A powder of a composition comprising a phenol compound having a methoxymethyl group, and a method of manufacturing thereof

Abstract

The objective of the present invention is to provide a novel form of the phenol compound represented by chemical formula (A1) and having a methoxymethyl group, which can be manufactured by a method suitable for industrial mass production, and which, when used by being heated and melted in the solid state, can reduce the required energy. As a solution, the present invention provides a powder comprising a composition that contains a phenol compound represented by chemical formula (A1) and having a methoxymethyl group, wherein the composition contains the phenol compound represented by chemical formula (A1) as Component A1, the compound represented by chemical formula (A2) as Component A2, and the compound represented by chemical formula (A3) as Component A3 in the following composition ratio, and the composition exhibits an endothermic peak onset temperature in the range of

Description

[Technical Field]

[0001] This invention relates to powders containing a phenolic compound having a methoxymethyl group and a method for manufacturing the same. More specifically, it relates to a novel form of the compound represented by the chemical formula (A1) described below (hereinafter sometimes referred to as compound A1) and a method for manufacturing the compound including a crystallization step. [Previous Technology]

[0002] Phenolic compounds containing hydroxymethyl or methoxymethyl groups have conventionally been used as curing agents for resins with phenolic hydroxyl groups or as crosslinking agents to enhance the film properties of photosensitive resins. Regarding phenolic compounds containing methoxymethyl groups, compounds represented by the chemical formula (A1) are known (compound A1). Regarding conventionally known methods for isolating compounds represented by chemical formula (A1), Patent Document 1 describes a method in which a hexahydroxymethyl compound (compound B, described below) serving as a precursor of the compound is reacted with methanol to synthesize compound A1, and the methanol is removed by vacuum distillation to achieve isolation. Patent Document 2 describes a method for synthesizing 2,6-dimethoxymethylphenol (III) from 2,6-dimethylphenol as a starting material, through acetylation, bromination of the methyl group, and methoxylation of the bromomethyl group, followed by a condensation reaction and deacetylation of the acetylated product of 2,6-dimethoxymethylphenol (III) to synthesize compound A1. Furthermore, a method for crystallization using ethanol is described as a post-reaction isolation method. Patent Document 3 describes concentrating a 20% propylene glycol monomethyl ether (PGME) solution of compound A1 with a purity of 80% using an evaporator to form a 50% propylene glycol monomethyl ether solution, and then allowing it to stand for 2 days to obtain white crystals of compound A1. Patent Document 4 describes concentrating a 20% ethyl lactate solution of compound A1 using an evaporator to form a 40% ethyl lactate (EL) solution, and then allowing it to stand at room temperature for 5 days to obtain a pale orange solid of compound A1. Patent Document 5 describes several manufacturing examples of compound A1. Synthesis Examples 5, 15, and 16 describe examples of manufacturing compound A1 and its dimers and trimers containing γ-butyrolactone solutions with different compositions and different solute concentrations. Furthermore, in Synthesis Example 17, similar to Patent Document 4, it is described that a 20% ethyl lactate solution of compound A1 is concentrated using an evaporator to form a 50% ethyl lactate solution, and then left to stand for 2 days to obtain white crystals of compound A1. [Prior Art Documents] [Patent Documents]

[0003] [Patent Document 1] International Publication No. 2024 / 082896 [Patent Document 2] Chinese Patent Application Publication No. 115959977 [Patent Document 3] International Publication No. 2016 / 148176 [Patent Document 4] Japanese Patent Application Publication No. 2009-227697 [Patent Document 5] Japanese Patent Application Publication No. 2024-52592 [Summary of the Invention]

[0004] [Problem to be Solved by the Invention] When preparing or using resin compositions containing phenolic compounds having hydroxymethyl or methoxymethyl groups on an industrial scale, the time required for melting limits the molding time after the onset of thermosetting. From the viewpoints of productivity and molding processability, it is desirable for phenolic compounds having hydroxymethyl or methoxymethyl groups to have low melting points and low heat of melting. The properties of compound A1 obtained by the single-isolation method described in Patent Document 1 are unclear. Since it is a distillation residue obtained by removing methanol from the synthesis reaction liquid of compound A1, it is also considered to have the properties of a blocky solid and a highly viscous substance, raising concerns about its difficulty in industrial manufacturing. In the manufacturing method described in Patent Document 2, compound A1 is synthesized from 2,6-dimethylphenol through five steps: acetyl protection, bromination, methoxy substitution, Friedel-Crafts acylation, and dehydration condensation. The numerous reaction steps make it unsuitable for large-scale industrial production. Furthermore, the properties of compound A1 obtained by crystallization with ethanol are unclear. In the methods for crystallizing compound A1 described in Patent Documents 3 and 4, crystallization to the point of being separable requires 2 or 5 days, which can be understood as a significantly slow crystallization method, unsuitable for industrial production of compound A1. Moreover, the inventors of this case studied previously known crystallization methods for compound A1, and as shown in the comparative examples below, found that the resulting crystals have problems such as high melting points and high fusion heat. When compound A1 is melt-mixed with resin to manufacture resin compositions and their hardened forms, a high melting point and high fusion heat require correspondingly high energy, resulting in poor efficiency and limiting the time available for molding after thermosetting during the melting process. In view of the above-mentioned problems discovered by the inventors of this case, the object of this invention is to provide a novel form of compound A1 that can be manufactured by a method suitable for mass industrial production, reducing the energy required for heating and melting in a solid state for use. [Means for solving the problem]

[0005] As a result of detailed research conducted by the inventors in order to solve the above-mentioned problems, the inventors discovered a novel state containing compound A1 by using a crystallization step with a specific solvent and thus completed the present invention. The composition containing compound A1 is a specific composition with a low melting point and low heat of fusion.

[0006] The present invention is as follows. 1. A powder containing a phenolic compound, wherein the aforementioned phenolic compound is represented by chemical formula (A1) and has a methoxymethyl group, the aforementioned composition contains, in the following composition ratio, a phenolic compound represented by chemical formula (A1) having a methoxymethyl group as component A1, a compound represented by chemical formula (A2) as component A2, and a compound represented by chemical formula (A3) as component A3, and the onset temperature of the endothermic peak obtained by differential scanning calorimetry is in the range of 50 to 65°C. [Composition ratio]: The composition is analyzed by liquid chromatography using a UV detector with a wavelength of 280 nm, and the detection area ratio of each component relative to the detection area of ​​all detected components is in the following range. Component A1: 83.0% area % or more, 88.0% area % or less; Component A2: 3.5% area % or more, 6.5% area % or less; Component A3: 0.01% area % or more, 3.0% area % or less. 2. A method for manufacturing the powder described in 1, comprising a crystallization step; wherein the aforementioned step involves crystallization from a solution comprising a composition containing a methoxymethyl phenol compound (compound A1) represented by chemical formula (A1), a chain aliphatic alcohol solvent having 3 to 5 carbon atoms, and a chain aliphatic hydrocarbon solvent having 5 to 10 carbon atoms; wherein the aforementioned composition contains the methoxymethyl phenol compound represented by chemical formula (A1) as component A1, the compound represented by chemical formula (A2) as component A2, and the compound represented by chemical formula (A3) as component A3 in the following composition ratios. [Composition Ratio]: The composition is analyzed by liquid chromatography using a UV detector with a wavelength of 280 nm, and the detection area ratios of the following components relative to the detection area of ​​all detected components are within the following ranges. Component A1: 83.0% area % or more, 88.0% area % or less; Component A2: 3.5% area % or more, 6.5% area % or less; Component A3: 0.01% area % or more, 3.0% area % or less. 3. A method for manufacturing the powder described above, comprising a crystallization step; wherein the aforementioned step involves crystallization from a solution comprising a composition containing a methoxymethyl phenolic compound (compound A1) represented by chemical formula (A1), a chain aliphatic carboxylic acid ester solvent having a total of 5 to 8 carbon atoms, and a cyclic aliphatic hydrocarbon solvent having a total of 5 to 8 carbon atoms; wherein the aforementioned composition contains the methoxymethyl phenolic compound represented by chemical formula (A1) as component A1, the compound represented by chemical formula (A2) as component A2, and the compound represented by chemical formula (A3) as component A3 in the following compositional ratios. [Composition Ratio]: The composition was analyzed by liquid chromatography using a UV detector with a wavelength of 280 nm. The detection area ratios of the following components are within the following ranges relative to the detection area of ​​all detected components.Component A1: 83.0% or more, 88.0% or less; Component A2: 3.5% or more, 6.5% or less; Component A3: 0.01% or more, 3.0% or less [Effects of the invention].

