Powder of composition containing phenol compound having methoxymethyl group, and production method therefor

Abstract

The present invention addresses the problem of providing a novel form of a phenol compound represented by chemical formula (A1) and having a methoxymethyl group, which can be produced by a production method suitable for industrial mass production, and with which it is possible to reduce the energy required when the same is used by heating and melting a solid thereof. As a means for solving said problem, provided is a powder of a composition containing a phenol compound represented by chemical formula (A1) and having a methoxymethyl group, said powder containing, at the compositional ratio below, a phenol compound represented by chemical formula (A1) and having a methoxymethyl group as a component A1, a compound represented by chemical formula (A2) as a component A2, and a compound represented by chemical formula (A3) as a component A3, wherein the onset temperature of an endothermic peak according to a differential scanning calorimetry analysis is in the range of 50-65°C. [Compositional ratio] The following ranges are the detection area proportions of the components relative to the detection areas of all components detected by liquid chromatography analysis of the composition using a 280-nm wavelength UV detector. Component A1: 83.0-88.0 area%, component A2: 3.5-6.5 area%, and component A3: 0.01-3.0 area%

Description

Powder of composition containing phenolic compound having methoxymethyl group and method for producing same

[0001] The present invention relates to a powder of a composition containing a phenolic compound having a methoxymethyl group and a method for producing the same, and more particularly to a novel embodiment of a compound represented by the following chemical formula (A1) (hereinafter, also referred to as compound A1) and a production method for producing the same, including a crystallization step.

[0002] Phenol compounds having a methylol group or a methoxymethyl group have been used as curing agents for resins having a phenolic hydroxyl group and as crosslinking agents for improving the film properties of photosensitive resins. A compound represented by chemical formula (A1) (compound A1) is known as a phenol compound having a methoxymethyl group. As a conventionally known method for isolating a compound represented by chemical formula (A1), Patent Document 1 describes a method in which a hexahydroxymethyl compound (compound B, described below), which is a precursor of this compound, is reacted with methanol to synthesize compound A1, and the methanol is then distilled off under reduced pressure to isolate the compound. Patent Document 2 describes a method in which 2,6-xylenol is used as a starting material and acetylated, the methyl group is brominated, and the bromomethyl group is methoxylated to synthesize 2,6-dimethoxymethylphenol (III), and an acylated product of 2,6-dimethoxymethylphenol (III) is subjected to a condensation reaction and deacetylation with 2,6-dimethoxymethylphenol (III), thereby synthesizing compound A1. Patent Document 3 describes a crystallization method using ethanol as an isolation method after the reaction. Patent Document 3 describes a method in which a 20% propylene glycol monomethyl ether (PGME) solution of compound A1 with a purity of 80% is concentrated using an evaporator to form a 50% propylene glycol monomethyl ether solution, which is then left to stand for two days to obtain white crystals of compound A1. Patent Document 4 describes that a 20% ethyl lactate solution of Compound A1 was concentrated using an evaporator to form a 40% ethyl lactate (EL) solution, which was then allowed to stand at room temperature for 5 days to yield a pale orange solid of Compound A1. Patent Document 5 describes several production examples of Compound A1, and Synthesis Examples 5, 15, and 16 describe production examples of Compound A1 in γ-butyrolactone solutions having different compositions containing Compound A1 and its dimer and trimer, and different solute concentrations. Furthermore, Synthesis Example 17 describes, similar to Patent Document 4, that a 20% ethyl lactate solution of Compound A1 was concentrated using an evaporator to form a 50% ethyl lactate solution, which was then allowed to stand for 2 days to yield white crystals of Compound A1.

[0003] International Publication No. 2024 / 082896 Chinese Patent Application Publication No. 115959977 International Publication No. 2016 / 148176 Japanese Patent Application Laid-Open No. 2009-227697 Japanese Patent Application Laid-Open No. 2024-52592

[0004] When preparing or using a resin composition containing a phenolic compound having a methylol or methoxymethyl group on an industrial scale, melting takes time, which causes thermosetting during melting and limits the moldable time. Therefore, from the standpoints of productivity and moldability, it is desirable for the phenolic compound having a methylol or methoxymethyl group to have a low melting point and a small heat of fusion. The properties of Compound A1 obtained by the isolation method described in Patent Document 1 are unknown. Since Compound A1 is the distillation residue obtained by distilling off methanol from the synthesis reaction solution of Compound A1, it may be in the form of a lumpy solid or a highly viscous substance, which may make it difficult to handle in industrial production. The production method described in Patent Document 2 uses 2,6-dimethylphenol as a raw material and synthesizes Compound A1 through five steps: acetyl protection, bromination, methoxy substitution, Friedel-Crafts acylation, and dehydration condensation. This requires many reaction steps and is not suitable for industrial mass production. Furthermore, the properties of Compound A1 obtained by the method of crystallization using ethanol are unknown. The methods for isolating crystals of compound A1 described in Patent Documents 3 and 4 require two or five days for crystallization to the point where isolation is possible, which indicates that the crystallization rate is extremely slow and that these methods are unsuitable for industrial production of compound A1. Furthermore, the present inventors have investigated conventional crystallization methods for compound A1 and have discovered problems, such as a high melting point and a large heat of fusion of the resulting crystals, as shown in the comparative examples described below. When melt-mixing compound A1 with a resin to produce a resin composition and a cured product thereof, a high melting point and a large heat of fusion require a correspondingly large amount of energy, which not only results in poor efficiency but also causes thermal curing during melting, limiting the time available for molding. In light of the above-mentioned problems discovered by the present inventors, an objective of the present inventors is to provide a novel form of compound A1 that can be produced by a production method suitable for industrial mass production and that reduces the energy required when used by heating and melting the solid.

[0005] As a result of intensive research to solve the above-mentioned problems, the present inventors have found a new form of compound A1 in which a composition containing compound A1 has a specific composition, a low melting point, and a small heat of fusion by employing a crystallization process using a specific solvent, and have completed the present invention.

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

[0007] The powder of the composition containing the phenolic compound having a methoxymethyl group (compound A1) represented by chemical formula (A1) of the present invention can be produced efficiently and more quickly in a crystallization step than by conventional methods for producing crystals of compound A1. Furthermore, compared with conventional compositions containing compound A1, the powder has a lower melting point and a smaller heat of fusion, making it very useful in melt-molding materials such as resin compositions containing compound A1, as it has excellent productivity and moldability.

