Method for producing triazolinedione adducts

Abstract

Provided is a method for producing a triazolinedione adduct, the method comprising a suspending / washing step for purifying, by suspending and washing, a crude product of a triazolinedione adduct represented by formula (1). (In the formula, R1 is an organic group, and A is a condensed ring that has a crosslinked structure and contains at least one aromatic ring.)

Description

[Technical Field]

[0001] The present invention relates to a method for producing a triazolinedione adduct. [Background technology]

[0002] In recent years, there has been an increasing need for the analysis of vitamin D and vitamin D metabolites in blood. As a method for analyzing vitamin D and vitamin D metabolites, a method has been proposed in which vitamin D and vitamin D metabolites are derivatized using a Cookson-type derivatization reagent, and then the derivatives are analyzed (see Patent Document 1 and Non-Patent Documents 1 to 4).

[0003] Specifically, under mild conditions, Cookson-type derivatization reagents undergo extremely rapid Diels-Alder reactions with diene derivatives such as vitamin D, quantitatively yielding ene compounds (see Non-Patent Documents 1 to 4). Utilizing this reaction property, vitamin D and other compounds that are difficult to quantify as they are reacted with Cookson-type derivatization reagents to convert them into ene compounds with high analytical sensitivity, which can then be quantified.

[0004] Examples of the Cookson-type derivatization reagent include triazolinedione compounds such as PTAD (4-phenyl-1,2,4-triazoline-3,5-dione) and DAPTAD (4-(4'-dimethylaminophenyl)-1,2,4-triazoline-3,5-dione).

[0005] However, triazolinedione compounds are unstable, and higher stability is required for handling them as manufacturing raw materials or quantitative reagents.

[0006] It is known that triazolinedione compounds undergo a reversible Diels-Alder reaction with polycyclic benzenes such as anthracene to give adducts (see Non-Patent Documents 5 and 6). That is, once the triazolinedione adduct is obtained, it undergoes a retro-Diels-Alder reaction to return to the starting triazolinedione compound and the polycyclic benzene upon heating (retro-Diels-Alder reaction).

[0007] By focusing on the above-mentioned properties, the stability of the triazolinedione compound can be ensured by converting the unstable triazolinedione compound into a stable adduct and then reacting it while returning it to the triazolinedione compound when used (see Patent Document 2).

[0008] The above triazolinedione adduct can be obtained by subjecting a triazolinedione compound and a fused ring compound containing at least two aromatic rings to a Diels-Alder reaction.

[0009] To obtain highly pure triazolinedione adducts, purification is generally performed after the Diels-Alder reaction. Methods for purification include column purification and recrystallization. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] Japanese Patent Application Laid-Open No. 2015-166740 [Patent Document 2] International Publication No. 2019 / 240143 [Non-patent literature]

[0011] [Non-Patent Document 1] S.Ogawa,et al.,Rapid Commun.Mass Spectrom,27(2013)2453-2460 [Non-patent document 2] S.Ogawa,et al.,Biomed.Chromatgr.,30(2016)938-945 [Non-patent document 3] S.Ogawa,et al.,J.Pharm.Biomed.Anal.,136(2017)126-133 [Non-patent document 4] KDBruycker,et al.,Chem.Rev.,116(2016)3919-3974 [Non-Patent Document 5] N.Roy,et al.,Chem.Asian.J,6(2011)2419-2425 [Non-patent document 6] VDKiseleva,et al.,Russ.J.Phys.Chem.A,88(2014)2073-2080 Summary of the Invention [Problem to be solved by the invention]

[0012] However, the conventional purification method of triazolinedione adducts by column purification is not suitable for large-scale synthesis, and the purification method by recrystallization, although suitable for large-scale synthesis, has the drawback of not being able to obtain high-purity triazolinedione adducts with high recovery rates.

[0013] The present invention has been made in view of the above-mentioned background art, and an object of the present invention is to provide a method for producing a triazolinedione adduct, which is suitable for large-scale synthesis and enables the triazolinedione adduct to be obtained with high purity and high recovery rate. [Means for solving the problem]

[0014] The present inventors have found that purification of the crude triazolinedione adduct by suspension washing is suitable for large-scale synthesis and allows the triazolinedione adduct to be obtained in high purity and high recovery, thereby completing the present invention.

[0015] That is, the configuration of the present invention is as follows.

[0016] Item 1: A method for producing a triazolinedione adduct, comprising a suspension washing step of purifying a crude product of a triazolinedione adduct represented by the following formula (1) by suspension washing.

[0017] [ka] (In the formula, R 1 is an organic group, and A is a fused ring having a bridged structure and containing at least one aromatic ring. Item 2: The method for producing a triazolinedione adduct according to Item 1, wherein the triazolinedione adduct is represented by the following formula (2):

[0018] [ka] (In the formula, R 2 is an organic group, and R 3 , R 4 , and R 5 are each independently a substituent selected from the group consisting of a halogen group, an amino group, a nitro group, an alkyl group having 1 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms, a heteroaryl group having 5 to 20 carbon atoms, and an acyl group having 2 to 20 carbon atoms, and l and m are each independently an integer of 0 to 4, and n is an integer of 0 to 2. Here, the aryl group and the heteroaryl group may have a substituent selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, a halogen group, a nitro group, and a dimethylamino group. Item 3. The method for producing a triazolinedione adduct according to Item 2, wherein the triazolinedione adduct is represented by the following formula (3):

[0019] [ka] (In the formula, R 2 , R 3 , R 4 , R 5 , l, m, and n are defined as in formula (2). Item 4. The method for producing a triazolinedione adduct according to Item 1, wherein the triazolinedione adduct is represented by the following formula (4):

[0020] [ka] (In the formula, R 2 is an organic group, and R 6 , R 7 , R 8 , and R 9 are each independently a substituent selected from the group consisting of a halogen group, an amino group, a nitro group, an alkyl group having 1 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms, a heteroaryl group having 5 to 20 carbon atoms, and an acyl group having 2 to 20 carbon atoms, p is an integer of 0 to 4, q is an integer of 0 to 2, and r and s are each independently 0 or 1. Here, the aryl group and the heteroaryl group may have a substituent selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, a halogen group, a nitro group, and a dimethylamino group. Item 5. The method for producing a triazolinedione adduct according to Item 4, wherein the triazolinedione adduct is represented by the following formula (5):

[0021] [ka] (In the formula, R 2 , R 6 , R 7 , R 8 , R 9 , p, q, r, and s have the same meanings as in formula (4). Item 6. The method for producing a triazolinedione adduct according to any one of Items 1 to 5, wherein the solvent used in the suspension washing is at least one selected from the group consisting of hydrocarbon alcohols, ketones, esters, and acetonitrile.

[0022] Item 7: A method for producing a triazolinedione adduct according to any one of Items 1 to 6, further comprising: a reaction step of subjecting a triazolinedione compound represented by the following formula (6) to a Diels-Alder reaction with a fused ring compound containing at least two aromatic rings to obtain a crude product of the triazolinedione adduct; and a pre-purification step of pre-purifying the crude product of the triazolinedione adduct obtained in the reaction step, wherein the pre-purification step comprises: a solvent substitution step of subjecting a liquid in which the crude product of the triazolinedione adduct is dissolved or suspended, to solvent substitution with a first hydrocarbon solvent; a washing step of filtering the liquid obtained by the solvent substitution step and washing the resulting filter cake with a second hydrocarbon solvent that is the same as or different from the first hydrocarbon solvent; and a dissolution step of dissolving the filter cake washed in the washing step in a halogenated solvent and filtering the resulting solution; and the crude product of the triazolinedione adduct pre-purified in the pre-purification step is purified by the suspension washing.

