Method for processing compounds, method for producing compounds or their reaction products, compound processing system, and replacement processing column.

Abstract

Provided is a compound treatment method comprising treating a compound by passing a solution containing the compound as a solute through a treatment column. The treatment column includes a macroporous monolith in a path through which the solution is passed. At least a portion of the solution is passed through at least a partial section of the macroporous monolith in a state where the compound or a reaction product of the compound is supersaturated. The treatment method is suitable for the treatment of a compound having a low solubility.

Description

Technical Field

[0001] The present invention relates to a method for treating a compound, a method for producing a compound or its reactant, a compound treatment system, and a treatment column for replacement.

Background Art

[0002] Separation and purification of compounds by liquid chromatography (hereinafter referred to as LC) are essential techniques in various fields including chemistry and pharmacy. According to LC, higher substance selectivity can be achieved compared to other separation and purification techniques such as recrystallization and nanofiltration. Conventionally, columns filled with particles such as silica gel as a separation medium have been widely used as LC treatment columns. As a treatment column different from the particle-packed column, Patent Document 1 discloses a column provided with a macroporous monolith having through-holes with a pore diameter of 500 nm or more and fine pores with a pore diameter of 5 to 100 nm formed on the inner wall surface of the through-holes, and having a three-dimensional network-like co-continuous structure between the through-holes and the skeleton.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] While LC (Luminography) offers high substance selectivity compared to other separation and purification techniques, it requires a large amount of solvent. Furthermore, compounds used as raw materials for organic electroluminescent (OLED) materials and pharmaceuticals often have planar structures in which aromatic rings are extended by π-conjugated systems. Highly planar π-conjugated aromatic compounds tend to form association states via so-called π-π stacking, resulting in low solubility in solvents. Treating compounds with low solubility using LC requires even larger amounts of solvent. However, to meet environmental protection demands, reducing the amount of solvent used in compound processing is desirable.

[0005] The present invention aims to provide a method and system for treating compounds that are suitable for treating compounds with low solubility. [Means for solving the problem]

[0006] The inventors of the present invention have discovered that a solution inside the macropores of a macroporous monolith can be in a stable state where solute precipitation is suppressed, even while being in a supersaturated state, and have completed the present invention.

[0007] The present invention The process involves treating the compound by passing a solution containing the compound as a solute through a processing column. The processing column is equipped with a macroporous monolith in the path through which the solution passes. The present invention provides a method for treating a compound, wherein at least a portion of the solution passes through at least a portion of the macroporous monolith in a supersaturated state with respect to the compound or its reactants.

[0008] Furthermore, the present invention, The present invention provides a method for producing a compound or a reactant thereof, which includes treating the compound by the processing method described above to obtain the treated compound or a reactant thereof.

[0009] Furthermore, the present invention, A processing system for processing compounds, A processing unit comprising a processing column through which a solution containing the aforementioned compound as a solute is passed, The system comprises a supply unit that supplies the solution to the processing unit, The processing column is equipped with a macroporous monolith in the path through which the solution passes. The present invention provides a compound processing system in which at least a portion of the solution passes through at least a portion of the macroporous monolith in a supersaturated state with respect to the compound or its reactants.

[0010] Furthermore, the present invention, A replacement processing column, The invention comprises a macroporous monolith and a container for housing the macroporous monolith. The processing column is equipped with the macroporous monolith in the path through which the solution containing the compound as a solute passes. The present invention provides a processing column for use in at least one selected from the group consisting of a method for processing the compound of the present invention, a method for producing the compound of the present invention or its reaction product, and a processing system for the compound of the present invention. [Effects of the Invention]

[0011] According to the present invention, a method and system for treating compounds that are suitable for treating compounds with low solubility can be provided. [Brief explanation of the drawing]

[0012] [Figure 1A] This is a schematic cross-sectional view showing an example of a processing column that can be used in the compound processing method and processing system of the present invention. [Figure 1B] This is a schematic cross-sectional view showing an example of a processing column that can be used in the compound processing method and processing system of the present invention. [Figure 2] This is a schematic diagram showing an example of a processing system for the compound of the present invention. [Figure 3] This is a schematic diagram showing an example of a processing system for the compound of the present invention. [Figure 4] This is a schematic diagram showing an example of a processing system for the compound of the present invention. [Figure 5] It is a schematic diagram showing an example of a treatment system for the compound of the present invention. [Figure 6] It is a schematic diagram showing an example of a treatment system for the compound of the present invention. [Figure 7] It is an observation image by a scanning electron microscope of the macroporous monolith produced in the example.

Mode for Carrying Out the Invention

[0013] The method for treating a compound according to the first aspect of the present invention includes treating the compound by passing a solution containing the compound as a solute through a treatment column, wherein the treatment column includes a macroporous monolith in a path through which the solution passes, at least a part of the solution passes through at least a part of the macroporous monolith in a supersaturated state with respect to the compound or a reactant of the compound.

[0014] In the second aspect of the present invention, for example, in the treatment method according to the first aspect, at least a part of the solution is recovered from the treatment column as a treatment solution in a supersaturated state with respect to the compound or the reactant.

[0015] In the third aspect of the present invention, for example, in the treatment method according to the first or second aspect, the solution is discharged from the treatment column without substantially precipitating the compound or the reactant from the solution inside the macroporous monolith.

[0016] In the fourth aspect of the present invention, for example, the treatment method according to any one of the first to third aspects further includes obtaining the solution in a supersaturated state with respect to the compound by solvent substitution of a stock solution containing the compound as a solute and being in a saturated or unsaturated state with respect to the compound, and supplying the obtained solution in a supersaturated state to the treatment column.

[0017] In a fifth embodiment of the present invention, for example, in the processing method according to the fourth embodiment, the raw solution containing a halogenated organic solvent is replaced with a solvent to obtain a solution substantially free of halogenated organic solvents.

[0018] In a sixth embodiment of the present invention, for example, in a processing method according to any one of the first to fifth embodiments, the solubility of the compound in the solvent of the solution at 25°C is 100 mg / mL or less.

[0019] In a seventh embodiment of the present invention, for example, in a processing method according to any one of the first to sixth embodiments, the solution having a pressure of atmospheric pressure ± 0.3 atmospheres is passed through the processing column.

[0020] In the eighth aspect of the present invention, for example, in the processing method according to any one of the first to seventh aspects, the compound is a liquid crystal compound or a π-conjugated aromatic compound.

[0021] In the ninth aspect of the present invention, for example, in the processing method according to any one of the first to eighth aspects, the solubility of the compound in toluene or ethyl acetate at 25°C is 1 / 3 or less of the solubility in halogen-substituted methane at 25°C.

[0022] In a tenth embodiment of the present invention, for example, in a processing method according to any one embodiment of the first to ninth embodiments, the compound is subjected to at least one processing selected from the group consisting of purification, reaction, and concentration.

[0023] A method for producing a compound or a reaction product thereof according to the 11th aspect of the present invention is: The method includes treating the compound by a compound treatment method according to any one of the first to tenth embodiments, thereby obtaining the treated compound or a reaction product of the compound.

[0024] In a twelfth aspect of the present invention, for example, the manufacturing method according to the eleventh aspect further includes precipitating the treated compound or the reactant without solvent substitution.

[0025] A compound processing system according to the 13th aspect of the present invention is A processing system for processing compounds, A processing unit comprising a processing column through which a solution containing the aforementioned compound as a solute is passed, The system comprises a supply unit that supplies the solution to the processing unit, The processing column is equipped with a macroporous monolith in the path through which the solution passes. At least a portion of the solution passes through at least a portion of the macroporous monolith in a supersaturated state with respect to the compound or its reactants.

[0026] In a fourteenth embodiment of the present invention, for example, in the processing system according to the thirteenth embodiment, the processing column is supplied with the supersaturated solution.

[0027] In a 15th aspect of the present invention, for example, in a processing system according to the 14th aspect, the supply unit includes a solvent replacement unit that solvent-replaces a raw solution containing the compound as a solute, which is saturated or unsaturated with respect to the compound, to obtain a supersaturated solution.

[0028] In a sixteenth aspect of the present invention, for example, in a processing system according to the fifteenth aspect, the solvent substitution unit obtains a solution substantially free of halogenated organic solvents from the raw solution containing halogenated organic solvents.

[0029] In a 17th aspect of the present invention, for example, in a processing system according to any one of the 13th to 16th aspects, the processing column comprises a container for housing the macroporous monolith, the container being made of a resin layer or glass layer with a thickness of 5 mm or less and in contact with the macroporous monolith.

[0030] In the eighteenth embodiment of the present invention, for example, a processing system according to any one of the thirteenth to seventeenth embodiments further comprises a solid-liquid separation unit that obtains the compound processed by the processing column as a solid from the processing solution discharged from the processing unit.

[0031] In a 19th embodiment of the present invention, for example, in a processing system according to the 18th embodiment, the solid-liquid separation unit precipitates the compound processed by the processing column from the processing solution without solvent replacement.

