JP2008212815A - Organic synthesis reactor and organic synthesis method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an organic synthesis reactor applied for organic synthesis reaction employing a carrier for crystallization separation, which requires no replacement of the reaction vessel in individual stages even in cases involving a multi-stage reaction, and is capable of causing an organic synthetic reaction to proceed with a high yield and a method of carrying out an organic synthetic reaction using the reactor. <P>SOLUTION: The organic synthesis reactor has a reaction chamber using a carrier for crystallization separation and allowing an organic synthetic reaction to proceed in it, a solution injecting mechanism injecting, into the reaction chamber, a solution containing the carrier for crystallization separation and a first reaction substrate reacting with the carrier, a solution discharging mechanism discharging the solution after the organic synthetic reaction using the carrier for crystallization separation, a filter arranged on the side of the solution discharging mechanism in the reaction chamber and a solvent inflow mechanism causing a solvent in which the carrier for crystallization separation after reaction with the first reaction substrate is dissolvable to flow into the reaction chamber. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an organic synthesis reaction apparatus suitably used for an organic synthesis reaction using a crystallization separation support and an organic synthesis reaction method using the organic synthesis reaction apparatus.

  Conventionally, in chemical processes, a method of separating a specific component dissolved in a liquid as a solid has been widely used. This is because solidification (crystallization) of only a specific component facilitates separation and purification after the reaction. In particular, in sequential multi-step synthesis such as compound library synthesis used in pharmaceutical development research in recent years, necessary or unnecessary compounds are solidified (crystallized) and solidified (crystallization) at the end of each reaction. By separating the crystallized substance, the target compound is purified without going through complicated steps.

  Such solidification (crystallization) of the specific component dissolved in the solution is realized by satisfying certain conditions in relation to the chemical properties, physical properties, and solvent of the compound.

  However, in many cases, the conditions for solidification (crystallization) must be empirically searched through trial and error. In particular, in sequential multi-step synthesis, it is necessary to study the solidification (crystallization) conditions based on the properties unique to the compounds synthesized in each step, which requires significant cost and time for process development. Was.

  In view of this, a carrier molecule having a linker has been proposed that senses a change in solution composition sensitively and reversibly changes between a dissolved state and an insolubilized (crystallized) state. Various compounds can be bound to such a carrier molecule via a linker, and the bound compound can be easily changed from a dissolved state to an insolubilized (crystallized) state or vice versa with the carrier molecule. Can change state. In addition, such a compound bound to a carrier can reversibly repeat a dissolved state and an insolubilized (crystallized) state under substantially the same conditions even when the chemical structure is changed by successive chemical reactions. .

  If such a carrier molecule that reversibly changes between a dissolved state and an insolubilized (crystallized) state is used, a compound to be separated from a uniform solution state while utilizing the knowledge of the liquid phase reaction of organic chemistry as it is Can be selectively insolubilized (crystallized). That is, after the liquid phase reaction, it was possible to separate a specific compound while leaving other soluble components in the solution.

As a carrier molecule having a linker that senses a change in solution composition and reversibly changes between a dissolved state and an insolubilized state, Patent Document 1 describes a change from the liquid phase state according to the change in the solution composition and / or the solution temperature. A carrier for crystallization separation, which is a compound that reversibly changes to a solid state, having a reaction site that binds to another compound, and the reaction site includes a carbon atom, an oxygen atom, a sulfur atom, and a nitrogen atom A support for crystallization separation is disclosed which has one or more atoms selected from the group consisting of, and binds to another compound via any one of a carbon atom, an oxygen atom, a sulfur atom, and a nitrogen atom. This support for crystallization separation not only facilitates process development, but also facilitates research and development of pharmaceuticals and the like in compound library synthesis, etc., and consequently technology in the biochemical and chemical industries. It is said that it can contribute to innovation.
International Publication WO2006 / 104166 Pamphlet

  However, when a multi-stage reaction or the like is performed using the crystallization separation support described in Patent Document 1, in one stage, the reaction is performed using one reaction vessel and the product is crystallized. After analysis, this must be transferred to another separation vessel to separate the product and by-products, and the product must be recovered from the separation vessel. In the next stage, the recovered product is transferred to a new container for reaction and further reacted, and crystallization, separation, and recovery are repeated.

  As described above, when the container is transferred at each stage of the multi-stage reaction, a part of the product may adhere to the container or the like and may not be completely recovered in each transfer operation. . In addition, the incomplete recovery of the product causes a decrease in yield at each stage, which is a major cause of significantly reducing the overall yield of the reaction. Such a decrease in the overall yield of the reaction was more prominent as the number of stages required in the reaction over multiple stages was increased.

  The present invention has been made in view of the problems as described above, and is a reaction apparatus for organic synthesis used in an organic synthesis reaction using a carrier for crystallization separation, which is used for a multi-stage reaction. However, it is not necessary to transfer the reaction vessel in each stage, and the organic synthesis reaction apparatus capable of proceeding the organic synthesis reaction with high yield and the organic apparatus using the organic synthesis reaction apparatus. The object is to provide a synthetic reaction method.

  The present inventors include a reaction chamber in which an organic synthesis reaction proceeds, a solution injection means for injecting a solution containing a crystallization separation carrier and a reaction substrate that reacts with the reaction chamber, and an external portion from the inside of the reaction chamber. A solution discharge means for discharging the solution after the organic synthesis reaction from the discharge pipe leading to, a filter provided on the solution discharge means side of the reaction chamber, and the reaction substrate and the reaction substrate through the filter The organic synthesis reaction apparatus comprising a solvent inflow means for allowing a solvent capable of dissolving the crystallization separation support to flow into the reaction chamber, and found that an organic synthesis reaction can be performed in a high yield, The present invention has been completed. Specifically, the present invention provides the following.

  (1) An organic synthesis reactor used for an organic synthesis reaction using a crystallization separation carrier, which is a compound that reversibly changes from a liquid phase state to a solid phase state with changes in solution composition and / or solution temperature. A reaction chamber in which an organic synthesis reaction using the crystallization separation support proceeds, and a solution containing the crystallization separation support and a first reaction substrate that reacts with the reaction chamber. Solution injection means, a solution discharge means for discharging the solution after performing the organic synthesis reaction using the crystallization separation support from a discharge pipe communicating with the outside of the reaction chamber, and the reaction chamber A filter provided on the solution discharge means side, and a solvent inflow for allowing a solvent capable of dissolving the crystallization separation carrier reacted with the first reaction substrate to flow into the reaction chamber from the discharge pipe through the filter Means having Synthesis reactor.