[0023] [ka] (In the formula, R 1 has the same meaning as in formula (1). Item 8: A method for producing a triazolinedione adduct according to any one of Items 1 to 6, further comprising: a reaction step of subjecting a triazolinedione compound represented by the following formula (6) and a fused ring compound containing at least two aromatic rings to a Diels-Alder reaction to obtain a crude product of the triazolinedione adduct; and a pre-purification step of pre-purifying the crude product of the triazolinedione adduct obtained in the reaction step, wherein the pre-purification step comprises: a dissolving step of adding a halogenated solvent to a liquid in which the crude product of the triazolinedione adduct is dissolved or suspended, to dissolve the crude product of the triazolinedione adduct, and filtering the liquid; a solvent substitution step of subjecting the filtrate obtained in the dissolving step to solvent substitution with a first hydrocarbon solvent; and a washing step of filtering the liquid obtained after solvent substitution in the solvent substitution step and washing the resulting filter cake with a second hydrocarbon solvent that is the same as or different from the first hydrocarbon solvent, and the crude product of the triazolinedione adduct pre-purified in the pre-purification step is purified by the suspension washing.

[0024] [ka] (In the formula, R 1 has the same meaning as in formula (1). Item 9. The method for producing a triazolinedione adduct according to Item 7 or 8, wherein the first hydrocarbon solvent is n-heptane.

[0025] Item 10. The method for producing a triazolinedione adduct according to any one of Items 7 to 9, wherein the second hydrocarbon solvent is n-hexane.

[0026] Item 11. The method for producing a triazolinedione adduct according to any one of Items 7 to 10, wherein the halogen-based solvent is dichloromethane. [Effects of the Invention]

[0027] According to the method for producing a triazolinedione adduct of the present invention, the crude product of the triazolinedione adduct is purified by suspension washing, which is suitable for large-scale synthesis and allows the triazolinedione adduct to be obtained with high purity and high recovery. [Brief explanation of the drawings]

[0028] [Figure 1] FIG. 1 is a schematic diagram illustrating an example of a method for producing a triazolinedione adduct of the present embodiment. [Figure 2] FIG. 2 is a schematic diagram illustrating another example of the method for producing a triazolinedione adduct of the present embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0029] Hereinafter, embodiments of the present invention will be described. Note that the present invention is not limited to the embodiments described below.

[0030] The method for producing a triazolinedione adduct of this embodiment includes a suspension washing step in which a crude product of the triazolinedione adduct (hereinafter also referred to as a "crude triazolinedione adduct") is purified by suspension washing. According to the method for producing a triazolinedione adduct of this embodiment, a preliminary purification step is carried out as necessary, followed by a suspension washing step, thereby making it suitable for large-scale synthesis and enabling the production of a triazolinedione adduct with high purity and high recovery rate to be obtained.

[0031] <Suspension washing process> In this embodiment, the target of the suspension washing step is a crude triazolinedione adduct or a crude triazolinedione adduct that has been subjected to a preliminary purification step. First, the crude triazolinedione adduct that is the target of the suspension washing step or the preliminary purification step in this embodiment will be described.

[0032] [Crude triazolinedione adduct to be subjected to the suspension washing process or preliminary purification process] In this embodiment, the triazolinedione adduct contained in the crude triazolinedione adduct that is subjected to the suspension washing step or the preliminary purification step is a triazolinedione adduct represented by the following formula (1).

[0033] [ka] (In the formula, R 1 is an organic group, and A is a fused ring having a bridged structure and containing at least one aromatic ring. In addition, R 1 is R in equation (6) described later. 1 Since it is the same as the above, the explanation will be omitted here.

[0034] The triazolinedione adduct is preferably a triazolinedione adduct represented by the following formula (2).

[0035] [ka] (In the formula, R 2is an organic group, and R 3 , R 4 , and R 5 are each independently a substituent selected from the group consisting of a halogen group, an amino group, a nitro group, an alkyl group having 1 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms, a heteroaryl group having 5 to 20 carbon atoms, and an acyl group having 2 to 20 carbon atoms, and l and m are each independently an integer of 0 to 4, and n is an integer of 0 to 2. Here, the aryl group and heteroaryl group may have a substituent selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, a halogen group, a nitro group, and a dimethylamino group. where R 2 may be substituted at any of the ortho, meta, and para positions of the benzene ring.

[0036] The triazolinedione adduct is more preferably a triazolinedione adduct represented by the following formula (3):

[0037] [ka] (In the formula, R 2 , R 3 , R 4 , R 5 , l, m, and n are defined as in formula (2).

[0038] In addition, R 2 is R in equation (7) described later. 2 Since it is the same as the above, the explanation will be omitted here.

[0039] The triazolinedione adduct is preferably a triazolinedione adduct represented by the following formula (4).

[0040] [ka] (In the formula, R 2 is an organic group, and R 6 , R 7 , R8 , and R 9 are each independently a substituent selected from the group consisting of a halogen group, an amino group, a nitro group, an alkyl group having 1 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms, a heteroaryl group having 5 to 20 carbon atoms, and an acyl group having 2 to 20 carbon atoms, p is an integer of 0 to 4, q is an integer of 0 to 2, and r and s are each independently 0 or 1. Here, the aryl group and heteroaryl group may have a substituent selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, a halogen group, a nitro group, and a dimethylamino group. where R 2 may be substituted at any of the ortho, meta, and para positions of the benzene ring.

[0041] The triazolinedione adduct is more preferably a triazolinedione adduct represented by the following formula (5).

[0042] [ka] (In the formula, R 2 , R 6 , R 7 , R 8 , R 9 , p, q, r, and s are defined as in formula (4). In addition, R 2 is R in equation (7) described later. 2 Since it is the same as the above, the explanation will be omitted here.

[0043] [Suspension washing] The crude triazolinedione adduct is subjected to suspension washing. The suspension washing here refers to a method in which the crude triazolinedione adduct is washed by mixing it with a solvent for a certain period of time while remaining as a solid without being completely dissolved.

[0044] In the method for producing a triazolinedione adduct of the present embodiment, the crude triazolinedione adduct can be purified by carrying out only the suspension washing step, but the crude triazolinedione adduct can also be purified by carrying out a preliminary purification step described below and then carrying out the suspension washing step.

[0045] (Solvent used in suspension washing) The solvent used for suspension washing is not particularly limited as long as it dissolves impurities and does not easily dissolve the crude triazolinedione adduct. From the viewpoint of achieving both the ability to remove impurities and the solubility of the crude triazolinedione adduct, the solvent used for suspension washing is preferably a hydrocarbon alcohol such as methanol, ethanol, isopropanol, etc.; a ketone such as acetone, methyl ethyl ketone, acetylacetone, etc.; an ester such as methyl acetate, ethyl acetate, propyl acetate, etc.; acetonitrile, etc.; more preferably an alcohol or a ketone; even more preferably a ketone such as acetylacetone, and most preferably acetone. Furthermore, the solvent used for suspension washing may be one type, or a mixture containing two or more types of solvents may be used.

[0046] (Amount of solvent used for suspension washing) The amount of solvent used in suspension washing is preferably 2.0 mL to 4.0 mL, more preferably 2.0 mL to 3.0 mL, and particularly preferably 2.0 mL, per 100 mg of the crude triazolinedione adduct or the triazolinedione adduct that has been subjected to a preliminary purification step.

[0047] (Temperature when performing suspension washing) Because the Diels-Alder reaction to obtain the triazolinedione adduct is a reversible reaction, the temperature during suspension washing must be a temperature that does not promote the reversion reaction. From the viewpoint of the stability of the triazolinedione adduct, the temperature during suspension washing is preferably in the range of 0 to 40°C, more preferably in the range of 0 to 25°C, and even more preferably in the range of 10 to 25°C. From the viewpoint of operational efficiency, the temperature during suspension washing is most preferably in the range of 20 to 25°C.

[0048] (Time required for suspension washing) The time for suspension washing is not limited as long as it is a time sufficient to remove impurities, but in order to obtain a triazolinedione adduct of higher purity, it is preferably 1 hour or more. From the viewpoint of achieving both high purity and operational efficiency, the time is more preferably 14 hours or more and 72 hours or less, and even more preferably 14 hours or more and 20 hours or less. Approximately 14 hours is most preferred.

[0049] (Number of times suspension washing is performed) The suspension washing can be repeated depending on the amount of impurities. When the washing is repeated, the same solvent or different solvents may be used.

[0050] [Recovery of triazolinedione adduct after suspension washing] The suspension washing allows the production of a high-purity triazolinedione adduct. To obtain a high-purity triazolinedione adduct from the liquid containing the triazolinedione adduct after the suspension washing, any commonly used solid-liquid separation method can be used without any particular limitation, and specific examples include filtration and centrifugation. Filtration is preferred because of its ease of handling when carried out on a large scale.