[0032] The processing column according to the 20th aspect of the present invention is A replacement processing column, The invention comprises a macroporous monolith and a container for housing the macroporous monolith. The processing column is equipped with the macroporous monolith in the path through which the solution containing the compound as a solute passes. A processing column used in at least one selected from the group consisting of a method for processing a compound according to any one of the first to tenth embodiments, a method for producing a compound or its reaction product according to the eleventh or twelfth embodiment, and a processing system for a compound according to any one of the thirteenth to nineteenth embodiments.

[0033] The present invention will be described in detail below, but the present invention is not limited to the following embodiments and can be modified and implemented as appropriate without departing from the spirit of the invention.

[0034] [Method for processing compounds] The compound processing method of this embodiment includes processing compound A by passing a solution (hereinafter referred to as "solution B") containing compound A as a solute through a processing column. The processing column is equipped with a macroporous monolith in the path through which solution B passes. At least a portion of solution B passes through at least a portion of the macroporous monolith in a supersaturated state with respect to compound A or its reactants. Passing through in a supersaturated state makes it possible to increase the processing rate of compound A per column weight (column load). Passing through in a supersaturated state also makes it possible to reduce the size of the processing column required to process the same weight of compound A. Depending on the type of processing, reactants of compound A may be generated, for example, inside the macroporous monolith, as they pass through the processing column. In this specification, "supersaturated state" means a state in which, for a solution containing a solute and a solvent that dissolves it at a certain temperature, an amount of solute exceeding the solubility of the solute in the solvent at that temperature is dissolved in the solvent. Furthermore, if the solvent is a mixed solvent, supersaturation is determined by the solubility in that mixed solvent.

[0035] In this specification, a macroporous monolith refers to a monolithic body having a three-dimensional network-like co-continuous structure of macropores and a framework. The uniformity of the pore size of macropores in a macroporous monolith is usually far higher than the uniformity of the void diameter between particles in a processing column packed with particles as a separation medium. Furthermore, the framework of a macroporous monolith generally has excellent strength due to its three-dimensional network structure. Therefore, fluctuations in the pore size of macropores during compound processing are suppressed. It is presumed that the high uniformity of the pore size of macropores in a macroporous monolith contributes to the stability of a supersaturated solution within the macropores. In addition, the capillary effect may be involved in the stability of the supersaturated solution. In the capillary effect, the growth of microcrystals of a compound attempting to precipitate is suppressed by spatial limitations. In this specification, "macropore" refers to a pore with a diameter of 50 nm or more, in accordance with the IUPAC definition. Furthermore, the term "mesopore" as described later refers to a pore intermediate between macropores and micropores (pores with a diameter of less than 2 nm), i.e., a pore with a diameter of 2 nm or more and less than 50 nm. The average pore diameter and pore diameter uniformity of each pore can be evaluated by general pore distribution measurements selected based on the expected average pore diameter, such as the mercury intrusion method for macropores and the nitrogen gas adsorption method for mesopores. More specifically, pore diameter uniformity can be evaluated by normal distribution analysis of the pore peaks shown in the pore distribution profile. The average pore diameter can be evaluated as the median diameter (d50).

[0036] The average pore size of the macropores is expressed by the median diameter (d50) determined by pore distribution measurement using the mercury intrusion method, and is, for example, 0.1 to 100 μm, but may also be 1 to 20 μm, or even 2 to 10 μm.

[0037] The uniformity of pore diameter in a macroporous monolith is expressed by the ratio of the full width at half maximum of the pore diameter distribution to the average pore diameter, determined by pore distribution measurement using the mercury intrusion method. This ratio is, for example, 10-50%, or 20-40%. For example, if the average pore diameter is 5 μm, the pore distribution graph may show macropores distributed in the range of 2.5-7.5 μm, 3-7 μm, 4-6 μm, or even 4.5-5.5 μm.

[0038] A macroporous monolith may have mesopores on the inner wall surface of the macropores. A macroporous monolith with mesopores typically has a hierarchical porous structure composed of macropores and mesopores. This hierarchical porous structure can contribute to improving the processing performance of the processing column. The average pore size of the mesopores is expressed by the median diameter (d50) determined by pore distribution measurement using nitrogen gas adsorption, and is, for example, 2 to 10 nm.

[0039] The specific surface area of ​​a macroporous monolith is, for example, 100 m². 2 / g or more, 200m 2 / g or more, 300m 2 / g or more, 400m 2 / g or more, 500m 2 / g or more, 600m 2 / g or more, 700m 2 / g or more, and even 800m 2 It may be more than / g.

[0040] Macroporous monoliths can be manufactured, for example, by a sol-gel reaction combined with a phase separation process. Furthermore, this method also allows for the production of macroporous monoliths having a hierarchical porous structure by selecting the manufacturing conditions. The above method is disclosed, for example, in Japanese Patent Publication No. 2014-148456, International Publication No. 1999 / 038006, Japanese Patent No. 4874976, Japanese Patent No. 5288804, U.S. Patent No. 7595350, Japanese Patent No. 6021738, and U.S. Patent No. 7892516. Macroporous monoliths disclosed in each of these publications may be used.

[0041] A macroporous monolith may be composed of inorganic materials, organic materials, or hybrid materials of inorganic and organic materials. Examples of inorganic materials include silica and metal oxides. Examples of metal oxides include oxides of at least one metal selected from the group consisting of aluminum, zirconium, titanium, hafnium, tin, gallium, germanium, and lead. Examples of organic materials include cellulose, epoxy resins, acrylic resins, and styrene-divinylbenzene copolymers. An example of a hybrid material is a composite of silicone resin and a silicon compound. The silicone resin may have a methylsiloxane skeleton. Examples of silicon compounds include SiN and SiC. The silicone resin skeleton may have functional groups on its surface. Examples of functional groups include alkyl groups such as ethyl groups, hydroxyl groups, ether groups, keto groups, epoxy groups, carboxyl groups, acyl groups, amino groups, amide groups, halo groups, and aromatic groups. However, the materials constituting the macroporous monolith are not limited to the above examples. Depending on their composition, macroporous monoliths composed of silica are suitable for regeneration using acid.

[0042] A macroporous monolith may have hydrophobic groups on the surface of its skeleton. Examples of hydrophobic groups include alkyl groups and aromatic groups. The alkyl group may be a linear alkyl group. The number of carbon atoms in the alkyl group may be between 1 and 35, between 4 and 25, or even between 8 and 20. A processing column comprising a macroporous monolith having hydrophobic groups on the surface of its skeleton is suitable for use as a reversed-phase column.

[0043] An example of a processing column is shown in Figure 1A. Processing column 1(1A) in Figure 1A comprises a container 3 and a macroporous monolith 2 housed in the container 3. The macroporous monolith 2 and the container 3 are in contact. However, other materials and / or layers may be placed between the macroporous monolith 2 and the container 3. The container 3 in Figure 1A can function as a protective covering for the macroporous monolith 2 and can also function as the outer casing of processing column 1A.

[0044] The processing column 1A is equipped with a macroporous monolith in the path through which solution B passes. The container 3 has a shape in which two cylinders 4A and 4B of different diameters are connected by a tapered portion 5. The diameter of cylinder 4A is larger than the diameter of cylinder 4B. The thickness of the container 3 may be substantially the same through cylinders 4A, 4B and the tapered portion 5. The purpose of the container 3 having substantially the same thickness is to allow for molding errors in the manufacturing process of the container 3, for example, the difference between the maximum thickness and the minimum thickness may be 0.5 mm or less. The upper end 6A and lower end 6B of the container 3 are open. The opening diameter of the upper end 6A is larger than the opening diameter of the lower end 6B. The macroporous monolith 2 is cylindrical and is positioned inside cylinder 4A so as not to create a gap between it and the inner circumferential surface 7 of cylinder 4A. A space 9 is provided above the macroporous monolith 2 inside cylinder 4A. Solution B is supplied to the processing column 1A from the upper end 6A, passes through the macroporous monolith 2, and is discharged from the lower end 6B. The supplied solution B passes sequentially through space 9, the macroporous monolith 2, the inside of the tapered section 5, and the inside of the cylinder 4B, forming a path 8 (see the arrow in Figure 1A). Space 9 can be provided with the function of temporarily storing solution B as it passes through the macroporous monolith 2. The volume of space 9 may be larger than the volume of the portion of the processing column 1A that houses the macroporous monolith 2.

[0045] The processing column 1A in Figure 1A does not have a filter and particle layer located upstream of the path 8 relative to the macroporous monolith 2. In other words, the solution B supplied to the processing column 1A can flow directly into the macroporous monolith 2 without passing through other components. This embodiment is suitable for suppressing the precipitation of compound A inside the processing column 1A when supplying a solution B that is supersaturated with respect to compound A. Both the filter and the particle layer may have surfaces that act as nuclei for the precipitation of compound A. Furthermore, as shown in Figure 1A, the processing column 1A does not necessarily have a filter and particle layer located downstream of the path 8 relative to the macroporous monolith 2.