  The reaction apparatus for organic synthesis described in (1) is used as follows. First, a solution containing a carrier for crystallization separation and a first reaction substrate that reacts with the carrier is injected into the reaction chamber by a solution injection means. Next, in the reaction chamber, the crystallization separation support and the first reaction substrate are reacted, and the crystallization separation support reacted with the first reaction substrate is crystallized. The solution in which the carrier for crystallization separation that has reacted with the first reaction substrate and dispersed is discharged to the outside of the reaction chamber by the solution discharge means, and a filter provided on the solution discharge means side of the reaction chamber is used. Then, the crystallization separation carrier reacted with the first reaction substrate is separated from the solution. Finally, a solvent capable of dissolving the crystallization separation carrier reacted with the first reaction substrate is allowed to flow from the discharge pipe through the filter into the reaction chamber, and the crystallization separation carrier reacted with the first reaction substrate is removed. Dissolve in solvent.

  Here, according to the reaction apparatus for organic synthesis described in (1), the reaction for the crystallization separation carrier and the first reaction substrate, and the reaction for the crystallization separation caused by the reaction with the first reaction substrate. Separation of the carrier from the solution can be performed using the same container. In addition, since the solvent that can react with the first reaction substrate and dissolve the separated crystallization separation carrier flows into the reaction chamber through the filter, the product attached to the filter can be easily recovered. You can also. Furthermore, by adding a new reaction substrate to the solvent that has flowed into the reaction chamber through the filter, the next-stage organic synthesis reaction can be performed in the same vessel. As a result, loss of product due to transfer of containers can be prevented, and at the time of product recovery, product loss due to product remaining on the filter can be minimized. it can. Therefore, according to the reaction apparatus for organic synthesis described in (1), the reaction can proceed with a high yield even in an organic synthesis reaction in multiple stages.

  (2) The reaction apparatus for organic synthesis according to (1), wherein the reaction chamber is a sealable container, and the reaction apparatus for organic synthesis includes a decompression unit that decompresses the interior of the reaction chamber.

  According to the organic synthesis reactor described in (2), after the crystallization separation support and the first reaction substrate are reacted, the solvent is volatilized by reducing the pressure in the reaction chamber. The solution composition of the solution containing the crystallization separation carrier reacted with the reaction substrate can be changed. Thereby, the carrier for crystallization separation reacted with the first reaction substrate can be easily crystallized.

  (3) The reaction apparatus for organic synthesis according to (1) or (2), further comprising stirring means for stirring the inside of the reaction chamber.

  (4) The stirring means is connected to power outside the reaction chamber and rotates in the reaction chamber, and a stirring blade provided at the reaction chamber side end of the rotation shaft. The reaction apparatus for organic synthesis as described in (3).

  According to the organic synthesis reaction apparatus described in (3) and (4), the reaction solution can be stirred by the stirring means when the crystallization separation support and the first reaction substrate are reacted. Thereby, the progress of the reaction between the carrier for crystallization separation and the first reaction substrate can be promoted to increase the yield of the product.

  (5) The solution injection means comprises a part of the rotating shaft and includes an injection pipe that communicates with the outside of the reaction chamber, and an outlet that communicates from the side surface of the injection pipe into the reaction chamber. ) A reaction apparatus for organic synthesis.

  The reaction apparatus for organic synthesis described in (5) uses a rotating shaft constituting a part of the stirring means as a solution injection means and injects the solution into the reaction chamber. According to the organic synthesis reactor according to (5), when injecting the solution into the reaction chamber, the injected solution comes into contact with the wall surface of the reaction chamber by injecting the solution from the side surface of the rotating shaft. The deposits attached to the wall surface can be washed away and recovered in the reaction solution. In addition, when the rotary shaft is rotated at the time of injecting the solution, it is possible to wash off the attached deposits and the like over the entire wall surface of the reaction chamber. As a result, the reactants remaining on the wall of the reaction chamber can be reduced. In addition, by washing the wall surface at each reaction stage, it is possible to prevent the reactants from the previous stage in the multistage reaction from entering the reaction solution of the next stage, reducing the possibility of unexpected by-products. can do.

  (6) The reaction apparatus for organic synthesis according to any one of (1) to (5), further comprising a discharge pipe decompression means for decompressing the inside of the discharge pipe.

  According to the organic synthesis reactor according to (6), when the crystallization separation support is separated from the solution in which the crystallization separation support that has reacted with the reaction substrate and is crystallized is dispersed, Therefore, the crystallization separation carrier and the solution can be separated efficiently.

  (7) An organic synthesis reaction method carried out using the organic synthesis reactor according to any one of (1) to (6), wherein the crystallization separation carrier and the first A first solution injection step of injecting a solution containing a reaction substrate into the reaction chamber; a first reaction step of reacting the carrier for crystallization separation and the first reaction substrate; and reaction with the first reaction substrate. A first crystallization step of crystallizing the crystallization separation carrier, a first separation step of filtering the solution in which the crystallization separation carrier reacted with the first reaction substrate is dispersed, using the filter, A solvent capable of dissolving the crystallization separation carrier reacted with the first reaction substrate is caused to flow back into the reaction chamber by the solvent inflow means, and the crystallization separation carrier reacted with the first reaction substrate is used as the solvent. A first recovery step for dissolving Machine synthesis reaction method.

  (8) A second solution in which a solution containing a second reaction substrate that reacts with the first reaction substrate bound to the crystallization separation support is further injected into the reaction chamber after the first recovery step. An injection step, a second reaction step for reacting the first reaction substrate and the second reaction substrate reacted with the crystallization separation carrier, and a crystallization separation carrier bound to the second reaction substrate. The second crystallization step for crystallization, the second separation step for filtering the solution in which the carrier for crystallization separation to which the second reaction substrate is bound is dispersed by the filter, and the solvent inflow means, A second recovery step in which a solvent capable of dissolving the crystallization separation carrier bound to the second reaction substrate is caused to flow back into the reaction chamber, and the crystallization separation carrier bound to the second reaction substrate is dissolved in the solvent; And the organic synthesis reaction method according to (7).

  The organic synthesis reaction methods described in (7) and (8) are obtained by capturing the organic synthesis reaction device described in any of (1) to (6) as a method invention. Therefore, the same effect as that obtained by using the organic synthesis reactor described in (1) to (6) can be obtained.