[0051] (Temperature at time of collection) The temperature during recovery must be a temperature that does not promote the reversion reaction of the Diels-Alder reaction. From the viewpoint of the stability of the triazolinedione adduct, the temperature during recovery is preferably in the range of 0 to 40°C, more preferably in the range of 0 to 25°C, and even more preferably in the range of 10 to 25°C. From the viewpoint of operational efficiency, the temperature during recovery is most preferably in the range of 20 to 25°C.

[0052] (Washing) After the triazolinedione adduct has been recovered by suspension washing, the resulting high-purity triazolinedione adduct can also be washed. The washing method is not particularly limited as long as it is a commonly used method. The solvent used for washing is not particularly limited as long as it is a solvent that can recover high-purity triazolinedione. From the viewpoints of the solubility of the triazolinedione adduct and the removal of impurities from the triazolinedione adduct, it is preferable to use acetone as the solvent used for washing.

[0053] (Drying method) The highly pure triazolinedione adduct obtained by solid-liquid separation can be dried by natural drying, air drying, vacuum drying, or the like.

[0054] [High purity triazolinedione adduct] The high-purity triazolinedione adduct obtained in this way has a low impurity content and is suitable as a derivatization reagent. Depending on the raw materials and manufacturing method, it is a pale pink to white solid. According to HPLC measurement, the chemical purity (HPLC purity) is usually about 98 to 99%.

[0055] [Effects of suspension washing] Although the details of why the suspension washing method yields a high-purity triazolinedione adduct are unclear, the inventors speculate as follows. Specifically, the impurities present during the production of the crude triazolinedione adduct are presumably impurities by-produced during the Diels-Alder reaction. During the suspension washing method, the crude triazolinedione adduct does not completely dissolve, remaining as a solid. By mixing the adduct with the solvent for a certain period of time, the impurities and the adduct undergo repeated dissolution and precipitation. This process also washes the interior of the crude triazolinedione adduct, allowing the impurities incorporated within to be removed. Because the proportion of impurities is small relative to the triazolinedione adduct, the inventors speculate that the high-purity triazolinedione adduct can be obtained by repeatedly dissolving and precipitating the adduct by mixing the adduct with the solvent for a certain period of time.

[0056] <Reaction process> The crude triazolinedione adducts to be subjected to the suspension washing step or the preliminary purification step are not particularly limited, but are typically obtained by the Diels-Alder reaction of a triazolinedione compound with a fused ring compound containing at least two aromatic rings. Similarly, a crude triazolinedione adduct can be produced by reacting a triazolinedione compound corresponding to the above triazolinedione compound with a fused ring compound containing at least two aromatic rings in the presence of a hypervalent iodine compound. In this case, the triazolinedione compound is produced as an intermediate product.

[0057] [Triazolinedione compounds] The triazolinedione compound serving as a raw material for the triazolinedione adduct represented by formula (1) is preferably a triazolinedione compound represented by the following formula (6).

[0058] [ka] (In the formula, R 1 is the same as formula (1). Preferably, R in the above formula (6) (formula (1)) 1 is a group selected from the group consisting of a phenyl group, a naphthyl group, an anthracenyl group, a nitrogen-containing heterocyclic group, and an alkyl group, each of which may have a substituent.

[0059] More preferably, R in the above formula (6) (formula (1)) 1 is a phenyl group which may have a substituent selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, a halogen group, a nitro group, and a dimethylamino group.

[0060] Furthermore, the triazolinedione compound serving as a raw material for the triazolinedione adduct represented by formula (2) or formula (4) is preferably a triazolinedione compound represented by the following formula (7).

[0061] [ka] (In the formula, R 2 is synonymous with formula (2) or formula (4). R in the above formula (7) (formula (2) or formula (4)) 2 may contain an oxygen atom or a nitrogen atom, and is preferably a group selected from the group consisting of a di-substituted amino group, a nitro group, an azide group, an alkoxy group, a halogen group, an alkylthio group, a sulfonyl group, a phosphate group, a carboxyl group, an ester group (-COOR (where R is a methyl group or an ethyl group)), a nitrile group, an amide group, a ferrocenyl group, and a quinoxalinyl group having a substituent. Here, the di-substituted amino group may have the same or different substituents selected from the group consisting of an alkyl group, an aralkyl group, and an aryl group.

[0062] Particularly preferably, R in the above formula (7) (formula (2) or formula (4)) 2 is a group selected from the group consisting of alkylamino groups, alkylaminoalkyl groups, dialkylamino groups, and dialkylaminoalkyl groups.

[0063] Most preferably, R in the above formula (7) (formula (2) or formula (4)) 2 is a group selected from the group consisting of a 4-dimethylaminophenyl group, a 4-diethylaminophenyl group, and a 4-dimethylaminomethylphenyl group.

[0064] [Fused ring compounds] Examples of fused ring compounds containing at least two aromatic rings include compounds having the following skeletons: In this embodiment, some of the hydrogen atoms in fused ring compounds having these skeletons may be substituted with a substituent selected from the group consisting of an alkyl group having 1 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms, and a heterocyclic group; and fused ring compounds having these skeletons may be fused with at least one group selected from a cyclic alkyl group having 1 to 20 carbon atoms, a phenyl group, and a heterocyclic group.

[0065] [ka]

[0066] [ka] [Diels-Alder reaction] Typically, a crude triazolinedione adduct can be produced by subjecting a triazolinedione compound represented by the above formula (6) to a Diels-Alder reaction with a fused ring compound containing at least two aromatic rings.

[0067] The Diels-Alder reaction can be carried out by mixing the triazolinedione compound represented by formula (6) with a fused ring compound containing at least two aromatic rings. Specifically, the reaction proceeds by stirring and mixing the two compounds in a reaction solvent.

[0068] Any additive may be added to the reaction system as long as it does not interfere with the reaction. For example, a desiccant may be added to prevent the triazolinedione compound from reacting with water. As the desiccant, an inorganic desiccant, specifically magnesium sulfate, may be used.

[0069] The conditions for the Diels-Alder reaction are described below.

[0070] (Reaction solvent used in Diels-Alder reaction) The reaction solvent used in the Diels-Alder reaction is preferably at least one selected from the group consisting of esters, halogen-containing hydrocarbons, aromatic hydrocarbons, ketones, amides, alkylnitriles, dialkyl ethers, and ureas.

[0071] The Diels-Alder reaction between the triazolinedione compound of formula (6) and a fused ring compound containing at least two aromatic rings is a reversible reaction. Therefore, to shift the reaction equilibrium to the product system, a reaction solvent that can crystallize the product triazolinedione adduct of formula (1) is preferred.

[0072] Examples of reaction solvents include aprotic solvents such as ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methylTHF), 1,4-dioxane, t-butyl methyl ether, 1,2-dimethoxyethane, diglyme, acetone, diethyl ketone, methyl ethyl ketone, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, toluene, xylene, mesitylene, dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), and 1,3-dimethyl-2-imidazolidinone (DMI). These solvents can be used alone or as a mixed solvent.

[0073] Among these, it is preferable to use at least one solvent selected from the group consisting of methylene chloride, chloroform, acetonitrile, 1,2-dimethoxyethane, toluene, and ethyl acetate as the reaction solvent, from the viewpoints of the crystallinity, yield, stability, safety, and cost of the product triazolinedione adduct represented by formula (1).

[0074] The amount of reaction solvent used in the Diels-Alder reaction is preferably 5 to 1000 ml per 1 g of reaction substrate.

[0075] (Diels-Alder reaction temperature) The Diels-Alder reaction between the triazolinedione compound of formula (6) and a fused ring compound containing at least two aromatic rings is reversible, so the reaction temperature must be set to a value that does not promote the reversion reaction. The reaction temperature is preferably in the range of -10 to 60°C, more preferably 0 to 40°C.

[0076] (Diels-Alder reaction time) The reaction time for reacting the triazolinedione compound represented by the above formula (6) with the fused ring compound containing at least two aromatic rings is preferably 10 minutes to 48 hours, more preferably 1 to 10 hours.

