JP7720171B2 - Chemical Solution Synthesis Equipment - Google Patents

Description

The present invention relates to a chemical liquid synthesis device that synthesizes chemical liquids that are delivered without coming into contact with the atmosphere, and in particular to a chemical liquid synthesis device that can suppress a decrease in synthesis efficiency.

In chemical synthesis devices used to chemically synthesize proteins, peptides, polymers, nucleic acids, etc., multiple chemical solutions (reagents) are supplied to a reaction vessel section to carry out chemical synthesis. For example, when synthesizing nucleic acids, a large number of carriers (porous beads) are placed inside the reaction vessel section, and while chemical solutions are sequentially supplied to this reaction vessel section, processes such as detritylation, coupling, oxidation, and capping are repeatedly carried out to sequentially bind bases to the beads.

As shown in Figure 7, a typical chemical synthesis apparatus includes a reaction vessel section 100 that contains a carrier 110 (see Figure 8) and receives a chemical solution, a chemical solution storage section such as a chemical solution tank 101 that stores the chemical solution to be supplied to the reaction vessel section 100, and a wastewater tank 102 that stores the wastewater discharged from the reaction vessel section 100. These are all connected by piping 103, and the chemical solution is pumped by pressure from a pressure supply source 107, allowing the chemical solution and the carrier 110 to undergo a synthesis reaction without coming into contact with the atmosphere (see, for example, Patent Document 1 below). Specifically, the reaction vessel section 100 has a chemical supply section 106 at its vertical lower end, through which the chemical is supplied, and a chemical discharge section 105 at its vertical upper end, through which the chemical is discharged. When the chemical is supplied from the selected chemical tank through piping 103 via chemical supply section 106 at the lower end, a synthetic reaction occurs between the chemical and the carrier in the reaction vessel section 100, and the reacted chemical is then discharged from chemical discharge section 105 at the upper end through piping 103 to the drain tank 102 (see Figure 8(a)).

As described above, the chemical solution is supplied to the reaction vessel section 100 from the chemical solution supply section 106 at the lower vertical end. That is, the chemical solution from the chemical solution supply section 106 at the lower end is accumulated while spreading radially within the reaction vessel section 2 due to the influence of gravity. This allows the chemical solution to be distributed throughout the reaction vessel section 2, improving the efficiency of synthesis with the carrier 110 compared to when the chemical solution is supplied from the upper end, and enabling chemical synthesis to be carried out efficiently between the carrier 110 and the chemical solution within the reaction vessel section 2.

Japanese Patent Application Laid-Open No. 2020-093236

However, with the above-described chemical solution synthesis apparatus, there was a risk of a decrease in synthesis efficiency in the reaction vessel section 100. Specifically, after storing chemical solution in the reaction vessel section 100 and carrying out a synthesis reaction, when the chemical solution is discharged from the chemical solution discharge section 105 at the upper end as shown in FIG. 8(a), a phenomenon occurs in which a portion of the carrier 110 remains attached to the top of the reaction vessel section 100 as shown in FIG. 8(b). In this state, if a small amount of chemical solution is to be stored in the reaction vessel section 100 and a reaction is to be carried out, supplying the chemical solution from the chemical solution supply section 106 prevents the chemical solution from reaching the attached carrier 110, resulting in a problem of insufficient reaction.

Furthermore, immediately after the chemical solution is supplied, some of the carriers may float on the surface of the chemical solution inside the reaction vessel section 100, and due to the pulsation of the liquid surface during chemical solution supply, these may adhere to the wall of the reaction vessel section 100. In such cases, the same problem as described above occurs, and if the chemical solution after supply has been completed does not reach the height position where the carriers are attached, the reaction cannot proceed sufficiently.

The present invention was made in consideration of the above-mentioned problems, and aims to provide a chemical solution synthesis device that delivers chemical solutions without contact with the atmosphere, and that can improve the synthesis efficiency between the carrier and chemical solution in the reaction vessel section.

In order to solve the above problems, the chemical solution synthesis apparatus of the present invention comprises a chemical solution storage section in which a chemical solution is stored, and a reaction vessel section in which the chemical solution is reacted with a carrier, and is a chemical solution synthesis apparatus in which the chemical solution is transferred from the chemical solution storage section to the reaction vessel section without coming into contact with the atmosphere, and is characterized in that it has a first chemical solution supply section connected to the reaction vessel section and through which the chemical solution is supplied to the reaction vessel section, and a chemical solution discharge section provided vertically above the first chemical solution supply section and comprising a second chemical solution supply section that prevents the carrier from adhering to the reaction vessel section, and the reaction vessel section is provided with an exhaust section that discharges gas from within the reaction vessel section and is positioned at a height position equal to or higher than the height position of the chemical solution discharge section .

The chemical solution synthesis apparatus described above includes a second chemical solution supply unit, which can prevent the carrier from adhering to the inner wall of the reaction vessel. That is, even if the surface of the chemical solution sways and causes the carrier to adhere to the inner wall of the reaction vessel, the chemical solution is supplied from the second chemical solution supply unit located above the surface of the chemical solution, preventing the carrier from adhering. Even if the carrier does adhere to the inner wall of the reaction vessel, the chemical solution can be washed back into the chemical solution. This facilitates contact with the chemical solution supplied from the first chemical solution supply unit located at the lower end, thereby improving the synthesis efficiency of the carrier and the chemical solution. Furthermore, the provision of an exhaust unit allows gas to be exhausted from within the reaction vessel, making it easier to supply the chemical solution from the second chemical solution supply unit.

Furthermore, in order to solve the above-mentioned problems, the chemical solution synthesis apparatus of the present invention comprises a chemical solution storage section in which a chemical solution is stored, and a reaction vessel section in which the chemical solution is reacted with a carrier, and the chemical solution is transferred from the chemical solution storage section to the reaction vessel section without coming into contact with the atmosphere, and is characterized in that it has a first chemical solution supply section connected to the reaction vessel section and through which the chemical solution is supplied to the reaction vessel section, and a chemical solution discharge section provided vertically above the first chemical solution supply section, and a second chemical solution supply section that drops the carrier adhering to the inner wall of the reaction vessel section after discharging the carrier from the chemical solution discharge section, and the reaction vessel section is provided with an exhaust section that discharges gas from within the reaction vessel section and is positioned at a height position equal to or higher than the height position of the chemical solution discharge section .