[0007] The powder of the present invention, containing a phenolic compound (compound A1) having a methoxymethyl group represented by the chemical formula (A1), exhibits faster crystal precipitation during the crystallization step compared to conventional methods for manufacturing compound A1, allowing for efficient manufacturing. Furthermore, compared to conventional compositions containing compound A1, it has a lower melting point and lower heat of fusion, resulting in excellent productivity and processability when melt-forming materials such as resin compositions containing compound A1, making it extremely useful.

Implementation Method

[0008] The present invention will be described in detail below. <Powder of the present invention containing a methoxymethylphenol compound represented by chemical formula (A1)> The powder of the present invention containing a methoxymethylphenol compound represented by chemical formula (A1) (compound A1) contains, in the following composition ratio, a methoxymethylphenol compound represented by chemical formula (A1) as component A1, a compound represented by chemical formula (A2) as component A2, and a compound represented by chemical formula (A3) as component A3, the onset temperature of the endothermic peak obtained by differential scanning calorimetry is in the range of 50 to 65°C. [Composition ratio]: The composition is analyzed by liquid chromatography using a UV detector with a wavelength of 280 nm, and the detection area ratio of each component relative to the detection area of ​​all detected components is in the following range. Component A1: 83.0% or more, less than 88.0% of area; Component A2: 3.5% or more, less than 6.5% of area; Component A3: 0.01% or more, less than 3.0% of area.

[0009] The powder of the present invention contains a phenolic compound having a methoxymethyl group (represented by chemical formula (A1)) comprising a methoxymethyl group as component A1, a compound having a methoxymethyl group as component A2, and a compound having a methoxymethyl group as component A3. The compound having a methoxymethyl group (represented by chemical formula (A2)) as component A2 is a dimer formed by two molecules of compound A1 through a reaction in which methylene chains are formed by the formation of methylene chains from the methoxymethyl groups of each other. The compound having a methoxymethyl group (represented by chemical formula (A3)) as component A3 is a trimer formed by three molecules of compound A1 through a reaction in which methylene chains are formed by the formation of methylene chains from the formation of methylene chains from the formation of methylene chains from the formation of methylene chains from the formation of methylene groups of each other. Regarding the aforementioned composition ratio in the powder containing compound A1 of the present invention, the range of the detection area ratio of each component is preferably as follows: component A1: 84.0 area% to 88.0 area%; component A2: 4.0 area% to 6.5 area%; and component A3: 0.1 area% to 2.0 area%; more preferably, component A1: 85.0 area% to 88.0 area%; component A2: 4.5 area% to 6.5 area%; and component A3: 0.3 area% to 2.0 area%; particularly preferably, component A1: 86.0 area% to 88.0 area%; component A2: 5.0 area% to 6.5 area%; and component A3: 0.5 area% to 1.0 area%. The analytical conditions for confirming the aforementioned composition ratio by liquid chromatography are based on the high-performance liquid chromatography (HPLC) analysis method described in the examples below. The onset temperature of the endothermic peak value of the powder containing compound A1, as determined by differential scanning calorimetry, is preferably in the range of 50 to 59°C, more preferably in the range of 50 to 58°C, even more preferably in the range of 51 to 56°C, and particularly preferably in the range of 51 to 54°C. The peak temperature of the endothermic peak value of the powder containing compound A1, as determined by differential scanning calorimetry, is preferably in the range of 63 to 73°C, more preferably in the range of 64 to 72°C, even more preferably in the range of 65 to 71°C, and particularly preferably in the range of 66 to 70°C. The heat of fusion of the powder containing compound A1, based on the endothermic peak value determined by differential scanning calorimetry, is preferably in the range of 65 to 77 mJ / mg, more preferably in the range of 66 to 75 mJ / mg, even more preferably in the range of 66 to 74 mJ / mg, and particularly preferably in the range of 66 to 70 mJ / mg.

[0010] <Method for Manufacturing Powder Containing a Composition of a Methoxymethylphenol Compound Represented by Chemical Formula (A1) of the Present Invention> The method for manufacturing powder containing a composition of a methoxymethylphenol compound represented by chemical formula (A1) (compound A1) of the present invention is characterized by comprising: a crystallization step, wherein crystals are precipitated from a solution containing the composition containing a methoxymethylphenol compound represented by chemical formula (A1) (compound A1), a chain aliphatic alcohol solvent having 3 to 5 carbon atoms, and a chain aliphatic hydrocarbon solvent having 5 to 10 carbon atoms, wherein the composition contains, in the following compositional ratio, a methoxymethylphenol compound represented by chemical formula (A1) as component A1, a compound represented by chemical formula (A2) as component A2, and a compound represented by chemical formula (A3) as component A3. This method is referred to as "Manufacturing Method 1". [Composition Ratio]: Liquid chromatography analysis of the components was performed using a 280nm UV detector. The detection area ratios of the following components relative to the detection area of ​​all detected components are as follows: Component A1: 83.0% ≥ 88.0% Component A2: 3.5% ≥ 6.5% Component A3: 0.01% ≥ 3.0%

[0011] Another method of manufacturing a powder containing a composition having a methoxymethylphenol compound (compound A1) represented by chemical formula (A1) according to the present invention is characterized by comprising: a crystallization step, wherein crystallization is performed from a solution containing the composition having a methoxymethylphenol compound (compound A1) represented by chemical formula (A1), a chain aliphatic carboxylic acid ester solvent with a total of 5 to 8 carbon atoms, and a cyclic aliphatic hydrocarbon solvent with a total of 5 to 8 carbon atoms, wherein the composition contains the methoxymethylphenol compound represented by chemical formula (A1) as component A1, a compound represented by chemical formula (A2) as component A2, and a compound represented by chemical formula (A3) as component A3 in the following composition ratio. This method may be referred to as "manufacturing method 2". [Composition ratio]: The composition is analyzed by liquid chromatography using a UV detector with a wavelength of 280 nm, and the detection area ratio of each component relative to the detection area of ​​all detected components is within the following range. Component A1: 83.0% or more, less than 88.0% of area; Component A2: 3.5% or more, less than 6.5% of area; Component A3: 0.01% or more, less than 3.0% of area.

[0012] In the manufacturing method of the present invention, manufacturing method 1 is preferred because it is easy to crystallize and can efficiently and with high yield obtain powder of compound A1.

[0013] (Containing a phenolic compound with methoxymethylity represented by chemical formula (A1)) In the manufacturing method of the present invention, the composition containing compound A1, which is commonly provided as a raw material in manufacturing methods 1 and 2, only needs to be in the aforementioned specific composition ratio, and the synthesis method is not particularly limited. It can also be a product that is extracted by isolation operation after the synthesis reaction. The form is also not particularly limited, and examples include: solid, oil, block, and powder. Regarding the aforementioned composition ratio, the preferred range for the detection area percentage of each component is: component A1: 84.0% to 88.0%; component A2: 4.0% to 6.5%; and component A3: 0.1% to 2.0%. More preferably, component A1: 85.0% to 88.0%; component A2: 4.5% to 6.5%; and component A3: 0.3% to 2.0%. Particularly preferably, component A1: 86.0% to 88.0%; component A2: 5.0% to 6.5%; and component A3: 0.5% to 1.0%.