[0046] The cross-sectional shape of the path 8 in processing column 1A is circular. The shape of the cross-section is not limited to a circle, and may be a polygon including a square, pentagon, and hexagon, or an ellipse. In this specification, the term "cross-section" refers to a cross-section perpendicular to the flow direction of solution B.

[0047] Processing column 1A is suitable for use in an open column system where solution B is passed through at atmospheric pressure or near atmospheric pressure. Piping may be connected to the lower end 6B by known fastening means such as ferrules or Luer locks. Processing column 1A may also be used in a flash column system where solution B is passed through at a moderate pressure relative to atmospheric pressure. In other words, processing column 1A may be an open column or a flash column. In this specification, an open column system means a system in which solution B having a relative pressure of -0.3 atmospheres or more and 0.3 atmospheres or less (atmospheric pressure ± 0.3 atmospheres) is passed through processing column 1. In this specification, a flash column system means a system in which solution B having a relative pressure of more than 0.3 atmospheres and 20 atmospheres or less, preferably 15 atmospheres or less, more preferably 10 atmospheres or less, even more preferably 5 atmospheres or less, and particularly preferably 3 atmospheres or less, is passed through processing column 1. In order to pass solution B with a positive relative pressure, for example, the solution B supplied to processing column 1 can be pressurized. To pass solution B, which has a negative relative pressure, through the column, for example, one can aspirate solution B being discharged from processing column 1.

[0048] Another example of a processing column is shown in Figure 1B. Processing column 1(1B) in Figure 1B is the same as processing column 1A in Figure 1A, except that the configuration of the container 3 is different. The container 3 of processing column 1B has a shape in which a cylinder 4B, a tapered section 5, a cylinder 4A, a tapered section 5, and a cylinder 4B are connected in order from the upper end 6A to the lower end 6B. Processing column 1B is suitable for use in a pressurized system through which a pressurized solution B is passed. Piping may be connected to the upper end 6A by known fastening means such as a ferrule nut or a Luer lock.

[0049] The thickness of container 3 may be, for example, 0.05 to 10 mm, 0.1 to 8 mm, or even 0.2 to 5 mm. The thickness of container 3 may also be 4 mm or less, 3 mm or less, 2 mm or less, 1.5 mm or less, 1.2 mm or less, 1 mm or less, 800 μm or less, 600 μm or less, 500 μm or less, 400 μm or less, 300 μm or less, 200 μm or less, or even 150 μm or less. The thickness of container 3 can be specified as the thickness in the portion where the macroporous monolith 2 is contained.

[0050] Examples of materials for container 3 include resin, glass, metal, and composite materials thereof. Container 3 may be composed of two or more materials. Various thermoplastic resins, thermosetting resins, elastomers, etc., can be used as resins. Examples of thermoplastic resins include polyolefin resins such as polyethylene and polypropylene. A resin with chemical resistance may be used, considering resistance to the solvent contained in solution B. Examples of chemically resistant resins include fluororesins such as polytetrafluoroethylene (PTFE) and perfluoroalkoxyalkanes (PFA), and polyetheretherketone (PEEK). Examples of glass include soda glass, borosilicate glass, and quartz glass. Container 3 may include transparent or translucent portions, or it may be entirely transparent or translucent. A container 3 including transparent or translucent portions, depending on its configuration, makes it easier to confirm the state of solution B inside the processing column 1, for example, whether or not compound A precipitates. In processing columns 1 used in open column or flash column systems, since the pressure of the supplied solution B is low, a resin layer or glass layer with a thickness of 5 mm or less may be used for container 3. The resin constituting the resin layer may be a polyolefin resin or a fluororesin. The glass layer may be a glass tube. The resin layer may be a resin tube, and the resin tube may be heat-shrinkable. With a heat-shrinkable resin tube (heat-shrinkable tube), it is possible to easily manufacture the processing column 1 without creating a gap between the macroporous monolith 2 and the container 3 by heat-shrinking the tube after placing the macroporous monolith 2 inside the tube. The thickness of the resin layer or glass layer may be 3.5 mm or less, 3 mm or less, 2.5 mm or less, 2 mm or less, 1.5 mm or less, 1.2 mm or less, 1 mm or less, 800 μm or less, 600 μm or less, 500 μm or less, 400 μm or less, 300 μm or less, 200 μm or less, and even 150 μm or less. The lower limit of the thickness is, for example, 50 μm or more, and may be 100 μm or more. For the processing column 1 used in the flash column method, the lower limit of the thickness is preferably 100 μm or more.

[0051] Container 3 may be a single layer or may have a multilayer structure containing two or more layers. For processing columns 1 used in open column or flash column systems, a single layer of resin with a thickness of 5 mm or less may be used for container 3.

[0052] Container 3 may contain a macroporous monolith 2 covered with a coating layer. Examples of the coating layer are the same as those of the resin layer described above. The strength of the container 3 containing the macroporous monolith 2 covered with the coating layer may be higher than that of the coating layer. Examples of the container 3 include PEEK containers, fluororesin containers, and metal containers.

[0053] Container 3 may constitute the outer casing of processing column 1.

[0054] The length of the processing column 1 is, for example, 20 to 1000 mm, or it may be 50 to 500 mm. The length of the processing column 1 can be determined according to the length of the macroporous monolith 2, the length of the container 3, the length of the tapered section 5, etc. The length of the macroporous monolith 2 is, for example, 5 to 500 mm, or it may be 10 to 250 mm. The length of the tapered section 5 is convenient to use if it is equal to or less than the length of the macroporous monolith 2, but it is not limited to this. The length of the container 3 is, for example, 10 to 500 mm, or it may be 20 to 250 mm.

[0055] The inner diameter of the portion of the processing column 1 containing the macroporous monolith 2 may be 10 mm or more, and may be 15 mm or more, 20 mm or more, 25 mm or more, 50 mm or more, or 100 mm or more. The upper limit of the inner diameter is, for example, 500 mm or less, and may be 400 mm or less, 300 mm or less, or even 250 mm or less. If the cross-sectional shape of the portion of the processing column 1 containing the macroporous monolith 2 is not circular, the length of the longest imaginary line segment connecting two points set on the circumference of the cross-section may be determined as the inner diameter.

[0056] The configuration of the processing column 1 is not limited to the above example, as long as the path 8 through which solution B passes is equipped with a macroporous monolith 2.

[0057] In the processing method of this embodiment, at least a portion of solution B passes through at least a portion of the macroporous monolith 2 in a supersaturated state with respect to compound A or its reactants. At least a portion of solution B may pass through all of the macroporous monolith 2 in a supersaturated state with respect to compound A or its reactants. Alternatively, all of solution B passed through the processing column 1 may pass through at least a portion or all of the macroporous monolith 2 in a supersaturated state with respect to compound A or its reactants.

[0058] In the processing method of this embodiment, at least a portion of solution B may be recovered from the processing column 1 as a processing solution in a supersaturated state with respect to compound A or a reactant of compound A.

[0059] The supersaturated treatment solution recovered from treatment column 1 typically loses its supersaturated state due to the loss of stability provided by the macropores of the macroporous monolith 2, and the contained compounds or reactants precipitate. However, precipitation does not necessarily occur immediately after discharge from treatment column 1. The precipitated compounds or reactants can be recovered by solid-liquid separation methods such as filtration. Furthermore, precipitation from a supersaturated state is similar to a recrystallization process, except that solvent replacement is not performed, and can contribute to the purification of compound A. The treatment method of this embodiment may further include precipitating compound A or its reactants treated by treatment column 1 from the treatment solution discharged from treatment column 1 without solvent replacement.

[0060] In the processing method of this embodiment, solution B may be discharged from the processing column 1 without substantially precipitating compound A or its reactants from solution B inside the macroporous monolith 2. Substantially preventing precipitation means limiting the amount of compound A or its reactants that precipitates to, for example, 1% by weight or less, preferably 0.5% by weight or less, and more preferably 0.1% by weight or less, of the total amount of compound A supplied to the processing column 1.

[0061] The processing column 1 may be supplied with solution B in a supersaturated state with respect to compound A, or with solution B in a saturated or unsaturated state.

[0062] In the processing method of this embodiment, a solution B in a saturated or unsaturated state with respect to compound A is supplied to the processing column 1, and at least a portion of solution B may be recovered from the processing column 1 as a supersaturated processing solution with respect to compound A or its reactants. This embodiment can be carried out, for example, by a concentration treatment of compound A or its reactants using the processing column 1. For concentration, a reversed-phase column may be selected as the processing column 1, and a solution B in which part or all of the solvent is hydrophilic may be supplied to the processing column 1. In this method, concentration due to hydrophobic interaction between compound A or its reactants and the reversed-phase column can be utilized. Depending on the concentration of the supplied solution B and the concentration status, a developing solvent, such as a hydrophilic solvent, may be supplied to the processing column 1 after supplying solution B. The solvent of solution B and the developing solvent may be the same or different.

