Purification method and production method for triazolinedione adducts

Abstract

To provide a purification method for triazolinedione adducts capable of reducing the coloration and improving the recovery rate.SOLUTION: The purification method for triazolinedione adducts includes a liquid-liquid washing step in which a crude triazolinedione adduct is subjected to liquid-liquid washing using an aqueous acid solution and an organic solvent. The triazolinedione adduct is a compound represented by formula (1) or (2) in the figure.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for purifying a triazoline dione adduct and a method for producing a triazoline dione adduct.

Background Art

[0002] In recent years, the need for analyzing vitamin D and vitamin D metabolites in blood has been increasing. As a method for analyzing vitamin D and vitamin D metabolites, a method of analyzing an ene compound obtained by subjecting a triazoline dione compound and a vitamin D or a vitamin D metabolite to a Diels-Alder reaction is known.

[0003] The triazoline dione compound reacts very rapidly with a diene derivative such as vitamin D under mild conditions, and an ene compound is quantitatively produced. Taking advantage of this reaction characteristic, a diene derivative with low analytical sensitivity is reacted with a triazoline dione compound, converted into an ene compound with high analytical sensitivity, and then the ene compound is quantitatively analyzed.

[0004] Examples of the triazoline dione compound include PTAD (4-phenyl-1,2,4-triazoline-3,5-dione) and DAPTAD (4-(4'-dimethylaminophenyl)-1,2,4-triazoline-3,5-dione).

[0005] However, the triazoline dione compound is unstable. Therefore, a method is known in which a triazoline dione compound and a condensed ring compound are subjected to a Diels-Alder reaction to convert them into a stable triazoline dione adduct for storage, and during use, while returning to the triazoline dione compound, it is subjected to a Diels-Alder reaction with vitamin D or a vitamin D metabolite (see, for example, Patent Document 1).

[0006] On the other hand, a method for producing a triazoline dione adduct including a suspension washing step of purifying a crude product of a specific triazoline dione adduct by suspension washing is known (see, for example, Patent Document 2).

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0008] Here, when a triazolinone adduct is produced by the method for producing a triazolinone adduct described in Patent Document 2, it may be colored pink. At this time, if the suspension washing step is carried out a plurality of times, the coloring of the triazolinone adduct is reduced, but the recovery rate of the triazolinone adduct decreases.

[0009] An object of the present invention is to provide a method for purifying a triazolinone adduct that can reduce coloring and improve the recovery rate.

Means for Solving the Problems

[0010] [1] A method for purifying a triazolinone adduct, comprising a liquid separation washing step of liquid separation washing a crude product of the triazolinone adduct using an aqueous acid solution and an organic solvent, wherein the triazolinone adduct is a compound represented by the following formula (1) or a compound represented by the following formula (2).

Chemical Formula

[0011] [2] The method for purifying a triazoline dione adduct according to [1], wherein the aqueous acid solution contains hydrogen chloride and / or acetic acid.

[0012] [3] The method for purifying a triazoline dione adduct according to [1] or [2], wherein the aqueous acid solution has a pH of 0 or more and 5.0 or less at 25°C.

[0013] [4] A reaction step of subjecting a triazoline dione compound represented by the following formula (3) and a condensed ring compound represented by the following formula (4) or a condensed ring compound represented by the following formula (5) to a Diels-Alder reaction to obtain a crude product of a triazoline dione adduct; and a purification step of purifying the crude product of the triazoline dione adduct by the method for purifying a triazoline dione adduct according to any one of [1] to [3]. A method for producing a triazoline dione adduct, comprising [Chemical formula] (In the formula, R 1 is synonymous with the above formula (1) and the above formula (2).) [Chemical formula] (In the formula, R 2 , R 3 , R 4 , l, m and n are synonymous with the above formula (1).) [Chemical] (wherein R 5 , R 6 , R 7 , R 8 , p, q, r and s have the same meanings as in the above formula (2).)