[0014] The synthesis method of compound A1 is illustrated by the following reaction formula. For example, a method for synthesizing a phenolic compound with hydroxymethyl group (represented by chemical formula (B)) containing hydroxymethyl group (hereinafter sometimes referred to as compound B) by reacting methanol in the presence of an acid catalyst to synthesize a phenolic compound with methoxymethyl group (represented by chemical formula (B)) containing hydroxymethyl group (hereinafter sometimes referred to as "methoxylation of hydroxymethyl group"). In the method for manufacturing powder containing compound A1 of the present invention, the composition containing compound A1 provided as a raw material is preferably a composition containing compound A1 synthesized by the "methoxylation of hydroxymethyl group," which is synthesized by reacting a phenolic compound with hydroxymethyl group (represented by chemical formula (B)) containing hydroxymethyl group with methanol in the presence of an acid catalyst. The following describes a method for manufacturing a composition containing compound A1 with a specific composition ratio by the "methoxylation of hydroxymethyl group" of the aforementioned synthesis method. The synthesis method of the phenolic compound with hydroxymethyl group (represented by chemical formula (B)) containing hydroxymethyl group (compound B) used in the aforementioned methoxylation of hydroxymethyl group is not particularly limited and can be synthesized by conventionally known methods. Examples of methods for synthesizing compound B include: reacting a phenolic compound (compound C) represented by chemical formula (C) with formaldehyde in the presence of an alkaline catalyst to synthesize a phenolic compound (compound B) represented by chemical formula (B) having a hydroxymethyl group.

[0015] The amount of methanol used in the methoxylation method of hydroxymethyl of the present invention is preferably in the range of 80 to 170 mol relative to 1 mol of compound B, more preferably in the range of 100 to 150 mol, and particularly preferably in the range of 110 to 140 mol. This methanol can also function as a reaction solvent.

[0016] Specific examples of acid catalysts used in the methoxylation process of hydroxymethyl groups according to the present invention include: sulfuric acid, hydrochloric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, cation exchange resin (acidic form), oxalic acid, phosphotungstic acid, or silicottitic acid, etc., preferably at least one of these compounds. Sulfuric acid is particularly preferred. The amount of acid catalyst used relative to 1 mole of compound B is preferably in the range of 0.5 to 2.5 moles, more preferably in the range of 1.0 to 2.0 moles, and particularly preferably in the range of 1.2 to 1.7 moles. The reaction temperature in the methoxylation process of hydroxymethyl groups according to the present invention is preferably in the range of 30 to 62°C, more preferably in the range of 45 to 62°C, and particularly preferably in the range of 58 to 62°C. After the reaction is completed, it is preferable to mix with an alkali such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate to neutralize the acid catalyst used in the reaction.

[0017] (Composition containing compound A1 after water washing treatment) The composition containing compound A1 provided as a raw material is preferably a composition containing compound A1 that has undergone water washing treatment. This water washing treatment is to remove water-soluble impurities (such as salts generated during the neutralization of acid catalysts) produced by the catalyst used in the synthesis reaction, the raw materials used, and metallic components contained in the alkali used for neutralization. This water washing treatment can be carried out by preparing a solution containing compound A1 and an organic solvent capable of dissolving the composition containing compound A1 and separating it from water, and then washing its organic layer with water. Examples of suitable compositions containing compound A1 for water washing treatment include: compositions containing compound A1 contained in the reaction liquid after the aforementioned synthesis reaction, and compositions containing compound A1 obtained prior by isolation, etc. When using a reaction solution containing the composition of compound A1 obtained after the aforementioned synthesis reaction, the solvent is replaced with an organic solvent that can be used to dissolve the composition containing compound A1 and separate it from water to prepare the solution. When using the previously obtained composition containing compound A1, it is mixed with an organic solvent that can be used to dissolve the composition containing compound A1 and separate it from water to prepare the solution. Examples of organic solvents that can be used to dissolve the composition containing compound A1 and separate it from water include: aromatic hydrocarbon solvents with 7 to 9 carbon atoms such as toluene and xylene; chain aliphatic ketone solvents with a total of 4 to 8 carbon atoms such as methyl ethyl ketone, methyl isobutyl ketone, and methyl isopentyl ketone; and chain aliphatic carboxylic acid ester solvents with a total of 5 to 8 carbon atoms such as butyl acetate and amyl acetate. Preferably, at least one organic solvent selected from these is used. Preferably, at least one organic solvent is used, selected from chain aliphatic ketone solvents with a total of 4 to 8 carbon atoms and chain aliphatic carboxylic acid ester solvents with a total of 5 to 8 carbon atoms. More preferably, at least one organic solvent is used, selected from methyl ethyl ketone, methyl isobutyl ketone, methyl isopentyl ketone, butyl acetate, and amyl acetate. Most preferably, at least one organic solvent is used, selected from methyl ethyl ketone, methyl isobutyl ketone, butyl acetate, and amyl acetate. The amount of the organic solvent used relative to the composition containing compound A1 can be appropriately adjusted according to the solubility of compound A1 in the organic solvent used, preferably in the range of 0.5 to 5.0 times by weight, more preferably in the range of 0.5 to 4.0 times by weight, even more preferably in the range of 0.8 to 3.0 times by weight, and most preferably in the range of 0.8 to 2.0 times by weight. The amount of water used during the washing process can be adjusted appropriately according to the amount of water-soluble impurities to be removed. The amount of water relative to the weight of the organic layer to be washed is preferably 0.5 to 3.0 times the weight, more preferably 0.5 to 2.5 times the weight, even more preferably 0.5 to 2.0 times the weight, and most preferably 0.5 to 1.5 times the weight.The number of times the organic layer is cleaned can be one or more depending on the amount of water-soluble impurities to be removed. From the viewpoint that the composition containing compound A1 can be directly used in the crystallization step of "Manufacturing Method 2" of the manufacturing method of the present invention as a solution dissolved in a chain aliphatic carboxylic acid ester solvent with a total number of carbon atoms of 5 to 8, it is preferable to use a chain aliphatic carboxylic acid ester solvent with a total number of carbon atoms of 5 to 8 in the water washing process.