[0063] An example of a reversed-phase column is a treatment column 1 equipped with a macroporous monolith 2 having hydrophobic groups on the surface of its skeleton. In the case where compound A is DACT-II as described later, the hydrophobic group may be a linear alkyl group having 8 to 18 carbon atoms, or an octadecyl group (18 carbon atoms).

[0064] In this specification, hydrophilic means that the solubility in 100g of water at 25°C is 1g or more, preferably 10g or more, and more preferably 25g or more. Examples of hydrophilic solvents are water, hydrophilic organic solvents, and mixed solvents thereof. Examples of hydrophilic organic solvents are alcohols such as methanol, ethanol, n-propanol, and 2-propanol, tetrahydrofuran (THF), acetone, and acetonitrile. However, hydrophilic solvents and hydrophilic organic solvents are not limited to the above examples. In an example where compound A is DACT-II, a THF / water mixed solution of DACT-II is supplied to processing column 1 as solution B, and then an acetone / methanol mixed solution is supplied to processing column 1 as the developing solvent. For the THF / water mixed solution of DACT-II, the concentration of DACT-II is, for example, 1 mg / mL, and the mixing ratio of THF and water is, for example, 1:1 (volume ratio). For the acetone / methanol mixed solution, the mixing ratio of acetone and methanol is, for example, 1:1 (volume ratio). The concentration and mixing ratio are not limited to the above examples.

[0065] The supersaturated solution B may be obtained, for example, by solvent substitution of a stock solution containing compound A as a solute, which is saturated or unsaturated with respect to compound A. In other words, the processing method of this embodiment may further include obtaining a supersaturated solution B with respect to compound A by solvent substitution of a stock solution containing compound A as a solute, which is saturated or unsaturated with respect to compound A. The obtained solution B can be supplied to processing column 1. For solvent substitution, methods such as adding and mixing a solvent different from the solvent of the stock solution, heating, cooling, reduced pressure, pressurization, distillation, and dialysis can be selected and applied. Multiple methods may be combined.

[0066] When replacing the solvent from the original solution, the solvent may be one-third or less of the solvent in which compound A's solubility at 25°C is 1 / 4 or less, one-fifth or less, or even one-seventh or less.

[0067] A solution B substantially free of halogenated organic solvents may be obtained by solvent substitution of the raw solution containing a halogenated organic solvent. Solution B substantially free of halogenated organic solvents typically contains a non-halogenated organic solvent as the solvent. "Substantially free of halogenated organic solvents" means that the content of halogenated organic solvents in the solution is, for example, 100 ppm or less, preferably 10 ppm or less, more preferably 1 ppm or less, and particularly preferably 0.1 ppm or less. ppm is based on weight.

[0068] Compound A, a π-conjugated aromatic compound, generally tends to have higher solubility in halogenated organic solvents than in non-halogenated organic solvents. This tendency is particularly strong when compound A has hydrophilic groups such as hydroxyl groups, carboxyl groups, amino groups, and amide groups. For this reason, it has been common technical knowledge that conventional LC treatments for π-conjugated aromatic compounds must use halogenated organic solvents that can ensure a certain level of solubility. Furthermore, depending on the type of LC treatment, it is necessary to supply the developing solvent after supplying the solution containing the compound to be treated to the treatment column. To prevent the precipitation of the compound in the treatment column, it has been common technical knowledge that the developing solvent must also be a halogenated organic solvent. However, halogenated organic solvents are considered solvents whose use should be reduced due to their harmfulness and environmental impact, and the demand for reduction is only increasing. In the treatment method of this embodiment, it is possible to stably flow a supersaturated solution through the treatment column 1. Therefore, the processing method of this embodiment is also suitable for processing in which a non-halogenated organic solvent is used as the solvent for solution B, and, if necessary, as the developing solvent. In other words, it is also suitable for meeting the requirement of dehalogenation.

[0069] Halogenated organic solvents are solvents that contain halogen atoms in their molecules. Examples of halogenated organic solvents are halogen-substituted methane, halogen-substituted ethane, and halogenated benzene. Examples of halogen-substituted methane are dichloromethane, chloroform, and carbon tetrachloride. An example of halogen-substituted ethane is chloroethane. An example of halogenated benzene is chlorobenzene. Halogenated organic solvents may also be congeners or derivatives of the above examples. However, halogenated organic solvents are not limited to the above examples. The stock solution may contain two or more halogenated organic solvents.

[0070] Non-halogenated organic solvents are solvents that do not contain halogen atoms in their molecules. Examples of non-halogenated organic solvents include toluene, benzene, xylene, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, dimethyl sulfoxide, N,N'-dimethylformamide, tetrahydrofuran, 1,4-dioxane, hexane, cyclohexane, heptane, pentane, methanol, ethanol, 1-propanol, 2-propanol, acetonitrile, and benzonitrile. However, non-halogenated organic solvents are not limited to the above examples. Solution B may contain two or more non-halogenated organic solvents, regardless of whether solvent substitution is performed or not.

[0071] Solvent replacement may be carried out at room temperature (25°C).

[0072] Solvent substitution can be carried out in one step or in two or more steps. Depending on the type of compound A, multi-step solvent substitution may be more suitable.

[0073] Porous membrane tubes may be used for solvent substitution. In one example of solvent substitution using a porous membrane tube, the solvent is substituted with a solvent having a higher boiling point than the solvent before substitution. The substitution is carried out, for example, as follows: A solution of compound A containing a halogenated organic solvent, such as a dichloromethane solution, is supplied to the porous membrane tube. The supplied solution is usually saturated or subsaturated with respect to compound A. Along with this, a non-halogenated organic solvent having a higher boiling point than the halogenated organic solvent, such as toluene or a mixed solvent of toluene and hexane, is supplied to the porous membrane tube and mixed in the tube. By creating a heated and reduced-pressure atmosphere in which the porous membrane tube supplying the compound A solution and the non-halogenated organic solvent is placed, the halogenated organic solvent with a relatively low boiling point is preferentially removed by permeating through the side walls of the porous tube, and a solution B of compound A containing the non-halogenated organic solvent as the main solvent is obtained. Due to the difference in solubility of compound A in halogenated and non-halogenated organic solvents, the obtained solution B may be supersaturated with respect to compound A. By controlling the temperature and pressure of the environment in which the porous membrane tube is placed, it is possible to obtain a solution B that is supersaturated with respect to compound A after being discharged from the porous membrane tube, while avoiding supersaturation of the solution inside the porous membrane tube. The obtained solution B can be supplied to the processing column 1. The porous membrane tube may be made of polytetrafluoroethylene. However, the porous membrane tube is not limited to the above example.

[0074] For compound A, the solubility of solution B in solvent at 25°C may be 100 mg / mL or less, 50 mg / mL or less, 33 mg / mL or less, 20 mg / mL or less, 10 mg / mL or less, 5 mg / mL or less, or even 3 mg / mL or less. The lower limit of solubility is, for example, 0.1 mg / mL or more, and may be 1 mg / mL or more.

[0075] Compound A may be an organic compound, and may have at least one selected from the group consisting of an aromatic ring, a sugar chain, and an amide bond. Compound A may also be a liquid crystal compound or a π-conjugated aromatic compound. Liquid crystal compounds and π-conjugated aromatic compounds tend to form π-π stacking structures in the solid phase, and therefore often have low solubility. The processing method of this embodiment is particularly advantageous when processing compound A, which has low solubility in solvents.

[0076] Examples of compound A include organic EL materials and pharmaceutical raw materials. In particular, organic EL materials are often π-conjugated aromatic compounds. Examples of organic EL materials are disclosed in Japanese Patent Publication No. 2020-205318, Japanese Patent No. 7184785, Japanese Patent No. 4490896, Japanese Patent No. 6886972, and U.S. Patent No. 11527728. Specific examples of organic EL materials include 9-[4-(4,6-diphenyl-1,3,5-triazine-2-yl)phenyl]-N,N,N',N'-tetraphenyl-9H-carbazole-3,6-diamine (DACT-II), as well as anthracene, carbazole, benzoxiaazole, and their derivatives. Compound A may also be a precursor of DACT-II. The structures of DACT-II and its precursor are shown below. [ka]

[0077] The solubility of compound A in non-halogenated organic solvents at 25°C may be 1 / 3 or less, 1 / 4 or less, 1 / 5 or less, or even 1 / 7 or less, of its solubility in halogenated organic solvents at 25°C. Examples of non-halogenated and halogenated organic solvents are as described above. Non-halogenated organic solvents that satisfy the above ratio of compound A may be toluene, ethyl acetate, acetone, acetonitrile, methanol, diethyl ether, tetrahydrofuran, or water, or toluene or ethyl acetate. Halogenated organic solvents that satisfy the above ratio of compound A may be halogen-substituted methane, dichloromethane or chloroform, or dichloromethane. As an example, the solubility of DACT-II and its precursors is shown in Table 1 below.

[0078] [Table 1]

[0079] Compound A is not limited to the examples given above.

[0080] In the processing method of this embodiment, solution B having a pressure of atmospheric pressure ± 0.3 atmospheres may be passed through the processing column 1. In other words, the processing method of this embodiment may be carried out using an open column method.