  In particular, the organic synthesis reaction method described in (8) is an organic synthesis reaction method in which a reaction is performed in multiple stages. The organic synthesis reaction method of the present invention is a method particularly suitable for carrying out a multi-stage reaction without lowering the overall yield even when a multi-stage reaction is performed.

  According to the present invention, the reaction of the crystallization separation support and the reaction substrate and the separation of the crystallization separation support that has reacted with the reaction substrate and crystallized from the solution can be performed using the same container. it can. In addition, since the solvent that can react with the reaction substrate and dissolve the separated crystallization separation carrier flows into the reaction chamber through the filter, the product attached to the filter can be easily recovered. Furthermore, by adding a new reaction substrate to the solvent that has flowed into the reaction chamber through the filter, the next-stage organic synthesis reaction can be performed in the same vessel. As a result, loss of product due to transfer of containers can be prevented, and at the time of product recovery, product loss due to product remaining on the filter can be minimized. it can. Therefore, even if it is an organic synthesis reaction in multiple stages, the reaction can be advanced with a high yield.

  Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings.

<Reaction equipment for organic synthesis>
FIG. 1 is a schematic view of a reaction apparatus 1 for organic synthesis according to the present invention. The organic synthesis reaction apparatus 1 of the present invention is an organic synthesis reaction using a crystallization separation carrier that is a compound that reversibly changes from a liquid phase state to a solid phase state with changes in solution composition and / or solution temperature. 1 is a reaction apparatus for organic synthesis 1 used in the above-mentioned reaction chamber 2 in which an organic synthesis reaction using a carrier for crystallization separation proceeds, and a carrier for crystallization separation in reaction chamber 2 and a first reaction that reacts therewith. In order to discharge the solution after performing the organic synthesis reaction using the crystallization separation carrier from the solution injection means 4 for injecting the solution containing the substrate and the discharge pipe 51 communicating from the inside of the reaction chamber 2 to the outside. The crystallization separation carrier reacted with the first reaction substrate can be dissolved through the solution discharge means 5, the filter 7 provided on the solution discharge means 5 side of the reaction chamber 2, and the filter 7 from the discharge pipe 51. Solvent inflow for allowing solvent to flow into reaction chamber 2 It includes a stage 8, the.

  In addition, the organic synthesis reactor 1 of the present invention includes a decompression means 9 for decompressing the interior of the reaction chamber 2, an agitation means 3 for agitating the interior of the reaction chamber 2, and a discharge pipe 51 through a filter 7 as necessary. In addition, an inert gas inflow unit 10 for allowing the inert gas to flow into the reaction chamber 2 and an exhaust pipe decompression unit 6 for decompressing the inside of the exhaust pipe 51 may be provided.

[Reaction room]
The organic synthesis reactor 1 of the present invention includes a reaction chamber 2 in which an organic synthesis reaction using a crystallization separation carrier proceeds. In the reaction chamber 2, the crystallization separation support dissolved in the solution in the reaction chamber 2 can be reacted with the reaction substrate that reacts therewith, and the solution composition and / or the solution temperature is changed after the reaction. By doing so, the carrier for crystallization separation reacted with the reaction substrate can be crystallized.

  The reaction chamber 2 has a structure in which the reaction solution can be stored for a certain time, and has a structure in which the solution can be injected and discharged by the solution injection means 4 and the solution discharge means 5. . Moreover, the reaction chamber 2 has a structure in which the reaction liquid can be stirred by the stirring means 3 provided as necessary, and the inside of the reaction chamber 2 can be reduced in pressure by the pressure reducing means 9 provided as necessary. It has a structure. When the reaction apparatus 1 for organic synthesis of the present invention includes the decompression means 9, the reaction chamber 2 preferably has a sealable structure. Specifically, it is preferable that a valve or the like is provided on each pipe leading to the reaction chamber 2 so that the reaction chamber 2 can be sealed by closing the valve.

  Further, the reaction chamber 2 may further have a structure in which the reaction solution can be heated and cooled by the temperature adjusting means. In the organic synthesis reactor 1 of the present invention, the crystallization separation carrier can be crystallized by cooling the reaction solution in which the crystallization separation carrier is dissolved, and the organic synthesis reaction is an endothermic reaction. In conducting the reaction, the reaction can be promoted by heating the reaction solution.

  The shape of the reaction chamber 2 is not particularly limited, and examples thereof include a cylindrical shape, a spherical shape, and a prismatic shape. Among these shapes, a cylindrical shape is preferable from the viewpoint that when the stirring means 3 is provided, the reaction solution hardly accumulates.

  When the reaction chamber 2 is cylindrical, the diameter of the bottom surface of the reaction chamber 2 is preferably 25 mm or more and 80 mm or less. When the diameter of the bottom surface of the reaction chamber 2 is 25 mm or more, the reaction liquid is easily mixed in the vertical direction. On the other hand, when the diameter of the bottom surface of the reaction chamber 2 is 80 mm or less, even when the volume of the reaction solution is small, a sufficient level of water can be maintained, and the reaction solution can be easily handled.

The volume of the reaction chamber 2 is preferably 50000 mm ³ or more and 1000000 mm ³ or less. By setting the volume of the reaction chamber 2 within the above range, an organic synthesis reaction of a scale that is usually performed can be suitably performed.

  Examples of the material constituting the reaction chamber 2 may include materials such as glass, polypropylene resin, polyethylene resin, fluororesin, and metal, such as corrosion resistance against the reaction solution, pressure resistance against reduced pressure, and heat resistance against heating. From the viewpoint, glass and fluororesin are preferable.

[Agitating means]
The organic synthesis reactor 1 of the present invention may be provided with a stirring means 3 for stirring the reaction chamber 2 as necessary. The stirring means 3 includes a rotating shaft 31 that is connected to power outside the reaction chamber 2 and rotates inside the reaction chamber 2, a stirring blade 32 provided at the end of the rotating shaft 31 on the reaction chamber 2 side, A rotating shaft-stirring blade stirring mechanism, a magnetic stirrer, and a mechanism for vibrating a glass container. Among these, a rotating shaft-stirring blade stirring mechanism can be particularly preferably used.

(Rotating shaft-stirring blade stirring mechanism)
When the rotating shaft-stirring blade stirring mechanism is provided as the stirring means 3, the length of the rotating shaft 31 inserted into the reaction chamber 2 is 60% or more and 95% or less of the height of the reaction chamber 2. It is preferable. When the length of the portion of the rotary shaft 31 inserted into the reaction chamber 2 is less than 60% of the height of the reaction chamber 2, the reaction solution is sufficiently used in an organic synthesis reaction performed on a normal scale. Mixing may not be possible. On the other hand, if the length of the portion of the rotating shaft 31 inserted into the reaction chamber 2 exceeds 95% of the height of the reaction chamber 2, the stirring blade 32 may come into contact with the bottom surface of the reaction chamber 2. Is not preferable.