[0018] <Preparation of the solution used in the crystallization step of the manufacturing method of the present invention> Not limited to the methoxylation method of hydroxymethyl, a solution containing a composition containing compound A1 synthesized by a known synthetic method and containing compounds A1, A2, and A3 can be prepared by replacing the solvent, such as methanol, used in the reaction with the organic solvent used in the crystallization step of the manufacturing method of the present invention, to prepare a solution containing the composition containing compound A1 and the organic solvent used in the crystallization step of the manufacturing method of the present invention. Furthermore, the composition containing compound A1 that has undergone water washing can be prepared by replacing the solvent with the organic solvent used in the crystallization step of the manufacturing method of the present invention, or by dissolving it in the organic solvent, to prepare a solution containing the composition containing compound A1 and the organic solvent used in the crystallization step of the manufacturing method of the present invention. The method of replacing the solvent can be exemplified by the following: After distilling off the organic solvent used in the reaction step to obtain a distillation residue containing the composition of compound A1, this residue is mixed with the organic solvent used in the crystallization step of the present invention to prepare a solution containing the composition of compound A1 used in the crystallization step of the present invention; the processes of "distilling off the organic solvent used in the reaction step from the reaction solution" and "mixing with the organic solvent used in the crystallization step of the present invention" are repeated to prevent the solution from drying out and to maintain its solution state, while replacing the solvent with the organic solvent used in the crystallization step of the manufacturing method of the present invention to prepare a solution containing the composition of compound A1 used in the crystallization step of the present invention. Regarding the distillation conditions for removing the organic solvent, it is preferably carried out under heating, under reduced pressure, or under heated and reduced pressure, more preferably under heated and reduced pressure. The temperature is preferably in the range of 25 to 60°C, more preferably in the range of 25 to 55°C, and even more preferably in the range of 30 to 50°C. The pressure is preferably under reduced pressure, more preferably below 70 kPa, and even more preferably below 50 kPa. When preparing a solution containing a composition containing compound A1 in the crystallization step of the manufacturing method of the present invention, manufacturing method 1 is preferably a method of preparing a solution by using a composition containing compound A1 and a chain aliphatic alcohol solvent with 3 to 5 carbon atoms, and then adding a chain aliphatic hydrocarbon solvent with 5 to 10 carbon atoms. Manufacturing method 2 is preferably a method of preparing a solution by using a composition containing compound A1 and a chain aliphatic carboxylic acid ester solvent with a total number of 5 to 8 carbon atoms, and then adding a cyclic aliphatic hydrocarbon solvent with 5 to 8 carbon atoms.

[0019] <Organic Solvent Used in the Crystallization Step of Manufacturing Method 1> Regarding the organic solvent used in the crystallization step of Manufacturing Method 1 of the present invention, namely, a chain aliphatic alcohol solvent with 3 to 5 carbon atoms, it is preferably a chain aliphatic alcohol solvent with 3 or 4 carbon atoms, more preferably a chain aliphatic alcohol solvent with 3 carbon atoms, and particularly preferably isopropanol. Specific examples of chain aliphatic alcohol solvents with 3 to 5 carbon atoms include: n-propanol, isopropanol (IPA), n-butanol, dibutanol, tributanol, isobutanol, n-pentanol, n-pentanol, dipentanol, isopentanol, tripentanol, etc. In the crystallization step of manufacturing method 1 of the present invention, it is preferable to use at least one solvent selected from these compounds, more preferably at least one solvent selected from n-propanol, isopropanol (IPA), n-butanol, isobutanol, n-pentanol, and isopentanol, even more preferably at least one solvent selected from n-propanol, isopropanol (IPA), n-butanol, and isobutanol, and particularly preferably isopropanol (IPA). Regarding the chain aliphatic hydrocarbon solvent with 5 to 10 carbon atoms used in the crystallization step of manufacturing method 1 of the present invention, it is preferably a chain aliphatic hydrocarbon solvent with 6 to 8 carbon atoms, more preferably a chain aliphatic hydrocarbon solvent with 7 or 8 carbon atoms, and even more preferably a chain aliphatic hydrocarbon solvent with 8 carbon atoms. Examples of chain aliphatic hydrocarbon solvents with 5 to 10 carbon atoms include hexane, heptane, octane, nonane, and decane. In the crystallization step of manufacturing method 1 of the present invention, it is preferable to use at least one solvent selected from the aforementioned compounds, more preferably at least one solvent selected from n-hexane, n-heptane, n-octane, isooctane (2,2,4-trimethylpentane), n-nonane, and n-decane, even more preferably at least one solvent selected from n-hexane, n-heptane, n-octane, and isooctane, and most preferably isooctane. In the crystallization step of manufacturing method 1 of the present invention, trace amounts of solvents other than the aforementioned organic solvents may be included, provided that the effects of the present invention are not impaired. The term "trace amounts" refers, for example, to the amount of organic solvents and water used in the aforementioned reaction steps and washing steps that remain therein after the removal steps have been performed.

[0020] In the crystallization step of manufacturing method 1 of the present invention, the amount of the aliphatic alcohol solvent with 3 to 5 carbon atoms used relative to compound A1 can be appropriately adjusted according to the solubility of compound A1 in the aliphatic alcohol solvent with 3 to 5 carbon atoms used. Preferably, it is in the range of 0.3 to 3.0 times by weight; more preferably, it is in the range of 0.5 to 2.0 times by weight; even more preferably, it is in the range of 0.5 to 1.5 times by weight; and most preferably, it is in the range of 0.6 to 1.3 times by weight. The amount of the aliphatic alcohol solvent with 3 to 5 carbon atoms used can be adjusted by the amount added, or it can be adjusted by removing it from the system by distillation. Furthermore, at the point where crystals precipitate from the crystallization solution, the amount of the aliphatic alcohol solvent with 3 to 5 carbon atoms used is 0.5 to 0.95 times by weight, more preferably 0.5 to 0.9 times by weight, even more preferably 0.55 to 0.9 times by weight, and particularly preferably 0.55 to 0.8 times by weight, relative to the total amount of the aliphatic alcohol solvent with 5 to 10 carbon atoms used. After crystallization, a aliphatic hydrocarbon solvent with 5 to 10 carbon atoms can be further added to the crystallization solution. In this case, ultimately, the amount of the aliphatic alcohol solvent with 3 to 5 carbon atoms used is preferably 0.1 to 0.5 times by weight, even more preferably 0.2 to 0.5 times by weight, relative to the total amount of the aliphatic alcohol solvent with 3 to 5 carbon atoms used and the aliphatic hydrocarbon solvent with 5 to 10 carbon atoms used.

[0021] <Conditions for the crystallization step in manufacturing method 1> In method 1 of the present invention for manufacturing powder containing compound A1, the temperature for crystallization is preferably in the range of 5 to 45°C, more preferably in the range of 5 to 35°C, even more preferably in the range of 5 to 30°C, and particularly preferably in the range of 5 to 20°C. Seed crystals may not be used during crystallization, but it is preferable to use them. There are no restrictions on the type of crystal used as a seed crystal. The amount of seed crystal used relative to the precipitated compound A1 is preferably in the range of 0.001 to 0.1 times by weight. After crystallization, from the viewpoint of yield, it is preferable to cool the crystallization solution. The cooling temperature is preferably in the range of 5 to 35°C, more preferably in the range of 5 to 30°C, and particularly preferably in the range of 5 to 20°C. There are no restrictions on the cooling rate of the crystallization solution, but it is preferably in the range of 3 to 15°C / h.

[0022] <Organic Solvent Used in the Crystallization Step of Manufacturing Method 2> The organic solvent used in the crystallization step of manufacturing method 2 of the present invention is a chain aliphatic carboxylic acid ester solvent with a total number of carbon atoms of 5 to 8, preferably a chain aliphatic carboxylic acid ester solvent with 6 or 7 carbon atoms, more preferably a chain aliphatic acetate ester solvent with 6 or 7 carbon atoms, even more preferably butyl acetate or amyl acetate, and most preferably butyl acetate. Examples of chain aliphatic carboxylic acid ester solvents with a total number of carbon atoms of 5 to 8 include, for example, butyl acetate, amyl acetate, etc., preferably at least one solvent selected from these compounds, and most preferably butyl acetate. The cyclic aliphatic hydrocarbon solvent with a total number of carbon atoms of 5 to 8 used in the crystallization step of manufacturing method 2 of the present invention is preferably a cyclic aliphatic hydrocarbon solvent with a total number of carbon atoms of 6 to 8, and more preferably a cyclic aliphatic hydrocarbon solvent with a total number of carbon atoms of 6. Specific examples of cyclic aliphatic hydrocarbon solvents with 5 to 8 carbon atoms include cyclopentane, cyclohexane, cycloheptane, methylcyclohexane, cyclooctane, and ethylcyclohexane. In the crystallization step of manufacturing method 2 of the present invention, it is preferable to use at least one solvent selected from these compounds, more preferably at least one solvent selected from cyclopentane, cyclohexane, methylcyclohexane, and ethylcyclohexane, even more preferably cyclohexane or methylcyclohexane, and most preferably cyclohexane. In the crystallization step of manufacturing method 2 of the present invention, trace amounts of solvents other than the aforementioned organic solvents may be included, provided it does not impair the effects of the present invention. The term "trace amounts" refers, for example, to the amount of organic solvents and water used in the aforementioned reaction steps and washing steps that remain therein after these removal steps have been performed.