According to the above-described chemical solution synthesis apparatus, since the second chemical solution supply unit is provided, after the chemical solution is discharged from the chemical solution discharge unit on the vertically upper side, the carrier attached to the inner wall of the reaction vessel unit can be dropped. That is, the chemical solution supplied from the second chemical solution supply unit comes into contact with the carrier attached to the inner wall of the reaction vessel unit, causing the carrier to drop along with the supplied chemical solution and return to the lower end of the reaction vessel unit. This facilitates contact with the chemical solution supplied from the first chemical solution supply unit on the lower end side, thereby improving the synthesis efficiency of the carrier and the chemical solution. Furthermore, by providing the discharge unit, gas can be discharged from within the reaction vessel unit, making it possible to easily supply the chemical solution from the second chemical solution supply unit.

The second chemical liquid supply unit may also be connected to the chemical liquid discharge unit, and the chemical liquid may be supplied by causing a reverse flow through the chemical liquid discharge unit.

With this configuration, the chemical can be supplied using the chemical discharge section, eliminating the need to form a separate port in the reaction vessel section dedicated to the second chemical supply section. Therefore, the second chemical supply section can be installed without unnecessarily complicating the piping.

Furthermore, the chemical liquid supplied from the second chemical liquid supply unit may be configured to be supplied along the side wall of the reaction vessel unit.

This configuration allows carriers that are attempting to adhere to the side walls of the reaction vessel section, or carriers that have already adhered, to be washed back, preventing the carriers from adhering to the side walls of the reaction vessel section and reducing synthesis efficiency.

The chemical solution in the reaction vessel section may also be discharged by backflowing through the first chemical solution supply section.

With this configuration, the first chemical liquid supply unit is located vertically below the chemical liquid discharge unit, which reduces adhesion of the carrier to the wall surface of the reaction vessel unit compared to when the chemical liquid is discharged from the chemical liquid discharge unit.

The reaction vessel section may also be configured to be provided with a guide member that guides the chemical solution supplied through the second chemical solution supply section to the side wall of the reaction vessel section.

With this configuration, the chemical solution delivered from the second chemical solution delivery section is guided to the side wall of the reaction vessel section by the guide member, making it easier for the guided chemical solution to flow along the side wall. This allows the carrier attached to the side wall to efficiently fall along with the chemical solution.

Specific examples of the guide member include using it in common with the filter, which simplifies the configuration.

Furthermore, the above-mentioned chemical solution may be used as a cleaning solution, and the same effect can be achieved by using a cleaning solution instead of a chemical solution.

The chemical solution synthesis device of the present invention, which delivers chemical solutions without contact with the atmosphere, can improve the synthesis efficiency between the carrier and chemical solution in the reaction vessel section.

1 is a schematic piping diagram of a chemical solution synthesizing apparatus according to the present invention. FIG. 2 is a diagram showing a reaction vessel portion of the chemical solution synthesis apparatus. FIG. 10 is a piping diagram showing a normal mode in which a chemical is supplied from a first chemical supply unit to a reaction vessel unit. 1A and 1B are diagrams showing the state in which the chemical solution is discharged from the reaction vessel section, in which (a) is a diagram showing the state in which the carrier has moved to the upper side while the chemical solution is being discharged from the chemical solution discharge section, and (b) is a diagram showing the state in which the carrier has stuck to the upper side after the chemical solution has been discharged from the chemical solution discharge section. FIG. 10 is a piping diagram showing a carrier return mode in which the chemical is supplied to the reaction vessel section by causing a reverse flow from the second chemical supply section to the chemical discharge section. FIG. 10 is a diagram showing a state in which another guide member is provided in the reaction vessel section. FIG. 1 is a schematic piping diagram of a conventional chemical liquid synthesizing apparatus. 1A and 1B are diagrams showing the state in which a chemical solution is discharged from a conventional reaction vessel section, in which (a) shows the state in which the carrier has moved upward when the chemical solution is being discharged from the chemical solution discharge section at the upper end, and (b) shows the state in which the carrier has stuck to the upper part after the chemical solution has been discharged from the chemical solution discharge section. FIG. 10 is a diagram showing a state in which the carrier floating in the reaction vessel section sinks into the chemical solution due to the supplied chemical solution. 1A and 1B are diagrams showing a configuration for transmitting the supplied chemical liquid along the side wall of the reaction vessel section, in which (a) shows a state in which the piping is stored within the wall surface of the lid section, and (b) shows a state in which the piping protrudes from the wall surface of the lid section.

An embodiment of the chemical solution synthesis apparatus of the present invention will be described using the drawings.

Figure 1 is a piping diagram showing a chemical liquid synthesis apparatus according to one embodiment of the present invention. While this embodiment describes an example in which a chemical liquid (reagent) is used as the fluid, the present invention is not limited to chemical liquids and can also be applied to chemical synthesis, mixing, etc. of liquids other than chemical liquids.

As shown in Figure 1, the chemical synthesis apparatus comprises a chemical tank 1, which is a chemical storage section for storing the chemical, a measuring section 3 for measuring the chemical, a reaction vessel section 2 containing carrier S (porous beads; see Figure 2), and a drainage tank 11, which is a storage vessel section for storing the drainage discharged from the reaction vessel section 2; all of these are connected by piping 4. The chemical supplied from the chemical tank 1 is measured in the measuring section 3 and then supplied to the reaction vessel section 2, where the chemical comes into contact with the carrier S and undergoes chemical synthesis. The chemical after chemical synthesis is then discharged by being pumped to the drainage tank 11. For example, when synthesizing nucleic acids, a certain amount of porous carrier S is contained in the reaction vessel section 2, and while measuring the chemical, the reaction vessel section 2 is sequentially supplied with the chemical, detritylation, coupling, oxidation, capping, and other processes are repeatedly performed to bind bases to the beads one after another.

The chemical tanks 1 are used to store reagents used in chemical synthesis. In the example shown in Figure 1, three chemical tanks 1 are shown, but in reality, many chemical tanks 1 are provided, and each chemical tank 1 is connected to the measuring unit 3 by piping 42. In other words, the chemical liquid contained in each chemical tank 1 is sent to the measuring unit 3 without mixing with the other chemical liquids.