[0081] In the processing method of this embodiment, a solution B having a relative pressure of more than 0.3 atmospheres and 20 atmospheres or less, preferably 15 atmospheres or less, more preferably 10 atmospheres or less, even more preferably 5 atmospheres or less, and particularly preferably 3 atmospheres or less, based on atmospheric pressure, may be passed through the processing column 1. In other words, the processing method of this embodiment may be carried out using a flash column method.

[0082] In the processing method of this embodiment, compound A may be subjected to at least one treatment selected from the group consisting of purification, reaction, and concentration. For each treatment, conditions such as the type of macroporous monolith, the solvent of solution B, and the temperature can be selected. For example, a reduction reaction may be carried out on compound A by using a macroporous monolith having Si-H groups on the surface of its skeleton, as disclosed in Japanese Patent Application Publication No. 2014-148456.

[0083] The processing method of this embodiment may include steps other than those described above, as long as it allows for the processing of compound A.

[0084] The compound processing method of this embodiment can be carried out, for example, by the compound processing system of this embodiment described later. However, the implementable processing apparatus and processing system are not limited to the examples described later.

[0085] [Method for producing compounds or their reaction products] The method for producing the compound or its reaction product according to this embodiment includes treating compound A by the processing method of this embodiment described above to obtain the treated compound A or a reaction product of compound A. The specific details of the processing are as described in the description of the processing method of this embodiment.

[0086] The manufacturing method of this embodiment may further include precipitating the treated compound A or its reaction product without solvent substitution.

[0087] The manufacturing method of this embodiment may, for example, yield organic EL materials or pharmaceutical raw materials. Examples of organic EL materials include DACT-II and its precursors. However, the compounds and reactants that can be produced by the manufacturing method of this embodiment are not limited to the above examples.

[0088] The manufacturing method of this embodiment can be carried out, for example, by a compound processing system of this embodiment, which will be described later. However, the applicable processing apparatus and processing system are not limited to the examples described later.

[0089] [Compound Processing System] A compound processing system capable of carrying out the above-described processing method and / or manufacturing method can be constructed by comprising a processing unit equipped with a processing column 1 and a supply unit that supplies solution B to the processing unit.

[0090] An example of a compound processing system of this embodiment is shown in Figure 2. The processing system 11 (11A) in Figure 2 comprises a processing unit 12 equipped with a processing column 1 through which solution B passes, and a supply unit 13 that supplies solution B to the processing unit 12. The supply unit 13 and the processing unit 12 are connected by a pipe 21 through which solution B passes. The pipe 21 is connected to the upper end 6A of the processing column 1 in the processing unit 12. The processing column 1 is equipped with a macroporous monolith 2 in the path through which solution B passes. At least a portion of solution B passes through at least a portion of the macroporous monolith 2 in a supersaturated state with respect to compound A or a reaction product of compound A. The processing system 11 can implement the compound processing method of this embodiment, and / or the method for producing the compound or its reaction product of this embodiment. Compound A is processed when solution B passes through the processing column 1 in the processing unit 12.

[0091] The processing column 1 is as described in the method for processing compounds, including preferred embodiments. An example of the processing column 1 includes a container 3 that houses a macroporous monolith 2, and the container 3 consists of a resin layer or glass layer with a thickness of 5 mm or less and is in contact with the macroporous monolith 2. The processing system 11 equipped with this processing column 1 is suitable for application in open column or flash column systems.

[0092] The processing column 1 may be supplied with solution B in a supersaturated state.

[0093] The supply unit 13 in Figure 2 includes a solvent replacement unit 15 that contains compound A as a solute and replaces the solvent in a raw solution that is saturated or unsaturated with respect to compound A to obtain a supersaturated solution B; a raw solution storage unit 16 that supplies the raw solution to the solvent replacement unit 15; and a solvent storage unit 17 that supplies the solvent to be replaced to the solvent replacement unit 15. The raw solution storage unit 16 and the solvent storage unit 17 and the solvent replacement unit 15 are connected by pipes 22 and 23, respectively. In the processing system 11 in Figure 2, the supersaturated solution B obtained by replacing the solvent in the raw solution can be supplied to the processing column 1.

[0094] In the solvent substitution section 15, a supersaturated solution B that is substantially free of halogenated organic solvents may be obtained from the raw solution containing halogenated organic solvents. In the solvent substitution section 15, various solvent substitutions as described in the explanation of the compound processing method of this embodiment may be performed.

[0095] The solvent replacement unit 15 may include at least one selected from the group consisting of a heating mechanism, a cooling mechanism, a pressurizing mechanism, and a depressurizing mechanism for removing the solvent contained in the raw solution. However, the solvent replacement unit 15 is not limited to the above example and may include any mechanism for replacing the solvent.

[0096] A more specific example of the processing system 11 equipped with a solvent replacement unit 15 is shown in Figure 3. The solvent replacement unit 15 in the processing system 11(11B) in Figure 3 is equipped with a porous membrane tube 18. The porous membrane tube 18 is connected to pipes 22 and 23 so that the raw solution can be supplied from the raw solution storage unit 16 and the solvent to be replaced from the solvent storage unit 17. The solvent replacement unit 15 is further equipped with a heating mechanism 19 that raises the temperature of the environment in which the porous membrane tube 18 is placed. In addition, a pressure adjustment mechanism (not shown) is connected to the solvent replacement unit 15, making it possible to change the pressure of the environment in which the porous membrane tube 18 is placed. The other configurations are the same as those of the processing system 11A in Figure 2. In the processing system 11B, for example, the solvent replacement described above can be performed using a porous membrane tube for solvent replacement. The solvent of the raw solution supplied to the porous membrane tube 18 may be a halogenated organic solvent, such as dichloromethane. The solvent to be substituted supplied to the porous membrane tube 18 may be a non-halogenated organic solvent, such as toluene or a mixed solvent of toluene and hexane. By mixing the original solution with the solvent to be substituted in the porous membrane tube 18 and creating a heated and reduced-pressure atmosphere in which the porous membrane tube 18 is placed, halogenated organic solvents with relatively low boiling points may be removed from the original solution, and a solution B of compound A containing a non-halogenated organic solvent as the main solvent may be obtained. The obtained solution B may be supersaturated with respect to compound A.

[0097] The supply unit 13 can have any configuration as long as it can supply solution B to the processing unit 1. The supply unit 13 does not have to include a solvent replacement unit 15. The supply unit 13 may also include a storage unit for solution B.

[0098] The processing column 1 may be supplied with solution B in a saturated or unsaturated state. An example of a processing system 1 in which saturated or unsaturated solution B is supplied to the processing column 1 is shown in Figures 4 and 5.

[0099] The processing system 11(11C) in Figure 4 comprises a processing unit 12 equipped with a processing column 1 through which solution B passes, and a supply unit 13 that supplies solution B to the processing unit 12. The supply unit 13 and the processing unit 12 are connected by a pipe 25 through which solution B passes. The pipe 25 is connected to the upper end 6A of the processing column 1 in the processing unit 12. The supply unit 13 in Figure 4 comprises a storage unit 31 in which solution B, which is saturated or unsaturated with respect to compound A, is stored. The processing column 1 is the reversed-phase column described above. The processing column 1 comprises, for example, a macroporous monolith 2 in which hydrophobic groups are arranged on the surface of the skeleton. The solvent of solution B stored in the storage unit 31 is hydrophilic. When compound A is DACT-II, an example of the solvent is a mixed solvent of a hydrophilic non-halogenated solvent and water, and an example of a non-halogenated solvent is THF. When compound A is DACT-II, the mixing ratio of water and THF may be 1:1 (by volume). The solvent in solution B stored in the storage section 31 may be a mixed solvent of a hydrophilic solvent and a non-hydrophilic solvent. An example of a mixed solvent when compound A is DACT-II is a mixed solvent of methanol and toluene, and the mixing ratio may be 2:1 (by volume).

[0100] When solution B containing a hydrophilic solvent is supplied from the storage unit 31 to the processing column 1, the concentration of compound A in solution B can be increased by hydrophobic interactions resulting from contact with the macroporous monolith 2. As a result, at least a portion of solution B passes through at least a portion of the macroporous monolith 2 in a supersaturated state with respect to compound A or its reactants. To prevent the precipitation of compound A due to the concentration of solution B, a developing solvent may be supplied to the processing column 1 after the supply of solution B. The concentration of solution B may mainly proceed in the portion where solution B flows into the macroporous monolith 2. A hydrophilic solvent is usually used as the developing solvent. A developing solvent with lower solubility of compound A compared to the solvent contained in solution B may also be used. An example of a developing solvent when compound A is DACT-II is an acetone / methanol mixed solvent, and the mixing ratio may be 1:1 (by volume). By supplying the developing solvent, at least a portion of the macroporous monolith 2 may be passed through solution B in a supersaturated state with respect to compound A or a reactant of compound A, while preventing the above-mentioned precipitation. For supplying the developing solvent, the processing system 11C is equipped with a developing solvent reservoir 32 and piping 26 for supplying the developing solvent to the processing column 1. The timing and number of times solution B and the developing solvent are supplied are not limited. However, normally, solution B and the developing solvent are not supplied simultaneously.