[0023] In the crystallization step of manufacturing method 2 of the present invention, the amount of aliphatic carboxylic acid ester solvent with a total carbon number of 5 to 8 relative to compound A1 can be appropriately adjusted according to the solubility of compound A1 in the aliphatic carboxylic acid ester solvent with a total carbon number of 5 to 8. Preferably, it is in the range of 0.5 to 3.0 times by weight, more preferably in the range of 0.5 to 2.5 times by weight, even more preferably in the range of 0.8 to 2.0 times by weight, and most preferably in the range of 0.8 to 1.5 times by weight. The amount of aliphatic carboxylic acid ester solvent with a total carbon number of 5 to 8 can be adjusted by the amount added or by removing it from the system by distillation. Furthermore, at the point at which crystals precipitate from the crystallization solution, the amount of the chain aliphatic carboxylic acid ester solvent with a total carbon number of 5 to 8 compared to the total amount of the chain aliphatic carboxylic acid ester solvent with a total carbon number of 5 to 8 compared to the total amount of the cyclic aliphatic hydrocarbon solvent with a total carbon number of 5 to 8, is preferably 0.1 to 0.95 times by weight, more preferably 0.1 to 0.7 times by weight, and particularly preferably 0.1 to 0.5 times by weight. After crystallization, a cyclic aliphatic hydrocarbon solvent with a total carbon number of 5 to 8 can be further added to the crystallization solution. In this case, ultimately, the total amount of the chain aliphatic carboxylic acid ester solvent with a total carbon number of 5 to 8 compared to the total amount of the cyclic aliphatic hydrocarbon solvent with a total carbon number of 5 to 8, preferably 0.1 to 0.5 times by weight, and more preferably 0.1 to 0.3 times by weight.

[0024] <Crystallization Step in Manufacturing Method 2: Crystallization Conditions> In manufacturing method 2 of the present invention, which produces a powder containing a composition of compound A1, the temperature at which crystallization occurs is preferably in the range of 5 to 50°C, more preferably in the range of 10 to 40°C, and particularly preferably in the range of 20 to 40°C. Seed crystals may not be used during crystallization, but it is preferable to use them. There are no restrictions on the type of crystal used as a seed crystal. The amount of seed crystal used is preferably in the range of 0.001 to 0.1 times the weight of the compound A1 to be precipitated. After crystallization, from the viewpoint of yield, it is preferable to cool the crystallization solution. The cooling temperature is preferably in the range of 5 to 35°C, more preferably in the range of 5 to 30°C, and particularly preferably in the range of 5 to 20°C. There are no restrictions on the cooling rate of the crystallization solution, but it is preferably in the range of 3 to 15°C / h.

[0025] <Subsequent Steps of Crystallization Step> The powder containing compound A1 obtained by the crystallization steps in the aforementioned manufacturing methods 1 and 2 can be separated and recovered from the crystallization liquid by filtration. In the manufacturing method of the present invention, it is preferable to further include a filtration step to filter out the crystals precipitated in the aforementioned crystallization step. During filtration, an organic solvent, such as the solvent used in the crystallization step, can be used to clean the filtered crystals. The solvent used can be removed by drying the filtered crystals. In the manufacturing method of the present invention, it is preferable to further include a drying step to dry the crystals filtered out in the aforementioned filtration step. The drying step is preferably carried out at a temperature in the range of 25 to 50°C, more preferably in the range of 25 to 45°C, and even more preferably in the range of 25 to 40°C. The pressure during drying can be atmospheric pressure or reduced pressure; in industrial applications, reduced pressure is preferred. Specifically, reduced pressure of 10 kPa or less is preferred, and reduced pressure of 5 kPa or less is even more preferred. Furthermore, in this invention, the aforementioned steps of reaction, neutralization, washing, crystallization, filtration, distillation, drying, packaging, melting, and cooling are preferably carried out in an inert gas environment such as nitrogen or argon, or in an environment with a lower oxygen level than air, in order to suppress oxidation, deterioration, and discoloration caused by the influence of oxygen. [Example]

[0026] The present invention will be specifically described below by way of examples and comparative examples, but the present invention is not limited by such examples or comparative examples. <Analytical Methods> 1. High-performance liquid chromatography (HPLC) analysis The purity of each component in the examples was calculated from the area ratio of the high-performance liquid chromatography (HPLC) charts measured under the following conditions. Apparatus: Prominence, manufactured by Shimadzu Corporation; Pump: LC-20AT; Column oven: CTO-20A; Detector: SPD-20A; Column: Shim-Pack CLC-ODS (inner diameter 6mm, length 150mm); Oven temperature: 50℃; Flow rate: 1mL / min; Mobile phase: (A) 0.2 vol% acetic acid aqueous solution, (B) methanol gradient conditions: (B) vol% 0-30min, 50%→100% 30-45min, 100%; Sample injection volume: 20μL; Detection wavelength: 280nm. 2. Differential scanning calorimetry (DSC): The powder was precisely weighed into an aluminum pot. Using a differential scanning calorimetry apparatus (Hitachi High-Tech Science Co., Ltd.: DSC7020), with an empty aluminum pot as a control, the determination was performed according to the following operating conditions. (Operating Conditions) Heating rate: 10℃ / min. Measurement temperature range: 30 to 400℃. Measurement environment: Nitrogen gas 50 mL / min. Sample volume: 4 to 5 mg