  Further, the shape of the stirring blade 32 is not particularly limited, and examples thereof include a propeller shape and a spatula shape.

  The rotation trajectory area of the stirring blade 32 is preferably 40% or more and 90% or less with respect to the cross-sectional area of the reaction chamber 2. By keeping the rotation locus area within this range, the reaction solution can be efficiently stirred.

[Solution injection means]
The organic synthesis reaction apparatus 1 of the present invention includes a solution injection means 4 for injecting into a reaction chamber 2 a solution containing a crystallization separation carrier and a first reaction substrate that reacts therewith. As the solution injection means 4, for example, a solution injection tube 41 connected to the upper wall surface of the reaction chamber 2 and having an opening on the upper inner wall can be mentioned. When such a solution injection tube 41 is provided, the solution injection tube 41 is preferably interrupted by a valve 92. By providing such a valve 92, the reaction chamber 2 can be sealed, and the inside of the reaction chamber 2 can be decompressed by the decompression means 9 provided as needed.

(Rotating shaft—solution injection means provided in a part of the stirring blade stirring mechanism)
The solution injection means 4 constitutes a part of the rotary shaft 31 provided in the rotary shaft-stirring blade stirring mechanism that is the stirring means 3, and an injection tube 43 that communicates with the outside of the reaction chamber 2, and a reaction chamber from the side of the injection tube 43. 2 and the outflow port 44 leading to the inside. In this case, the injection tube 43 has a structure in which a part of the rotating shaft 31 is hollow, and is provided with an outlet 44 that communicates with the reaction chamber 2 at the end of the hollow portion on the reaction chamber 2 side. The outlet 44 may be an outlet 44a provided directly on the side surface of the rotary shaft 31 as shown in FIG. 2A, or may be relative to the rotary shaft 31 as shown in FIG. It may be an outflow port 44b provided at the tip of the outflow pipe 45b protruding at a predetermined angle.

  By injecting the solution into the reaction chamber 2 by injecting the solution into the reaction chamber 2 by providing the solution injection means 4 in a part of the rotating shaft-stirring blade stirring mechanism, the injected solution reacts. Contact with the wall surface of the chamber 2, the adhering matter and the like adhering to the wall surface can be washed away and recovered in the reaction solution. In addition, when rotating the rotary shaft 31 during the injection of the solution, the attached deposits and the like can be washed out over the entire wall surface of the reaction chamber 2. As a result, the reactants remaining on the wall surface of the reaction chamber 2 can be reduced. In addition, by cleaning the wall surface in each reaction stage, it is possible to prevent the reactants in the previous stage in the multistage reaction from being mixed into the reaction solution in the next stage, and reduce the possibility of the formation of unexpected by-products. be able to.

[Solution discharging means]
The organic synthesis reactor 1 of the present invention is a solution discharge means for discharging a solution after performing an organic synthesis reaction using a support for crystallization separation from a discharge pipe 51 communicating from the inside of the reaction chamber 2 to the outside. 5 is provided. Specific examples of the solution discharge means 5 include a means provided with a discharge pipe 51 having an opening at the bottom of the reaction chamber 2 and a storage tank for temporarily storing a solution leaking from the discharge pipe 51. it can. The discharge pipe 51 is preferably provided with a valve 53 in order to seal the reaction chamber 2.

[Discharge pipe decompression means]
The reactor for organic synthesis 1 of the present invention may be provided with a discharge pipe decompression means 6 for decompressing the inside of the discharge pipe 51 as necessary. By providing the discharge pipe decompression means 6, the reaction solution can be efficiently discharged from the reaction chamber 2. As the discharge pipe decompression means 6, the inside of the discharge pipe 51 may be directly decompressed from the end portion of the discharge pipe 51, but when the solution discharge means 5 is provided with a storage tank 52, the inside of the storage tank 52. The discharge pipe 51 connected thereto may be indirectly depressurized by sealing and depressurizing. For the decompression of the discharge pipe 51, a decompressor such as an aspirator, a diaphragm type vacuum pump, and a vacuum pump such as a hydraulic rotary vacuum pump can be used. In addition, a valve 62 may be provided between the decompression device and the storage tank 52 so that the degree of decompression of the discharge pipe 51 can be appropriately adjusted.

[filter]
A filter 7 is provided on the solution discharge means 5 side of the reaction chamber 2. By providing the filter 7, when the reaction solution is discharged by the solution discharging means 5, the crystallized crystallization separation carrier can be easily separated from the reaction solution. The filter 7 needs to be provided so as to cover at least the entire opening on the reaction chamber 2 side of the discharge pipe 51 provided in the solution discharge means 5, but from the viewpoint of preventing the filter 7 from being clogged. It is preferably provided over the entire bottom surface of the reaction chamber 2. In this case, it is preferable that a gap is provided between the filter 7 and the bottom surface of the reaction chamber 2 from the viewpoint of allowing the reaction solution to pass through the entire surface of the filter 7.

  Examples of the material constituting the filter 7 include glass fiber, cellulose, fluororesin such as tetrafluoroethylene resin (PTFE), polyethersulfone, polypropylene resin, and polyethylene resin. Among these, glass fiber and fluororesin are preferable from the viewpoint of strength and filtration reliability.

  The filter 7 is preferably provided in the reaction chamber 2 so as to be detachable. However, the filter 7 is detached even when the solvent inflow means 8 described later, the inert gas inflow means 10 provided as necessary, or the like is implemented. It is preferable that it is sufficiently fixed so that it does not occur.

[Solvent inflow means]
The reaction apparatus 1 for organic synthesis of the present invention has a solvent inflow for allowing a solvent capable of dissolving the crystallization separation carrier that has reacted with the first reaction substrate to flow into the reaction chamber 2 from the discharge pipe 51 through the filter 7. Means 8 are provided. As such a solvent inflow means 8, specifically, in the organic synthesis reactor 1 in which a solvent inflow pipe 81 branched from the discharge pipe 51 is formed as shown in FIG. And a means for allowing the solvent to flow in. A valve 53 that is a three-way valve is preferably provided at the branch point between the solvent inflow pipe 81 and the discharge pipe 51. By switching the flow path with the valve 53, it is possible to select the inflow of the solvent into the reaction chamber 2 and the discharge of the solution from the reaction chamber 2 to the storage tank 52.