[0101] The processing system 11 (11D) in Figure 5 is an example of a processing system that supplies a solution B containing a mixed solvent of a first solvent and a second solvent to a processing column 1 in a saturated or unsaturated state. The supply unit 13 of the processing system 11D comprises a storage unit 31 in which the solution B containing the first solvent is stored, and a mixed solvent storage unit 33 in which the second solvent is stored. The mixed solvent storage unit 33 is connected by piping 27 to piping 27 that supplies the solution B to the processing column 1. The solution B stored in the storage unit 31 is unsaturated with respect to compound A. Between the first solvent and the second solvent, the first solvent has a higher solubility of compound A. Therefore, it is possible to increase the concentration of compound A stored in the storage unit 31 compared to when the solution B containing the mixed solvent is stored from the beginning. This means that the amount of compound A stored can be increased when the volume of the storage unit 31 is the same. The configuration of the other processing system 11D is the same as that of processing system 11C shown in Figure 4.

[0102] In processing system 11D, solution B from storage unit 31 and a second solvent from mixed solvent storage unit 33 are mixed in piping 25, allowing the resulting solution B, which is saturated or unsaturated with respect to compound A, to be supplied to processing column 1. Mixing does not necessarily have to be performed in piping 25. The supply unit 13 of processing system 11D may further include a mixing unit for mixing solution B from storage unit 31 and the second solvent. By supplying the mixed solution B to processing column 1, at least a portion of solution B passes through at least a portion of the macroporous monolith 2 in a supersaturated state with respect to compound A or its reactants. Furthermore, after supplying the mixed solution B to processing column 1, the developing solvent may be supplied to processing column 1 as described above in the description of processing system 11C.

[0103] Another example of the compound processing system of this embodiment is shown in Figure 6. The processing system 11(11E) in Figure 6 has the same configuration as the processing system 11A in Figure 2, except that it further includes a solid-liquid separation unit 14 that obtains compound A, in other words, compound A or a reaction product of compound A, processed by the processing column 1, as a solid from the processing solution discharged from the processing unit 12, and a pipe 24 connecting the processing unit 12 and the solid-liquid separation unit 14. The pipe 24 is connected to the lower end 6B of the processing column 1 provided in the processing unit 12. In the solid-liquid separation unit 14, compound A processed in the processing column 1 may be precipitated without solvent replacement. The precipitated processed compound A may be removed by solid-liquid separation means such as filtration, and the solid-liquid separation unit 14 may have a mechanism for this purpose. The processing systems 11A to D in Figures 2 to 5 may also include a solid-liquid separation unit 14.

[0104] In the compound processing system of this embodiment, solution B may be supplied to the processing unit 12 at a pressure of atmospheric pressure ± 0.3 atmospheres. In other words, the processing system of this embodiment may be an open column system or a flash column system.

[0105] The compound processing system of this embodiment may include any other devices or mechanisms besides those described above.

[0106] [Processing column] The processing column of this embodiment is a replacement processing column comprising a macroporous monolith 2 and a container 3 that houses the macroporous monolith 2. Processing column 1 has the macroporous monolith 2 in the path through which solution B passes. The macroporous monolith 2 is located in a path 8 through which solution B passes, which is provided inside the container 3. Examples of processing columns, including preferred embodiments, are the same as the example of processing column 1 described in the method for processing compounds. The processing column of this embodiment may be a replacement column used in the method for processing compounds of this embodiment, a replacement column used in the method for producing compounds or their reactants of this embodiment, or a replacement column used in the processing system for compounds of this embodiment. Examples of processing columns of this embodiment are shown in Figures 1A and 1B.

[0107] The processing column in this embodiment may be equipped with a flow rate criterion as a guideline for replacement. With a flow rate criterion, the column can be replaced based on the flow rate at a predetermined pressure, which indicates the degree of clogging of the processing column. For example, if the initial flow rate when acetone is flowed under a pressure of 0.1 atmospheres was 10 mL / min, the processing column may be replaced when the flow rate has decreased to half of the initial flow rate, or 5 mL / min or less, due to use. [Examples]

[0108] The present invention will be described in more detail below with reference to examples. The present invention is not limited to the examples shown below.

[0109] (Fabrication of macroporous monoliths) Macroporous monoliths were prepared according to the methods described in K. Nakanishi, Y. Yamasaki, H. Kaji and N. Soga, JSST, 1994, 2, 227-231 and R. Miyamoto, Y. Ando, ​​C. Kurusu, H. Bai, K. Nakanishi and M. Ippommatsu, J. Sep. Sci., 2013, 36, 1890-1896. Specifically, the following steps were taken: Tetraethoxysilane was dissolved in a nitric acid solution containing polyethylene oxide (weight-average molecular weight less than 100,000) to allow hydrolysis and condensation reactions to proceed and obtain a homogeneous sol solution. Next, the obtained sol solution was gelled in a cylindrical container. Then, the obtained gel was hydrothermally treated in the presence of ammonia, and subsequently dried and calcined to obtain a macroporous monolith having a cylindrical shape with an outer diameter of 22 mm and a height of 150 mm. Figure 7 shows a scanning electron microscope (SEM) image of the obtained macroporous monolith. A JEOL JSM-IT500HR SEM was used. As shown in Figure 7, the fabricated macroporous monolith had a co-continuous structure in which the through-pores (macropores) and the framework were intertwined and extended in a three-dimensional network. Pore distribution measurements were also performed on the fabricated macroporous monolith using the mercury intrusion method. Based on the pore distribution results, the average pore diameter of the macropores was 5 μm, the uniformity of the pore diameter was 20% as expressed by the ratio of the full width at half maximum of the pore diameter distribution to the average pore diameter, and the range of the pore diameter distribution was 4 to 6 μm.

[0110] (Preparation of processing column A with a macroporous monolith) The macroporous monolith prepared above was cut to a height of 100 mm (volume 40 mL), and a glass tube and a glass funnel were placed at the upper and lower ends, respectively. The monolith was then covered with a heat-shrinkable tube made of tetrafluoroethylene-hexafluoropropylene copolymer (FEP) to create a treatment column A having the shape shown in Figure 1A. The thickness of the heat-shrinkable tube after coating was 0.5 mm. The glass tube and glass funnel were covered integrally with the macroporous monolith by the heat-shrinkable tube to prevent solvent leakage.

[0111] (Preparation of treatment column B packed with silica gel particles) Spherical silica gel particles (WakoSil 300N, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., particle size 40-73 μm, pore size 7 nm) were dispersed in a mixed solvent of hexane:ethyl acetate = 8:1 (volume ratio) to prepare a slurry. Next, the prepared slurry was poured into a glass column tube with a glass stopcock (inner diameter 20 mm) and allowed to settle to prepare a comparative example, treatment column B, which was equipped with cylindrical packing material with a diameter of 20 mm and a length of 100 mm.

[0112] (DACT-II fabrication) In this example, DACT-II was used as compound A. DACT-II and its precursor were synthesized according to the following procedure, based on H. Kaji et al., "Purely organic electroluminescent material realizing 100% conversion from electricity to light", Nat. Commun., 2015, 6, 8476.

[0113] 9-benzyl-3,6-dibromo-9H-carbazole and diphenylamine were reacted in dry toluene under reflux in the presence of tris(dibenzylideneacetone)dipalladium(O) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl as catalysts, and sodium butoxyl. Next, the reaction mixture was extracted with water and ethyl acetate, and the extract was purified and isolated by silica gel column chromatography to obtain the reaction product. Next, the obtained reaction product was dissolved in dimethyl sulfoxide and mixed with a 1 mol / L solution of potassium butoxide in tetrahydrofuran, and oxygen gas was bubbled over it while stirring. After the reaction, the mixture was mixed with distilled water to obtain a precipitate, from which the crude product of DACT-II precursor (N,N,N',N'-tetraphenyl-9H-carbazole-3,6-diamine) was obtained. Next, the above precursor and 2-(4-bromophenyl)-4,6-diphenyl-1,3,5-triazine were reacted in dry toluene under reflux in the presence of tris(dibenzylideneacetone)dipalladium(O) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl catalysts and sodium butoxyte. The reaction mixture was then extracted with water and ethyl acetate, and silica gel particles were dispersed in the resulting ethyl acetate solution. The solution was then filtered to obtain the crude product of DACT-II. The purity of the crude product of DACT-II was 83%. The purity of the crude product of DACT-II was evaluated by purity analysis using high-performance liquid chromatography.