[0008] 1 is a graph showing the change over time in the concentration of compound A1 in the supernatant of the crystallization solution analyzed by liquid chromatography during the crystallization step in Example 1. FIG. 2 is a chart showing a differential scanning calorimetry (DSC) analysis of the powder of the composition containing compound A1 obtained in Example 1. FIG. 3 is a chart showing a differential scanning calorimetry (DSC) analysis of the powder of the composition containing compound A1 obtained in Example 2. FIG. 4 is a chart showing a differential scanning calorimetry (DSC) analysis of the powder of the composition containing compound A1 obtained in Example 3. FIG. 5 is a graph showing the change over time in the concentration of compound A1 in the supernatant of the crystallization solution analyzed by liquid chromatography during the crystallization step in Example 4. FIG. 6 is a chart showing the change over time in the concentration of compound A1 in the supernatant of the crystallization solution analyzed by liquid chromatography during the crystallization step in Comparative Example 1. FIG. 1 shows a differential scanning calorimetry (DSC) analysis chart of the powder of the composition containing compound A1 obtained in Comparative Example 2. FIG. 2 shows a differential scanning calorimetry (DSC) analysis chart of the powder of the composition containing compound A1 obtained in Comparative Example 3. FIG. 3 shows a differential scanning calorimetry (DSC) analysis chart of the powder of the composition containing compound A1 obtained in Comparative Example 4. FIG. 4 shows a differential scanning calorimetry (DSC) analysis chart of the powder of the composition containing compound A1 obtained in Comparative Example 5. FIG. 5 shows a differential scanning calorimetry (DSC) analysis chart of the powder of the composition containing compound A1 obtained in Comparative Example 6.

[0009] The present invention will be described in detail below. <Powder of composition containing a phenolic compound having a methoxymethyl group represented by chemical formula (A1) of the present invention> The powder of composition containing a phenolic compound having a methoxymethyl group represented by chemical formula (A1) of the present invention (compound A1) contains a phenolic compound having a methoxymethyl group 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 compositional ratios, and is characterized by having an endothermic peak onset temperature in the range of 50 to 65°C as determined by differential scanning calorimetry. [Compositional ratio]: The detected area ratios of the following components to the detected areas of all components detected by liquid chromatography analysis of the composition using a UV detector at a wavelength of 280 nm are within the following ranges: Component A1: 83.0 area% to 88.0 area% Component A2: 3.5 area% to 6.5 area% Component A3: 0.01 area% to 3.0 area%

[0010] The powder composition of the present invention containing a phenolic compound having a methoxymethyl group represented by chemical formula (A1) (compound A1) contains a phenolic compound having a methoxymethyl group 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 compound represented by chemical formula (A2) (sometimes referred to as "compound A2"), which is component A2, is a dimer in which two molecules of compound A1 are bonded together through a methylene chain formed by a reaction in which the methoxymethyl groups of each molecule form a methylene chain. The compound represented by chemical formula (A3) (sometimes referred to as "compound A3"), which is component A3, is a trimer in which three molecules of compound A1 are bonded together through a methylene chain formed by a reaction in which the methoxymethyl groups of each molecule form a methylene chain. Regarding the composition ratios in the powder of the composition containing compound A1 of the present invention, the ranges of the detected area ratios of each component are preferably 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%, and 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 liquid chromatography analysis to confirm the above composition ratios are based on the high performance liquid chromatography (HPLC) analysis method described in the Examples below. The onset temperature of the endothermic peak in a powder of the composition containing compound A1 of the present invention, as measured 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 powder of the composition containing compound A1 of the present invention has an endothermic peak top temperature measured by differential scanning calorimetry in the range of preferably 63 to 73° C., more preferably 64 to 72° C., even more preferably 65 to 71° C., and particularly preferably 66 to 70° C. The powder of the composition containing compound A1 of the present invention has a heat of fusion based on the endothermic peak measured by differential scanning calorimetry in the range of preferably 65 to 77 mJ / mg, more preferably 66 to 75 mJ / mg, even more preferably 66 to 74 mJ / mg, and particularly preferably 66 to 70 mJ / mg.

[0011] <Method for Producing Powder of Composition Containing a Phenol Compound Having a Methoxymethyl Group Represented by Chemical Formula (A1) of the Present Invention> One method for producing a powder of a composition containing a phenol compound having a methoxymethyl group represented by chemical formula (A1) (Compound A1) of the present invention includes a crystallization step of precipitating crystals from a solution containing a composition containing a phenol compound having a methoxymethyl group represented by chemical formula (A1) (Compound A1), the composition containing a phenol compound having a methoxymethyl group 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) in the following compositional ratios: a chain aliphatic alcohol solvent having 3 to 5 carbon atoms and a chain aliphatic hydrocarbon solvent having 5 to 10 carbon atoms. This method is referred to as "Production Method 1." [Compositional Ratio]: The ratio of the detection area of ​​each of the following components to the detection area of ​​all components detected by liquid chromatography analysis of the composition using a UV detector at a wavelength of 280 nm is within the following ranges. Component A1: 83.0 area% or more and 88.0 area% or less Component A2: 3.5 area% or more and 6.5 area% or less Component A3: 0.01 area% or more and 3.0 area% or less

[0012] Another method for producing a powder of a composition containing a phenolic compound having a methoxymethyl group represented by chemical formula (A1) (Compound A1) of the present invention includes a crystallization step of precipitating crystals from a solution containing a linear aliphatic carboxylic acid ester solvent having 5 to 8 carbon atoms and a cyclic aliphatic hydrocarbon solvent having 5 to 8 carbon atoms, the composition containing a phenolic compound having a methoxymethyl group represented by chemical formula (A1) (Compound A1) as Component A1, a compound represented by chemical formula (A2) as Component A2, and a compound represented by chemical formula (A3) in the following compositional ratios. This method is sometimes referred to as "Production Method 2." [Compositional Ratio]: The ratio of the detection area of ​​each of the following components to the detection area of ​​all components detected by liquid chromatography analysis of the composition using a UV detector at a wavelength of 280 nm is within the following ranges. Component A1: 83.0 area% or more and 88.0 area% or less Component A2: 3.5 area% or more and 6.5 area% or less Component A3: 0.01 area% or more and 3.0 area% or less

[0013] Among the production methods of the present invention, Production Method 1 is preferred because crystallization proceeds more easily and powder of Compound A1 can be obtained efficiently and in high yield.

[0014] (Composition containing a phenol compound having a methoxymethyl group represented by chemical formula (A1)) In the production method of the present invention, which is common to Production Methods 1 and 2, the composition containing compound A1 used as a raw material is not particularly limited by its synthesis method as long as it has the specific composition ratio described above. It may be a product that has been extracted once by an isolation procedure after the synthesis reaction. There is also no particular limitation on the form, and it may be in the form of a solid, oil, lump, or powder. With regard to the composition ratio, the ranges of the detected area proportions of each component are preferably 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%, and 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%.