[0077] (Amount of fused ring compound used) When reacting the triazolinedione compound represented by the formula (6) with a fused ring compound containing at least two aromatic rings, the amount of the fused ring compound used is not particularly limited as long as it is an amount that allows all of the triazolinedione compound to react, but it is preferably in the range of 1.0 to 10,000 equivalents per equivalent of the triazolinedione compound.

[0078] The Diels-Alder reaction usually terminates when the starting triazolinedione compound represented by formula (6) or the fused ring compound containing at least two aromatic rings disappears. After the Diels-Alder reaction is terminated, the reaction mixture containing the triazolinedione adduct may be separated into solid and liquid forms by filtration, centrifugation, or other methods, followed by drying by air drying, air drying, vacuum drying, or other methods to isolate and use the crude triazolinedione adduct. Alternatively, the crude triazolinedione adduct may be used in the next step as a dissolved or suspended liquid without isolating it. When a preliminary purification step is performed, it is more efficient to use the crude triazolinedione adduct in its dissolved or suspended form.

[0079] The crude triazolinedione adduct obtained in this manner is usually a purple to white solid, although this depends on the raw materials and production method. The chemical purity (HPLC purity) measured by HPLC is usually about 91 to 97%.

[0080] <Preliminary purification process> In the method for producing a triazolinedione adduct of this embodiment, the crude triazolinedione adduct can be purified by carrying out only the suspension washing step, but the crude triazolinedione adduct can also be purified by carrying out the preliminary purification step and then carrying out the suspension washing step.

[0081] The pre-purification step can be carried out, for example, by the following two methods (pre-purification steps (1) and (2)) (see FIGS. 1 and 2).

[0082] (1) The liquid obtained in the reaction step, in which the crude triazolinedione adduct is dissolved or suspended, is subjected to solvent substitution with a first hydrocarbon solvent to thoroughly precipitate the triazolinedione adduct (solvent substitution step). This is followed by filtration, and the resulting filter cake is washed with a second hydrocarbon solvent, which may be the same as or different from the first hydrocarbon solvent (washing step). This operation allows for the removal of low-polarity impurities. The filter cake is then dissolved in a halogenated solvent, and any remaining inorganic compounds, such as inorganic desiccants, are removed by filtration to obtain a solution of the crude triazolinedione adduct that has been subjected to the preliminary purification step, dissolved in the halogenated solvent (dissolution step). Here, the halogenated solvent can be removed from the solution to obtain the crude triazolinedione adduct that has been subjected to the preliminary purification step, as a solid, which is the target of the suspension washing step.

[0083] (2) A halogen-based solvent is added to the liquid in which the crude triazolinedione adduct is dissolved or suspended, obtained in the reaction step, to dissolve the crude triazolinedione adduct, and any inorganic compounds, such as inorganic desiccants, that remain undissolved are removed by filtration (dissolution step). The resulting filtrate is then subjected to solvent substitution with a first hydrocarbon solvent to precipitate the triazolinedione adduct (solvent substitution step). Filtration is then performed, and the resulting filter cake is washed with a second hydrocarbon solvent, which may be the same as or different from the first hydrocarbon solvent, to remove low-polarity impurities, yielding the crude triazolinedione adduct, which has been subjected to the preliminary purification step, as a solid, which is then subjected to the suspension washing step (washing step).

[0084] These operations as preliminary purification steps enable the removal of low-polarity impurities resulting from the reversion reaction of the Diels-Alder reaction carried out during the production of the crude triazolinedione adduct, as well as inorganic compounds used during the production process.

[0085] Specifically, low-polarity impurities dissolve in hydrocarbon solvents, but the triazolinedione adduct does not, so the low-polarity impurities can be removed in the solvent substitution step and the washing step.Furthermore, the inorganic compounds used in the production are insoluble in halogen-based solvents, but the triazolinedione adduct does dissolve in halogen-based solvents, so the inorganic compounds can be removed in the dissolution step.

[0086] In other words, by carrying out a preliminary purification step before the suspension washing step, a crude triazolinedione adduct with fewer impurities can be used as the raw material for the suspension washing step, and the triazolinedione adduct can be highly purified.

[0087] <Preliminary purification step (1)> The preliminary purification step (1) is carried out in the order of a solvent substitution step, a washing step, and a dissolution step. Details and conditions of each step are described below.

[0088] <Solvent substitution process> The solvent substitution step is carried out immediately after the production of the crude triazolinedione adduct, without isolating the crude triazolinedione adduct from the liquid in which the crude triazolinedione adduct is dissolved or suspended.

[0089] In the solvent substitution step, the crude triazolinedione adduct is dissolved or suspended in the reaction solvent used in the Diels-Alder reaction, and the solvent is substituted with a first hydrocarbon solvent, causing the triazolinedione adduct to precipitate and become suspended in the first hydrocarbon solvent.

[0090] Since the triazolinedione adduct has low solubility in the first hydrocarbon solvent, solvent substitution can sufficiently precipitate crystals of the triazolinedione adduct, while the low-polarity impurities are dissolved in the first hydrocarbon solvent.

[0091] The method of solvent substitution is not particularly limited as long as it sufficiently precipitates crystals of the triazolinedione adduct, but from the viewpoint of process simplicity, a method in which the triazolinedione adduct is partially or completely dissolved in the reaction solvent, a first hydrocarbon solvent (usually a poor solvent for the target substance) is added, and the solvent is removed under reduced pressure to precipitate the triazolinedione adduct is preferred. As long as the triazolinedione adduct is sufficiently precipitated, the reaction solvent before solvent substitution may remain. The conditions for solvent substitution are as described below.

[0092] (First hydrocarbon solvent) The first hydrocarbon solvent is not particularly limited as long as it is a solvent that sufficiently precipitates the triazolinedione adduct, but is preferably a hydrocarbon solvent having 5 to 15 carbon atoms. Taking into account the solvent substitution method described above, the first hydrocarbon solvent desirably has a higher boiling point than the reaction solvent used in the synthesis of the crude triazolinedione adduct, and is more preferably a hydrocarbon solvent having 7 to 9 carbon atoms. Specific examples of the first hydrocarbon solvent include n-heptane, n-octane, and n-nonane. From the viewpoint of operational efficiency, it is most preferable to use n-heptane as the first hydrocarbon solvent.

[0093] (Temperature when solvent substitution is performed) The temperature during solvent substitution must be set so as not to promote the reversion reaction, since the Diels-Alder reaction that produces the triazolinedione adduct is a reversible reaction. From the viewpoint of the stability of the triazolinedione adduct, the temperature during solvent substitution is preferably set in the range of 0 to 40°C, more preferably in the range of 0 to 25°C, and even more preferably in the range of 10 to 25°C. The temperature is most preferably set in the range of 20 to 25°C.

[0094] (Amount of first hydrocarbon solvent added when performing solvent substitution) The amount of the first hydrocarbon solvent to be added is not particularly limited as long as it is an amount that allows the triazolinedione adduct to be sufficiently precipitated, but it is preferable to use 50 to 200 mL of the first hydrocarbon solvent per 1.0 g of crude triazolinedione adduct.

[0095] <Cleaning process> The liquid containing the precipitated triazolinedione adduct and the first hydrocarbon solvent is filtered to obtain a residue containing the triazolinedione adduct. At this time, the low-polarity impurities can be separated because they are dissolved in the hydrocarbon solvent.

[0096] The temperature at which filtration is carried out must be a temperature that does not promote the reversion reaction, since the Diels-Alder reaction that produces the triazolinedione adduct is a reversible reaction. From the viewpoint of the stability of the triazolinedione adduct, the temperature at which filtration is carried out is preferably in the range of 0 to 40°C, more preferably in the range of 0 to 25°C, and even more preferably in the range of 10 to 25°C. The temperature is most preferably in the range of 20 to 25°C.

[0097] After filtration, the filter cake containing the triazolinedione adduct is washed with a second hydrocarbon solvent, which may be the same as or different from the first hydrocarbon solvent. This operation allows for the removal of low-polarity impurities. The second hydrocarbon solvent can be the same as the first hydrocarbon solvent.

[0098] <Dissolution process> Thereafter, the residue containing the triazolinedione adduct is dissolved in a halogen-based solvent.