[0027] <Example 1> 1731 g (54.11 mol) of methanol and 57.7 g (0.59 mol) of sulfuric acid were added to a 5 L four-necked flask equipped with a stirrer, thermometer, and cooler, and heated to 60 °C. 192.4 g (0.40 mol) of a phenolic compound (compound B) containing hydroxymethyl groups (represented by chemical formula (B)) was added, and the mixture was stirred at 60 °C for 6 hours. The reaction solution was then cooled, and an aqueous solution of sodium hydroxide and phosphoric acid was added for neutralization. Methanol was removed by distillation under reduced pressure (temperature range of 30 to 50 °C, pressure range of less than 50 kPa). 462.0 g of water and 462.0 g of butyl acetate were added and stirred. The mixture was allowed to stand for 30 minutes, and the aqueous layer was removed. The organic layer was then washed with water several times to obtain 816 g of a washed organic layer containing compound A1. The HPLC analysis of the obtained organic layer containing compound A1, performed using the above method, showed that component A1 accounted for 86.9% of the area, component A2 for 5.6% of the area, and component A3 for 0.6% of the area. A portion (263g) of the cleaned organic layer containing compound A1 was transferred to a four-necked flask equipped with a stirrer, thermometer, and cooler. 177g of the solvent in the organic layer was removed by distillation under reduced pressure, yielding a distillation residue. HPLC analysis of the obtained distillation residue, performed using the above method, showed that the composition containing compound A1 contained 86.9% of the area, component A2 for 5.6% of the area, and component A3 for 0.6% of the area. To prepare the crystallization solution containing compound A1 as described above, 54.4 g of isopropanol (IPA) was added to the distillation residue and dissolved. Then, 22.0 g of isooctane was added, and the mixture was cooled to 30°C (at this point, the weight of IPA in the crystallization solution was 0.7 times the total weight of IPA and isooctane; this is referred to as "0.7 times the weight of crystallization solution" in Figure 1). 1.4 g of crystallized compound A1 was added as a seed crystal, and the mixture was cooled to 15°C over 1 hour. The mixture was then stirred at 15°C for 20.5 hours, resulting in crystallization. Then, 44.5 g of isooctane was mixed over 2 hours, and the mixture was stirred at 15°C for 21 hours (at this point, the weight of IPA in the crystallization solution was 0.4 times the total weight of IPA and isooctane; this is referred to as "0.4 times the weight of crystallization solution" in Figure 1). The mixture of 120 g of isooctane was further stirred at 15°C for 17 hours over 4.5 hours (at this point, the amount of IPA in the crystallization solution was 0.2 times the weight of IPA; this is recorded as "0.2 times the weight of crystallization solution" in Figure 1). During the crystallization process, samples of the supernatant were taken, and the concentration of compound A1 in the supernatant was analyzed by liquid chromatography to confirm the change in concentration over time. The results are shown in Figure 1.This result confirms that during continuous crystallization in a 0.7-weight-fold crystallizing solution, the concentration of compound A1 in the supernatant gradually decreased. This is presumably due to the rapid crystal growth. Furthermore, it was found that adding isooctane further reduced the concentration of compound A1, leading to further crystal precipitation. The precipitated crystals were filtered and dried to obtain 63.2 g of powder containing compound A1 (yield 86.9%). HPLC analysis of the obtained powder containing compound A1 using the above method showed that component A1 accounted for 87.2% of the area, component A2 for 5.7% of the area, and component A3 for 0.7% of the area. Differential scanning calorimetry (DSC) analysis of the obtained powder containing compound A1 showed an onset temperature of 55.9°C, an endothermic peak temperature of 68.2°C, and a heat of fusion based on the observed endothermic peak of 77.0 mJ / mg. The DSC analysis chart is shown in Figure 2.

[0028] <Example 2> 456.1 g (14.25 mol) of methanol and 15.3 g (0.16 mol) of sulfuric acid were added to a 1 L four-necked flask equipped with a stirrer, thermometer, and cooler, and the mixture was heated to 60 °C. 50.8 g (0.1 mol) of compound B was added, and the mixture was stirred at 60 °C for 8 hours. The reaction mixture was then cooled, and an aqueous solution of sodium hydroxide and phosphoric acid was added for neutralization. Methanol was removed by distillation under reduced pressure (temperature range of 30 to 50 °C, pressure range of less than 50 kPa). 114.4 g of water and 114.4 g of butyl acetate were added and stirred. The mixture was allowed to stand for 30 minutes, and the aqueous layer was removed. The organic layer was then washed with water several times to obtain a cleaned organic layer containing compound A1. 106.8 g of the solvent from the organic layer was distilled off from the flask by distillation under reduced pressure to obtain a distillation residue. The HPLC analysis of the distillation residue obtained by the above method showed that, in the composition containing compound A1, component A1 accounted for 86.6% by area, component A2 for 6.3% by area, and component A3 for 0.7% by area. To prepare a crystallization solution containing the aforementioned composition of compound A1, 31.5 g of IPA was added to the obtained distillation residue and heated to 47°C to dissolve it. Then, 22.0 g of isooctane was added, and the solution was cooled to 30°C (at this point, the weight of IPA in the crystallization solution was 0.59 times the total weight of IPA and isooctane). 0.9 g of crystals of compound A1 were added as seed crystals, and the solution was cooled to 15°C over 1.5 hours. Then, 103.9 g of isooctane was added dropwise over 2.5 hours, and the solution was stirred for 18 hours (at this point, the weight of IPA in the crystallization solution was 0.14 times the total weight of IPA and isooctane). The precipitated crystals were filtered and dried to obtain 48.9 g of powder containing compound A1 (yield 82.2%). HPLC analysis of the obtained powder containing compound A1 was performed using the above method. The results showed that component A1 accounted for 86.9% of the area, component A2 for 6.2% of the area, and component A3 for 0.7% of the area. DSC analysis of the obtained powder containing compound A1 showed an initial temperature of 55.0 °C, a peak temperature of 68.1 °C, and a heat of fusion based on the observed endothermic peak value of 73.2 mJ / mg. The DSC analysis results are shown in Figure 3.

[0029] <Example 3> 2883 g (90.1 mol) of methanol and 96.1 g (0.98 mol) of sulfuric acid were added to a 5 L four-necked flask equipped with a stirrer, thermometer, and cooler, and the mixture was heated to 60 °C. 320.3 g (0.66 mol) of compound B was added, and the mixture was stirred at 60 °C for 6 hours. The reaction mixture was then cooled, and an aqueous solution of sodium hydroxide and phosphoric acid was added for neutralization. Methanol was removed by distillation under reduced pressure (temperature range of 30 to 50 °C, pressure range below 50 kPa). 762.5 g of water and 833.3 g of butyl acetate were added and stirred. The mixture was allowed to stand for 30 minutes, and the aqueous layer was removed. The organic layer was then washed with water several times to obtain a cleaned organic layer containing compound A1. 790.9 g of the solvent from the organic layer was distilled off from the flask by distillation under reduced pressure to obtain a distillation residue. The HPLC analysis of the distillation residue obtained by the above method showed that, in the composition containing compound A1, component A1 accounted for 86.4% by area, component A2 for 6.2% by area, and component A3 for 0.7% by area. To prepare a crystallization solution containing the aforementioned composition of compound A1, 214.6 g of IPA was added to the distillation residue at 47°C to dissolve it. Then, 142.9 g of isooctane was added, and the mixture was cooled to 30°C (at this point, the weight of IPA in the crystallization solution was 0.60 times the total weight of IPA and isooctane). 6.4 g of crystals of compound A1 were added as seed crystals, and the mixture was cooled to 15°C over 3 hours. Then, 711.7 g of isooctane was added dropwise over 1 hour, and the mixture was stirred for 18 hours (at this point, the weight of IPA in the crystallization solution was 0.20 times the total weight of IPA and isooctane). The precipitated crystals were filtered and dried to obtain 311.4 g of powder containing compound A1 (yield 82.9%). HPLC analysis of the obtained powder containing compound A1 was performed using the above method. The results showed that component A1 accounted for 86.5% of the area, component A2 for 6.3% of the area, and component A3 for 0.8% of the area. Differential scanning calorimetry (DSC) analysis of the obtained powder containing compound A1 showed an initial temperature of 51.8 °C, a peak temperature of 68.1 °C for the endothermic peak, and a heat of fusion based on the observed endothermic peak of 67.4 mJ / mg. The DSC analysis results are shown in Figure 4.