[0015] An example of a method for synthesizing compound A1 is a method (hereinafter sometimes referred to as the "hydroxymethyl group methoxylation method") in which a phenolic compound having a hydroxymethyl group represented by chemical formula (B) (hereinafter sometimes referred to as compound B) is reacted with methanol in the presence of an acid catalyst to synthesize a phenolic compound having a methoxymethyl group represented by chemical formula (A1), as shown in the following reaction formula: In the method for producing a powder of a composition containing compound A1 of the present invention, the composition containing compound A1 used as a raw material is preferably a composition containing compound A1 synthesized by the "hydroxymethyl group methoxylation method", which is the method for producing a powder of a composition containing compound A1, by reacting a phenolic compound having a hydroxymethyl group represented by chemical formula (B) with methanol in the presence of an acid catalyst. A method for producing a composition containing Compound A1 with a specific composition ratio by the "hydroxymethyl group methoxylation method" of the synthesis method is described below. The synthesis method for the phenol compound having a hydroxymethyl group (Compound B) represented by chemical formula (B) used in the hydroxymethyl group methoxylation method is not particularly limited, and the compound can be synthesized by a conventionally known method. An example of a method for synthesizing Compound B is a method in which a trisphenol compound (Compound C) represented by chemical formula (C) is reacted with formaldehyde in the presence of a basic catalyst to synthesize a phenol compound having a hydroxymethyl group (Compound B) represented by chemical formula (B).

[0016] The amount of methanol used in the method for methoxylation of a hydroxymethyl group according to the present invention is preferably in the range of 80 to 170 moles, more preferably in the range of 100 to 150 moles, and particularly preferably in the range of 110 to 140 moles, per mole of compound B. This methanol can also serve as a reaction solvent.

[0017] Specific examples of the acid catalyst used in the methoxylation method of a hydroxymethyl group according to the present invention include sulfuric acid, hydrochloric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, cation exchange resin (acid type), oxalic acid, and heteropolyacids such as phosphotungstic acid and silicotungstic acid. It is preferable to use at least one of these compounds. Among these, sulfuric acid is particularly preferable. The amount of the acid catalyst used is preferably in the range of 0.5 to 2.5 mol, more preferably 1.0 to 2.0 mol, and particularly preferably 1.2 to 1.7 mol, per mol of compound B. The reaction temperature in the methoxylation method of a hydroxymethyl group according to the present invention is preferably in the range of 30 to 62°C, more preferably 45 to 62°C, and particularly preferably 58 to 62°C. After completion of the reaction, it is preferable to neutralize the acid catalyst used in the reaction by mixing with a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate.

[0018] (Composition Containing Compound A1 After Water-Washing Treatment) The composition containing Compound A1 used as a raw material is preferably a composition containing Compound A1 that has been subjected to a water-washing treatment to remove the catalyst used in the synthesis reaction, water-soluble impurities (such as salts produced by neutralization of the acid catalyst) generated during the catalyst deactivation treatment, and metals contained in the raw materials used or the base used in the neutralization. The water-washing treatment can be performed by preparing a solution of the composition containing Compound A1 and an organic solvent that dissolves the composition containing Compound A1 and separates it from water, and then washing the organic layer with water. Examples of compositions containing Compound A1 to be subjected to the water-washing treatment include compositions containing Compound A1 contained in the reaction solution after the synthesis reaction and compositions containing Compound A1 that have been isolated once. When a reaction solution containing a composition containing Compound A1 after the synthesis reaction is used, the solution is prepared by solvent substitution from the organic solvent used in the reaction, such as methanol, with an organic solvent that can dissolve the composition containing Compound A1 and separate it from water. When a composition containing compound A1 that has been extracted is used, a solution is prepared by mixing it with an organic solvent that can dissolve the composition containing compound A1 and separate it from water. Examples of organic solvents that can dissolve the composition containing compound A1 and separate it from water include aromatic hydrocarbon solvents having 7 to 9 carbon atoms, such as toluene and xylene, chain aliphatic ketone solvents having 4 to 8 carbon atoms in total, such as methyl ethyl ketone, methyl isobutyl ketone and methyl isoamyl ketone, and chain aliphatic carboxylic acid ester solvents having 5 to 8 carbon atoms in total, such as butyl acetate and amyl acetate. It is preferable to use at least one organic solvent selected from these.Among these, it is more preferable to use at least one organic solvent selected from chain aliphatic ketone solvents having a total of 4 to 8 carbon atoms and chain aliphatic carboxylic acid ester solvents having a total of 5 to 8 carbon atoms, it is even more preferable to use at least one organic solvent selected from methyl ethyl ketone, methyl isobutyl ketone, methyl isoamyl ketone, butyl acetate, and amyl acetate, and it is particularly preferable to use at least one organic solvent selected from methyl ethyl ketone, methyl isobutyl ketone, butyl acetate, and amyl acetate. The amount of the organic solvent used relative to the amount of the composition containing compound A1 can be adjusted appropriately in consideration of the solubility of compound A1 in the organic solvent used, but is 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 particularly preferably in the range of 0.8 to 2.0 times by weight. The amount of water used in the water washing treatment can be adjusted appropriately taking into account the amount of water-soluble impurities to be removed, but is preferably in the range of 0.5 to 3.0 times by weight, more preferably 0.5 to 2.5 times by weight, even more preferably 0.5 to 2.0 times by weight, and particularly preferably 0.5 to 1.5 times by weight, relative to the weight of the organic layer to be washed. The organic layer may be washed once or multiple times taking into account the amount of water-soluble impurities to be removed. Using a chain aliphatic carboxylic acid ester solvent having 5 to 8 carbon atoms in total for the water washing treatment is also preferable from the viewpoint that the composition containing Compound A1 in a solution state dissolved in a chain aliphatic carboxylic acid ester solvent having 5 to 8 carbon atoms in total can be used as is in the crystallization step in "Production Method 2" of the production method of the present invention.