[0014] [5] The method for producing a triazoline dione adduct according to [4], further comprising a preliminary purification step of preliminarily purifying the crude product of the triazoline dione adduct, and purifying the preliminarily purified crude product of the triazoline dione adduct, wherein the preliminary purification step includes a solvent substitution step of substituting the solvent contained in the liquid containing the crude product of the triazoline dione adduct with a first hydrocarbon solvent to precipitate the triazoline dione adduct, a filtration step of filtering the liquid in which the triazoline dione adduct has precipitated to obtain a filtrate, a washing step of washing the filtrate with a second hydrocarbon solvent, a dissolution step of adding a halogenated solvent to the washed filtrate to dissolve the triazoline dione adduct in the halogenated solvent, and a second filtration step of filtering the liquid in which the triazoline dione adduct has dissolved to obtain a filtrate.

[0015] [6] The method for producing a triazoline dione adduct according to [4], further comprising a preliminary purification step of preliminarily purifying the crude product of the triazoline dione adduct, and purifying the preliminarily purified crude product of the triazoline dione adduct, wherein the preliminary purification step includes a dissolution step of adding a halogenated solvent to the liquid containing the crude product of the triazoline dione adduct to dissolve the triazoline dione adduct, a first filtration step of filtering the liquid in which the triazoline dione adduct has dissolved to obtain a filtrate, a solvent substitution step of substituting the solvent contained in the filtrate with a first hydrocarbon solvent to precipitate the triazoline dione adduct, a second filtration step of filtering the liquid in which the triazoline dione adduct has precipitated to obtain a filtrate, and a washing step of washing the filtrate with a second hydrocarbon solvent. [Advantages of the Invention]

[0016] According to the present invention, it is possible to provide a method for purifying a triazoline dione adduct that can reduce coloring and improve the recovery rate.

Mode for Carrying Out the Invention

[0017] Hereinafter, embodiments of the present invention will be described.

[0018] [Method for Purifying Triazoline Dione Adduct] The method for purifying a triazoline dione adduct according to this embodiment includes a liquid separation washing step of liquid separation washing a crude product of the triazoline dione adduct using an aqueous acid solution and an organic solvent. For this reason, the coloring of the triazoline dione adduct is reduced, and the recovery rate of the triazoline dione adduct is improved. Here, the triazoline dione adduct is a compound represented by the following formula (1) or a compound represented by the following formula (2).

Chemical formula

[0019] In Formula (1) and Formula (2), R 1 may be substituted at any of the ortho position, meta position, and para position, but is preferably substituted at the para position. Further, R 1 is preferably a dialkylamino group or a dialkylaminoalkyl group from the viewpoint of reducing coloring and improving the recovery rate, and more preferably a dimethylamino group or a diethylamino group.

[0020] In R of Formula (1) and Formula (2)1 In this case, the alkoxy group constituting the alkoxycarbonyl group is, for example, a methoxy group or an ethoxy group.

[0021] R in formula (1) 2 , R 3 and R 4 In this case, the number of carbon atoms of the alkyl group is, for example, 1 or more and 20 or less, the number of carbon atoms of the aralkyl group is, for example, 7 or more and 20 or less, the number of carbon atoms of the alkenyl group is, for example, 2 or more and 20 or less, the number of carbon atoms of the aryl group is, for example, 6 or more and 20 or less, the number of carbon atoms of the heteroaryl group is, for example, 5 or more and 20 or less, and the number of carbon atoms of the acyl group is, for example, 2 or more and 20 or less. Further, the number of carbon atoms of the alkyl group as a substituent of the aryl group and the heteroaryl group is, for example, 1 or more and 6 or less.

[0022] R in formula (2) 5 , R 6 and R 7 In this case, the number of carbon atoms of the alkyl group is, for example, 1 or more and 20 or less, the number of carbon atoms of the aralkyl group is, for example, 7 or more and 20 or less, the number of carbon atoms of the alkenyl group is, for example, 2 or more and 20 or less, the number of carbon atoms of the aryl group is, for example, 6 or more and 20 or less, the number of carbon atoms of the heteroaryl group is, for example, 5 or more and 20 or less, and the number of carbon atoms of the acyl group is, for example, 2 or more and 20 or less. Further, the number of carbon atoms of the alkyl group as a substituent of the aryl group and the heteroaryl group is, for example, 1 or more and 6 or less.

[0023] Examples of the crude product of the triazoline dione adduct include a reaction product obtained by subjecting a triazoline dione compound and a condensed ring compound to a Diels-Alder reaction, and a preliminary purification product obtained by preliminarily purifying the reaction product.