[0030] <Example 4> 330g of a portion of the cleaned organic layer containing the composition of compound A1 obtained in Example 1 was taken out and placed into another four-necked flask equipped with a stirrer, thermometer and cooler. The solvent of 106.8g of the organic layer was removed by distillation under reduced pressure to obtain a concentrated solution. 49.8g of cyclohexane was added to the concentrated solution at 55°C (at this time, the weight of butyl acetate in the crystallization solution was 0.7 times the weight of the total weight of butyl acetate and cyclohexane; it is recorded as "0.7 times the weight of crystallization solution" in the graph of Figure 5). The solution was then cooled to 35°C, and 0.1g of crystals of compound A1 were added as seed crystals. The solution was cooled to 15°C over 3 hours and stirred at 15°C for 17 hours. Then, 66.4 g of cyclohexane was added dropwise over 1 hour, and the mixture was stirred at 15°C for 22 hours (at this point, the weight of butyl acetate in the crystallization solution was 0.5 times the total weight of butyl acetate and cyclohexane; this is recorded as "0.5 times the weight of crystallization solution" in Figure 5). Next, 133 g of cyclohexane was added dropwise over 1.5 hours, and the mixture was stirred at 15°C for 22 hours (at this point, the weight of butyl acetate in the crystallization solution was 0.3 times the total weight of butyl acetate and cyclohexane; this is recorded as "0.3 times the weight of crystallization solution" in Figure 5). During the above crystallization steps, the supernatant was sampled, and the concentration of compound A1 in the supernatant was analyzed by liquid chromatography to confirm the change in concentration over time. The results are shown in Figure 5. By changing the ratio of butyl acetate to cyclohexane in the butyl acetate and cyclohexane solution of compound A1, the concentration of compound A1 in the supernatant decreased, and crystals precipitated from the crystallization solution. On the other hand, during the continuous crystallization operation at this solvent ratio, there was no significant decrease in the concentration of compound A1, indicating that crystal growth was not rapid. The precipitated crystals were filtered and dried to obtain 29.9 g of powder containing compound A1 (yield 32.8%). HPLC analysis of the obtained powder containing compound A1 was performed using the above method, and the results showed that component A1 accounted for 86.5% of the area, component A2 for 4.5% of the area, and component A3 for 0.8% of the area. Differential scanning calorimetry (DSC) analysis of the obtained powder containing compound A1 showed an initial temperature of 63.7 °C, a peak temperature of 69.2 °C for the endothermic peak, and a heat of fusion based on the observed endothermic peak of 71.4 mJ / mg. The DSC analysis chart is shown in Figure 6.

[0031] The HPLC analysis results of the crystallization solution and the obtained powder in Examples 1 to 4 above, as well as the DSC analysis results of the obtained powder, are shown in Table 1.

[0032] [Table 1] Experimental Example Example 1 Example 2 Example 3 Example 4 Use solvents IPA Isooctane IPA Isooctane IPA Isooctane Butyl acetate Cyclohexane Analysis object Analytical methods Measured values Crystallization solution containing compound A1 HPLC Compound A1 (area%) 86.9 86.6 86.4 86.9 Compound A2 (area%) 5.6 6.3 6.2 5.6 Compound A3 (area%) 0.6 0.7 0.7 0.6 Powder containing compound A1 HPLC Compound A1 (area%) 87.2 86.9 86.5 86.5 Compound A2 (area%) 5.7 6.2 6.3 4.5 Compound A3 (area%) 0.7 0.7 0.8 0.8 DSC Starting temperature (°C) 55.9 55.0 51.8 63.7 Peak temperature (°C) 68.2 68.1 68.1 69.2 Heat of fusion (mJ / mg) 77.0 73.2 67.4 71.4

[0033] <Comparative Example 1> 202g of a portion of the cleaned organic layer containing compound A1 obtained in Example 1 was taken into another four-necked flask equipped with a stirrer, thermometer, and cooler. The solvent of 118g of the organic layer was removed by distillation under reduced pressure to obtain distillation residue. In order to prepare a crystallization solution containing compound A1 of the aforementioned composition, 117.9g of methanol was added to the distillation residue at 40°C. The solution was then cooled to 15°C over 3 hours, and 1.4g of crystals of compound A1 were added as seed crystals. The mixture was stirred at 15°C for 19 hours (referred to as "1.0 times by weight crystallization solution" in the graph of Figure 7). Then, 27.0g of water was added dropwise over 2.5 hours, and the mixture was stirred at 15°C for 20.5 hours (at this point, the weight of methanol in the crystallization solution was 0.8 times the total weight of methanol and water; referred to as "0.8 times by weight crystallization solution" in the graph of Figure 7). Another 5 hours were spent adding 43.3g of water, and the mixture was stirred at 15°C for 18 hours (at this point, the weight of methanol in the crystallization solution was 0.6 times the total weight of methanol and water; this is recorded as "0.6 times the weight of crystallization solution" in Figure 7). Then, 54.1g of water was added dropwise over 2.5 hours, resulting in the formation of highly viscous oil in the crystallization solution (at this point, the weight of methanol in the crystallization solution was 0.45 times the total weight of methanol and water). Compound A1 could not be isolated from this crystallization solution. During the above crystallization process, the supernatant was sampled, and the concentration of compound A1 in the supernatant was analyzed by liquid chromatography to confirm the concentration change over time. The results are shown in Figure 7. Adding water to the methanol solution of compound A1 and the water-methanol solution to change the methanol-water ratio reduced the concentration of compound A1 in the supernatant, but oil formation still occurred, and compound A1 could not be precipitated as crystals. On the other hand, it was also learned that during the continuous crystallization operation according to this solvent ratio, almost no decrease in the concentration of compound A1 occurred.

[0034] <Comparative Example 2> Using the powder containing compound A1 obtained in Example 1, an ethanol solution containing 40% by weight of compound A1 was prepared by dissolving it in ethanol at 45°C in a glass solenoid. The solenoid was sealed and cooled in a refrigerator (approximately 4°C) for 3 days, resulting in the precipitation of powder. The precipitated powder was filtered and dried. The obtained powder containing compound A1 was analyzed by HPLC using the above method, and the results showed that it contained 90.9% by area of ​​component A1, 2.9% by area of ​​component A2, and 0.3% by area of ​​component A3. The obtained powder containing compound A1 was analyzed by differential scanning calorimetry (DSC), and the onset temperature was 65.4°C, the peak temperature of the endothermic peak was 70.1°C, and the heat of fusion based on the observed endothermic peak was 80.6 mJ / mg. The DSC analysis chart is shown in Figure 8.

[0035] <Comparative Example 3> Using the powder containing compound A1 obtained in Example 1, a methanol solution containing 40% by weight of compound A1 was prepared by dissolving it in methanol at 45°C in a glass solenoid. The solenoid was sealed and cooled in a refrigerator (approximately 4°C) for 3 days, resulting in the precipitation of powder. The precipitated powder was filtered and dried. The obtained powder containing compound A1 was analyzed by HPLC using the above method, and the results showed that it contained 90.8% by area of ​​component A1, 2.9% by area of ​​component A2, and 0.3% by area of ​​component A3. The obtained powder containing compound A1 was analyzed by differential scanning calorimetry (DSC), and the onset temperature was 67.2°C, the peak temperature of the endothermic peak was 71.5°C, and the heat of fusion based on the observed endothermic peak was 77.6 mJ / mg. The DSC analysis chart is shown in Figure 9.

[0036] <Comparative Example 4> Using the powder containing compound A1 obtained in Example 1, a solution of ethyl lactate containing 40% by weight of compound A1 was prepared by dissolving it in ethyl lactate at 45°C in a glass solenoid. The solenoid was sealed and cooled in a refrigerator (approximately 4°C) for 3 days, resulting in the precipitation of powder. The precipitated powder was filtered and dried. The obtained powder containing compound A1 was analyzed by HPLC using the above method, and the results showed that it contained 93.3% by area of ​​component A1, 2.0% by area of ​​component A2, and 0.2% by area of ​​component A3. The obtained powder containing compound A1 was analyzed by differential scanning calorimetry (DSC), and the onset temperature was 68.7°C, the peak temperature of the endothermic peak was 72.9°C, and the heat of fusion based on the observed endothermic peak was 85.1 mJ / mg. The DSC analysis chart is shown in Figure 10.

