Method for producing crystals of phenolic compounds having a methoxymethyl group

Abstract

The present invention provides a method for efficiently producing crystals of compound A1, which can rapidly crystallize in a crystallization step and is suitable for industrial mass production. [Solution] A method for producing crystals of a phenolic compound having a methoxymethyl group represented by chemical formula (A1), comprising a crystallization step of precipitating crystals from a solution containing a phenolic compound having a methoxymethyl group represented by chemical formula (A1), a chain aliphatic alcohol solvent having 3 to 4 carbon atoms, and an aliphatic hydrocarbon solvent having 6 to 8 carbon atoms.

Description

[Technical Field]

[0001] The present invention relates to a method for producing crystals of a phenolic compound having a methoxymethyl group. Specifically, the present invention relates to a method for producing crystals of a compound represented by the following chemical formula (A1) (hereinafter, sometimes referred to as compound A1), which includes a crystallization step. [Background technology]

[0002] Phenol compounds having a methylol group or a methoxymethyl group have been used conventionally as curing agents for resins having a phenolic hydroxyl group, or as crosslinking agents for improving the film properties of photosensitive resins. A compound represented by chemical formula (A1) (compound A1) is known as a phenolic compound having a methoxymethyl group. [ka] As a conventionally known method for isolating the compound represented by chemical formula (A1), Patent Document 1 describes a method in which a hexahydroxymethyl compound (compound B, which will be described later), which is a precursor of this compound, is reacted with methanol to synthesize compound A1, and the methanol is distilled off under reduced pressure to isolate the compound. Patent Document 2 describes a method for synthesizing compound A1 by using 2,6-xylenol as a starting material, acetylating it, brominating the methyl group, and methoxylating the bromomethyl group to synthesize 2,6-dimethoxymethylphenol (III), and then condensing and deacetylating an acylated product of 2,6-dimethoxymethylphenol (III) with 2,6-dimethoxymethylphenol (III). Crystallization using ethanol is described as an isolation method after the reaction. Patent Document 3 describes that a 20% propylene glycol monomethyl ether (PGME) solution of compound A1 with a purity of 80% was concentrated using an evaporator to give a 50% propylene glycol monomethyl ether solution, which was then left to stand for two days to obtain white crystals of compound A1. Patent Document 4 describes that a 20% solution of compound A1 in ethyl lactate was concentrated using an evaporator to give a 40% solution in ethyl lactate (EL), which was then left at room temperature for 5 days to obtain 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 dimers and trimers and different solute concentrations. Furthermore, Synthesis Example 17 describes, similar to Patent Document 4, concentrating a 20% ethyl lactate solution of Compound A1 using an evaporator to make a 50% ethyl lactate solution, which was then left to stand for two 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 Laid-Open No. 2009-227697 [Patent Document 5] Japanese Patent Application Publication No. 2024-52592 Summary of the Invention [Problem to be solved by the invention]

[0004] The properties of compound A1 obtained by the isolation method described in Patent Document 1 are unknown. Because it is a 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 be difficult to handle in industrial production. In the manufacturing method described in Patent Document 2, compound A1 is synthesized using 2,6-dimethylphenol as a raw material 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 with ethanol are unknown. The methods for isolating crystals of compound A1 described in Patent Documents 3 and 4 require 2 days or 5 days to crystallize the compound until isolation is possible, and it is clear that these methods have a significantly slow crystallization rate, making them unsuitable for industrial production of compound A1. In view of the above-mentioned problems found by the present inventors, an object of the present invention is to provide a method for efficiently producing crystals of compound A1, which can rapidly carry out crystallization in the crystallization step and is suitable for industrial mass production. [Means for solving the problem]

[0005] The present inventors have conducted extensive research to solve the above-mentioned problems, and have found that by employing a crystallization process using a specific solvent, crystallization can be carried out quickly, and crystals of compound A1 can be produced in high yield in an efficient manner suitable for industrial production, thereby completing the present invention.