A pressure adjustment means 6 is connected to the chemical tank 1, and this pressure adjustment means 6 is configured to pump the chemical liquid from the chemical tank 1. The pressure adjustment means 6 has a gas tank 61 filled with gas and a pipe 41 connecting the gas tank 61 to the chemical tank 1, and the gas from the gas tank 61 can be supplied to the chemical tank 1 through this pipe 41. That is, by supplying gas from the gas tank 61, the pressure in the chemical tank 1 is adjusted to the pressure of the gas tank 61, and a pressure difference with the pressure in the metering unit 3 is created, thereby sending the chemical liquid from the chemical tank 1 to the metering unit 3. Then, by adjusting the pressure of the gas tank 61, the flow rate of the chemical liquid being sent from the chemical tank 1 can be adjusted. That is, by increasing the pressure difference between the pressure in the liquid chemical tank 1 and the metering unit 3, the liquid chemical delivery speed from the liquid chemical tank 1 increases, allowing for a larger amount of liquid chemical to be delivered; and by decreasing the pressure difference between the pressure in the liquid chemical tank 1 and the metering unit 3, the liquid chemical delivery speed from the liquid chemical tank 1 decreases, allowing for a smaller amount of liquid chemical to be delivered.

In this embodiment, one of the chemical tanks 1 also contains a cleaning liquid. When a specific chemical liquid is being delivered, if it cannot be mixed with a previously delivered chemical liquid, this cleaning liquid is delivered after the previous chemical liquid has been delivered and before the subsequent chemical liquid is delivered, to clean the reaction vessel section 2 and piping 4. This cleaning liquid is also contained in a chemical tank 1 (chemical tank 1a in Figure 1) that has the same configuration as the chemical liquid described above, and the delivery of the cleaning liquid is also performed with the same configuration as the chemical liquid described above.

In addition, pipes 41 and 42 are provided with valves 51. These valves 51 selectively connect the target chemical tank 1 to the metering unit 3. That is, when the valve 51 of the chemical tank 1 selected as the supply target is opened (open state), gas is supplied from the gas tank 61 to pressurize the chemical tank 1, thereby controlling the pressure in the chemical tank 1 to be greater than the pressure in the metering unit 3, and the chemical liquid in the selected chemical tank 1 is sent to the metering unit 3 through pipe 42. Note that pipes 41, 42, etc. will be simply referred to as pipe 4 unless there is a need to distinguish between them.

In addition, in this embodiment, an example is described in which the pressure adjustment means 6 uses a gas tank 61, but instead of the gas tank 61, a gas supply source installed in the building in which the chemical synthesis apparatus is installed may be used. Furthermore, the gas used in this gas tank 61 is a gas (such as argon gas) that does not react with the chemical in the chemical tank 1.

The measuring unit 3 also accurately measures the supplied chemical solution. In this embodiment, it measures the mass of the supplied chemical solution, enabling accurate measurement of the amount of chemical solution to react with the carrier S in the reaction vessel section 2. That is, the measuring unit 3 has a measuring vessel 31 and a load cell (not shown) connected to the measuring vessel 31, and the chemical solution stored in the measuring vessel 31 is measured by the load cell.

A pipe 42 is connected to the upper end of the measuring container 31, and a pipe 43 is connected to the lower end. The chemical solution delivered from the chemical solution tank 1 is supplied through the pipe 42, and the measured chemical solution is discharged through the pipe 43. Specifically, when the valve 51 of the pipe 4 connecting the selected chemical solution tank 1 and the measuring container 31 is open, the selected chemical solution tank 1 is pressurized by the gas tank 61, and the chemical solution is supplied to the measuring container 31 through the pipe 42. Then, in the reaction container section 2, the amount of chemical solution required for one synthesis reaction is measured and the liquid delivery is stopped at the same time, so that the chemical solution required for the synthesis reaction is stored in the measuring container 31. The measured chemical solution is then delivered from the measuring container 31 to the reaction container section 2 through the pipe 43.

The liquid is delivered from the measuring unit 3 by a gas tank 62 (pressure adjustment means 6). Specifically, a separate gas tank 62 is connected to the measuring container 31, allowing gas to be supplied from the gas tank 62 to the measuring container 31. By supplying gas from the gas tank 62 to the measuring container 31, the pressure in the measuring container 31 is adjusted, and the differential pressure between the measuring unit 3 and the reaction container 2 is adjusted, allowing the liquid chemical in the measuring container 31 to be delivered to the reaction container 2. In the example of Figure 1, the liquid chemical after metering is supplied to the reaction container 2 via piping 43 and piping 44. Note that a gas supply source installed in the building may also be used for the gas tank 62.

The reaction vessel section 2 also provides a reaction field where chemical synthesis occurs by bringing the carrier S contained in the reaction vessel section 2 into contact with the supplied chemical solution, etc. In this embodiment, the reaction vessel section 2 is a cylindrical glass tube extending in one direction, and the carrier S is housed within the reaction vessel section 2 (see Figure 2). A first chemical solution supply section 71, to which the chemical solution is supplied, and a chemical solution discharge section 72, from which the chemical solution is discharged, are connected to both vertical ends of the reaction vessel section 2. That is, the reaction vessel section 2 is supplied with the chemical solution through the first chemical solution supply section 71, and discharged with the chemical solution through the chemical solution discharge section 72. In this embodiment, the chemical solution discharge section 72 is provided on the vertically upper side, and the first chemical solution supply section 71 is provided on the vertically lower side.

The first chemical liquid supply unit 71 supplies the chemical liquid to the vertically lower side of the reaction vessel section 2, and in this embodiment, is formed by the first port 21a and the piping 44. That is, as shown in FIG. 2, the reaction vessel section 2 has the first port 21a on the vertically lower side, and the piping 44 is connected to this first port 21a. Therefore, the chemical liquid delivered from the metering section 3 through the piping 43 is supplied to the reaction vessel section 2 via the three-way valve 53 and the piping 44. When the chemical liquid is supplied from the first chemical liquid supply unit 71, the supplied chemical liquid spreads radially in the reaction vessel section 2 due to the influence of gravity and accumulates therein. This allows the chemical liquid to be distributed throughout the reaction vessel section 2, allowing the chemical liquid to be chemically synthesized with the carrier S contained in the reaction vessel section 2 without waste.