[0099] The halogen-based solvent is not particularly limited as long as it dissolves the triazolinedione adduct, which is the product. From the viewpoint of ease of removal, it is preferable to use dichloromethane as the halogen-based solvent.

[0100] Since the Diels-Alder reaction to obtain the triazolinedione adduct is a reversible reaction, the temperature during dissolution must be a temperature that does not promote the reversion reaction. From the viewpoint of the stability of the triazolinedione adduct, the temperature during dissolution is preferably in the range of 0 to 40°C, more preferably in the range of 0 to 25°C, and even more preferably in the range of 10 to 25°C. The most preferred range is 20 to 25°C.

[0101] The amount of halogenated solvent used is not critical as long as it is an amount that can completely dissolve the triazolinedione adduct, but it is preferable to use 50 to 200 mL of halogenated solvent per 1.0 g of the filter cake containing the triazolinedione adduct.

[0102] After dissolving the triazolinedione adduct in a halogen-based solvent, the inorganic compounds such as the inorganic desiccant that remain undissolved are removed by filtration. The filtration method is not particularly limited as long as it is a commonly used method.

[0103] The temperature at which filtration is carried out must be a temperature that does not promote the reversion reaction, since the Diels-Alder reaction that produces the triazolinedione adduct is a reversible reaction. From the viewpoint of the stability of the triazolinedione adduct, the temperature at which filtration is carried out is preferably in the range of 0 to 40°C, more preferably in the range of 0 to 25°C, and even more preferably in the range of 10 to 25°C. The temperature is most preferably in the range of 20 to 25°C.

[0104] In order to obtain the triazolinedione adduct as a solid from a solution in which the triazolinedione adduct is dissolved in a halogenated solvent, it is necessary to remove the solvent. The method for removing the solvent is not particularly limited as long as it is a commonly used method such as solvent distillation or vacuum distillation.

[0105] The crude triazolinedione adduct subjected to the preliminary purification step (1) may be dried before the suspension washing step, and the drying method is not particularly limited. Specifically, the crude triazolinedione adduct subjected to the preliminary purification step (1) can be dried by natural drying, air drying, vacuum drying, etc.

[0106] In this way, a crude triazolinedione adduct that has been subjected to the preliminary purification step (1) is obtained, which is the target of the suspension washing step.

[0107] <Preliminary purification step (2)> The preliminary purification step (2) is basically the same as the preliminary purification step (1), but is carried out in the order of a dissolution step, a solvent substitution step, and a washing step. The details and conditions of each step are as described below.

[0108] <Dissolution process> The dissolution step is carried out immediately after the production of the crude triazolinedione adduct, without isolating the crude triazolinedione adduct from the liquid in which the crude triazolinedione adduct is dissolved or suspended. In the dissolution step, all of the triazolinedione adduct remaining in the solvent used in the Diels-Alder reaction is dissolved in a halogen-based solvent.

[0109] The halogen-based solvent is not particularly limited as long as it dissolves the triazolinedione adduct that is the product. From the viewpoint of ease of removal, it is preferable to use dichloromethane as the halogen-based solvent.

[0110] Because the Diels-Alder reaction to obtain the triazolinedione adduct is a reversible reaction, the temperature during dissolution must be a temperature that does not promote the reversion reaction. From the viewpoint of the stability of the triazolinedione adduct, the temperature during dissolution is preferably in the range of 0 to 40°C, more preferably in the range of 0 to 25°C, and even more preferably in the range of 10 to 25°C. From the viewpoint of operational efficiency, the temperature during dissolution is most preferably in the range of 20 to 25°C.

[0111] The amount of the halogenated solvent used is not critical as long as it is an amount that can completely dissolve the triazolinedione adduct, but it is preferable to use 50 to 200 mL of the halogenated solvent per 1.0 g of the crude triazolinedione adduct.

[0112] After dissolving the triazolinedione adduct in a halogen-based solvent, inorganic compounds such as inorganic desiccants that remain undissolved are removed by filtration.

[0113] The temperature at which filtration is carried out must be a temperature that does not promote the reversion reaction, since the Diels-Alder reaction that produces the triazolinedione adduct is a reversible reaction. From the viewpoint of the stability of the triazolinedione adduct, the temperature at which filtration is carried out is preferably in the range of 0 to 40°C, more preferably in the range of 0 to 25°C, and even more preferably in the range of 10 to 25°C. From the viewpoint of operational efficiency, the temperature at which filtration is carried out is most preferably in the range of 20 to 25°C.

[0114] <Solvent substitution process> The triazolinedione adduct contained in the filtrate obtained in the dissolution step is dissolved in the reaction solvent and halogenated solvent used in the Diels-Alder reaction.

[0115] The solvent substitution step changes the triazolinedione adduct from a state in which it is dissolved in the reaction solvent and halogenated solvent used in the Diels-Alder reaction to a state in which it is suspended in the first hydrocarbon solvent.

[0116] Because the triazolinedione adduct has low solubility in the first hydrocarbon solvent, the above-mentioned solvent substitution can sufficiently precipitate the triazolinedione adduct crystals. While any solvent substitution method can be used as long as sufficient crystals of the triazolinedione adduct are obtained, from the viewpoint of process simplicity, a preferred method is to add a first hydrocarbon solvent (usually a poor solvent for the target substance) to the triazolinedione adduct dissolved entirely in the reaction solvent and halogenated solvent used in the Diels-Alder reaction, and then remove the solvent under reduced pressure to precipitate the triazolinedione adduct. As long as the triazolinedione adduct is sufficiently precipitated, the reaction solvent and halogenated solvent used in the Diels-Alder reaction before solvent substitution may remain. The conditions for solvent substitution are described below.

[0117] (First hydrocarbon solvent) The first hydrocarbon solvent is not particularly limited as long as it is a solvent that sufficiently precipitates the triazolinedione adduct, but is preferably a hydrocarbon solvent having 5 to 15 carbon atoms. Taking into account the solvent substitution method described above, the first hydrocarbon solvent desirably has a higher boiling point than the reaction solvent and halogenated solvent used in the synthesis of the crude triazolinedione adduct, and is more preferably a hydrocarbon solvent having 7 to 9 carbon atoms. Specific examples of the first hydrocarbon solvent include n-heptane, n-octane, and n-nonane. From the viewpoint of operational efficiency, it is most preferable to use n-heptane as the first hydrocarbon solvent.

[0118] (Temperature when solvent substitution is performed) The temperature during solvent substitution must be such that it does not promote the reversion reaction, since the Diels-Alder reaction that produces the triazolinedione adduct is a reversible reaction. From the viewpoint of the stability of the triazolinedione adduct, the temperature during solvent substitution is preferably in the range of 0 to 40°C, more preferably in the range of 0 to 25°C, and even more preferably in the range of 10 to 25°C. From the viewpoint of operational efficiency, the temperature is most preferably in the range of 20 to 25°C.

[0119] (Amount of first hydrocarbon solvent when performing solvent substitution) The amount of the first hydrocarbon solvent to be added is not particularly limited as long as it is an amount that allows the triazolinedione adduct to be sufficiently precipitated, but it is preferable to use 50 to 200 mL of the first hydrocarbon solvent per 1.0 g of crude triazolinedione adduct.

[0120] <Cleaning process> The liquid containing the precipitated triazolinedione adduct and the first hydrocarbon solvent is filtered to obtain the triazolinedione adduct.

[0121] The temperature at which filtration is carried out must be a temperature that does not promote the reversion reaction, since the Diels-Alder reaction that produces the triazolinedione adduct is a reversible reaction. From the viewpoint of the stability of the triazolinedione adduct, the temperature at which filtration is carried out is preferably in the range of 0 to 40°C, more preferably in the range of 0 to 25°C, and even more preferably in the range of 10 to 25°C. From the viewpoint of operational efficiency, the temperature is most preferably in the range of 20 to 25°C.

[0122] After filtration, the filter cake containing the triazolinedione adduct is washed with a second hydrocarbon solvent, which may be the same as or different from the first hydrocarbon solvent. This operation allows for the removal of low-polarity impurities. The second hydrocarbon solvent can be the same as the first hydrocarbon solvent.