[0024] The acid contained in the aqueous acid solution is not particularly limited as long as it does not adversely affect the triazoline dione adduct. For example, inorganic acids such as hydrogen chloride, nitric acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, formic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid can be mentioned, and two or more of them may be used in combination. Among these, hydrogen chloride and acetic acid are preferred.

[0025] The pH of the aqueous acid solution at 25°C is preferably 0 or more and 5.0 or less, and more preferably 1.5 or more and 3.5 or less. When the pH of the aqueous acid solution at 25°C is 0 or more, the recovery rate of the triazoline dione adduct is improved, and when it is 5.0 or less, the coloring of the triazoline dione adduct is reduced. The pH of the aqueous phase after liquid separation and washing is substantially the same as the pH of the aqueous acid solution.

[0026] The organic solvent is not particularly limited as long as it can dissolve the triazoline dione adduct and constitutes a solvent or mixed solvent that can be phase-separated from the aqueous acid solution. For example, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, ethanol, acetone, acetonitrile, tetrahydrofuran, chloroform, and dichloromethane can be mentioned, and two or more of them may be used in combination. Among these, ethyl acetate is preferred.

[0027] The amount of the organic solvent used relative to 100 mg of the crude product of the triazoline dione adduct is not particularly limited, but for example, it is 5 mL or more and 1000 mL or less. The volume ratio of the aqueous acid solution to the organic solvent is not particularly limited, but for example, it is 0.1 or more and 10 or less.

[0028] The Diels - Alder reaction in which the triazoline dione adduct is formed is a reversible reaction. Therefore, the temperature for liquid separation and washing of the crude product of the triazoline dione adduct is not particularly limited as long as it does not promote the reverse reaction of the Diels - Alder reaction, but for example, it is 0°C or more and 40°C or less.

[0029] The number of times of liquid separation and washing of the crude product of the triazoline dione adduct is usually once, but when there are many impurities, it may be two or more times. When the number of times of liquid separation and washing of the crude product of the triazoline dione adduct is two or more times, the aqueous acid solution and the organic solvent used may be the same or different.

[0030] Incidentally, when the crude product of the triazoline dione adduct is subjected to liquid separation and washing, an organic phase containing the triazoline dione adduct is obtained, and the organic phase may be washed with an aqueous acid solution. Here, the aqueous acid solution used for washing may be the same as or different from the aqueous acid solution used for liquid separation and washing.

[0031] When the organic solvent is distilled off from the organic phase, the triazoline dione adduct is recovered. The temperature for distilling off the organic solvent is not particularly limited as long as it does not promote the reverse reaction of the Diels-Alder reaction. For example, it is 0°C or higher and 40°C or lower.

[0032] The recovered triazoline dione adduct may be dried. The drying method of the triazoline dione adduct is not particularly limited, and examples thereof include natural drying method, blowing drying method, and vacuum drying method. The temperature for drying the triazoline dione adduct is not particularly limited as long as it does not promote the reverse reaction of the Diels-Alder reaction. For example, it is 0°C or higher and 40°C or lower.

[0033] [Production method of triazoline dione adduct] The production method of the triazoline dione adduct of the present embodiment includes a reaction step of subjecting a triazoline dione compound represented by the following formula (3) and a condensed ring compound represented by the following formula (4) or a condensed ring compound represented by the following formula (5) to a Diels-Alder reaction to obtain a crude product of the triazoline dione adduct. [Chemical formula] (In the formula, R 1 has the same meaning as in formula (1) and formula (2).) [Chemical formula] (In the formula, R 2 , R 3 , R 4 , l, m, and n are synonymous with formula (1).) [Chemical formula] (In the formula, R 5 , R 6 , R 7 , R 8 , p, q, r, and s are synonymous with formula (2).)

[0034] When the preliminary purification process described later is carried out, a liquid containing the crude product of the triazoline dione adduct is used. Here, the liquid containing the crude product of the triazoline dione adduct is, for example, a liquid in which a part of the triazoline dione adduct is dissolved and the remainder of the triazoline dione adduct is suspended.