The chemical discharge section 72 discharges the chemical liquid from the vertically upper side of the reaction vessel section 2, and in this embodiment is formed by the second port 21b and the piping 45. That is, as shown in Figure 2, the reaction vessel section 2 has the second port 21b on the vertically upper side, and the piping 45 is connected to this second port 21b.

Furthermore, a drainage tank 11 (described below) is provided downstream of the reaction vessel section 2, and the reaction vessel section 2 and drainage tank 11 are connected by piping 45. In other words, the chemical solution in the reaction vessel section 2 can be discharged from the chemical solution discharge section 72 through piping 45.

Furthermore, downstream of the reaction vessel section 2, a drainage tank 11 is provided as a storage vessel section for storing chemical liquids and the like drained from the reaction vessel section 2 after the reaction is completed. The drainage tank 11 is formed to have a larger capacity than the reaction vessel section 2, and is formed to have a capacity that can store chemicals even when they are drained from the reaction vessel section 2 multiple times. In this embodiment, the chemical liquid after the reaction is discharged to the drainage tank 11 via the chemical liquid discharge section 72. In other words, the reaction chemical liquid is discharged into the drainage tank 11 through the chemical liquid discharge section 72 when gas is supplied from the gas tank 62 to pressurize the reaction vessel section 2. In this way, the chemical liquid synthesis apparatus of the present invention is configured to transport the chemical liquid from the chemical liquid tank 1 to the drainage tank 11 without coming into contact with the atmosphere.

The chemical solution synthesis apparatus is also provided with a second chemical solution supply unit 73 (see Figure 1) in addition to the first chemical solution supply unit 71. The second chemical solution supply unit 73 prevents the carrier S from adhering to the reaction vessel section 2 and allows the carrier S adhering to the reaction vessel section 2 to fall. In this embodiment, the second chemical solution supply unit 73 is formed by piping 46 connected to piping 43 by three-way valve 53, and this piping 46 is connected to piping 45 by three-way valve 55. The second chemical solution supply unit 73 then delivers the measured chemical solution from piping 43 via the three-way valve 53 through piping 46, and then delivers the chemical solution to the reaction vessel section 2 via piping 45 via the three-way valve 55. In other words, the second chemical solution supply unit 73 supplies the chemical solution to the reaction vessel section 2 by causing the chemical solution discharge unit 72 to flow backward. When chemical liquid is supplied from this second chemical liquid supply unit 73, the chemical liquid flows along the side wall 22a of the reaction vessel unit 2, causing the carrier adhering to the reaction vessel unit 2 to fall off.

Furthermore, as the chemical solution supplied from the second chemical solution supply unit 73 flows along the side wall 22a of the reaction vessel section 2, it flows back the carriers S that would otherwise adhere to the side wall 22a of the reaction vessel section 2, preventing the carriers S from adhering to the side wall 22a. Furthermore, as shown in FIG. 9 , when the chemical solution is supplied from the second chemical solution supply unit 73, the flow of the chemical solution directly hits the carriers S floating on the liquid surface, sinking the carriers, thereby preventing the carriers S from adhering to the side wall 22a of the reaction vessel section 2. In particular, as the chemical solution flows along the side wall 22a of the reaction vessel section 2, the flow of the chemical solution directly hits the carriers S floating on the liquid surface near the side wall 22a. This makes it easier for the chemical solution to blend with the carriers S than when the chemical solution is supplied from the first chemical solution supply unit 71 below. Furthermore, the swaying of the liquid surface caused by the chemical solution supply can sink the carriers S that would otherwise adhere to the side wall 22a. This prevents the carriers S from adhering to the side wall 22a.

Furthermore, pipe 44 is connected to pipe 45 via pipe 48 by valve 58, and reaction vessel section 2 is connected to drain tank 11 via pipes 44, 48, and 45. In other words, the chemical liquid supplied to reaction vessel section 2 from second chemical liquid supply section 73 can be discharged by backflowing through first chemical liquid supply section 71.

In the above explanation, chemical liquids were used as the target, but cleaning liquids can also be used instead. Even when cleaning liquids are used, the measuring and delivery are performed in the same manner as chemical liquids.

As shown in FIG. 2, the reaction vessel section 2 has a reaction vessel body 22 that contains the carrier S (beads), and lid sections 23 that are provided at both axial ends of the reaction vessel body 22. The lid section 23 is provided with a first port 21a and a second port 21b, with the chemical solution being supplied from the first port 21a and discharged from the second port 21b.

A filter 24 is provided at the inlet/outlet of the reaction vessel body 22, blocking the flow path leading from the reaction vessel body 22 to the first port 21a and the second port 21b. This allows impurities to be removed if they are contained in the chemical solution supplied through the first port 21a or the second port 21b. Furthermore, when the chemical solution after reaction is discharged from the reaction vessel section 2, the filter 24 prevents the carrier S from being discharged, preventing the carrier S in the reaction vessel section 2 from leaking to the outside.

The filter 24 is formed in a circular, flat plate shape, and its outer edge is disposed so as to abut a wall surface continuous with the side wall 22a of the reaction vessel body 22. That is, the reaction vessel body 22 has a protruding portion that connects to the lid portion 23, and the filter 24 is disposed so as to abut the wall surface of the protruding portion. As a result, the chemical solution supplied from the second port 21b flows along the side wall 22a of the reaction vessel body 22 and is supplied into the reaction vessel body 22. That is, when the chemical solution is supplied from the second port 21b, i.e., when the chemical solution is supplied from the second chemical solution supply portion 73 and then backflows through the chemical solution discharge portion 72, the chemical solution permeates the filter 24 and moves across the entire surface of the filter 24, as shown by the arrows in FIG. 2 . As the chemical solution continues to be supplied, it becomes impossible for the filter 24 to retain the chemical solution. However, because the outer edge of the filter 24 is continuous with the side wall 22a of the reaction vessel main body 22, the chemical solution that cannot be retained within the filter 24 is pulled by the surface tension of the side wall 22a, and flows down the side wall 22a. In other words, the filter 24 functions as a guide member 8 that guides the chemical solution to the side wall 22a of the reaction vessel main body 22.