[0123] In this way, a crude triazolinedione adduct that has been subjected to the preliminary purification step (2) is obtained, which is the target of the suspension washing step. The triazolinedione adduct that has been subjected to the preliminary purification step (2) may be dried before the suspension washing step is carried out, and the drying method is not particularly limited. Specifically, the crude triazolinedione adduct that has been subjected to the preliminary purification step (2) can be dried by natural drying, air drying, vacuum drying, or the like. [Example]

[0124] Next, examples of the present invention will be described, but the present invention is not limited to these examples.

[0125] <Chemical (HPLC) Purity Measurement> In this example, the purity of the triazolinedione adduct was measured using HPLC under the following conditions: The chemical (HPLC) purity was calculated as the area % of the triazolinedione adduct in the HPLC measurement.

[0126] (Measurement conditions) Apparatus: High-performance liquid chromatograph (Waters 2695) Detector: UV-visible spectrophotometer (Waters 2489) Detection wavelength: 210 nm Column: Inertsil ODS-3 (5 μm, 4.6 × 250 mm) (GL Sciences) Mobile phase A: Acetonitrile Mobile phase B: distilled water Mobile phase delivery: Mobile phase A and mobile phase B were changed as follows to control the concentration gradient. Column temperature: constant temperature around 40°C Injection volume: 10μL Sample concentration: 0.1 mg / mL Eluent: Mobile phase A / mobile phase B=50 / 50 (0~10min) Mobile phase A / mobile phase B=50 / 50→95 / 5 (10~20min) Mobile phase A / Mobile phase B=95 / 5 (20~50min) Mobile phase A / Mobile phase B=95 / 5→50 / 50 (50~55min) Mobile phase A / mobile phase B = 50 / 50 (55-60 min) (gradient conditions) Mobile phase A: Acetonitrile Mobile phase B: distilled water <Calculation of yield after preliminary purification step> The yield of the triazolinedione adduct in this example was calculated from the ratio of the amount of substance of the triazolinedione adduct after the preliminary purification step to the amount of substance of the raw material.

[0127] <Calculation of recovery rate after suspension washing process> The recovery rate of the triazolinedione adduct in this example was calculated from the ratio of the mass of the triazolinedione adduct after the suspension washing step to the mass of the triazolinedione adduct before the suspension washing step.

[0128] Example 1 (Reaction step and preliminary purification step (1) of 5,10-dihydro-2-(4-dimethylaminophenyl)-5-phenyl-5,10[1',2']-benzeno-1H-[1,2,4]triazolo[1,2-b]phthalazine-1,3(2H)-dione (DAP-PA)) In a flask, 7.55 g (34.3 mmol) of 4-(4'-dimethylaminophenyl)-1,2,4-triazolidine-3,5-dione, 7.55 g (34.3 mmol) of iodosylbenzene, 8.72 g (34.3 mmol) of 9-phenylanthracene, 7.55 g of magnesium sulfate, and 377 ml of ethyl acetate were added, and the mixture was stirred at room temperature for 24 hours to obtain a suspension of crude triazolinedione adduct (DAP-PA).

[0129] 380 ml of heptane was added to the resulting suspension, and the ethyl acetate was removed under reduced pressure (solvent substitution step). The suspension was then filtered and washed with 380 ml of hexane (washing step). The triazolinedione adduct (DAP-PA) on the filter paper was then dissolved in 380 ml of dichloromethane and filtered (dissolution step). The dichloromethane was then removed from the filtrate, and the mixture was dried to obtain the triazolinedione adduct (DAP-PA). The resulting triazolinedione adduct (DAP-PA) was 5,10-dihydro-2-(4-dimethylaminophenyl)-5-phenyl-5,10[1',2']-benzeno-1H-[1,2,4]triazolo[1,2-b]phthalazine-1,3(2H)-dione (DAP-PA), with a yield of 11.5 g, a yield of 70.9%, and a chemical purity (HPLC) of 96.6%.

[0130] (DAP-PA suspension washing process (using acetone)) In a flask, 230 ml of acetone was added to 11.5 g of the triazolinedione adduct (DAP-PA), and the mixture was stirred at room temperature for about 14 hours to obtain a suspension.

[0131] The resulting suspension was filtered and washed with 35 ml of acetone to remove impurities. The filtered solid was dried under reduced pressure to obtain the triazolinedione adduct (DAP-PA). The chemical purity (HPLC) was 99.4%, and the recovery rate was 69.5%. The results are shown in Table 1.

[0132] [Reaction scheme] The reaction scheme carried out in the reaction step of Example 1 is shown below.

[0133] [ka] [Physical property evaluation] The obtained DAP-PA was subjected to various analyses, and the results are shown below. MP:>200℃ IR(KBr):1774,1714cm -1 1 H-NMR (CDCl3): δ 7.86(d,J=8.8Hz,2H),7.49-7.60(m,5H),7.32(dt,J=1.2,7.6Hz,2H),7.23(dt,J=1.2Hz,7.8Hz,2H ),7.03(d,(d,J=8.0Hz,2H),6.78(d,J=9.2Hz,2H),6.56(d,J=9.2Hz,2H),6.39(s,1H),2.88(s,6H) <Example 2> (Reaction step and preliminary purification step (1) of 5,10-dihydro-2-(4-dimethylaminophenyl)-5-methyl-5,10[1',2']-benzeno-1H-[1,2,4]triazolo[1,2-b]phthalazine-1,3(2H)-dione (DAP-MA)) In a flask, 7.55 g (34.3 mmol) of 4-(4'-dimethylaminophenyl)-1,2,4-triazolidine-3,5-dione, 7.55 g (34.3 mmol) of iodosylbenzene, 6.59 g (34.3 mmol) of 9-methylanthracene, 7.55 g of magnesium sulfate, and 377 ml of ethyl acetate were added, and the mixture was stirred at room temperature for 24 hours to obtain a suspension of crude triazolinedione adduct (DAP-MA).

[0134] 380 ml of heptane was added to the resulting suspension, and the ethyl acetate was removed under reduced pressure (solvent substitution step). The suspension was then filtered and washed with 380 ml of hexane (washing step). The triazolinedione adduct (DAP-MA) on the filter paper was then dissolved in 380 ml of dichloromethane and filtered (dissolution step). The dichloromethane was then removed from the filtrate, and the mixture was dried to obtain the triazolinedione adduct (DAP-MA). The resulting triazolinedione adduct (DAP-MA) was 5,10-dihydro-2-(4-dimethylaminophenyl)-5-methyl-5,10[1',2']-benzeno-1H-[1,2,4]triazolo[1,2-b]phthalazine-1,3(2H)-dione (DAP-MA), with a yield of 7.24 g, a yield of 51.4%, and a chemical purity (HPLC) of 96.7%.

[0135] (DAP-MA suspension washing process (using acetone)) In a flask, 145 ml of acetone was added to 7.24 g of the triazolinedione adduct (DAP-MA), and the mixture was stirred at room temperature for about 14 hours to obtain a suspension.

[0136] The resulting suspension was filtered and washed with 22 ml of acetone to remove impurities. The filtered solid was dried under reduced pressure to obtain the triazolinedione adduct (DAP-MA). The chemical purity (HPLC) was 98.9%, and the recovery rate was 65.3%. The results are shown in Table 1.

[0137] [Reaction scheme] The reaction scheme carried out in the reaction step of Example 2 is shown below.

[0138] [ka] [Physical property evaluation] The obtained DAP-MA was subjected to various analyses, and the results are shown below. MP:>218℃ IR(KBr):1765,1708cm -1 1 H-NMR (CDCl3): δ 7.46(dd,J=1.6,6.8Hz,4H),7.26-7.34(m,4H),6.95(d,J=9.2Hz,2H),6.62(d,J=8.8Hz,2H),6.31(s,1H),2.91(s,6H),2.69(s,3H) Example 3 (Reaction process and preliminary purification process (1) of 5,10-dihydro-2-(4-dimethylaminophenyl)-5,10[1',2']-benzeno-1H-[1,2,4]triazolo[1,2-b]phthalazine-1,3(2H)-dione (DAP-A)) In a flask, 7.55 g (34.3 mmol) of 4-(4'-dimethylaminophenyl)-1,2,4-triazolidine-3,5-dione, 7.55 g (34.3 mmol) of iodosylbenzene, 6.11 g (34.3 mmol) of anthracene, 7.55 g of magnesium sulfate, and 377 ml of ethyl acetate were added, and the mixture was stirred at room temperature for 24 hours to obtain a suspension of crude triazolinedione adduct (DAP-A).