[0035] In addition, in the presence of a hypervalent iodine compound, by reacting a triazolidinedione compound corresponding to the triazoline dione compound represented by formula (3) with a condensed ring compound represented by formula (4) or a condensed ring compound represented by formula (5), a liquid containing a triazoline dione adduct can be obtained in the same manner as above. In this case, a triazoline dione compound represented by formula (3) is generated as an intermediate product.

[0036] The Diels-Alder reaction proceeds, for example, by stirring and mixing in a reaction solvent. The reaction solvent is not particularly limited, and examples thereof include ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 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, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone. Two or more of these may be used in combination. Among these, from the viewpoint of the yield of the triazoline dione adduct, methylene chloride, chloroform, acetonitrile, 1,2-dimethoxyethane, toluene and ethyl acetate are preferable. The amount of the reaction solvent used is not particularly limited, but is, for example, 5 mL or more and 1000 mL or less per 1 g of the reaction substrate.

[0037] In addition, a desiccant may be used to suppress the side reaction between the triazoline dione compound represented by the formula (3) and water. The desiccant is not particularly limited, and examples thereof include magnesium sulfate.

[0038] The equivalent ratio of the condensed ring compound represented by the formula (4) or the condensed ring compound represented by the formula (5) to the triazoline dione compound represented by the formula (3) is not particularly limited, but is, for example, 1 or more and 10000 or less. The reaction temperature of the Diels-Alder reaction is not particularly limited as long as it does not promote the reverse reaction, and is, for example, 0°C or higher and 40°C or lower. The reaction time of the Diels-Alder reaction is not particularly limited, and is, for example, 10 minutes or more and 48 hours or less.

[0039] The method for producing a triazoline dione adduct according to this embodiment further includes a preliminary purification step of preliminarily purifying a crude product of the triazoline dione adduct, and a purification step of purifying the crude product of the preliminarily purified triazoline dione adduct (preliminary purified product of the triazoline dione adduct) by the purification method of the triazoline dione adduct according to this embodiment. Here, the preliminary purification step includes a solvent substitution step of substituting the solvent contained in the liquid containing the crude product of the triazoline dione adduct with a first hydrocarbon-based solvent to precipitate the triazoline dione adduct, a first filtration step of filtering the liquid in which the triazoline dione adduct has precipitated to obtain a filtrate, a washing step of washing the filtrate with a second hydrocarbon-based solvent, a dissolution step of adding a halogen-based solvent to the washed filtrate to dissolve the triazoline dione adduct contained in the filtrate in the halogen-based solvent, and a second filtration step of filtering the liquid in which the triazoline dione adduct has dissolved to obtain a filtrate. Thereby, low-polarity organic compounds and inorganic compounds are removed.

[0040] When the solvent (for example, reaction solvent) contained in the liquid containing the crude product of the triazoline dione adduct is substituted with a first hydrocarbon-based solvent, the triazoline dione adduct precipitates. When substituting the solvent contained in the liquid containing the crude product of the triazoline dione adduct with a first hydrocarbon-based solvent, for example, after adding the first hydrocarbon-based solvent to the liquid containing the crude product of the triazoline dione adduct, the solvent contained in the liquid containing the crude product of the triazoline dione adduct is distilled off. At this time, if the triazoline dione adduct has precipitated sufficiently, the solvent contained in the liquid containing the crude product of the triazoline dione adduct may remain.

[0041] As the first hydrocarbon solvent, as long as the solubility of the triazoline dione adduct is low and the boiling point is higher than that of the solvent contained in the liquid containing the crude product of the triazoline dione adduct, it is not particularly limited. For example, n-heptane, n-octane, and n-nonane can be mentioned. Among these, n-heptane is preferred because it is easy to distill off. The amount of the first hydrocarbon solvent used is not particularly limited as long as the triazoline dione adduct is sufficiently precipitated. For example, when assuming a recovery rate of 100%, it is 50 mL or more and 200 mL or less with respect to 1.0 g of the triazoline dione adduct. The temperature at which the solvent contained in the liquid containing the crude product of the triazoline dione adduct is replaced with the first hydrocarbon solvent is not particularly limited as long as it does not promote the reverse reaction of the Diels-Alder reaction. For example, it is 0°C or higher and 40°C or lower.