In addition to the second port 21b, the reaction vessel section 2 is also equipped with an exhaust port 91 as an exhaust section 9. This exhaust section 9 is used to exhaust gas (including gas and bubbles) from within the reaction vessel section 2. This exhaust port 91 is connected to a pipe 49 that is connected to a drainage tank 11, and fluid discharged from the exhaust port 91 is discharged to the drainage tank 11 through this pipe 49. This pipe 49 is equipped with a valve 59 that allows the flow of fluid discharged from the exhaust port 91 to be controlled. That is, when the valve 59 is open and the reaction vessel body 22 is pressurized, the fluid within the reaction vessel body 22 is discharged through the pipe 49, and when the valve 59 is closed, the flow of fluid discharged from the exhaust port 91 can be stopped.

Like the second port 21b, the exhaust port 91 is provided in the lid 23 and is positioned at a height equal to or higher than the chemical solution discharge portion 72. In this embodiment, the chemical solution discharge portion 72 is formed by the second port 21b and the piping 45, and the piping 45 extends until it contacts the filter 24. That is, the exhaust port 91 is positioned at the lower end of the chemical solution discharge portion 72, i.e., higher than position P where the piping 45 contacts the filter 24. This allows for smooth supply of chemical solution from the second port 21b. When chemical solution is supplied from the second port 21b, the pressure inside the reaction vessel body 22 increases. However, by opening the exhaust port 91, the exhaust port 91 is positioned higher than the piping 45, preventing the chemical solution supplied from the second port 21b from being directly discharged from the exhaust port 91. Therefore, gas inside the reaction vessel body 22 is efficiently discharged from the exhaust port 91, allowing for smooth supply of chemical solution from the second port 21b.

Furthermore, because the pipe 45 of the chemical discharge unit 72 abuts against the filter 24, the chemical liquid pumped from the second chemical supply unit 73 through the pipe 45 passes through the filter 24 and is directly introduced into the reaction vessel body 22. In other words, if the pipe 45 were separated from the filter 24, there is a risk that the chemical liquid pumped from the pipe 45 would flow over the surface of the filter 24 and attempt to flow directly into the exhaust port 91. However, because the pipe 45 abuts against the filter 24, the supplied chemical liquid flows through the filter 24 and enters the reaction vessel body 22, preventing the chemical liquid from being directly discharged from the exhaust port 91 before entering the reaction vessel body 22.

The nucleic acid synthesizer also has a control device (not shown), which controls each valve and the pressure adjustment means 6, thereby controlling the flow of the chemical solution. In other words, the control device also controls the supply and discharge of the chemical solution to the reaction vessel section 2, and controls the normal supply mode and carrier return mode, which will be described later.

Normal supply mode is a mode in which the chemical solution is supplied from the first chemical solution supply unit 71. Specifically, as shown in FIG. 3, three-way valve 53 is set to an open state in the direction of flow from pipe 43 to pipe 44, valve 52 is set to an open state, and three-way valve 55 is set to an open state in the direction of flow to pipe 45, so that the chemical solution measured by the metering unit 3 is supplied to the reaction vessel unit 2 via the first chemical solution supply unit 71. Here, the open/closed state of each valve is indicated by white (open) and black (closed). Then, as the metering vessel 31 is pressurized by the gas tank 62, a pressure difference is generated relative to the reaction vessel unit 2, and the chemical solution is sent from the metering vessel 31. The chemical solution supplied to the reaction vessel unit 2 comes into contact with the carrier S inside the reaction vessel unit 2, causing a synthesis reaction.

This normal supply mode is the main chemical supply mode used, enabling efficient synthesis reactions. Specifically, by supplying chemical from the first chemical supply unit 71, the chemical is introduced from below the reaction vessel section 2, allowing the chemical to be distributed throughout the reaction vessel section 2. Chemical introduced into the reaction vessel section 2 from the lower piping 44 is affected by gravity and spreads radially while remaining within the reaction vessel section 2, where chemical synthesis occurs with the entire carrier S contained in the reaction vessel section 2. If the chemical were introduced from above, gravity would cause the chemical supplied from the second port 21b to proceed directly to the first port 21a, preventing it from spreading radially. Therefore, while the chemical introduced from above undergoes chemical synthesis with the carrier S located axially directly below the second port 21b, it is less likely to react with the carrier S located radially outward, potentially leaving unreacted carriers S in localized areas. Therefore, the normal supply mode allows for efficient reaction between the carrier S and the chemical in the reaction vessel section 2 and is used as a normal chemical supply path.

When the reaction between the chemical solution supplied to the reaction vessel section 2 and the carrier S is completed, the chemical solution is discharged. That is, by pressurizing the gas tank 62, the chemical solution is discharged from the second port 21b and then discharged into the drain tank 11 via the piping 45 (see Figure 4(a)).

The carrier return mode allows carriers adhering to the sidewall of the reaction vessel section 2 to fall and return the carriers to their original position (the lower end of the reaction vessel section 2). This carrier return mode is a chemical supply mode in the opposite direction to the normal supply mode, in which the chemical is delivered from the upper end of the reaction vessel section 2. In this embodiment, the chemical is delivered from the second chemical supply section 73 through the chemical discharge section 72. Typically, in a chemical synthesis apparatus in which each processing section is connected by piping and a synthesis reaction is performed without exposing the chemical to the atmosphere, the above-described normal supply mode alone can efficiently perform a synthesis reaction with the carrier S, eliminating the need for a separate path for supplying the chemical from the upper side of the reaction vessel section 2. However, when the reaction vessel section 2 contains a carrier S, if the chemical is discharged from the upper second port 21b as in the normal supply mode, the chemical may remain attached to the sidewall 22a (particularly the upper portion) of the reaction vessel body 22 and the upper filter 24 (see Figure 4(b)). In this way, if the amount of the next chemical solution to be used in the synthesis reaction is small while the carrier S is still attached, even if the chemical solution is supplied to the reaction vessel section 2, it is difficult for the chemical solution to come into contact with the attached carrier S, making it difficult to carry out the synthesis reaction efficiently. To solve this problem, the carrier return mode is executed, and the chemical solution introduced from above washes off the attached carrier S, thereby increasing the synthesis efficiency of the chemical solution and carrier S.