[0139] 380 ml of heptane was added to the resulting suspension, and the ethyl acetate was removed under reduced pressure (solvent substitution step). The suspension was then filtered and washed with 380 ml of hexane (washing step). The triazolinedione adduct (DAP-A) on the filter paper was then dissolved in 380 ml of dichloromethane and filtered (dissolution step). The dichloromethane was then removed from the filtrate, and the mixture was dried to obtain the triazolinedione adduct (DAP-A). The resulting triazolinedione adduct (DAP-A) was 5,10-dihydro-2-(4-dimethylaminophenyl)-5,10[1',2']-benzeno-1H-[1,2,4]triazolo[1,2-b]phthalazine-1,3(2H)-dione (DAP-A), with a yield of 5.71 g, a yield of 42.0%, and a chemical purity (HPLC) of 95.9%.

[0140] (DAP-A suspension washing process (using acetone)) In a flask, 114 ml of acetone was added to 5.71 g of the triazolinedione adduct (DAP-A), and the mixture was stirred at room temperature for about 14 hours to obtain a suspension.

[0141] The resulting suspension was filtered and washed with 17 ml of acetone to remove impurities. The filtered solid was dried under reduced pressure to obtain the triazolinedione adduct (DAP-A). The chemical purity (HPLC) was 99.0%, and the recovery rate was 65.0%. The results are shown in Table 1.

[0142] [Reaction scheme] The reaction scheme carried out in the reaction step of Example 3 is shown below.

[0143] [ka] [Physical property evaluation] The obtained DAP-A was subjected to various analyses, and the results are shown below. MP: 217~218℃ IR(KBr):1780,1717cm -1 1 H-NMR (CDCl3): δ 7.48(dd,J=6.3Hz,4H),7.30(dd,J=6.3Hz,4H),6.91(d,J=9.0Hz,2H),6.62(d,J=9.0Hz,2H),6.31(s,2H),2.91(s,6H)

[0144] [Table 1] Example 4 (DAP-PA reaction process, preliminary purification process (1), and suspension washing process (using methyl ethyl ketone)) Crude triazolinedione adduct (DAP-PA) was synthesized in the same manner as in Example 1, and after carrying out the preliminary purification step (1), 2.0 ml of methyl ethyl ketone was added to 0.1 g of the triazolinedione adduct (DAP-PA), and the mixture was stirred at room temperature for about 14 hours to obtain a suspension.

[0145] The resulting suspension was filtered and washed with 10 ml of methyl ethyl ketone to remove impurities. The filtered solid was dried under reduced pressure to obtain the triazolinedione adduct (DAP-PA). The chemical purity (HPLC) was 99.1%, and the recovery rate was 52.0%. The results are shown in Table 2.

[0146] <Example 5> (DAP-PA reaction process, preliminary purification process (1), and suspension washing process (using acetylacetone)) Crude triazolinedione adduct (DAP-PA) was synthesized in the same manner as in Example 1, and after carrying out the preliminary purification step (1), 2.0 ml of acetylacetone was added to 0.1 g of the triazolinedione adduct (DAP-PA), and the mixture was stirred at room temperature for about 14 hours to obtain a suspension.

[0147] The resulting suspension was filtered and washed with 10 ml of acetylacetone to remove impurities. The filtered solid was dried under reduced pressure to obtain the triazolinedione adduct (DAP-PA). The chemical purity (HPLC) was 99.0%, and the recovery rate was 53.0%. The results are shown in Table 2.

[0148] Example 6 (DAP-PA reaction process, preliminary purification process (1), and suspension washing process (using ethanol)) Crude triazolinedione adduct (DAP-PA) was synthesized in the same manner as in Example 1, and after carrying out the preliminary purification step (1), 2.0 ml of ethanol was added to 0.1 g of the triazolinedione adduct (DAP-PA), and the mixture was stirred at room temperature for about 14 hours to obtain a suspension.

[0149] The resulting suspension was filtered and washed with 10 ml of ethanol to remove impurities. The filtered solid was dried under reduced pressure to obtain the triazolinedione adduct (DAP-PA). The chemical purity (HPLC) was 98.3%, and the recovery rate was 77.7%. The results are shown in Table 2.

[0150] Example 7 (DAP-PA reaction step, preliminary purification step (1), and suspension washing step (using acetonitrile)) Crude triazolinedione adduct (DAP-PA) was synthesized in the same manner as in Example 1, and after carrying out the preliminary purification step (1), 2.0 ml of acetonitrile was added to 0.1 g of the triazolinedione adduct (DAP-PA), and the mixture was stirred at room temperature for about 14 hours to obtain a suspension.

[0151] The resulting suspension was filtered and washed with 10 ml of acetonitrile to remove impurities. The filtered solid was dried under reduced pressure to obtain the triazolinedione adduct (DAP-PA). The chemical purity (HPLC) was 98.2%, and the recovery rate was 62.0%. The results are shown in Table 2.

[0152] Example 8 (DAP-PA reaction step, preliminary purification step (1), and suspension washing step (using ethyl acetate)) Crude triazolinedione adduct (DAP-PA) was synthesized in the same manner as in Example 1, and after carrying out the preliminary purification step (1), 2.0 ml of ethyl acetate was added to 0.1 g of the triazolinedione adduct (DAP-PA), and the mixture was stirred at room temperature for about 14 hours to obtain a suspension.

[0153] The resulting suspension was filtered and washed with 10 ml of ethyl acetate to remove impurities. The filtered solid was dried under reduced pressure to obtain the triazolinedione adduct (DAP-PA). The chemical purity (HPLC) was 98.7%, and the recovery rate was 50.0%. The results are shown in Table 2.

[0154] [Table 2] Example 9 (DAP-PA reaction process, preliminary purification process (1), and suspension washing process (using methyl acetate)) Crude triazolinedione adduct (DAP-PA) was synthesized in the same manner as in Example 1, and after carrying out the preliminary purification step (1), 2.0 ml of methyl acetate was added to 0.1 g of the triazolinedione adduct (DAP-PA), and the mixture was stirred at room temperature for about 14 hours to obtain a suspension.

[0155] The resulting suspension was filtered and washed with 10 ml of methyl acetate to remove impurities. The filtered solid was dried under reduced pressure to obtain the triazolinedione adduct (DAP-PA). The chemical purity (HPLC) was 98.9%, and the recovery rate was 51.0%. The results are shown in Table 3. Example 10 (DAP-PA reaction process and suspension washing process (using acetone)) A crude triazolinedione adduct (DAP-PA) was synthesized in the same manner as in Example 1, and the resulting suspension was evaporated to remove ethyl acetate. 114 ml of acetone was then added to the resulting crude triazolinedione adduct (DAP-PA), and the mixture was stirred at room temperature for approximately 14 hours to obtain a suspension.

[0156] The resulting suspension was filtered and washed with 17 ml of acetone to remove impurities. The filtered solid was dried under reduced pressure to obtain the triazolinedione adduct (DAP-PA). The chemical purity (HPLC) was 93.1%, and the recovery rate was 75.0%. The results are shown in Table 3.

[0157] Example 11 (DAP-PA reaction process and suspension washing process (using ethanol)) A crude triazolinedione adduct (DAP-PA) was synthesized in the same manner as in Example 1, and the resulting suspension was evaporated to remove ethyl acetate. 114 ml of ethanol was then added to the resulting crude triazolinedione adduct (DAP-PA), and the mixture was stirred at room temperature for approximately 14 hours to obtain a suspension.

[0158] The resulting suspension was filtered and washed with 17 ml of ethanol to remove impurities. The filtered solid was dried under reduced pressure to obtain the triazolinedione adduct (DAP-PA). The chemical purity (HPLC) was 90.7%, and the recovery rate was 85.0%. The results are shown in Table 3.