[0042] When the liquid in which the triazoline dione adduct has precipitated is filtered, the low-polarity organic compounds contained in the filtrate are removed. The temperature at which the liquid in which the triazoline dione adduct has precipitated is filtered is not particularly limited as long as it does not promote the reverse reaction of the Diels-Alder reaction. For example, it is 0°C or higher and 40°C or lower.

[0043] When the filter cake is washed with the second hydrocarbon solvent, the low-polarity organic compounds are removed. As the second hydrocarbon solvent, as long as the solubility of the triazoline dione adduct is low, it is not particularly limited. For example, n-hexane, n-heptane, and n-octane can be mentioned. Among these, n-hexane is preferred because it is easy to distill off. Here, the second hydrocarbon solvent may be the same as or different from the first hydrocarbon solvent.

[0044] When a halogen-based solvent is added to the washed filtrate, the triazoline dione adduct contained in the filtrate dissolves in the halogen-based solvent. Next, when the liquid in which the triazoline dione adduct is dissolved is filtered, the inorganic compounds contained in the filtrate are removed. The halogen-based solvent is not particularly limited as long as the solubility of the triazoline dione adduct is high, but dichloromethane is preferred because it is easy to distill off. The amount of the halogen-based solvent used is not particularly limited as long as the triazoline dione adduct is sufficiently dissolved. For example, it is 50 mL or more and 200 mL or less with respect to 1.0 g of the filtrate. The temperature at which the triazoline dione adduct contained in the washed filtrate is dissolved in the halogen-based solvent is not particularly limited as long as it does not promote the reverse reaction of the Diels-Alder reaction. For example, it is 0°C or more and 40°C or less. The temperature at which the solution of the triazoline dione adduct is filtered is not particularly limited as long as it does not promote the reverse reaction of the Diels-Alder reaction. For example, it is 0°C or more and 40°C or less.

[0045] After filtering the liquid in which the triazoline dione adduct is dissolved, when the solvent is distilled off from the filtrate, a crude product of the triazoline dione adduct is obtained. Here, after distilling off the solvent from the filtrate, it may be dried. The drying method is not particularly limited, and examples include natural drying, forced-air drying, and vacuum drying. The drying temperature is not particularly limited as long as it does not promote the reverse reaction of the Diels-Alder reaction. For example, it is 0°C or more and 40°C or less.

[0046] Note that the preliminary purification step may not be carried out. In this case, for example, after filtering the liquid containing the crude product of the triazoline dione adduct, the filtrate is dried to obtain the crude product of the triazoline dione adduct. The drying method of the filtrate is not particularly limited, and examples include natural drying, forced-air drying, and vacuum drying. The temperature at which the filtrate is dried is not particularly limited as long as it does not promote the reverse reaction of the Diels-Alder reaction. For example, it is 0°C or more and 40°C or less.

[0047] Alternatively, instead of the preliminary purification step, a second preliminary purification step may be carried out. The second preliminary purification step includes a dissolution step of adding a halogen-based solvent to a liquid containing a crude product of the triazoline dione adduct to dissolve the triazoline dione adduct, a first filtration step of filtering the liquid in which the triazoline dione adduct is dissolved to obtain a filtrate, a solvent substitution step of substituting the solvent contained in the filtrate with a first hydrocarbon-based solvent to precipitate the triazoline dione adduct, a second filtration step of filtering the liquid in which the triazoline dione adduct has precipitated to obtain a filter cake, and a washing step of washing the filter cake with a second hydrocarbon-based solvent.

[0048] The second preliminary purification step is the same as the preliminary purification step except that it is carried out in the order of the dissolution step, the first filtration step, the solvent substitution step, the second filtration step, and the washing step.

[0049] When a halogen-based solvent is added to a liquid containing a crude product of the triazoline dione adduct, for example, the triazoline dione adduct that is not dissolved in the reaction solvent dissolves in the halogen-based solvent. Next, when the liquid in which the triazoline dione adduct is dissolved is filtered, the inorganic compounds contained in the filter cake are removed. Next, when the solvent contained in the filtrate is substituted with a first hydrocarbon-based solvent, the triazoline dione adduct precipitates. Next, when the liquid in which the triazoline dione adduct has precipitated is filtered, the low-polarity organic compounds contained in the filtrate are removed. Next, when the filter cake is washed with a second hydrocarbon-based solvent, the low-polarity organic compounds are removed. Note that after washing the filter cake with a second hydrocarbon-based solvent, it may be dried.