[0019] <Preparation of Solution Used in the Crystallization Step of the Production Method of the Present Invention> A composition containing Compound A1 and a solution containing an organic solvent to be used in the crystallization step of the production method of the present invention can be prepared by solvent-substitution from the organic solvent, such as methanol, used in the reaction of a reaction solution containing a composition containing Compound A1, including Compound A1, Compound A2, and Compound A3, synthesized by a known synthesis method, including but not limited to the above-mentioned method for methoxylation of a hydroxymethyl group, with the organic solvent to be used in the crystallization step of the production method of the present invention. Furthermore, the composition containing Compound A1 that has undergone the above-mentioned water-washing treatment can be washed and then solvent-substitution with the organic solvent to be used in the crystallization step of the production method of the present invention, or can be dissolved in that organic solvent to prepare a composition containing Compound A1 and a solution containing an organic solvent to be used in the crystallization step of the production method of the present invention. Examples of the solvent substitution method include a method in which the organic solvent used in the reaction step is distilled off to obtain a distillation residue of a composition containing compound A1, which is then mixed with the organic solvent used in the crystallization step of the present invention to prepare a solution containing a composition containing compound A1 to be used in the crystallization step of the present invention; and a method in which the organic solvent used in the reaction step is distilled off from the reaction solution and mixed with the organic solvent used in the crystallization step of the present invention repeatedly, thereby maintaining the solution state without drying, and then performing solvent substitution with the organic solvent used in the crystallization step of the production method of the present invention to prepare a solution containing a composition containing compound A1 to be used in the crystallization step of the present invention. The distillation conditions for distilling off the organic solvent are preferably under heating, reduced pressure, or heating and reduced pressure, and more preferably under heating and reduced pressure. The temperature is preferably in the range of 25 to 60°C, more preferably 25 to 55°C, and even more preferably 30 to 50°C. The pressure is preferably under reduced pressure, more preferably 70 kPa or less, and even more preferably 50 kPa or less.In preparing a solution containing a composition containing compound A1 to be used in the crystallization step in the production method of the present invention, in Production Method 1, a method is preferred in which a solution of a composition containing compound A1 and a chain aliphatic alcohol solvent having 3 to 5 carbon atoms is prepared, and then a chain aliphatic hydrocarbon solvent having 5 to 10 carbon atoms is added; and in Production Method 2, a method is preferred in which a solution of a composition containing compound A1 and a chain aliphatic carboxylic acid ester solvent having a total of 5 to 8 carbon atoms is prepared, and then a cyclic aliphatic hydrocarbon solvent having 5 to 8 carbon atoms is added.

[0020] <Organic solvent used in the crystallization step in production method 1> As the chain aliphatic alcohol solvent having 3 to 5 carbon atoms, which is the organic solvent used in the crystallization step in production method 1 of the present invention, a chain aliphatic alcohol solvent having 3 or 4 carbon atoms is preferred, a chain aliphatic alcohol solvent having 3 carbon atoms is more preferred, and of these, isopropanol is particularly preferred. Specific examples of chain aliphatic alcohol solvents having 3 to 5 carbon atoms include n-propanol, isopropyl alcohol (IPA), n-butanol, sec-butanol, tert-butanol, isobutanol, n-pentyl alcohol, n-amyl alcohol, sec-amyl alcohol, isoamyl alcohol, and tert-amyl alcohol. In the crystallization step in Production Method 1 of the present invention, it is preferable to use at least one solvent selected from these compounds, and it is more preferable to use at least one solvent selected from n-propanol, isopropyl alcohol (IPA), n-butanol, isobutanol, n-amyl alcohol, and isoamyl alcohol. It is even more preferable to use at least one solvent selected from n-propanol, isopropyl alcohol (IPA), n-butanol, and isobutanol, and isopropyl alcohol (IPA) is particularly preferred. As the chain aliphatic hydrocarbon solvent having 5 to 10 carbon atoms used in the crystallization step of Production Method 1 of the present invention, chain aliphatic hydrocarbon solvents having 6 to 8 carbon atoms are preferred, chain aliphatic hydrocarbon solvents having 7 or 8 carbon atoms are more preferred, and chain aliphatic hydrocarbon solvents having 8 carbon atoms are even more preferred. Specific examples of chain aliphatic hydrocarbon solvents having 5 to 10 carbon atoms include hexane, heptane, octane, nonane, and decane.In the crystallization step in Production Method 1 of the present invention, it is preferable to use at least one solvent selected from these compounds, and it is more preferable to use at least one solvent selected from n-hexane, n-heptane, n-octane, isooctane (2,2,4-trimethylpentane), n-nonane, and n-decane. It is even more preferable to use at least one solvent selected from n-hexane, n-heptane, n-octane, and isooctane, with isooctane being particularly preferable. In the crystallization step in Production Method 1 of the present invention, a small amount of a solvent other than the above-mentioned organic solvent may be contained, as long as it does not impair the effects of the present invention. "Small amount" means, for example, the amount of the organic solvent or water used in the above-mentioned reaction step, water washing treatment, or other steps that remains after the steps of removing these organic solvents or water.

[0021] The amount of the chain aliphatic alcohol solvent having 3 to 5 carbon atoms used relative to Compound A1 in the crystallization step of Production Method 1 of the present invention can be appropriately adjusted in consideration of the solubility of Compound A1 in the chain aliphatic alcohol solvent having 3 to 5 carbon atoms used, but is preferably in the range of 0.3 to 3.0 times by weight, more preferably 0.5 to 2.0 times by weight, even more preferably 0.5 to 1.5 times by weight, and particularly preferably 0.6 to 1.3 times by weight. The amount of the chain aliphatic alcohol solvent having 3 to 5 carbon atoms used can be adjusted by the amount added, or can be adjusted by removing it from the system by distillation. Furthermore, at the time of precipitating crystals from the crystallization solution, the amount of the chain aliphatic alcohol solvent having 3 to 5 carbon atoms relative to the total amount of the chain aliphatic alcohol solvent having 3 to 5 carbon atoms and the chain aliphatic hydrocarbon solvent having 5 to 10 carbon atoms is in the range of 0.5 to 0.95 times by weight, preferably 0.5 to 0.9 times by weight, more preferably 0.55 to 0.9 times by weight, and particularly preferably 0.55 to 0.8 times by weight. After the crystals are precipitated, further chain aliphatic hydrocarbon solvent having 5 to 10 carbon atoms may be added to the crystallization solution. In such a case, the amount of the chain aliphatic alcohol solvent having 3 to 5 carbon atoms relative to the total amount of the chain aliphatic alcohol solvent having 3 to 5 carbon atoms and the chain aliphatic hydrocarbon solvent having 5 to 10 carbon atoms is ultimately preferably in the range of 0.1 to 0.5 times by weight, particularly preferably 0.2 to 0.5 times by weight.

[0022] <Conditions for the Crystallization Step in Production Method 1> In Production Method 1 of the present invention for producing a powder of a composition containing Compound A1, the temperature at which crystals are precipitated 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. When precipitating crystals, seed crystals do not need to be used, but it is preferable to use seed crystals. There are no restrictions on the crystals used as seed crystals. The amount of seed crystals used is preferably in the range of 0.001 to 0.1 times by weight relative to Compound A1 to be precipitated. After precipitating the crystals, it is preferable to cool the crystallization solution from the viewpoint of yield, and 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 rate at which the crystallization solution is cooled, but it is preferably in the range of 3 to 15°C / h.