[0159] Example 12 (DAP-PA reaction step, preliminary purification step (2), and suspension washing step (using acetone)) Crude triazolinedione adduct (DAP-PA) was synthesized in the same manner as in Example 1. 380 ml of dichloromethane was added to the resulting suspension to completely dissolve the crude triazolinedione adduct (DAP-PA), and the solution was then filtered (dissolution step). Subsequently, 380 ml of heptane was added to the filtrate, and the dichloromethane and ethyl acetate were removed under reduced pressure (solvent substitution step). Subsequently, the suspension was filtered and washed with 380 ml of hexane (washing step). Subsequently, the residue was dried to obtain triazolinedione adduct (DAP-PA). The yield was 70.9%, and the chemical purity (HPLC) was 96.6%. Next, 114 ml of acetone was added to the obtained triazolinedione adduct (DAP-PA), and the mixture was stirred at room temperature for approximately 14 hours to obtain a suspension.

[0160] The resulting suspension was filtered and washed with 17 ml of acetone to remove impurities. The filtered solid was dried under reduced pressure to obtain the triazolinedione adduct (DAP-PA). The chemical purity (HPLC) was 99.4%, and the recovery rate was 68.5%. The results are shown in Table 3.

[0161] Example 13 (DAP-PA reaction step, preliminary purification step (2), and suspension washing step (using ethanol)) Crude triazolinedione adduct (DAP-PA) was synthesized in the same manner as in Example 1. 380 ml of dichloromethane was added to the resulting suspension to completely dissolve the crude triazolinedione adduct (DAP-PA), and the solution was then filtered (dissolution step). Subsequently, 380 ml of heptane was added to the filtrate, and the dichloromethane and ethyl acetate were removed under reduced pressure (solvent substitution step). Subsequently, the suspension was filtered and washed with 380 ml of hexane (washing step). The residue was then dried to obtain triazolinedione adduct (DAP-PA). The yield was 70.9%, and the chemical purity (HPLC) was 96.6%. Next, 114 ml of ethanol was added to the obtained triazolinedione adduct (DAP-PA), and the mixture was stirred at room temperature for approximately 14 hours to obtain a suspension.

[0162] The resulting suspension was filtered and washed with 17 ml of ethanol to remove impurities. The filtered solid was dried under reduced pressure to obtain the triazolinedione adduct (DAP-PA). The chemical purity (HPLC) was 98.3%, and the recovery rate was 77.5%. The results are shown in Table 3.

[0163] [Table 3] <Comparative Example 1> (DAP-PA Reaction Step, Pre-purification Step (1), and Recrystallization Step) Crude triazolinedione adduct (DAP-PA) was synthesized in the same manner as in Example 1, and after carrying out the preliminary purification step (1), 13.0 ml of tetrahydrofuran and 39.0 ml of ethanol were added to 0.1 g of the triazolinedione adduct (DAP-PA) at 25°C to completely dissolve the triazolinedione adduct (DAP-PA), and the mixture was allowed to stand at 0°C for approximately 14 hours to allow it to recrystallize.

[0164] The precipitated solid was collected by filtration and washed with 5.0 ml of a tetrahydrofuran / ethanol (1 / 3) mixed solvent. The collected solid was then dried under reduced pressure to obtain the triazolinedione adduct (DAP-PA). The chemical purity (HPLC) was 97.1%, and the recovery rate was 30.0%. The results are shown in Table 4.

[0165] [Table 4]

Claims

1. A reaction step of subjecting a triazolinedione compound represented by the following formula (7) to a Diels-Alder reaction with a fused ring compound having an anthracene skeleton to obtain a crude product of a triazolinedione adduct represented by the following formula (2): a pre-purification step of pre-purifying the crude product of the triazolinedione adduct; a suspension washing step of purifying the crude product of the triazolinedione adduct pre-purified in the pre-purification step by suspension washing; The preliminary purification step includes a solvent substitution step of performing solvent substitution on a liquid in which the crude product of the triazolinedione adduct is dissolved or suspended, with a first hydrocarbon solvent; a washing step of filtering the liquid obtained by the solvent substitution step and washing the filter cake with a second hydrocarbon solvent that is the same as or different from the first hydrocarbon solvent; and a dissolving step of dissolving the filter cake washed in the washing step in a halogenated solvent and filtering the mixture. 【Chemical 1】 (In the formula, R 2 s are the same or different and are selected from the group consisting of a di-substituted amino group having a substituent selected from the group consisting of an alkyl group, an aralkyl group, and an aryl group, a nitro group, an azide group, an alkoxy group, a halogen group, an alkylthio group, a sulfonyl group, a phosphate group, a carboxyl group, an ester group (-COOR (wherein R is a methyl group or an ethyl group)), a nitrile group, an amide group, a ferrocenyl group, and a quinoxalinyl group having a substituent.) 【Chemistry 2】 (In the formula, R 2 has the same meaning as in formula (7), R 3 , R 4 , and R 5 each independently represent a substituent selected from the group consisting of a halogen group, an amino group, a nitro group, an alkyl group having 1 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms, a heteroaryl group having 5 to 20 carbon atoms, and an acyl group having 2 to 20 carbon atoms; l and m each independently represent an integer of 0 to 4, and n represents an integer of 0 to 2. Here, the aryl group having 6 to 20 carbon atoms and the heteroaryl group having 5 to 20 carbon atoms may have a substituent selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, a halogen group, a nitro group, and a dimethylamino group.)

2. A reaction step of subjecting a triazolinedione compound represented by the following formula (7) to a Diels-Alder reaction with a fused ring compound having an anthracene skeleton to obtain a crude product of a triazolinedione adduct represented by the following formula (2): a pre-purification step of pre-purifying the crude product of the triazolinedione adduct; a suspension washing step of purifying the crude product of the triazolinedione adduct pre-purified in the pre-purification step by suspension washing; The preliminary purification step includes a dissolving step of adding a halogenated solvent to a liquid in which the crude product of the triazolinedione adduct is dissolved or suspended, thereby dissolving the crude product of the triazolinedione adduct, and filtering the resultant mixture; a solvent substitution step of subjecting the filtrate obtained in the dissolving step to solvent substitution with a first hydrocarbon solvent; and a washing step of filtering the liquid obtained after solvent substitution in the solvent substitution step, and washing the resulting filter cake with a second hydrocarbon solvent that is the same as or different from the first hydrocarbon solvent. 【Chemistry 3】 (In the formula, R 2 s are the same or different and are selected from the group consisting of a di-substituted amino group having a substituent selected from the group consisting of an alkyl group, an aralkyl group, and an aryl group, a nitro group, an azide group, an alkoxy group, a halogen group, an alkylthio group, a sulfonyl group, a phosphate group, a carboxyl group, an ester group (-COOR (wherein R is a methyl group or an ethyl group)), a nitrile group, an amide group, a ferrocenyl group, and a quinoxalinyl group having a substituent.) 【Chemistry 4】 (In the formula, R 2 has the same meaning as in formula (7), R 3 , R 4 , and R 5 each independently represent a substituent selected from the group consisting of a halogen group, an amino group, a nitro group, an alkyl group having 1 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms, a heteroaryl group having 5 to 20 carbon atoms, and an acyl group having 2 to 20 carbon atoms; l and m each independently represent an integer of 0 to 4, and n represents an integer of 0 to 2. Here, the aryl group having 6 to 20 carbon atoms and the heteroaryl group having 5 to 20 carbon atoms may have a substituent selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, a halogen group, a nitro group, and a dimethylamino group.)

3. The method for producing a triazolinedione adduct according to claim 1 or 2, wherein the triazolinedione adduct is represented by the following formula (3): 【Chemistry 5】 (In the formula, R ２ , R ３ , R ４ , R ５ , l, m, and n are the same as those in formula (2).

4. The method for producing a triazolinedione adduct according to any one of claims 1 to 3, wherein the solvent used in the suspension washing is at least one selected from the group consisting of hydrocarbon alcohols, ketones, esters, and acetonitrile.

5. The method for producing a triazolinedione adduct according to any one of claims 1 to 4, wherein the first hydrocarbon solvent is n-heptane.

6. The method for producing a triazolinedione adduct according to any one of claims 1 to 5, wherein the second hydrocarbon solvent is n-hexane.

7. The method for producing a triazolinedione adduct according to any one of claims 1 to 6, wherein the halogen-based solvent is dichloromethane.

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