[0050] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments, and the above embodiments may be appropriately modified within the scope of the gist of the present invention.

Examples

[0051] Examples of the present invention will be described below. However, the present invention is not limited to the examples.

[0052] <Chemical purity> Using a high-performance liquid chromatograph 2695 (manufactured by Waters), a column Inertsil ODS-3 (5 μm, 4.6 × 250 mm) (manufactured by GL Sciences), and an ultraviolet-visible spectrophotometric detector 2489 (manufactured by Waters), the chemical purity of the triazolinone adduct was measured under the following measurement conditions. Here, the chemical purity of the triazolinone adduct is the area ratio of the peak derived from the triazolinone adduct in the HPLC spectrum. Detection wavelength: 210 nm Column temperature: Constant temperature around 40 °C Sample injection volume: 10 μL Sample concentration: 0.1 mg / mL

[0053] When feeding the eluent, the volume ratio of mobile phase A (acetonitrile) and mobile phase B (water) was changed as follows. Mobile phase A / Mobile phase B = 50 / 50 (0 - 10 min) Mobile phase A / Mobile phase B = 50 / 50 → 95 / 5 (10 - 20 min) Mobile phase A / Mobile phase B = 95 / 5 (20 - 50 min) Mobile phase A / Mobile phase B = 95 / 5 → 50 / 50 (50 - 55 min) Mobile phase A / Mobile phase B = 50 / 50 (55 - 60 min)

[0054] <Yield of triazolinone adduct> The yield of the triazolinone adduct was calculated from the ratio of the amount of substance of the preliminary purified product of the triazolinone adduct to the amount of substance of the reaction substrate.

[0055] <Recovery rate of triazolinone adduct> The recovery rate of the triazolinone adduct was calculated from the ratio of the mass of the triazolinone adduct after the purification step to the mass of the preliminary purified product of the triazolinone adduct before the purification step.

[0056] <pH of acid aqueous solution> Using a pH meter (manufactured by Toa DKK), the pH of the acid aqueous solution was measured at 25 °C.

[0057] <Example 1> (Reaction process) 7.55 g (34.3 mmol) of 4-(4'-dimethylaminophenyl)-1,2,4-triazolidine-3,5-dione, 7.55 g (34.3 mmol) of iodobenzene, 8.72 g (34.3 mmol) of 9-phenylanthracene, 7.55 g of magnesium sulfate and 377 mL of ethyl acetate were placed in a flask, and then stirred at room temperature for 24 hours to obtain a liquid containing a crude product of DAP-PA as a triazolinedione adduct. At this time, DAP is formed as an intermediate product. Here, DAP-PA means (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. Also, DAP means 4-(4'-dimethylaminophenyl)-1,2,4-triazolidinedione.

Chemical formula

[0058] (Preliminary purification process) After adding 380 mL of n-heptane to the liquid containing the crude product of DAP-PA, ethyl acetate was distilled off under reduced pressure to precipitate DAP-PA. Next, the liquid in which DAP-PA had precipitated was filtered, and the filtrate was washed with 380 mL of n-hexane. Next, the DAP-PA contained in the washed filtrate was dissolved in 380 mL of dichloromethane and then filtered. Next, dichloromethane was distilled off from the filtrate and then dried to obtain a preliminary purified product of DAP-PA. The preliminary purified product of DAP-PA was colored purple, had a yield of 11.5 g, a chemical purity of 96.6%, and a yield of 70.9%.

[0059] (Purification process) 0.1 g of the preliminary purification product of DAP-PA was dissolved in 26 mL of ethyl acetate to obtain a solution of the preliminary purification product of DAP-PA. Then, the solution of the preliminary purification product of DAP-PA and 10 mL of 0.1 M hydrochloric acid with a pH of 1.0 were placed in a separatory funnel and washed by liquid separation. Next, after washing the organic phase twice with 0.1 M hydrochloric acid, ethyl acetate was distilled off from the organic phase. Next, the residue was dried under reduced pressure to obtain DAP-PA. DAP-PA was colored light pink, had a chemical purity of 97.5%, and a recovery rate of 80%.