  When the solvent flows into the reaction chamber 2, it is preferable to release the gas in the reaction chamber 2 to the outside by opening a valve 92 provided in the solution injection means 4. The flow rate when the solvent is allowed to flow into the reaction chamber 2 is 0.2 ml / sec or more and 2.0 ml / sec or less from the viewpoint of efficiently dissolving the crystallization separation carrier attached to the filter 7. Is preferred.

  In the solvent inflow means 8, the solvent that can react with the first reaction substrate and dissolve the separated carrier for crystallization separation is allowed to flow into the reaction chamber 2 through the filter 7, and is attached to the filter 7. The product can be easily recovered. Thereby, the yield of the whole reaction can be raised.

[Inert gas inflow means]
The organic synthesis reactor 1 of the present invention includes an inert gas inflow means 10 for allowing an inert gas to flow into the reaction chamber 2 from the discharge pipe 51 through the filter 7 as necessary. Also good. Examples of the inert gas inflow means 10 include a means for causing the inert gas to flow into the reaction chamber 2 using the solvent inflow pipe 81 described above. Similarly to the case where the solvent is caused to flow in by the solvent inflow means 8, also in the case where the inert gas is caused to flow in by the inert gas inflow means 10, the reaction chamber is opened by opening the valve 92 provided in the solution injection means 4. It is preferable to release the gas in 2 to the outside.

  When the inert gas is allowed to flow into the reaction chamber 2 during the organic synthesis reaction, the reaction solution is uniformly stirred to promote the smooth progress of the reaction and the crystallization separation support is crystallized. However, the filter 7 is not clogged. Moreover, since the solvent in the reaction solution is vaporized by supplying an inert gas to the reaction solution after the reaction, it can be used as a means for changing the solution composition of the reaction solution.

[Pressure reduction means]
The organic synthesis reactor 1 of the present invention includes a decompression means 9 for decompressing the interior of the reaction chamber 2. The decompression means 9 is not particularly limited. For example, as shown in FIG. 1, the inside of the reaction chamber 2 is decompressed by sucking gas from a decompression tube 91 having an opening on the side surface of the reaction chamber 2. The means to do can be mentioned. Here, in order to achieve the decompression of the reaction chamber 2 by the decompression means 9, the reaction chamber 2 preferably has a sealable structure. Specifically, as described above, it is preferable to provide a valve at the branch point between the solution injection pipe 41 and the discharge pipe 51 and the solvent inflow pipe 81 to block the inflow of gas from the outside. Also, the pressure reducing pipe 91 is preferably provided with a valve 92. This makes it possible to easily adjust the degree of decompression in the reaction chamber 2. For reducing the pressure in the reaction chamber 2, an aspirator, a vacuum pump such as a diaphragm vacuum pump, and a hydraulic rotary vacuum pump can be used.

  By reducing the pressure inside the reaction chamber 2 by the pressure reducing means 9, the volatile solvent contained in the reaction solution can be volatilized and the solution composition can be changed. Here, since the crystallization separation carrier used in the organic synthesis reaction method described later is easily crystallized by a change in the solution composition, the crystallization separation carrier is crystallized by carrying out the decompression means 9. Can be analyzed.

  The organic synthesis reactor 1 of the present invention may be used by connecting a plurality of units. Thereby, an organic synthesis reaction like a continuous amide formation reaction and a continuous esterification reaction can be advanced efficiently. Further, in the organic synthesis reaction apparatus 1 of the present invention, the organic synthesis reaction apparatus 1 which is controlled so as to be able to automatically perform operations such as opening / closing of each valve and starting / stopping of a vacuum pump, etc. It belongs to the range.

<Organic synthesis reaction method>
The organic synthesis reaction method of the present invention is an organic synthesis reaction method carried out using the organic synthesis reaction apparatus 1 described above, wherein a solution containing the crystallization separation carrier and the first reaction substrate is reacted by the solution injection means 4. A first solution injection step for injecting into the chamber 2; a first reaction step for reacting the crystallization separation support and the first reaction substrate; and a crystallization separation support reacted with the first reaction substrate. A first crystallization step, a first separation step of filtering the solution in which the carrier for crystallization separation that has reacted with the first reaction substrate is dispersed by the filter 7, and the solvent inflow means 8. A first recovery step in which a solvent capable of dissolving the crystallization separation carrier reacted with the substrate is caused to flow back into the reaction chamber 2 and the crystallization separation carrier reacted with the first reaction substrate is dissolved in the solvent. This is an organic synthesis reaction method.

  In addition, in the organic synthesis reaction method of the present invention, after the first recovery step, a solution containing a second reaction substrate that reacts with the first reaction substrate bound to the crystallization separation support is further added to the reaction chamber 2. A second solution injecting step for injecting into the substrate, a second reaction step for reacting the first reaction substrate and the second reaction substrate reacted with the carrier for crystallization separation, and a crystal to which the second reaction substrate is bound. A second crystallization step for crystallizing the crystallization separation carrier, a second separation step for filtering the solution in which the crystallization separation carrier to which the second reaction substrate is bound is dispersed by the filter 7, and a solvent inflow means 8 Thus, a solvent capable of dissolving the crystallization separation carrier bonded to the second reaction substrate is caused to flow back into the reaction chamber 2 and the crystallization separation carrier bonded to the second reaction substrate is dissolved in the solvent. And a recovery step.

[First solution injection step / Second solution injection step]
In the first solution injection step and the second solution injection step, the solution injection means 4 binds the solution containing the crystallization separation support and the first reaction substrate, and the crystallization separation support, respectively. A solution containing a second reaction substrate that reacts with one reaction substrate is injected into the reaction chamber 2.

(Crystal separation carrier)
The carrier for crystallization separation is not particularly limited as long as it is a compound that reversibly changes from a liquid phase state to a solid phase state with a change in solution composition and / or solution temperature. / 104166 pamphlet for crystallization separation can be suitably used.