[0114] (Preparation of Solution B1) The supersaturated solution B1 to be supplied to the processing column was prepared as follows: 0.36 g of crude DACT-II composition was dissolved in 20 mL of dichloromethane. Next, 20 mL of toluene was added to the resulting solution, and then the dichloromethane was removed using a rotary evaporator. The volume of the solution after removal of dichloromethane was 15 mL. Next, 20 mL of hexane was added dropwise while stirring the entire mixture for 1 minute. In this way, a supersaturated solution B1 of DACT-II was obtained. The supersaturated state of DACT-II in this solution is only stable temporarily. Therefore, within a few minutes before DACT-II began to precipitate, loading to processing column A was carried out according to the procedure of Example 1.

[0115] (Example 1) The prepared treatment column A was first washed with 50 mL of acetone, followed by 100 mL of hexane. The prepared solution B1 was loaded into treatment column A by pouring it into a glass tube before DACT-II precipitated. Next, a solvent mixture of hexane and ethyl acetate in an 8:1 (volume ratio) was flowed from the top of treatment column A at a flow rate of 20 mL / min to attempt purification of DACT-II using treatment column A. DACT-II did not precipitate inside treatment column A, but was discharged as a supersaturated solution from a glass funnel connected to the bottom of treatment column A. The solution discharged from treatment column A was collected in 5 mL or 10 mL fractions as desired. DACT-II eluted after 80 mL had been collected from the start of the first fraction collection, and thereafter, 80 mL of the supersaturated DACT-II fraction was recovered. From the recovered fraction, it was confirmed that purification with a purity of 97% and a recovery rate of 80% was possible. The concentration of DACT-II in the recovered solution was 3.6 mg / mL, which is higher than the solubility of DACT-II in the developing solvent used (1 mg / mL), and confirms that purification in a supersaturated state is possible. Furthermore, DACT-II began to precipitate from the supersaturated solution approximately 5 minutes after recovery.

[0116] (Comparative Example 1) We attempted to purify DACT-II in the same manner as in Example 1, except that we used treatment column B instead of treatment column A. However, DACT-II precipitated at the top of treatment column B, causing the column to become blocked, making purification of DACT-II impossible.

[0117] (Example 2) The macroporous monolith prepared above was crushed to obtain aggregates of monolith fragments (particle size 500-1000 μm). 0.72 g of the obtained aggregates was added to a 13 mL dichloromethane solution of 0.36 g of crude DACT-II composition. Next, 160 mL of hexane was added while stirring the mixture. The aggregates turned orange and maintained their fluidity in the solution. It was presumed that DACT-II was adsorbed inside the monolith fragments and remained in a stable state without precipitating on the surface of the aggregates.

[0118] Next, the above solution, including the aggregates, was poured into a glass tube and loaded onto treatment column A. Then, a solvent mixture of hexane and ethyl acetate in an 8:1 (volume ratio) was flowed from the top of treatment column A at a flow rate of 20 mL / min to attempt purification of DACT-II using treatment column A. DACT-II did not precipitate inside treatment column A, but was discharged as a supersaturated solution from a glass funnel connected to the bottom of treatment column A. The solution discharged from treatment column A was collected as needed in 5 mL or 10 mL fractions. DACT-II eluted after 55 mL had been collected from the start of the first fraction collection, and thereafter, 60 mL of supersaturated DACT-II fraction was recovered. From the recovered fraction, it was confirmed that purification with a purity of 94% and a recovery rate of 87% was possible. The concentration of DACT-II in the recovered solution was 5.2 mg / mL, which is higher than the solubility of DACT-II in the developing solvent used (1 mg / mL), and confirms that purification in a supersaturated state is possible. From the supersaturated solution, DACT-II began to precipitate approximately 5 minutes after recovery.

[0119] (Comparative Example 2) 1.37 g of silica gel particles used to prepare treatment column B were added to a 13 mL dichloromethane solution of crude DACT-II composition (0.36 g). Next, 90 mL of hexane was added while stirring the mixture. During the addition, the silica gel turned a strong yellow color, lost its fluidity in the solution, and eventually adhered to the bottom of the container. It was presumed that the DACT-II precipitated on the surface of the silica gel particles upon addition of hexane. Next, the adhered aggregates were crushed with a spatula to give them some fluidity, and then the aggregates were poured into a glass tube and loaded into treatment column B. Next, a solvent mixture of hexane and ethyl acetate in an 8:1 (volume ratio) was flowed from the top of treatment column B at a flow rate of approximately 20 mL / min to attempt purification of DACT-II using treatment column B. The yellow-adhered components gradually dissolved and flowed into the interior of treatment column B, but they continued to accumulate at the column inlet even after 200 mL of the developing solvent had been flowed.

[0120] (Preparation of DACT-II precursor solution B2) 1.5 g of the crude DACT-II precursor was dissolved in 60 mL of dichloromethane. Next, 60 mL of hexane was added dropwise while stirring the mixture for 1 minute. In this way, a supersaturated solution B2 of the DACT-II precursor was obtained. The supersaturated state of the DACT-II precursor in this solution is only stable temporarily. Therefore, within a few minutes before the DACT-II precursor began to precipitate, the solution was loaded onto processing column A according to the procedure of Example 3.

[0121] (Example 3) The prepared solution B2 was loaded onto treatment column A by pouring it into a glass tube before the DACT-II precursor precipitated. Next, a solvent mixture of hexane and dichloromethane in a 6:4 (volume ratio) was flowed from the top of treatment column A at a flow rate of 20 mL / min to attempt purification of the DACT-II precursor using treatment column A. The DACT-II precursor did not precipitate inside treatment column A, but was discharged as a supersaturated solution from a glass funnel connected to the bottom of treatment column A. The solution discharged from treatment column A was optionally collected in 5 mL or 10 mL fractions. The DACT-II precursor eluted after 30 mL of the first fraction was collected, and thereafter, 210 mL of the supersaturated DACT-II precursor fraction was recovered. From the recovered fraction, it was confirmed that purification with a purity of 95% and a recovery rate of 94% was possible. The concentration of DACT-II precursor in the recovered solution was 6.7 mg / mL, which is higher than the solubility of DACT-II precursor in the developing solvent used (3 mg / mL), and confirms that purification in a supersaturated state is possible.

[0122] (Comparative Example 3) We attempted to purify the DACT-II precursor in the same manner as in Example 3, except that we used treatment column B instead of treatment column A. However, the DACT-II precursor precipitated at the top of treatment column B, causing the column to become blocked, making purification of the DACT-II precursor impossible.

[0123] (Preparation of treatment column C packed with silica gel particles) Spherical silica gel particles (WakoSil 300N, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., particle size 40-73 μm, pore size 7 nm) were dispersed in a mixed solvent of hexane:ethyl acetate = 8:1 (volume ratio) to prepare a slurry. Next, the prepared slurry was poured into a glass column tube with a glass stopcock (inner diameter 50 mm) and allowed to settle to prepare a comparative example treatment column C equipped with a cylindrical packing material (silica gel volume = 300 mL) with a diameter of 50 mm and a length of 150 mm.

[0124] (Comparative Example 4) The purification of the DACT-II precursor was attempted in the same manner as in Example 3, except that treatment column C was used instead of treatment column A. The DACT-II precursor precipitated at the top of treatment column C, but the precipitated DACT-II was gradually redissolved by continuing to flow the developing solvent. The DACT-II precursor eluted after 520 mL was recovered from the start of the initial fraction recovery, and a total of 480 mL of DACT-II precursor fraction was recovered thereafter. From the recovered fraction, it was confirmed that purification with a purity of 95% and a recovery rate of 99% was possible based on the values ​​within the fraction. The concentration of DACT-II in the recovered solution was 3.1 mg / mL, which is within the error range compared to the solubility of DACT-II in the developing solvent used (3 mg / mL), confirming that purification in a supersaturated state was not achieved. The amount of silica gel particles required for purification in Comparative Example 4 (300 mL) was 7.5 times that of the macroporous monolith (40 mL) in Example 3. Furthermore, the amount of solvent required for purification was 1000 mL (520 + 480), which is nearly four times the amount used in Example 3 (240 mL (30 + 210)).

[0125] (Preparation of processing column D with a macroporous monolith) The macroporous monolith prepared above was cut to a height of 130 mm and loaded into a polypropylene empty reservoir (inner diameter 22 mm x length 130 mm, thickness 1.5 mm) equipped with Luer lock connectors at the inlet and outlet to create processing column D.

[0126] (Preparation of treatment column E packed with silica gel particles) Silica gel particles with a particle size of 20-40 μm were packed into a polypropylene empty reservoir (12 mm inner diameter x 80 mm length) equipped with Luer lock connectors at the inlet and outlet to prepare the comparative example, treatment column E.

[0127] (Preparation of Solution B3) The supersaturated solution B3 to be supplied to the processing column was prepared as follows: 0.36 g of crude DACT-II product was dissolved in 10 mL of chloroform. Next, 4 mL of toluene was added to the resulting solution, and then the chloroform was removed using a rotary evaporator. The volume of the solution after removal of chloroform was 4 mL. Next, 8 mL of hexane was added dropwise while stirring the entire mixture over a period of 30 seconds. In this way, a supersaturated solution B3 of DACT-II was obtained. The supersaturated state of DACT-II in this solution is only stable temporarily. Therefore, within a few minutes before DACT-II began to precipitate, loading to processing column D was carried out according to the procedure of Example 4.