[0060] Here, a NanoDrop One / One C (manufactured by Thermo fisher scientific) was used to compare the absorbances of DAP-PA (preliminary purification product) before and after the purification process. Specifically, after dissolving 5 mg of DAP-PA (preliminary purification product) in 10 mL of chloroform, the absorbances at a wavelength of 345 nm were compared. As a result, the absorbances of DAP-PA (preliminary purification product) before and after the purification process were 0.16 and 0.04, respectively, and it can be seen that the coloring of DAP-PA was reduced compared to Comparative Example 5 described below.

[0061] The various analysis results of DAP-PA are shown below. MP: >200 °C IR (KBr): 1774 cm -1 , 1714 cm -1 1 H-NMR (CDCl 3 ): δ 7.86 (d, J = 8.8 Hz, 2H), 7.49 - 7.60 (m, 5H), 7.32 (dt, J = 1.2, 7.6 Hz, 2H), 7.23 (dt, J = 1.2 Hz, 7.8 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.78 (d, J = 9.2 Hz, 2H), 6.56 (d, J = 9.2 Hz, 2H), 6.39 (s, 1H), 2.88 (s, 6H)

[0062] <Comparative Example 1> As follows, in the purification process, DAP-PA was obtained in the same manner as in Example 1, except that instead of washing by liquid separation, it was washed by suspension.

[0063] (Purification Process) 0.1 g of the preliminary purified product of DAP-PA, 2 mL of acetone, and a stir bar were placed in a screw tube, stirred at room temperature for about 14 hours for suspension washing, and then filtered under reduced pressure. Next, the filtrate was washed with acetone and then dried under reduced pressure to obtain DAP-PA. DAP-PA was colored pink, had a chemical purity of 99.4%, and a recovery rate of 70%.

[0064] [[Comparative Example 2]] DAP-PA was obtained in the same manner as in Comparative Example 1 except that the purification process was carried out 3 times. DAP-PA was colored light pink and had a recovery rate of 34%.

[0065] [[Comparative Example 3]] DAP-PA was obtained in the same manner as in Comparative Example 1 except that ethanol was used instead of acetone in the purification process. DAP-PA was colored dark pink, had a chemical purity of 98.3%, and a recovery rate of 78%.

[0066] [[Comparative Example 4]] DAP-PA was obtained in the same manner as in Comparative Example 3 except that the purification process was carried out 3 times. DAP-PA was colored light pink and had a recovery rate of 46%.

[0067] [[Comparative Example 5]] DAP-PA was obtained in the same manner as in Example 1 except that water was used instead of 0.1 M hydrochloric acid in the purification process. DAP-PA was colored pink, had a chemical purity of 96.6%, and a recovery rate of 99%.

[0068] Here, when the absorbances of DAP-PA (preliminary purified product) before and after the purification process were compared in the same manner as in Example 1, the absorbances of DAP-PA (preliminary purified product) before and after the purification process were 0.16 and 0.08, respectively.

[0069] Table 1 shows the results of the coloring and recovery rates of Example 1 and Comparative Examples 1 to 5. [[Table 1]]

[0070] From Table 1, it can be seen that in Example 1, the coloring of DAP-PA is reduced and the recovery rate of DAP-PA is improved. In contrast, in Comparative Examples 1 and 3, since suspension washing was performed instead of liquid separation washing, the coloring of DAP-PA was not reduced. Also, in Comparative Examples 2 and 4, since suspension washing was performed three times, the recovery rate of DAP-PA decreased. Furthermore, in Comparative Example 5, since no acid was used during liquid separation washing, the coloring of DAP-PA was not reduced.