In carrier return mode, the chemical liquid is supplied from the second chemical liquid supply unit 73. Specifically, as shown in FIG. 5, three-way valve 53 is set to an open state in the direction of flow from pipe 43 to pipe 46, and three-way valve 55 is set to an open state in the direction of flow from pipe 46 to the reaction vessel section 2, so that the chemical liquid measured by the metering section 3 is supplied from the second chemical liquid supply unit 73 to the reaction vessel section 2 via the chemical liquid discharge unit 72. That is, as in the normal supply mode, the metering vessel 31 is pressurized by the gas tank 62, creating a pressure difference with respect to the reaction vessel section 2, and the chemical liquid is sent from the metering vessel 31.

When chemical liquid is supplied to the reaction vessel section 2, the chemical liquid supplied through the first port 21a is guided by the filter 24 (guide member 8) to the side wall 22a of the reaction vessel section main body 22. That is, the chemical liquid that has penetrated the filter 24 penetrates into the filter 24 as shown by the arrows in Figure 2, and moves across the entire surface of the filter 24. Then, because the outer edge of the filter 24 is continuous with the side wall 22a of the reaction vessel section main body 22, any chemical liquid that cannot be retained within the filter 24 is pulled by surface tension with the side wall 22a and flows down the side wall 22a. As a result, the chemical liquid flowing down the side wall 22a lifts the carrier S (see Figure 4(b)) attached to the side wall 22a from the side wall 22a, causing the carrier S to fall toward the lower end of the reaction vessel section 2 along with the flow of the chemical liquid. This allows the carriers S attached to the sidewall 22a of the reaction vessel section 2 to return to their original position (the lower end of the reaction vessel section), improving the efficiency of synthesis between the carriers S and the chemical solution. In other words, compared to when the carriers S remain attached to the sidewall 22a, the chemical solution can come into contact with all of the carriers, allowing the synthesis reaction to be carried out more efficiently.

Furthermore, as described above, this carrier return mode not only washes away carriers S already adhered to the side wall 22a of the reaction vessel section 2, but also prevents carriers S floating in the chemical solution from adhering to the side wall 22a. That is, the chemical solution supplied from the second chemical solution supply section 73 flows along the side wall 22a of the reaction vessel section 2, and this flow of chemical solution directly hits carriers S floating on the liquid surface, causing them to sink. In other words, even before the chemical solution in the reaction vessel section 2 is discharged, it is possible to prevent carriers S from adhering to the side wall 22a of the reaction vessel section 2. Furthermore, even if the liquid surface is disturbed by the supply of chemical solution and carriers S attempt to adhere to the side wall 22a, the chemical solution flowing along the side wall 22a washes back the carriers S, preventing carriers S from adhering to the side wall 22a.

In this carrier return mode, the chemical solution supplied from the second chemical solution supply unit 73 flows along the side wall 22a of the reaction vessel unit 2 due to the guide member 8 (filter 24 in this embodiment) that guides the chemical solution to the side wall 22a of the reaction vessel unit 2. This allows the chemical solution to be supplied directly from the vertically upper side of the reaction vessel unit 2 (chemical solution discharge unit 72 in this embodiment). As described above, chemical solution introduced from above does not easily spread radially and therefore is less likely to react with the carriers S located radially outward. However, in this embodiment, the chemical solution is supplied along the side wall 22a of the reaction vessel unit 2, allowing the chemical solution to be supplied to the carriers S located radially outward. Therefore, this carrier return mode can also be used as a normal chemical solution supply means for the reaction vessel unit 2. This carrier return mode allows the chemical solution to be supplied to the reaction vessel unit 2 while preventing the carriers S from adhering to the side wall 22a of the reaction vessel unit 2.

Here, in order to store the chemical liquid in the reaction vessel section 2 in carrier return mode, valve 52 is set to a closed state. As the chemical liquid is supplied to the reaction vessel section 2 and pressurized, the chemical liquid cannot be transferred beyond a certain amount. Therefore, in carrier return mode, exhaust section 9 is set to an open state, allowing gas (mainly gas, including bubbles) inside the reaction vessel section 2 to escape to the drain tank 11, making it possible to store the chemical liquid regardless of the amount of chemical liquid being transferred.

However, if the exhaust unit 9 is always set to an open state, the fluid (mainly gas) inside the reaction vessel unit 2 is discharged, which may result in the chemical solution being discharged from the exhaust unit 9 without passing through the filter 24, depending on the type of filter 24 (fluid resistance caused by the filter 24). Therefore, in the carrier return mode, the chemical solution is supplied by alternately switching between a chemical solution supply state and a vessel discharge state. Here, the chemical solution supply state refers to a state in which the exhaust unit 9 is closed, and the second chemical solution supply unit 73 and the chemical solution discharge unit 72 are in a liquid delivery state, thereby supplying the chemical solution. Furthermore, the vessel discharge state refers to a state in which the second chemical solution supply unit 73 and the chemical solution discharge unit 72 are in a liquid delivery stopped state, and the exhaust unit 9 is open.

In other words, when the chemical liquid is supplied from the second port 21b while the valve 59 is closed and the exhaust port 9 is closed in the chemical liquid supply state, the pressure in the reaction vessel section 2 increases. However, because the exhaust port 9 is closed, the chemical liquid is introduced into the reaction vessel section body against the fluid resistance of the filter 24. If this state continues, the pressure inside the reaction vessel section 2 increases, preventing the chemical liquid supplied from the chemical liquid discharge port 72 from entering. When the pressure in the reaction vessel section 2 reaches a certain level, the valve 59 is opened, and the three-way valve 55 is closed to stop the chemical liquid supply and switch to the container discharge state. This discharges the fluid inside the reaction vessel section 2, thereby restoring the increased pressure. The chemical liquid is then supplied again to the chemical liquid supply state. In this way, by switching between the chemical liquid supply state and the container discharge state, the chemical liquid can be supplied without passing through the filter 24 and being discharged from the exhaust port 9. The timing for switching between the chemical supply state and the container discharge state can be set to a predetermined timing that allows the chemical to be introduced smoothly by controlling the pressure of the reaction container section 2 or by time control, etc.

