

When the control device receives the signal from the sensor P1, the control device closes the gas valve 57 to stop the chemical solution flowing back (backflow stopping step). In this way, by performing the above-mentioned forward flow step, forward flow stop step, backflow step, and backflow stop step, the chemical solution reciprocates in the reaction container 2, so that the beads and the chemical solution in the reaction container 2 are stirred, and the chemical synthesis reaction is carried out. It can be promoted. By performing a stirring process that repeats these forward flow process, forward flow stop process, reverse flow process, and back flow stop process, the chemical solution in the reaction container 2 is further agitated, and the chemical solution is easily distributed throughout the reaction container 2. Therefore, the entire beads in the reaction container 2 can be reacted uniformly. If the circulation line 7 is circulated multiple times in the forward liquid feeding direction, the beads may be biased in the circulation direction, preventing the chemical solution from spreading over the entire beads and reducing the reaction efficiency, but the stirring step is still necessary. By doing so, the problem of uneven beads can be solved and the efficiency of chemical synthesis can be improved.

Further, the stirring control means also has a local stirring function. That is, by displacing the liquid surface position of the chemical solution multiple times at a predetermined position in the reaction container 2, the chemical solution and the beads in the reaction container 2 can be intensively collided with each other and stirred. Thereby, stirring efficiency can be improved. For example, the above-described forward flow step, forward flow stop step, backflow step, and backflow stop step may be repeated at the positions of sensor P21 and sensor P22 to perform local stirring. Then, this local stirring can be performed multiple times at different positions. For example, it can be performed at three positions: the position of sensor P21, sensor P22, the position of sensor P23, sensor P24, and the position of sensor P25, sensor P26. can. This allows intensive stirring at each selected position. Alternatively, the sensors may be freely selected to perform local stirring, such as sensor P21 and sensor P23, or sensor P21 and sensor P26. In this way, by performing local stirring multiple times at different positions in the reaction vessel 2 using the circulation route, it is possible to locally intensively stir the reaction vessel 2. It is possible to suppress as much as possible the unreacted beads remaining in the chamber. If the target position of the local stirring step is set in a portion of the reaction vessel 2 where unreacted beads remain, the problem of unreacted beads remaining can be efficiently solved.

As described above, according to the chemical liquid synthesis apparatus in the above embodiment, liquid feeding through the circulation line 7 connected to the primary pipe 44 and the secondary pipe 45 is performed by supplying gas into the circulation line 7. Therefore, there are no sliding parts or the like in the parts that come into contact with the chemical solution, and problems caused by damage to the sliding parts, which are conventional, can be completely eliminated. In addition, since there is no liquid feeding drive source in the wetted parts, parts such as the primary piping 44, secondary piping 45, circulation line 7, valves, etc. must be replaced with new ones for single-use applications. However, there is no need to replace the liquid feeding drive source with a new one, and it can be used for single use at low cost.

Further, in the above embodiment, an example was explained in which the circulator 72 uses a versatile tube-shaped pipe, but a container connected to the circulation pipe 71 in the circulation line 7, for example, a cylindrical container is used. There may be.

Furthermore, in the above embodiment, an example was described in which the pressure adjustment means 10 is used as the drive source for feeding liquid from the reaction container 2 to the circulator 72 and the drive source for feeding the liquid from the circulator 72 to the reaction container 2. , each may be an independent liquid feeding drive source. Even in this case, by using both liquid feeding drive sources as gas supply sources, the liquid feeding driving sources do not come into contact with the chemical solution, making it possible to create a configuration that can be used for single use at low cost. .

Further, in the above embodiment, the agitation control means is performed by supplying the chemical solution from the circulation line 7 and causing it to flow back into the circulation line 7. It may also be carried out by refluxing the water.

2 Reaction vessel 4 Piping 7 Circulation line 8 Connector part 10 Pressure adjustment means 44 Primary piping 45 Secondary piping 47a First gas supply piping 47b Second gas supply piping 71 Circulation piping 72 Circulator 81a' Sealing part 85 Insertion part

Claims (3)

a reaction container in which the chemical solution is reacted;
a primary pipe that is connected to the reaction container and mainly supplies a chemical solution to the reaction container;
a secondary pipe connected to the reaction container and arranged downstream in the liquid feeding direction when viewed from the primary pipe;
a circulation line connected to the primary piping and the secondary piping;
It is equipped with
The liquid feeding through the circulation line is performed by supplying gas into the circulation line,
A chemical liquid synthesis apparatus characterized in that the circulation line is provided with a circulator having a capacity greater than that of the reaction container . The circulation line includes a connector part that connects the circulation pipe through which the chemical solution is sent and the circulator, and the connector part includes a circulation pipe formed with a diameter smaller than that of the circulator. A sealed part is formed to seal the insertion part that is inserted into the circulatory system, and a liquid feeding gas pipe that supplies gas for feeding the chemical solution in the circulation line is connected to this sealed part, and gas is supplied from the liquid feeding gas piping. 2. The chemical liquid synthesis apparatus according to claim 1, wherein when the chemical liquid is supplied, the chemical liquid in the circulatory system is pressed through a diameter difference between the circulation pipe and the circulatory system. 3. The chemical liquid synthesis apparatus according to claim 2, wherein the circulator is a pipe formed to have a larger diameter than the circulation pipe.

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