Claims

1. including a liquid-liquid washing step of liquid-liquid washing the crude product of the triazoline dione adduct using an aqueous acid solution and an organic solvent, wherein the triazoline dione adduct is a compound represented by the following formula (1) or a compound represented by the following formula (2), a method for purifying a triazoline dione adduct. 【Chemical 1】 (wherein R １ is a group selected from the group consisting of a disubstituted amino group having one or two substituents selected from the group consisting of an alkyl group, an aralkyl group and an aryl group, a disubstituted aminoalkyl group having one or two substituents 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 alkoxycarbonyl group, a nitrile group, an amide group, a ferrocenyl group and a quinoxalinyl group having a substituent, R ２ , R ３ and R ４ are each independently a group selected from the group consisting of a halogen group, an amino group, a nitro group, an alkyl group, an aralkyl group, an alkenyl group, an aryl group, a heteroaryl group and an acyl group, l and m are each independently an integer of 0 or more and 4 or less, n is an integer of 0 or more and 2 or less, and the aryl group and heteroaryl group in R ２ , R ３ and R ４ may have a substituent selected from the group consisting of an alkyl group, a halogen group, a nitro group and a dimethylamino group.). 【Chemical 2】 (wherein R １ is a group selected from the group consisting of a disubstituted amino group having one or two substituents selected from the group consisting of an alkyl group, an aralkyl group, and an aryl group, a disubstituted aminoalkyl group having one or two substituents 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 alkoxycarbonyl group, a nitrile group, an amide group, a ferrocenyl group, and a quinoxalinyl group having a substituent, R ５ , R ６ and R ７ are each independently a group selected from the group consisting of a halogen group, an amino group, a nitro group, an alkyl group, an aralkyl group, an alkenyl group, an aryl group, a heteroaryl group, and an acyl group, p is an integer of 0 or more and 4 or less, q is an integer of 0 or more and 2 or less, r and s are each independently 0 or 1, and the aryl group and heteroaryl group in R ５ , R ６ and R ７ may have a substituent selected from the group consisting of an alkyl group, a halogen group, a nitro group, and a dimethylamino group.).

2. The method for purifying a triazoline dione adduct according to claim 1, wherein the aqueous acid solution contains hydrogen chloride and / or acetic acid.

3. The method for purifying a triazoline dione adduct according to claim 1 or 2, wherein the aqueous acid solution has a pH of 0 or more and 5.0 or less at 25°C.

4. a reaction step of obtaining a crude product of a triazoline dione adduct by subjecting a triazoline dione compound represented by the following formula (3) and a condensed ring compound represented by the following formula (4) or a condensed ring compound represented by the following formula (5) to a Diels-Alder reaction; a method for producing a triazoline dione adduct, comprising a purification step of purifying the crude product of the triazoline dione adduct by the method for purifying a triazoline dione adduct according to claim 1 or 2. 【Chemical Formula 3】 (wherein R １ is synonymous with the formula (1) and the formula (2).) [Chemical Formula 4] (wherein, R ２ , R ３ , R ４ , l, m and n are as defined in the above formula (1).) 【Chemical Formula 5】 (wherein R ５ , R ６ , R ７ , R ８ , p, q, r and s are as defined in the above formula (2).)

5. further including a preliminary purification step of preliminarily purifying the crude product of the triazoline dione adduct, purifying the preliminarily purified crude product of the triazoline dione adduct, wherein the preliminary purification step includes a solvent substitution step of substituting the solvent contained in the liquid containing the crude product of the triazoline dione adduct with a first hydrocarbon solvent to precipitate the triazoline dione adduct, a filtration step of filtering the liquid in which the triazoline dione adduct has precipitated to obtain a filtrate, a washing step of washing the filtrate with a second hydrocarbon solvent, a dissolution step of adding a halogenated solvent to the washed filtrate to dissolve the triazoline dione adduct in the halogenated solvent, and a second filtration step of filtering the liquid in which the triazoline dione adduct has dissolved to obtain a filtrate, the method for producing a triazoline dione adduct according to claim 4.

6. further including a preliminary purification step of preliminarily purifying the crude product of the triazoline dione adduct, purifying the preliminarily purified crude product of the triazoline dione adduct, The preliminary purification step includes a dissolution step of adding a halogen-based solvent to a liquid containing a crude product of the triazolinone adduct to dissolve the triazolinone adduct, a first filtration step of filtering the liquid in which the triazolinone adduct is dissolved to obtain a filtrate, a solvent substitution step of substituting the solvent contained in the filtrate with a first hydrocarbon-based solvent to precipitate the triazolinone adduct, a second filtration step of filtering the liquid in which the triazolinone adduct has precipitated to obtain a filter product, and a washing step of washing the filter product with a second hydrocarbon-based solvent. The method for producing a triazolinone adduct according to claim 4.

Images