The control device is also configured to perform a residual liquid transfer operation so that all of the measured chemical liquid is supplied to the reaction vessel section 2. In this embodiment, the residual liquid transfer operation is performed using the gas-liquid sensor 32a, and after the gas-liquid sensor 32a turns OFF, an additional liquid transfer operation is performed to transfer the residual liquid. Specifically, the gas-liquid sensor 32a is provided in the piping 45, and is capable of detecting whether or not the chemical liquid is present in the piping 45. This gas-liquid sensor 32a turns ON as the chemical liquid passes through, and then turns OFF, thereby detecting that the passage of the chemical liquid has been completed. The residual liquid in the piping 45 can be transferred by determining in advance, from the installation position of the gas-liquid sensor 32a, how much of the chemical liquid in the piping 45 needs to be transferred to the reaction vessel section 2 through the liquid transfer operation. For example, if the chemical liquid remaining in second port 21b from the mounting position of gas-liquid sensor 32a is completely transferred to reaction vessel section 2 by alternating between the chemical liquid supply state and the vessel discharge state three times, the residual liquid transfer operation can be performed from the point when gas-liquid sensor 32a changes from ON to OFF, alternating between the chemical liquid supply state and the vessel discharge state three times each, thereby reliably transferring the residual liquid from piping 45. This residual liquid transfer operation allows for flexible setting of the sensor mounting position. In other words, while it is usually preferable to mount the sensor near the reaction vessel to minimize the amount of residual liquid in piping 4 when detecting the completion of liquid transfer, the above-described residual liquid transfer operation allows the chemical liquid remaining in piping 4 after the sensor reaction to be transferred without leaving it in piping 4, without affecting the sensor mounting position, allowing the sensor to be mounted in the desired location.

The residual liquid transfer operation is also performed in the normal supply mode. That is, in the normal supply mode, a gas-liquid sensor 32b is provided in the piping 44, and after this gas-liquid sensor 32b changes from ON to OFF, the measuring container 31 is pressurized by the gas tank 62 for a predetermined time, causing the liquid remaining in the first port 21a to be transferred from the gas-liquid sensor 32b to the reaction container section 2 without any residue. Note that, in the above embodiment, an example was described in which the residual liquid transfer operation in the carrier return mode is controlled by the number of times the chemical liquid supply state and the container discharge state are repeated, but it may also be controlled by the time the chemical liquid supply state is in effect.

In the above explanation, chemical liquid was used as the target, but cleaning liquid can also be used instead, and even when cleaning liquid is used as the target, the flow of cleaning liquid is controlled by the above-mentioned control device.

As described above, the chemical solution synthesis apparatus, which is equipped with the second chemical solution supply unit 73, can prevent the carrier S from adhering to the inner wall of the reaction vessel section 2. In other words, even if the carrier S attempts to adhere to the inner wall of the reaction vessel section 2 due to the fluctuation of the chemical solution level, the carrier S is prevented from adhering by being supplied from the second chemical solution supply unit 73, which is located above the chemical solution level. Even if the carrier S does adhere to the inner wall of the reaction vessel section 2, it can be washed back to the chemical solution side. Note that while the above embodiment has mainly described the side wall 22a, the inner wall of the reaction vessel section 2 refers to the inner wall of the reaction vessel section 2 formed by the reaction vessel section main body 22 and lid section 23.

Furthermore, according to the chemical solution synthesis apparatus of the above embodiment, since it is equipped with a second chemical solution supply unit 73 in addition to the first chemical solution supply unit 71, the carriers adhering to the inner wall of the reaction vessel unit 2 can be dropped after the chemical solution is discharged from the chemical solution discharge unit 72 on the vertically upper side. In other words, when the chemical solution supplied from the second chemical solution supply unit 73 comes into contact with the adhering carriers, the carriers are dropped along with the supplied chemical solution, and the carriers can be returned to the lower end of the reaction vessel unit 2. This makes it easier for the carriers to come into contact with the chemical solution supplied from the first chemical solution supply unit 71 on the lower end side, thereby improving the reaction efficiency between the carriers and the chemical solution.

In addition, in the above embodiment, an example was described in which the second chemical liquid supply unit 73 is connected to the chemical liquid discharge unit 72, and the chemical liquid sent from the second chemical liquid supply unit 73 is supplied to the reaction vessel unit 2 through the chemical liquid discharge unit 72. However, the chemical liquid may also be supplied directly from the second chemical liquid supply unit 73 to the reaction vessel unit 2. Specifically, in FIG. 2, a third port (not shown) may be provided in addition to the second port 21b and discharge port 91 on the upper end side lid of the reaction vessel unit 2, and piping 46 may be connected to this third port, so that the measured chemical liquid and cleaning liquid are supplied to the reaction vessel unit 2 through piping 46 and the third port.

In addition, in the above embodiment, an example was described in which the chemical solution is supplied to the reaction vessel section 2 by alternately switching between the chemical solution supply state and the vessel discharge state in the carrier return mode, but the chemical solution may be supplied only in the chemical solution supply state. In other words, if the carriers S adhering to the reaction vessel body 22 can be removed in one chemical solution supply state, the chemical solution may be supplied in only one chemical solution supply state to perform the synthesis reaction.

In addition, in the above embodiment, the gas-liquid sensors 32a and 32b are used to detect whether the liquid transfer has been completed. However, other sensors that can detect the chemical liquid in the pipe 4 may also be used. For example, a capacitance-type proximity sensor or a transmission-type photomicrosensor may be used.

In addition, while the above embodiment describes an example in which the guide member 8 is a filter 24, any member that guides the delivered chemical solution to the side wall 22a of the reaction vessel section 2 may be used. For example, as shown in FIG. 6, a conical member may be provided near the entrance/exit of the reaction vessel section 2, with its outer edge directed toward a wall surface that is continuous with the side wall 22a of the reaction vessel main body 22. Even with such a member, the chemical solution supplied from the second port 21b flows down the side wall 22a of the reaction vessel main body 22 and is supplied into the reaction vessel main body 22, allowing the carrier S adhering to the side wall 22a to be washed away.