[0023] <Organic Solvent Used in the Crystallization Step in Production Method 2> As the organic solvent used in the crystallization step in Production Method 2 of the present invention, a chain aliphatic carboxylic acid ester solvent having a total of 5 to 8 carbon atoms is preferably a chain aliphatic carboxylic acid ester solvent having 6 or 7 carbon atoms, more preferably a chain aliphatic acetic acid ester solvent having 6 or 7 carbon atoms, and among these, butyl acetate or amyl acetate is even more preferred, with butyl acetate being particularly preferred. Specific examples of chain aliphatic carboxylic acid ester solvents having a total of 5 to 8 carbon atoms include butyl acetate and amyl acetate. It is preferable to use at least one solvent selected from these compounds, with butyl acetate being particularly preferred. As the cyclic aliphatic hydrocarbon solvent having 5 to 8 carbon atoms used in the crystallization step in Production Method 2 of the present invention, a cyclic aliphatic hydrocarbon solvent having 6 to 8 carbon atoms is preferably a cyclic aliphatic hydrocarbon solvent having 6 to 8 carbon atoms, more preferably a cyclic aliphatic hydrocarbon solvent having 6 carbon atoms. Specific examples of cyclic aliphatic hydrocarbon solvents having 5 to 8 carbon atoms include cyclopentane, cyclohexane, cycloheptane, methylcyclohexane, cyclooctane, ethylcyclohexane, and the like. In the crystallization step in Production 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, further preferably cyclohexane or methylcyclohexane, and particularly preferably cyclohexane. In the crystallization step in Production Method 2 of the present invention, a small amount of a solvent other than the above-mentioned organic solvent may be contained, as long as the effect of the present invention is not impaired. "Small amount" means, for example, the amount of the organic solvent or water used in the above-mentioned reaction step, water washing treatment, or other step that remains after the step of removing them.

[0024] The amount of the chain aliphatic carboxylic acid ester solvent having 5 to 8 carbon atoms in total relative to Compound A1 used in the crystallization step of Production Method 2 of the present invention can be appropriately adjusted in consideration of the solubility of Compound A1 in the chain aliphatic carboxylic acid ester solvent having 5 to 8 carbon atoms in total used, but is preferably in the range of 0.5 to 3.0 times by weight, more preferably 0.5 to 2.5 times by weight, even more preferably 0.8 to 2.0 times by weight, and particularly preferably 0.8 to 1.5 times by weight. The amount of the chain aliphatic carboxylic acid ester solvent having 5 to 8 carbon atoms in total used can be adjusted by the amount added, or can be adjusted by removing it from the system by distillation. Furthermore, at the time of precipitating crystals from the crystallization solution, the amount of the chain aliphatic carboxylic acid ester solvent having 5 to 8 carbon atoms in total relative to the total amount of the chain aliphatic carboxylic acid ester solvent having 5 to 8 carbon atoms in total and the cyclic aliphatic hydrocarbon solvent having 5 to 8 carbon atoms in total is in the range of 0.1 to 0.95 times by weight, preferably in the range of 0.1 to 0.9 times by weight, more preferably in the range of 0.1 to 0.7 times by weight, and particularly preferably in the range of 0.1 to 0.5 times by weight. After the crystals have been precipitated, further cyclic aliphatic hydrocarbon solvent having 5 to 8 carbon atoms in total may be added to the crystallization solution. In such a case, the amount of the chain aliphatic carboxylic acid ester solvent having 5 to 8 carbon atoms in total relative to the total amount of the chain aliphatic carboxylic acid ester solvent having 5 to 8 carbon atoms in total and the cyclic aliphatic hydrocarbon solvent having 5 to 8 carbon atoms in total is preferably in the range of 0.1 to 0.5 times by weight, particularly preferably in the range of 0.1 to 0.3 times by weight.

[0025] <Crystallization Step in Production Method 2: Crystallization Conditions> In Production Method 2 of the powder of a composition containing Compound A1 of the present invention, the temperature at which crystals are precipitated 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. When precipitating crystals, seed crystals do not need to be used, but it is preferable to use seed crystals. There are no limitations on the crystals used as seed crystals. The amount of seed crystals used is preferably in the range of 0.001 to 0.1 times by weight relative to Compound A1 to be precipitated. After precipitating the crystals, it is preferable to cool the crystallization solution from the viewpoint of yield, and 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 is no limitation on the cooling rate of the crystallization solution, but it is preferably in the range of 3 to 15°C / h.

[0026] <Steps After the Crystallization Step> The powder of the composition containing compound A1 obtained by the crystallization step in Production Methods 1 and 2 can be separated and recovered from the crystallization solution by filtration. The production method of the present invention preferably further includes a filtration step in which the crystals precipitated in the crystallization step are filtered out. During filtration, the filtered crystals can be washed with an organic solvent, such as the solvent used in the crystallization step. The crystals obtained by filtration can be dried to remove the solvent used. The production method of the present invention preferably further includes a drying step in which the crystals filtered out in the filtration step are dried. The drying step can be carried out at a temperature preferably 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 may be normal pressure or reduced pressure, but reduced pressure is preferred for industrial use. Specifically, a reduced pressure of 10 kPa or less is more preferred, and a reduced pressure of 5 kPa or less is even more preferred. It is preferable that the above-described steps of the present invention, such as the reaction, neutralization, water washing, crystallization, filtration, distillation, drying, packaging, melting, and cooling, are carried out in an inert gas atmosphere such as nitrogen or argon, or in an atmosphere with an oxygen concentration lower than that of air, in order to suppress oxidation, deterioration, coloration, and the like due to the influence of oxygen.

[0027] The present invention will be described in detail below with reference to examples and comparative examples, but the present invention is not limited to these examples and comparative examples. <Analytical Methods> 1. High-Performance Liquid Chromatography (HPLC) Analysis In the examples, the purity of each component was calculated from the area ratio of the high-performance liquid chromatograph (HPLC) chart 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 6 mm, length 150 mm) Oven temperature: 50°C Flow rate: 1 mL / min Mobile phase: (A) 0.2% vol. acetic acid aqueous solution, (B) methanol Gradient conditions: (B) vol. % acetic acid 0-30 min, 50% → 100%, 30-45 min, 100% Sample injection volume: 20 μL Detection wavelength: 280 nm Differential Scanning Calorimetry (DSC) The powder was precisely weighed into an aluminum pan and measured using a differential scanning calorimeter (Hitachi High-Tech Science Corporation: DSC7020) under the following operating conditions, with an empty aluminum pan as a control. (Operating conditions) Heating rate: 10°C / min. Measurement temperature range: 30 to 400°C. Measurement atmosphere: Nitrogen 50 mL / min. Sample amount: 4 to 5 mg.