[0128] (Example 4) The prepared treatment column D was first washed with 50 mL of acetone, followed by 100 mL of hexane. The prepared solution B3 was loaded directly into the column before DACT-II precipitated. A syringe was used for loading. Next, a solvent mixture of hexane and ethyl acetate in an 8:1 (volume ratio) was flowed from the column inlet at a flow rate of 20 mL / min using an HPLC pump to attempt purification of DACT-II using treatment column D. DACT-II did not precipitate inside treatment column D, but was discharged from the outlet of treatment column D as a supersaturated solution. DACT-II eluted after 70 mL had been collected from the start of the initial fraction collection, and thereafter, 40 mL of the supersaturated DACT-II fraction was recovered. From the recovered fraction, it was confirmed that purification with a purity of 92% and a recovery rate of 80% was possible. The concentration of DACT-II in the recovered solution was 7.5 mg / mL, which is higher than the solubility of DACT-II in the developing solvent used (1.1 mg / mL), and it was confirmed that purification in a supersaturated state was possible.

[0129] (Comparative Example 5) The prepared treatment column E was first washed with 10 mL of acetone, followed by 20 mL of hexane. The prepared solution B3 was loaded directly into the column before DACT-II precipitated. A syringe was used for loading. Next, an attempt was made to purify DACT-II using treatment column E by flowing a solvent mixture of hexane and ethyl acetate in an 8:1 (volume ratio) from the column inlet at a flow rate of 5 mL / min using an HPLC pump. Although treatment column E did not become blocked, DACT-II precipitated throughout treatment column E as the solution was discharged from the outlet of treatment column E. The amount of DACT-II precipitated inside treatment column E reached 20% by weight of the loaded amount, making purification impossible.

[0130] (Examples 5-7) Purification of DACT-II using treatment column D was attempted in the same manner as in Example 4, except that the mixed solvent shown in Table 2 below was used as the developing solvent. In all cases, DACT-II did not precipitate inside treatment column D, but was discharged from the outlet of treatment column D as a supersaturated solution. The solubility of DACT-II in each developing solvent used (at 25°C), the amount of supersaturated DACT-II fraction recovered, the concentration of DACT-II in the fraction, and the purity and recovery rate of DACT-II as a precipitate spontaneously precipitated from the discharged fraction are shown in Table 3 below, along with the results from Example 4.

[0131] [Table 2]

[0132] [Table 3]

[0133] As shown in Table 3, in all examples, including Example 7 which used a developing solvent with a very low solubility of DACT-II (0.3 mg / mL), it was confirmed that DACT-II could be purified to a supersaturated state and high purity. The purity of DACT-II in solution B3 used for purification was 83%.

[0134] (Reference example) DACT-II was recrystallized and purified by solvent diffusion. This was performed by adding 100 mL of hexane in a layer to a toluene solution (concentration 35 mg / mL) of DACT-II dissolved in a 40°C water bath, and then allowing it to stand at room temperature for 3 days. The purity of the resulting DACT-II was 93.9%.

[0135] (Preparation of a processing column F equipped with a macroporous monolith) Treatment column F was prepared in the same manner as treatment column A, except that the macroporous monolith had a diameter of 33 mm and a height of 100 mm.

[0136] (Preparation of Solution B4) The supersaturated solution B4 to be supplied to processing column F was prepared as follows: 1.5 g of DACT-II was dissolved in 20 mL of dichloromethane. Next, 20 mL of toluene was added to the resulting solution, and then the dichloromethane was removed using a rotary evaporator. The volume of the solution after removal of dichloromethane was 20 mL. Next, 20 mL of hexane was added dropwise while stirring the entire mixture over a period of 30 seconds. In this way, a supersaturated solution B4 of DACT-II was obtained. The supersaturated state of DACT-II in this solution is only stable temporarily. Therefore, within a few minutes before DACT-II began to precipitate, the loading to processing column F was carried out according to the procedure of Example 8.

[0137] (Example 8) The prepared treatment column F was first washed with 100 mL of acetone, followed by 200 mL of hexane. The prepared solution B4 was loaded directly into the column before DACT-II precipitated. Next, a solvent mixture of hexane and toluene in a 3:2 (volume ratio) was flowed through the column inlet at a flow rate of 20 mL / min using a hand pump to attempt purification of DACT-II using treatment column F. DACT-II did not precipitate inside treatment column F, but was discharged from the outlet of treatment column F as a supersaturated solution. 119 mL of the supersaturated DACT-II fraction was recovered. The purity of DACT-II in the recovered fraction was 99.4%, and the recovery rate was 96.8%. The purity of DACT-II as a precipitate that naturally precipitated from the discharged fraction was over 99.9%, and the recovery rate was 61%. Furthermore, the concentration of DACT-II in the recovered solution was 11 mg / mL, which is higher than the solubility of DACT-II in the developing solvent used (5 mg / mL), confirming that purification in a supersaturated state is possible. [Industrial applicability]

[0138] The compound processing method of the present invention can be used, for example, for the purification, concentration, and reaction of compounds. Examples of compounds include organic EL materials and pharmaceutical raw materials.

Claims

1. The process involves treating the compound by passing a solution containing the compound as a solute through a processing column. The processing column is equipped with a macroporous monolith in the path through which the solution passes. A method for treating a compound, wherein at least a portion of the solution passes through at least a portion of the macroporous monolith in a supersaturated state with respect to the compound or a reactant of the compound.

2. The processing method according to claim 1, wherein at least a portion of the solution is recovered from the processing column as a processing solution in a supersaturated state with respect to the compound or the reactant.

3. The processing method according to claim 1, wherein the solution is discharged from the processing column without substantially precipitating the compound or the reactant from the solution within the macroporous monolith.

4. The present invention further includes obtaining a solution containing the aforementioned compound as a solute, in which the raw solution is saturated or unsaturated with respect to the aforementioned compound, by solvent replacement, The processing method according to claim 1, wherein the supersaturated solution obtained is supplied to the processing column.

5. The processing method according to claim 4, wherein the raw solution containing a halogenated organic solvent is subjected to solvent replacement to obtain a solution substantially free of halogenated organic solvents.

6. The processing method according to claim 1, wherein the solubility of the compound in the solvent of the solution at 25°C is 100 mg / mL or less.

7. The processing method according to claim 1, wherein the solution having a pressure of atmospheric pressure ± 0.3 atmospheres is passed through the processing column.

8. The processing method according to claim 1, wherein the compound is a liquid crystal compound or a π-conjugated aromatic compound.

9. The treatment method according to claim 1, wherein the solubility of the compound in toluene or ethyl acetate at 25°C is 1 / 3 or less of the solubility in halogen-substituted methane at 25°C.

10. The processing method according to claim 1, wherein the compound is subjected to at least one processing selected from the group consisting of purification, reaction, and concentration.

11. A method for producing a compound or a reactant thereof, comprising treating the compound by the treatment method described in claim 1 to obtain the treated compound or a reactant thereof.

12. A method for producing a compound or a reactant according to claim 11, further comprising precipitating the treated compound or the reactant without solvent substitution.

13. A processing system for processing compounds, A processing unit comprising a processing column through which a solution containing the aforementioned compound as a solute is passed, The system comprises a supply unit that supplies the solution to the processing unit, The processing column is equipped with a macroporous monolith in the path through which the solution passes. At least a portion of the solution passes through at least a portion of the macroporous monolith in a supersaturated state with respect to the compound or reactants of the compound. A system for processing compounds.

14. The processing system according to claim 13, wherein the processing column is supplied with the supersaturated solution.

15. The aforementioned supply unit, The processing system according to claim 14, further comprising a solvent replacement unit that includes the above compound as a solute and replaces the solvent of a raw solution which is saturated or unsaturated with respect to the above compound to obtain a supersaturated solution.

16. The processing system according to claim 15, wherein the solvent substitution unit obtains a solution substantially free of halogenated organic solvents from the raw solution containing halogenated organic solvents.

17. The processing column comprises a container for housing the macroporous monolith, The processing system according to claim 13, wherein the container is made of a resin layer or glass layer with a thickness of 5 mm or less and is in contact with the macroporous monolith.

18. The processing system according to claim 13, further comprising a solid-liquid separation unit that obtains the compound processed by the processing column as a solid from the processing solution discharged from the processing unit.

19. The processing system according to claim 18, wherein the solid-liquid separation unit precipitates the compound processed by the processing column from the processing solution without solvent replacement.

20. A replacement processing column, The invention comprises a macroporous monolith and a container for housing the macroporous monolith. The processing column is equipped with the macroporous monolith in the path through which the solution containing the compound as a solute passes. A processing column for use in at least one selected from the group consisting of a method for processing a compound according to any one of claims 1 to 10, a method for producing a compound or its reaction product according to claim 11 or 12, and a processing system for a compound according to any one of claims 13 to 19.

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