[0037] <Comparative Example 5> The same amount of the same sample as in Example 1 was used, and the distillation residue was obtained by the same method, up to the distillation operation performed under reduced pressure by heating in Example 1. HPLC analysis of the obtained distillation residue showed that, in the composition containing compound A1, component A1 accounted for 86.9% by area, component A2 for 5.6% by area, and component A3 for 0.6% by area. To prepare a crystallization solution containing compound A1, 292 g of propylene glycol monomethyl ether (PGME) was added to dissolve it. A portion of this solution was transferred to a polypropylene spiral tube and sealed. The spiral tube was cooled in a refrigerator (approximately 4°C) for 4 years, resulting in the precipitation of powder. The precipitated powder was filtered and dried. HPLC analysis of the obtained powder containing compound A1 using the above method showed that it contained 94.3% by area, component A2 for 0.9% by area, and component A3 for 0.1% by area. The powder containing compound A1 was analyzed by differential scanning calorimetry (DSC). The initial temperature was 70.4 °C, the peak temperature of the endothermic peak was 75.2 °C, and the heat of fusion based on the observed endothermic peak was 92.5 mJ / mg. The DSC analysis chart is shown in Figure 11.

[0038] <Comparative Example 6> A portion of the cleaned organic layer containing the composition containing compound A1 obtained in Example 1 was taken into a polypropylene spiral tube and sealed. The spiral tube was cooled in a refrigerator (approximately 4°C) for 2 weeks, resulting in the precipitation of powder. The precipitated powder was filtered and dried. The yield of the powder containing the composition containing compound A1 was 15%. The obtained powder containing the composition containing compound A1 was analyzed by HPLC using the above method, and the results showed that it contained 94.4% area of ​​component A1, 1.6% area of ​​component A2, and 0.2% area of ​​component A3. The obtained powder containing the composition containing compound A1 was analyzed by differential scanning calorimetry (DSC), and the onset temperature was 71.1°C, the peak temperature of the endothermic peak was 75.0°C, and the heat of fusion based on the observed endothermic peak was 92.1 mJ / mg. The DSC analysis chart is shown in Figure 12.

[0039] The HPLC analysis results of the crystallization solution and the obtained powder in the aforementioned Comparative Examples 1 to 6, and the DSC analysis results of the obtained powder are shown in Table 2.

[0040] [Table 2] Experimental Example Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Use solvents Methanol water ethanol methanol Ethyl lactate PGME Butyl acetate Analysis object Analytical methods Measured values Crystallization solution containing compound A1 HPLC Compound A1 (area%) 86.9 87.2 87.2 87.2 86.9 86.9 Compound A2 (area%) 5.6 5.7 5.7 5.7 5.6 5.6 Compound A3 (area%) 0.6 0.7 0.7 0.7 0.6 0.6 Powder containing compound A1 HPLC Compound A1 (area%) Unable to obtain powder 90.9 90.8 93.3 94.3 94.4 Compound A2 (area%) 2.9 2.9 2.0 0.9 1.6 Compound A3 (area%) 0.3 0.3 0.2 0.1 0.2 DSC Starting temperature (°C) 65.4 67.2 68.7 70.4 71.1 Peak temperature (°C) 70.1 71.5 72.9 75.2 75.0 Heat of fusion (mJ / mg) 80.6 77.6 85.1 92.5 92.1

[0041] It was found that the powders obtained by the crystallization methods of the compositions containing compound A1 in Comparative Examples 2 to 6 had high heat of fusion, resulting in poor efficiency when heated and melted for use. On the other hand, it was found that the powders obtained by the crystallization methods of the compositions containing compound A1 in Examples 1 to 4 had low heat of fusion because they had specific compositions and the starting temperature in DSC analysis was a specific temperature. Furthermore, it was found that the crystallization methods of Examples 1 to 3 did not produce oil, and powders containing compounds A1 could be obtained with a high yield of 82.2% to 86.9%, and the powder properties could be obtained easily. Therefore, they were suitable for large-scale industrial production and could efficiently manufacture powders containing compounds A1. [Simplified Explanation of the Diagram]

[0042] Figure 1 is a graph showing the concentration of compound A1 in the supernatant of the crystallization solution during the crystallization step of Example 1 by liquid chromatography analysis and its change over time. Figure 2 is a graph showing the differential scanning calorimetry (DSC) analysis of the powder containing compound A1 obtained in Example 1. Figure 3 is a graph showing the differential scanning calorimetry (DSC) analysis of the powder containing compound A1 obtained in Example 2. Figure 4 is a graph showing the differential scanning calorimetry (DSC) analysis of the powder containing compound A1 obtained in Example 3. Figure 5 is a graph showing the concentration of compound A1 in the supernatant of the crystallization solution during the crystallization step of Example 4 by liquid chromatography analysis and its change over time. Figure 6 is a graph showing the differential scanning calorimetry (DSC) analysis of the powder containing compound A1 obtained in Example 4. Figure 7 is a graph showing the concentration of compound A1 in the supernatant of the crystallization solution during the crystallization step in Comparative Example 1, analyzed by liquid chromatography, and its change over time. Figure 8 is a graph showing the differential scanning calorimetry (DSC) analysis of the powder containing compound A1 obtained in Comparative Example 2. Figure 9 is a graph showing the differential scanning calorimetry (DSC) analysis of the powder containing compound A1 obtained in Comparative Example 3. Figure 10 is a graph showing the differential scanning calorimetry (DSC) analysis of the powder containing compound A1 obtained in Comparative Example 4. Figure 11 is a graph showing the differential scanning calorimetry (DSC) analysis of the powder containing compound A1 obtained in Comparative Example 5. Figure 12 is a graph showing the differential scanning calorimetry (DSC) analysis of the powder containing compound A1 obtained in Comparative Example 6.

Claims

1. A powder containing a phenolic compound, wherein, The aforementioned phenolic compound is represented by chemical formula (A1) and contains a methoxymethyl group. The aforementioned composition contains, in the following proportions: a phenolic compound represented by chemical formula (A1) as component A1, a compound represented by chemical formula (A2) as component A2, and a compound represented by chemical formula (A3) as component A3. The onset temperature of the endothermic peak obtained by differential scanning calorimetry analysis is in the range of 50 to 65°C. The aforementioned proportions are obtained by liquid chromatography analysis of the composition using a UV detector with a wavelength of 280 nm. The detection area ratios of the following components relative to the detection area of ​​all detected components are in the following ranges: Component A1: 83.0% to 88.0% Component A2: 3.5% to 6.5% Component A3: 0.01% to 3.0% 2. A method for manufacturing the powder described in claim 1, comprising a crystallization step; wherein, The aforementioned step involves crystallization from a solution containing a methoxymethyl phenolic compound (compound A1) represented by chemical formula (A1), isopropanol, and isooctane; wherein the aforementioned composition contains the methoxymethyl phenolic compound (A1) as component A1, a compound (A2) as component A2, and a compound (A3) as component A3 in the following compositional ratios; the aforementioned compositional ratios are determined by liquid chromatography analysis of the composition using a UV detector with a wavelength of 280 nm, and the detection area ratios of each component relative to the detection area of ​​all detected components are within the following ranges: Component A1: 83.0% to 88.0% Component A2: Component A3: 3.5% to 6.5% area Area percentage above 0.01% and area percentage below 3.0%.

3. A method for manufacturing the powder described in claim 1, comprising a crystallization step; wherein, The aforementioned step involves crystallization from a solution containing a composition comprising a methoxymethylphenol compound (compound A1) represented by chemical formula (A1), butyl acetate, and cyclohexane; wherein the aforementioned composition contains the methoxymethylphenol compound (A1) as component A1, a compound (A2) as component A2, and a compound (A3) as component A3 in the following compositional ratios; the aforementioned compositional ratios are determined by liquid chromatography analysis of the composition using a UV detector with a wavelength of 280 nm, and the detection area ratios of each component relative to the detection area of ​​all detected components are within the following ranges: Component A1: 83.0% to 88.0% Component A2: Component A3: 3.5% to 6.5% area Area percentage above 0.01% and area percentage below 3.0%.

Images