（式中、
Ｘは、炭素、酸素、硫黄、及び、窒素原子から選ばれる１以上の原子であり、
Ｒ_１〜Ｒ_３３は、同一でも異なっていてもよく、置換基を有してもよい炭素数１〜６０の炭化水素基、置換基を有してもよい炭素数１〜６０のアシル基、及び、水素、の群から選ばれるいずれかであり、
且つ、それぞれ、Ｒ_１〜Ｒ_５の少なくとも１つ、Ｒ_６〜Ｒ_１０の少なくとも１つ、Ｒ_１１〜Ｒ_１６の少なくとも１つ、Ｒ_１７〜Ｒ_２２の少なくとも１つ、Ｒ_２３〜Ｒ_２７の少なくとも１つ、及び、Ｒ_２８〜Ｒ_３３の少なくとも１つは、置換基を有してもよい炭素数８以上の炭化水素基、又は、置換基を有してもよい炭素数８以上のアシル基を示す。） Specific examples include those represented by the following chemical formulas (A) to (F).

(Where
X is one or more atoms selected from carbon, oxygen, sulfur and nitrogen atoms,
R _{1 to} R ₃₃ may be the same or different and each may have a substituent, a C 1-60 hydrocarbon group, a C 1-60 acyl group that may have a substituent, And any one selected from the group of hydrogen,
And at least one of R _{1 to} R ₅ , at least one of R _{6 to} R ₁₀ , at least one of R _{11 to} R ₁₆ , at least one of R _{17 to} R ₂₂ , and R _{23 to} R ₂₇ , respectively. At least one and at least one of R _{28 to} R ₃₃ is a hydrocarbon group having 8 or more carbon atoms which may have a substituent, or an acyl having 8 or more carbon atoms which may have a substituent. Indicates a group. )

（式中、
Ｘは、炭素、酸素、硫黄、又は、窒素原子であり、
Ｙは、炭素、酸素、硫黄、及び、窒素原子から選ばれる１以上の原子を有する反応部位であり、
Ｒ_３４は、炭素数１〜６０の炭化水素基であり、
ｎは、１〜５の整数を示す。） As another example of the carrier for crystallization separation of the present invention, one represented by the following chemical formula (G) can be given.

(Where
X is a carbon, oxygen, sulfur or nitrogen atom,
Y is a reaction site having one or more atoms selected from carbon, oxygen, sulfur, and nitrogen atoms;
R ₃₄ is a hydrocarbon group having 1 to 60 carbon atoms,
n shows the integer of 1-5. )

(solvent)
The solvent used for dissolving the carrier for crystallization separation, the first reaction substrate, and the second reaction substrate is not particularly limited as long as these compounds can be dissolved. Examples thereof include halogenated hydrocarbons, chain ethers, cyclic ethers, cyclic hydrocarbons having 4 to 40 carbon atoms, or chain hydrocarbons. More specifically, for example, dichloromethane, tetrahydrofuran and the like can be mentioned. These may be used alone, or these solvents may be used in combination with cyclohexane, methylcyclohexane, decalin and the like.

  The concentration at which the crystallization separation carrier of the present invention is dissolved in the solvent can be appropriately selected according to the solvent used, the crystallization separation carrier, the nature of the reaction substrate to be bound to the crystallization separation carrier, and the like. However, it is usually 0.01 g / ml or more and 0.1 g / ml or less.

[First reaction step / Second reaction step]
In the first reaction step and the second reaction step, the crystallization separation support and the first reaction substrate, and the first reaction substrate and the second reaction substrate reacted with the crystallization separation support, respectively. React. Such a reaction is not particularly limited, and various chemical reactions in a liquid phase can be used. For example, a method of reacting by forming an ester bond or an amide bond can be mentioned.

  In the first reaction step and the second reaction step, it is preferable to perform heating, addition of a catalyst, stirring, and the like as necessary. Thereby, it is possible to effectively promote the progress of the organic synthesis reaction. Examples of the catalyst that can be used in the organic synthesis reaction include a solid catalyst, a homogeneous catalyst, and an enzyme. However, the catalyst is not limited to these catalysts, and any catalyst can be used.

[First crystallization step / Second crystallization step]
In the first crystallization step and the second crystallization step, the crystallization separation support reacted with the first reaction substrate and the crystallization separation support bound to the second reaction substrate are combined. Crystallization is carried out while maintaining. The first crystallization step and the second crystallization step are particularly limited as long as crystallization can be performed while maintaining the state in which the compound to be crystallized is bonded to the crystallization separation support. However, for example, means for changing the solution composition and / or means for changing the solution temperature can be preferably used.

(Means for changing the solution composition)
The means for changing the solution composition is not particularly limited as long as it is a means capable of changing the composition of the solution in which the carrier for crystallization separation to which the compound to be crystallized is bonded is dissolved.

  In the present invention, preferred means for changing the solution composition include, for example, a means for further adding a solvent having a high affinity for the solvent constituting the reaction solution and used for dissolving the crystallization separation carrier. It is done. The solvent having high affinity may be the same solvent as the solvent used for dissolving the crystallization separation carrier or a different solvent. For example, when a solvent such as dichloromethane or tetrahydrofuran is used alone as a soluble solvent, or when these solvents are used in combination with cyclohexane, methylcyclohexane, decalin, or the like, acetonitrile, dimethylformamide, methanol, etc. are used as solvents having high affinity. Can be used.

  Another preferred means for changing the solution composition is, for example, a means for concentrating a solvent in which the support for crystallization separation in a state where the reaction substrate is bound is dissolved. Here, the concentration means that a part or all of the solvent is distilled off. Specific examples include a method of distilling off the solvent using the decompression means 9 and a method of volatilizing the solvent using the inert gas inflow means 10.

(Means for changing the solution temperature)
The means for changing the solution temperature is not particularly limited as long as it can change the temperature of the reaction solution. In the present invention, for example, a means for cooling the solution can be mentioned. For example, when cyclohexane is used as a soluble solvent for dissolving the carrier for crystallization separation, crystallization can be achieved by cooling to 5 ° C. In addition, when a means for cooling the solvent is used as a means for changing the solution temperature, ODS particles (silica gel having an octadecyl group bonded to the surface), a substance that becomes a crystallization nucleus, such as carrasbys, is added. Growth can be facilitated.

[First separation step / Second separation step]
In the first separation step and the second separation step, respectively, a solution in which the crystallization separation carrier reacted with the first reaction substrate is dispersed, and a crystallization separation carrier to which the second reaction substrate is bound. The dispersed solution is filtered through the filter 7. When filtering these solutions, the solution discharge means 5 mentioned above can be used. At this time, the inside of the discharge pipe 51 is preferably decompressed by the discharge pipe decompression means 6.