[0028] 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-neck flask equipped with a stirrer, thermometer, and condenser and heated to 60°C. 192.4 g (0.40 mol) of a phenolic compound (compound B) having a hydroxymethyl group represented by chemical formula (B) was added thereto and stirred at 60°C for 6 hours. The reaction solution was then cooled, and neutralized by adding an aqueous sodium hydroxide solution and an aqueous phosphoric acid solution. The methanol was removed by distillation under heating and reduced pressure (temperature in the range of 30 to 50°C, pressure in the range of 50 kPa or less), and 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 repeatedly washed with water, yielding 816 g of a washed organic layer containing compound A1. As a result of HPLC analysis of the obtained organic layer using the above method, the composition containing compound A1 was found to be 86.9 area% of component A1, 5.6 area% of component A2, and 0.6 area% of component A3. 263 g of a portion of the obtained organic layer containing the washed composition containing compound A1 was separated and placed in a four-neck flask equipped with a separate stirrer, thermometer, and condenser. 177 g of the solvent from the organic layer was distilled off under heating and reduced pressure to obtain a distillation residue. As a result of HPLC analysis of the obtained distillation residue using the above method, the composition containing compound A1 was found to be 86.9 area% of component A1, 5.6 area% of component A2, and 0.6 area% of component A3. To prepare a crystallization solution of a composition containing Compound A1, 54.4 g of isopropyl alcohol (IPA) was added to the obtained distillation residue and dissolved, followed by the addition of 22.0 g of isooctane and cooling to 30 ° C. (At this time, the weight of IPA relative to the total weight of IPA and isooctane in the crystallization solution was 0.7 times by weight. In the graph of FIG. 1, this is referred to as "0.7 times by weight crystallization solution"). 1.4 g of Compound A1 crystals were added as seed crystals, cooled to 15 ° C. over 1 hour, and stirred at 15 ° C. for 20.5 hours, resulting in the precipitation of crystals. Next, 44.5 g of isooctane was added over 2 hours and stirred at 15 ° C. for 21 hours (At this time, the weight of IPA relative to the total weight of IPA and isooctane in the crystallization solution was 0.4 times by weight. In the graph of FIG. 1, this is referred to as "0.4 times by weight crystallization solution").Further, 120 g of isooctane was added over 4.5 hours and the mixture was stirred at 15°C for 17 hours (at this time, the amount of IPA relative to the amount of IPA and isooctane in the crystallization solution was 0.2 times by weight. This is shown in the graph in Figure 1 as "0.2 times by weight crystallization solution"). During the crystallization process, 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 1. From these results, it was confirmed that the concentration of compound A1 in the supernatant of the crystallization solution decreased during the crystallization operation in the "0.7 times by weight crystallization solution." This was presumably due to the progression of crystal growth, revealing that crystallization was rapid. By adding isooctane, the concentration of compound A1 decreased, and it was revealed that further crystals were precipitated. The precipitated crystals were filtered and dried, yielding 63.2 g of a powder composition containing compound A1 (yield 86.9%). The obtained powder of the composition containing compound A1 was subjected to HPLC analysis using the method described above, and the results showed that component A1 was 87.2 area %, component A2 was 5.7 area %, and component A3 was 0.7 area %. Differential scanning calorimetry (DSC) analysis of the obtained powder of the composition containing compound A1 showed an onset temperature of 55.9°C, an endothermic peak top 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.

[0029] 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-neck flask equipped with a stirrer, thermometer, and condenser and heated to 60°C. 50.8 g (0.1 mol) of compound B was added thereto and stirred at 60°C for 8 hours. The reaction solution was then cooled, and neutralized by adding an aqueous sodium hydroxide solution and an aqueous phosphoric acid solution. Methanol was removed by distillation under heating and reduced pressure (temperature in the range of 30 to 50°C, pressure in the range of 50 kPa or less), and 114.4 g of water and 114.4 g of butyl acetate were added and stirred, and the mixture was allowed to stand for 30 minutes to remove the aqueous layer. The organic layer was then repeatedly washed with water multiple times to obtain an organic layer containing a washed compound A1. 106.8 g of the solvent in the organic layer was distilled off from the flask under heating and reduced pressure to obtain a distillation residue. As a result of HPLC analysis of the obtained distillation residue by the above method, the composition containing compound A1 was 86.6 area% of component A1, 6.3 area% of component A2, and 0.7 area% of component A3. To prepare a crystallization solution of the composition containing compound A1, 31.5 g of IPA was added to the obtained distillation residue and heated to 47 ° C. to dissolve. Then, 22.0 g of isooctane was added and cooled to 30 ° C. (The weight of IPA relative to the total weight of IPA and isooctane in the crystallization solution at this time was 0.59 times by weight). 0.9 g of crystals of compound A1 were added as seed crystals and cooled to 15 ° C. over 1.5 hours. Then, 103.9 g of isooctane was added dropwise over 2.5 hours and stirred for 18 hours (The weight of IPA relative to the total weight of IPA and isooctane in the crystallization solution at this time was 0.14 times by weight). The precipitated crystals were filtered and dried to obtain 48.9 g of a powder of a composition containing compound A1 (yield 82.2%). The obtained powder of the composition containing compound A1 was subjected to HPLC analysis using the method described above, and the results showed that component A1 was 86.9 area %, component A2 was 6.2 area %, and component A3 was 0.7 area %. The onset temperature of the obtained powder of the composition containing compound A1 by DSC analysis was 55.0 ° C., the top temperature of the endothermic peak was 68.1 ° C., and the heat of fusion based on the observed endothermic peak was 73.2 mJ / mg. The DSC analysis chart is shown in Figure 3.

[0030] 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-neck flask equipped with a stirrer, thermometer, and condenser and heated to 60°C. 320.3 g (0.66 mol) of compound B was added thereto and stirred at 60°C for 6 hours. The reaction solution was then cooled, and neutralized by adding an aqueous sodium hydroxide solution and an aqueous phosphoric acid solution. Methanol was removed by distillation under heating and reduced pressure (temperature in the range of 30 to 50°C, pressure in the range of 50 kPa or less), and 762.5 g of water and 833.3 g of butyl acetate were added and stirred, and the mixture was allowed to stand for 30 minutes to remove the aqueous layer. The organic layer was then repeatedly washed with water to obtain an organic layer containing a washed compound A1. 790.9 g of the solvent in the organic layer was distilled off from the flask under heating and reduced pressure to obtain a distillation residue. As a result of HPLC analysis of the obtained distillation residue by the above method, the composition containing compound A1 was 86.4 area% of component A1, 6.2 area% of component A2, and 0.7 area% of component A3. To prepare a crystallization solution of the composition containing compound A1, 214.6 g of IPA was added to the obtained distillation residue at 47 ° C. and dissolved. Then, 142.9 g of isooctane was added and cooled to 30 ° C. (At this time, the weight of IPA relative to the total weight of IPA and isooctane in the crystallization solution was 0.60 times by weight). 6.4 g of crystals of compound A1 were added as seed crystals and cooled to 15 ° C. over 3 hours. Then, 711.7 g of isooctane was added dropwise over 1 hour and stirred for 18 hours (At this time, the weight of IPA relative to the total weight of IPA and isooctane in the crystallization solution was 0.20 times by weight). The precipitated crystals were filtered and dried to obtain 311.4 g of a powder of a composition containing compound A1 (yield 82.9%). The obtained powder of the composition containing compound A1 was subjected to HPLC analysis using the method described above, and the results showed that component A1 was 86.5 area %, component A2 was 6.3 area %, and component A3 was 0.8 area %. Differential scanning calorimetry (DSC) analysis of the obtained powder of the composition containing compound A1 revealed an onset temperature of 51.8 ° C, a top temperature of the endothermic peak of 68.1 ° C, and a heat of fusion based on the observed endothermic peak of 67.4 mJ / mg. The DSC analysis chart is shown in Figure 4.