In addition, in the above embodiment, an example was described in which the filter 24 was provided in the reaction vessel section 2, but it may also be provided in the chemical solution discharge section 72. For example, as shown in FIG. 6, it may be provided in the piping 4 connected to the first port section 21a and the exhaust port 91.

In the above embodiment, an example was described in which the guide member 8 (filter 24) guides the chemical solution supplied from the second chemical solution supply unit 73 (in the above embodiment, the piping 45 inserted into the second port 21b) to the side wall 22a of the reaction vessel section 2. However, even without the guide member 8, the lid section 23 may be configured to have a wall surface that is continuous with the side wall 22a of the reaction vessel section 2, and the chemical solution supplied may be configured to flow along that wall surface. Specifically, as shown in FIG. 10(a), the lid section 23 is formed with an insertion hole 23b that penetrates all the way to the bottom surface 23a, and a piping 45 is inserted through the insertion hole 23b. The tip of the piping 45 is provided in contact with the inner wall of the insertion hole 23b. This allows the chemical solution f supplied from the piping 45 to flow to the side wall 22a of the reaction vessel section 2. That is, because the tip of the pipe 45 is in contact with the inner wall of the insertion hole 23b, the chemical solution f supplied from the pipe 45 flows along the inner wall of the insertion hole 23b due to surface tension as it flows out of the opening of the pipe 45. The inner wall of the insertion hole 23b is continuous with the side wall 22a of the reaction vessel section 2 via the bottom surface 23a of the lid section 23, so the chemical solution f flowing along the inner wall of the insertion hole 23b flows from the bottom surface 23a along the side wall 22a. By configuring the pipe 45 so that it is continuous from the opening to the side wall 22a of the reaction vessel section 2, the supplied chemical solution f can flow along the side wall 22a of the reaction vessel section 2.

10(a) illustrates an example in which the opening of the pipe 45 is housed within the insertion hole 23b. However, as shown in FIG. 10(b), the opening of the pipe 45 may protrude beyond the bottom surface 23a of the lid. Even in this case, the chemical solution f that flows out of the opening of the pipe 45 can flow through the bottom surface 23a to the side wall 22a of the reaction vessel section 2 due to surface tension. In other words, a configuration in which the chemical solution f that flows out of the opening of the pipe 45 is continuously formed on the side wall 22a of the reaction vessel section 2 includes a configuration in which the chemical solution f that flows out of the opening of the pipe 45 ultimately flows along the side wall 22a due to surface tension. This prevents the carrier S from adhering to the inner wall of the reaction vessel section 2 (the inner wall of the reaction vessel section 2, including the side wall 22a of the reaction vessel section main body 22 and the bottom surface 23a of the lid section 23). Even if the carrier S does adhere, the adhering carrier S can be dropped and returned to the chemical solution side.

REFERENCE SIGNS LIST 1 Chemical solution storage section 2 Reaction vessel section 3 Measuring section 4 Piping 8 Guide member 9 Discharge section 11 Drain tank (storage vessel section)
21a First port 21b Second port 24 Filter 31 Measuring container 32 Gas-liquid sensor 71 First chemical liquid supply section 72 Chemical liquid discharge section 73 Second chemical liquid supply section 91 Discharge port S Carrier (beads)

Claims (8)

a medicinal solution storage section in which a medicinal solution is stored;
a reaction vessel section in which the chemical solution and the carrier are reacted;
A chemical solution synthesis apparatus comprising: a chemical solution storage unit; ... reaction vessel unit; and a chemical solution synthesis device for synthesizing a chemical solution, the chemical solution being transferred from the chemical solution storage unit to the reaction vessel unit without being exposed to the atmosphere.
a second chemical solution supply unit that includes a first chemical solution supply unit connected to the reaction vessel unit and through which a chemical solution is supplied to the reaction vessel unit, and a chemical solution discharge unit that is provided vertically above the first chemical solution supply unit , and that prevents the carrier from adhering to the reaction vessel unit;
The chemical solution synthesis apparatus is characterized in that the reaction vessel section has an exhaust section for discharging gas from the reaction vessel section, which is arranged at a height position equal to or higher than the height position of the chemical solution discharge section . a medicinal solution storage section in which a medicinal solution is stored;
a reaction vessel section in which the chemical solution and the carrier are reacted;
A chemical solution synthesis apparatus comprising: a chemical solution storage unit; ... reaction vessel unit; and a chemical solution synthesis device for synthesizing a chemical solution, the chemical solution being transferred from the chemical solution storage unit to the reaction vessel unit without being exposed to the atmosphere.
a first chemical liquid supply unit connected to the reaction vessel unit and supplying a chemical liquid to the reaction vessel unit; and a chemical liquid discharge unit provided vertically above the first chemical liquid supply unit,
a second chemical solution supply unit that drops the carrier adhering to the inner wall of the reaction vessel unit after the chemical solution is discharged from the chemical solution discharge unit ;
The chemical solution synthesis apparatus is characterized in that the reaction vessel section has an exhaust section for discharging gas from the reaction vessel section, which is arranged at a height position equal to or higher than the height position of the chemical solution discharge section . The chemical solution synthesis apparatus of claim 1 or 2, characterized in that the second chemical solution supply unit is connected to the chemical solution discharge unit, and the chemical solution is supplied by flowing back through the chemical solution discharge unit. A chemical liquid supply device according to any one of claims 1 to 3, characterized in that the chemical liquid supplied from the second chemical liquid supply unit is supplied along the side wall of the reaction vessel unit. A chemical solution synthesis apparatus according to any one of claims 1 to 4, characterized in that the chemical solution in the reaction vessel section is discharged by backflowing through the first chemical solution supply section. The chemical solution synthesis apparatus according to any one of claims 1 to 5 , characterized in that the reaction vessel section is provided with a guide member that guides the chemical solution supplied through the second chemical solution supply section to a side wall of the reaction vessel section. 7. The chemical solution synthesizing apparatus according to claim 6 , wherein the guide member is also used as a filter. 8. The chemical solution synthesizing apparatus according to claim 1, wherein a cleaning solution is used instead of the chemical solution.