[First recovery process / Second recovery process]
In the first recovery step, the solvent inflow means 8 causes the solvent capable of dissolving the crystallization separation carrier that has reacted with the first reaction substrate to flow back into the reaction chamber 2 to react with the first reaction substrate. The carrier for precipitation separation is dissolved in a solvent. In the second recovery step, the solvent inflow means 8 causes the solvent capable of dissolving the crystallization separation carrier bound to the second reaction substrate to flow back into the reaction chamber 2 to bind to the second reaction substrate. The obtained carrier for crystallization separation is dissolved in a solvent. Here, as the solvent used in the first recovery step and the second recovery step, in the first solution injection step and the second solution injection step, the carrier for crystallization separation, the first reaction substrate, A solvent similar to the solvent in which the second reaction substrate is dissolved can be used.

  After performing the first recovery step, the second solution injection step described above is performed, and the second reaction step, the second crystallization step, the second separation step, and the second recovery step are performed. can do. Similarly, after carrying out the second recovery step, a reaction solution containing the third reaction substrate is injected, and the third reaction substrate is reacted with the second reaction substrate to which the crystallization separation support is bound. The reaction product can be crystallized and separated, and the reaction product can be recovered in a soluble solvent. Thus, the organic synthesis reaction method of the present invention can suitably carry out an organic synthesis reaction in multiple stages.

  Examples of the multistage organic synthesis reaction to which the organic synthesis reaction method of the present invention can be applied include a peptide synthesis reaction, a nucleotide synthesis reaction, and a sugar chain synthesis reaction.

  Next, the present invention will be described in detail with reference to examples. In addition, this invention is not limited to the Example shown below at all.

<Example 1; peptide synthesis reaction>
[Introduction reaction to a carrier for crystallization separation of amino acids]
91.3 mg (0.1 mmol) of Compound 1 ((3,4,5-trioctadecyloxyphenyl) methane-1-ol) was dissolved in 5 ml of tetrahydrofuran (THF) and charged into a reaction apparatus for organic synthesis by solution injection means. did. Specifically, after adjusting the state of each valve included in the organic synthesis reactor as shown in FIG. 3A (valve 42; open, valve 53; closed, valve 62; closed, valve 92; open) The solution was injected from the injection tube. Next, a solution prepared by dissolving 706 mg (0.2 mmol) of Fmoc-Leu-OH, 42 μl (0.3 mmol) of N, N′-diisopropylcarbodiimide (DIPCI) in 5 ml of tetrahydrofuran (THF), and further, N, N-dimethyl 12 mg (0.1 mmol) of -4-aminopyridine (DMAP) was injected into the reaction chamber from the injection tube. After adjusting the state of each valve provided in the organic synthesis reactor as shown in FIG. 3B (valve 42; closed, valve 53; closed, valve 62; closed, valve 92; closed), the stirring means Stir at room temperature for 1 hour. After confirming the completion of the reaction by thin layer chromatography, the pressure was reduced by a pressure reducing means until the volume of the reaction solution reached about 3 ml. At this time, the state of each valve included in the organic synthesis reactor was adjusted as shown in FIG. 3C (valve 42; closed, valve 53; closed, valve 62; closed, valve 92; open).

Here, after adjusting the state of each valve included in the reaction apparatus for organic synthesis as shown in FIG. 3 (d) (valve 42; open, valve 53; solvent inflow pipe → reaction chamber, valve 62; closed, valve 92 Closed), nitrogen gas was caused to flow into the reaction chamber by the inert gas inflow means, and the reaction solution was blown up to the top of the glass filter. Next, the product (compound 2) was crystallized by carrying out the stirring means while adding 30 ml of acetonitrile by the solution injection means, and stirred for 5 minutes, and then the stirring was stopped. After adjusting the state of each valve provided in the organic synthesis reactor as shown in FIG. 3 (e) (valve 42; open, valve 53; reaction chamber → reservoir, valve 62; open, valve 92; closed), The pressure reduction pump connected to the discharge pipe pressure reduction pipe was started, and the reaction solution was filtered. The above reaction was shown below.

[Deprotection reaction]
After adjusting the state of each valve included in the reaction apparatus for organic synthesis as shown in FIG. 3 (a) (valve 42; open, valve 53; closed, valve 62; closed, valve 92; open), the solution injection means Then, 10 ml of tetrahydrofuran (THF) was injected into the reaction chamber. This was stirred by a stirring means to completely dissolve the compound 2 remaining on the glass filter. Further, 30 μl of diazabicycloundecene (DBU) was injected by the solution injection means, and the state of each valve included in the organic synthesis reactor was adjusted as shown in FIG. 3B (valve 42; closed, Valve 53; closed, valve 62; closed, valve 92; closed). The mixture was stirred at room temperature for 20 minutes using a stirring means, and the completion of the reaction was confirmed by thin layer chromatography.

  After adjusting the state of each valve included in the reactor for organic synthesis as shown in FIG. 3 (a) (valve 42; open, valve 53; closed, valve 62; closed, valve 92; open), 200 μl of 1M HCl Added. Next, after adjusting the state of each valve included in the organic synthesis reactor as shown in FIG. 3 (c) (valve 42; closed, valve 53; closed, valve 62; closed, valve 92; open), pressure reducing means The pressure in the reaction chamber was reduced. At the same time, the mixture was stirred by a stirring means and concentrated until the volume of the reaction solution was about 3 ml.

Here, after adjusting the state of each valve included in the reaction apparatus for organic synthesis as shown in FIG. 3 (d) (valve 42; open, valve 53; solvent inflow pipe → reaction chamber, valve 62; closed, valve 92 Closed), nitrogen gas was caused to flow into the reaction chamber by the inert gas inflow means, and the reaction solution was blown up to the top of the glass filter. Next, the product (compound 3) was crystallized by carrying out the stirring means while adding 20 ml of acetonitrile by the solution injection means, and after stirring for 5 minutes, the stirring was stopped. After adjusting the state of each valve provided in the organic synthesis reactor as shown in FIG. 3 (e) (valve 42; open, valve 53; reaction chamber → reservoir, valve 62; open, valve 92; closed), The pressure reduction pump connected to the discharge pipe pressure reduction pipe was started, and the reaction solution was filtered. The above reaction was shown below.