[0031] Example 4 A portion (330 g) of the organic layer containing the washed composition containing Compound A1 obtained in Example 1 was transferred to a four-neck flask equipped with a separate stirrer, thermometer, and condenser. 106.8 g of the solvent in the organic layer was distilled off under reduced pressure with heating to obtain a concentrated solution. 49.8 g of cyclohexane was added to the concentrated solution at 55°C (the weight of butyl acetate relative to the total weight of butyl acetate and cyclohexane in the crystallization solution at this time was 0.7 times by weight; this is indicated as "0.7 times by weight crystallization solution" in the graph in Figure 5). The solution was then cooled to 35°C, and 0.1 g of Compound A1 crystals were added as seed crystals. The solution was then cooled to 15°C over 3 hours and stirred at 15°C for 17 hours. Thereafter, 66.4 g of cyclohexane was added dropwise over 1 hour, and the mixture was stirred at 15°C for 22 hours (at this time, the weight of butyl acetate relative to the total weight of butyl acetate and cyclohexane in the crystallization solution was 0.5 times by weight. In the graph in Figure 5, this is indicated as "0.5 times by weight crystallization solution"). Furthermore, 133 g of cyclohexane was added dropwise over 1.5 hours, and the mixture was stirred at 15°C for 22 hours (at this time, the weight of butyl acetate relative to the total weight of butyl acetate and cyclohexane in the crystallization solution was 0.3 times by weight. In the graph in Figure 5, this is indicated as "0.3 times by weight crystallization solution"). During the crystallization process, 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. In a butyl acetate and cyclohexane solution of Compound A1, by changing the ratio of butyl acetate to cyclohexane, the concentration of Compound A1 in the supernatant decreased, and crystals were precipitated from the crystallization solution. On the other hand, the concentration of compound A1 did not decrease significantly while the crystallization operation was continued with the solvent ratio unchanged, revealing that crystal growth was not rapid. The precipitated crystals were filtered and dried to obtain 29.9 g of a powder composition containing compound A1 (yield 32.8%). The obtained powder composition containing compound A1 was analyzed by HPLC using the above method, and the results showed that component A1 was 86.5 area %, component A2 was 4.5 area %, and component A3 was 0.8 area %.The powder of the composition containing compound A1 obtained was analyzed by differential scanning calorimetry (DSC), and the onset temperature was 63.7°C, the top temperature of the endothermic peak was 69.2°C, and the heat of fusion based on the observed endothermic peak was 71.4 mJ / mg. The DSC analysis chart is shown in Figure 6.

[0032] Table 1 shows the results of HPLC analysis of the crystallized solutions and the resulting powders in Examples 1 to 4, as well as the results of DSC analysis of the resulting powders.

[0033]

[0034] Comparative Example 1: A portion (202 g) of the washed organic layer containing Compound A1 obtained in Example 1 was transferred to a four-neck flask equipped with a separate stirrer, thermometer, and condenser. 118 g of the solvent from the organic layer was distilled off under reduced pressure with heating to obtain a distillation residue. To prepare a crystallized solution of a composition containing Compound A1, 117.9 g of methanol was added to the distillation residue at 40°C. The solution was then cooled to 15°C over 3 hours, and 1.4 g of Compound A1 crystals were added as seed crystals. The mixture was stirred at 15°C for 19 hours (referred to as "1.0 weight-fold crystallized solution" in the graph in Figure 7). 27.0 g of water was then added dropwise over 2.5 hours, followed by stirring at 15°C for 20.5 hours (the weight of methanol relative to the total weight of methanol and water in the crystallized solution at this time was 0.8 times the weight of the total weight of methanol and water; this is referred to as "0.8 weight-fold crystallized solution" in the graph in Figure 7). Further, 43.3 g of water was added dropwise over 5 hours, and the mixture was stirred at 15°C for 18 hours (at this time, the weight of methanol relative to the total weight of methanol and water in the crystallization solution was 0.6 times by weight; this is indicated as "0.6 times by weight crystallization solution" in the graph in Figure 7). Subsequently, 54.1 g of water was added dropwise over 2.5 hours, resulting in oil-out in the crystallization solution, and a highly viscous oil appeared (at this time, the weight of methanol relative to the total weight of methanol and water in the crystallization solution was 0.45 times by weight). Compound A1 could not be isolated from this crystallization solution. During the crystallization process, 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 7. Although the concentration of Compound A1 in the supernatant was reduced by adding water to the methanol solution and the water and methanol solution, oil-out occurred, and Compound A1 could not be precipitated as crystals. On the other hand, it was also revealed that the concentration of compound A1 hardly decreased while the crystallization procedure was continued, provided that the solvent ratio remained the same.

[0035] Comparative Example 2: The powder of the composition containing compound A1 obtained in Example 1 was dissolved in ethanol at 45°C in a glass screw tube to prepare an ethanol solution containing 40% by weight of compound A1. The screw tube was sealed with a lid and cooled in a refrigerator (approximately 4°C) for 3 days, resulting in the precipitation of a powder. The precipitated powder was filtered and dried. The obtained powder of the composition containing compound A1 was subjected to HPLC analysis using the method described above, and it was found to contain 90.9 area% of component A1, 2.9 area% of component A2, and 0.3 area% of component A3. Differential scanning calorimetry (DSC) analysis of the obtained powder of the composition containing compound A1 revealed an onset temperature of 65.4°C, a top temperature of the endothermic peak of 70.1°C, and a heat of fusion based on the observed endothermic peak of 80.6 mJ / mg. The DSC analysis chart is shown in Figure 8.

[0036] Comparative Example 3: The powder of the composition containing compound A1 obtained in Example 1 was dissolved in methanol at 45°C in a glass screw tube to prepare a methanol solution containing 40% by weight of compound A1. The screw tube was sealed with a lid and cooled in a refrigerator (approximately 4°C) for 3 days, resulting in the precipitation of a powder. The precipitated powder was filtered and dried. The obtained powder of the composition containing compound A1 was subjected to HPLC analysis using the method described above, and was found to contain 90.8 area% of component A1, 2.9 area% of component A2, and 0.3 area% of component A3. Differential scanning calorimetry (DSC) analysis of the obtained powder of the composition containing compound A1 revealed an onset temperature of 67.2°C, a top temperature of the endothermic peak of 71.5°C, and a heat of fusion based on the observed endothermic peak of 77.6 mJ / mg. The DSC analysis chart is shown in Figure 9.

[0037] Comparative Example 4: The powder of the composition containing compound A1 obtained in Example 1 was dissolved in ethyl lactate at 45°C in a glass screw tube to prepare an ethyl lactate solution containing 40% by weight of compound A1. The screw tube was sealed with a lid and cooled in a refrigerator (approximately 4°C) for 3 days, resulting in the precipitation of a powder. The precipitated powder was filtered and dried. The obtained powder of the composition containing compound A1 was subjected to HPLC analysis using the method described above, and was found to contain 93.3 area% of component A1, 2.0 area% of component A2, and 0.2 area% of component A3. Differential scanning calorimetry (DSC) analysis of the obtained powder of the composition containing compound A1 revealed an onset temperature of 68.7°C, a top temperature of the endothermic peak of 72.9°C, and a heat of fusion based on the observed endothermic peak of 85.1 mJ / mg. The DSC analysis chart is shown in Figure 10.

[0038] Comparative Example 5: The same amount of the same sample as in Example 1 was used, up to the operation of distilling off the solvent from the organic layer by distillation under heating and reduced pressure, and a distillation residue was obtained by the same method. As a result of HPLC analysis of the obtained distillation residue using the above method, the composition containing compound A1 was found to have a composition containing 86.9 area% of component A1, 5.6 area% of component A2, and 0.6 area% of component A3. To prepare a crystallized solution of the composition containing compound A1 having the above composition, 292 g of propylene glycol monomethyl ether (PGME) was added and dissolved. A portion of this solution was transferred to a polypropylene screw tube and sealed with a lid. The screw tube was cooled in a refrigerator (approximately 4°C) for 4 years, and a powder precipitated. The precipitated powder was filtered and dried. The obtained powder of the composition containing compound A1 was subjected to HPLC analysis using the above method, and the results were 94.3 area% of component A1, 0.9 area% of component A2, and 0.1 area% of component A3. The powder of the composition containing compound A1 obtained was analyzed by differential scanning calorimetry (DSC), and the onset temperature was 70.4°C, the top 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.

[0039] Comparative Example 6 A portion of the organic layer containing the washed composition containing compound A1 obtained in Example 1 was transferred to a polypropylene screw tube and sealed with a lid. The screw tube was cooled in a refrigerator (approximately 4°C) for two weeks, resulting in the precipitation of a powder. The precipitated powder was filtered and dried. The yield of the powder of the composition containing compound A1 was 15%. The obtained powder of the composition containing compound A1 was subjected to HPLC analysis using the method described above, and the results showed that component A1 was 94.4 area %, component A2 was 1.6 area %, and component A3 was 0.2 area %. Differential scanning calorimetry (DSC) analysis of the obtained powder of the composition containing compound A1 revealed an onset temperature of 71.1°C, a top temperature of the endothermic peak of 75.0°C, and a heat of fusion based on the observed endothermic peak of 92.1 mJ / mg. The DSC analysis chart is shown in Figure 12.

[0040] Table 2 shows the results of HPLC analysis of the crystallized solutions and the resulting powders in Comparative Examples 1 to 6, as well as the results of DSC analysis of the resulting powders.

[0041]

[0042] It was revealed that the powders obtained by the crystallization methods of compositions containing compound A1 in Comparative Examples 2 to 6 had large heats of fusion and were less efficient when used after heating and melting. On the other hand, the powders obtained by the crystallization methods of compositions containing compound A1 in Examples 1 to 4 had specific compositions and specific onset temperatures in DSC analysis, indicating that they had small heats of fusion. Furthermore, the crystallization methods of Examples 1 to 3 enabled the production of powders of compositions containing compound A1 in high yields of 82.2 to 86.9% without oiling out, and in powder form that was easy to handle, demonstrating that powders of compositions containing compound A1 could be efficiently produced in a manner suitable for industrial mass production.

Claims

1. A powder composition containing a phenolic compound having a methoxymethyl group 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 ratios, wherein the onset temperature of the endothermic peak in differential scanning calorimetry analysis is in the range of 50 to 65°C. [Composition ratio]: The detected area ratio of each of the following components to the detected area of ​​all components detected by liquid chromatography analysis of the composition using a UV detector at a wavelength of 280 nm is within the following ranges: Component A1: 83.0 area% to 88.0 area% Component A2: 3.5 area% to 6.5 area% Component A3: 0.01 area% to 3.0 area% 2. A method for producing the powder according to claim 1, comprising a composition containing a phenolic compound having a methoxymethyl group represented by chemical formula (A1) (compound A1), containing as component A1 a phenolic compound having a methoxymethyl group represented by chemical formula (A1), as component A2 a compound represented by chemical formula (A2), and as component A3 a compound represented by chemical formula (A3) in the following composition ratios, and a crystallization step of precipitating crystals from a solution containing isopropyl alcohol and isooctane. [Composition ratio]: The detected area ratios of the following components to the detected areas of all components detected by liquid chromatography analysis of the composition using a UV detector at a wavelength of 280 nm are within the following ranges: Component A1: 83.0 area% to 88.0 area%, Component A2: 3.5 area% to 6.5 area%, Component A3: 0.01 area% to 3.0 area%.

3. A method for producing the powder described in claim 1, comprising a composition containing a phenolic compound having a methoxymethyl group represented by chemical formula (A1) (compound A1), which contains as component A1 a phenolic compound having a methoxymethyl group represented by chemical formula (A1), as component A2 a compound represented by chemical formula (A2), and as component A3 a compound represented by chemical formula (A3) in the following composition ratios, and a crystallization step of precipitating crystals from a solution containing butyl acetate and cyclohexane. [Composition ratio]: The detected area ratio of each of the following components to the detected area of ​​all components detected by liquid chromatography analysis of the composition using a UV detector at a wavelength of 280 nm is within the following ranges: Component A1: 83.0 area% or more and 88.0 area% or less Component A2: 3.5 area% or more and 6.5 area% or less Component A3: 0.01 area% or more and 3.0 area% or less

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