[Peptide elongation reaction]
After adjusting the state of each valve included in the reaction apparatus for organic synthesis as shown in FIG. 3 (a) (valve 42; open, valve 53; closed, valve 62; closed, valve 92; open), the solution injection means Then, 10 ml of tetrahydrofuran (THF) was injected into the reaction chamber. This was stirred by a stirring means to completely dissolve the compound 3 remaining on the glass filter. 78 mg (0.2 mmol) of Fmoc-Phe-OH, 75.85 mg (0.2 mmol) of 1- [bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxide hexafluorophosphate (HBTU), 1 -A solution in which 27 mg (0.2 mmol) of hydroxybenzotriazole (HOBt) was dissolved in 5 ml of tetrahydrofuran (THF), and 68 μl (0.4 mmol) of N, N-diisopropylethylamine (DIPEA) were injected into the reaction chamber from the injection tube. did. Here, the state of each valve included in the organic synthesis reactor is adjusted as shown in FIG. 3B (valve 42; closed, valve 53; closed, valve 62; closed, valve 92; closed), and then stirred. Stir by means at room temperature for 30 minutes. The completion of the reaction was confirmed by thin layer chromatography.

Here, after adjusting the state of each valve included in the reaction apparatus for organic synthesis as shown in FIG. 3 (d) (valve 42; open, valve 53; solvent inflow pipe → reaction chamber, valve 62; closed, valve 92 Closed), nitrogen gas was caused to flow into the reaction chamber by the inert gas inflow means, and the reaction solution was blown up to the top of the glass filter. Next, the product (compound 4) was crystallized by carrying out the stirring means while adding 20 ml of acetonitrile by the solution injection means, and stirred for 5 minutes, and then the stirring was stopped. After adjusting the state of each valve provided in the organic synthesis reactor as shown in FIG. 3 (e) (valve 42; open, valve 53; reaction chamber → reservoir, valve 62; open, valve 92; closed), The pressure reduction pump connected to the discharge pipe pressure reduction pipe was started, and the reaction solution was filtered. The above reaction was shown below.

By repeating the deprotection reaction and the peptide extension reaction three times each, Fmoc-Tyr (tBu) -Gly-Gly-Phe-Leu is bound to the carrier for crystallization separation via the C-terminal carboxyl group of leucine. Compound 8 was obtained. The outline of the reaction is shown below. Table 1 shows the reagents used in the peptide elongation reaction and their input amounts. The overall yield of the reaction was 90%.

It is drawing which shows the outline of the reaction apparatus 1 for organic synthesis of this invention. 4 is a drawing showing a rotating shaft-stirring blade stirring mechanism constituting the solution injection means 4. It is drawing which showed the specific adjustment method of the valve in an Example.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Reaction apparatus for organic synthesis 2 Reaction chamber 3 Stirring means 31 Rotating shaft 32 Stirring blade 4 Solution injection means 41 Solution injection pipe 42 Valve 5 Solution discharge means 51 Discharge pipe 52 Storage tank 53 Valve 6 Discharge pipe decompression means 61 Discharge pipe decompression pipe 62 Valve 7 Filter 8 Solvent inflow means 81 Solvent inflow pipe 9 Pressure reducing means 91 Pressure reducing pipe 92 Valve 10 Deactivated gas inflow means

Claims (8)

A reaction apparatus for organic synthesis used in an organic synthesis reaction using a support for crystallization separation, which is a compound that reversibly changes from a liquid phase state to a solid phase state with a change in solution composition and / or solution temperature. ,
A reaction chamber in which an organic synthesis reaction proceeds using the carrier for crystallization separation,
Solution injection means for injecting into the reaction chamber a solution containing the crystallization separation support and a first reaction substrate that reacts therewith,
A solution discharge means for discharging the solution after performing the organic synthesis reaction using the crystallization separation support from a discharge pipe communicating from the inside of the reaction chamber to the outside;
A filter provided on the solution discharge means side of the reaction chamber;
A reaction apparatus for organic synthesis comprising: a solvent inflow means for allowing a solvent capable of dissolving the crystallization separation carrier that has reacted with the first reaction substrate to flow into the reaction chamber from the discharge pipe through the filter. . The reaction chamber is a sealable container;
The reaction apparatus for organic synthesis according to claim 1, wherein the reaction apparatus for organic synthesis includes a decompression unit that decompresses the interior of the reaction chamber.   Furthermore, the reaction apparatus for organic synthesis | combination of Claim 1 or 2 provided with the stirring means which stirs the inside of the said reaction chamber. The stirring means is
A rotating shaft connected to power outside the reaction chamber and rotating inside the reaction chamber;
The reaction apparatus for organic synthesis according to claim 3, further comprising a stirring blade provided at an end of the rotating shaft on the reaction chamber side. The solution injection means comprises:
An injection tube that forms part of the rotating shaft and communicates with the outside of the reaction chamber;
The reaction apparatus for organic synthesis according to claim 4, comprising an outlet that communicates with the reaction chamber from a side surface of the injection tube.   Furthermore, the reaction apparatus for organic synthesis | combination in any one of Claim 1 to 5 provided with the exhaust pipe decompression means for decompressing the inside of the said exhaust pipe. An organic synthesis reaction method carried out using the organic synthesis reactor according to any one of claims 1 to 6,
A first solution injection step of injecting a solution containing the crystallization separation support and the first reaction substrate into a reaction chamber by the solution injection means;
A first reaction step of reacting the carrier for crystallization separation and the first reaction substrate;
A first crystallization step of crystallizing the crystallization separation carrier reacted with the first reaction substrate;
A first separation step of filtering the solution in which the carrier for crystallization separation that has reacted with the first reaction substrate is dispersed by the filter;
A solvent capable of dissolving the crystallization separation carrier reacted with the first reaction substrate is caused to flow back into the reaction chamber by the solvent inflow means, and the crystallization separation carrier reacted with the first reaction substrate is returned to the solvent. And a first recovery step for dissolving in an organic synthesis reaction method. After the first recovery step, further
A second solution injection step of injecting a solution containing a second reaction substrate that reacts with the first reaction substrate bound to the crystallization separation support into the reaction chamber;
A second reaction step of reacting the first reaction substrate reacted with the crystallization separation carrier and the second reaction substrate;
A second crystallization step of crystallizing the support for crystallization separation to which the second reaction substrate is bound;
A second separation step of filtering the solution in which the carrier for crystallization separation to which the second reaction substrate is bound is dispersed by the filter;
A solvent capable of dissolving the crystallization separation carrier bound to the second reaction substrate is caused to flow back into the reaction chamber by the solvent inflow means, and the crystallization separation carrier bound to the second reaction substrate is returned to the solvent. The organic synthesis reaction method of Claim 7 which has a 2nd collection | recovery process made to melt | dissolve in.

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