[0006] The present invention is as follows. 1. A method for producing crystals of a phenolic compound having a methoxymethyl group represented by chemical formula (A1), comprising a crystallization step of precipitating crystals from a solution containing a phenolic compound having a methoxymethyl group represented by chemical formula (A1), a chain aliphatic alcohol solvent having 3 to 4 carbon atoms, and an aliphatic hydrocarbon solvent having 6 to 8 carbon atoms. [ka] 2. The method for producing crystals according to 1., wherein the chain aliphatic alcohol solvent having 3 to 4 carbon atoms is at least one selected from n-propanol, isopropyl alcohol, n-butanol, and isobutanol, and the aliphatic hydrocarbon solvent having 6 to 8 carbon atoms is at least one selected from hexane, cyclohexane, octane, and isooctane. [Effects of the Invention]

[0007] The method of the present invention for producing crystals of a phenolic compound having a methoxymethyl group (compound A1) represented by chemical formula (A1) provides faster crystal precipitation in the crystallization step, a superior yield, and is suitable for industrial production and allows efficient production, compared to conventional methods for producing crystals of compound A1. [Brief explanation of the drawings]

[0008] [Figure 1] 1 is a graph showing the change over time in the concentration of Compound A1 in the supernatant of the crystallization solution during the crystallization step in Example 1, analyzed by liquid chromatography. [Figure 2] 1 is a chart showing a differential scanning calorimetry (DSC) analysis of the crystals of Compound A1 obtained in Example 1. FIG. [Figure 3] FIG. 2 shows a differential scanning calorimetry (DSC) analysis chart of the crystals of Compound A1 obtained in Example 2. [Figure 4] FIG. 1 shows a differential scanning calorimetry (DSC) analysis chart of the crystals of Compound A1 obtained in Example 3. [Figure 5] 1 is a graph showing the change over time in the concentration of compound A1 in the supernatant of the crystallization solution during the crystallization step in Comparative Example 1, analyzed by liquid chromatography. [Figure 6] FIG. 2 is a chart showing a differential scanning calorimetry (DSC) analysis of the crystals of Compound A1 obtained in Comparative Example 2. [Figure 7] FIG. 2 is a chart showing a differential scanning calorimetry (DSC) analysis of the crystals of Compound A1 obtained in Comparative Example 3. [Figure 8] FIG. 1 shows a differential scanning calorimetry (DSC) analysis chart of the crystals of Compound A1 obtained in Comparative Example 4. [Figure 9] FIG. 1 shows a differential scanning calorimetry (DSC) analysis chart of the crystals of Compound A1 obtained in Comparative Example 5. [Figure 10] FIG. 1 shows a differential scanning calorimetry (DSC) analysis chart of the crystals of Compound A1 obtained in Comparative Example 6. [Figure 11] 1 is a graph showing the change over time in the concentration of compound A1 in the supernatant of the crystallization solution during the crystallization step in Comparative Example 7, analyzed by liquid chromatography. [Figure 12] FIG. 1 shows a differential scanning calorimetry (DSC) analysis chart of the crystals of Compound A1 obtained in Comparative Example 7. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention will be described in detail below. <Method for producing crystals of the phenol compound having a methoxymethyl group represented by chemical formula (A1) of the present invention> The method for producing crystals of a phenolic compound having a methoxymethyl group (compound A1) represented by chemical formula (A1) of the present invention is characterized by including a crystallization step of precipitating crystals from a solution containing a phenolic compound having a methoxymethyl group represented by chemical formula (A1), a chain aliphatic alcohol solvent having 3 to 4 carbon atoms, and an aliphatic hydrocarbon solvent having 6 to 8 carbon atoms.

[0010] (Phenol compound having a methoxymethyl group represented by chemical formula (A1)) In the present invention, there is no particular limitation on the compound A1 used as a raw material, and there is no particular limitation on the method for synthesizing compound A1. Compound A1 may be a product obtained by an isolation procedure after the synthesis reaction. There is no particular limitation on the form, and it may be a solid, oil, lump, or powder. The detection area ratio of compound A1 to the detection areas of all components detected by liquid chromatography analysis using a UV detector at a wavelength of 280 nm is preferably in the range of 75.0 area% or more and 100 area% or less, more preferably in the range of 80.0 area% or more and 100 area% or less, even more preferably in the range of 83.0 area% or more and 100 area% or less, and particularly preferably in the range of 85.0 area% or more and 100 area% or less. Compound A1 may contain, as impurities, a compound represented by chemical formula (A2) (sometimes referred to as "compound A2"), which is a dimer in which two molecules of compound A1 are bonded together via a methylene chain through a reaction in which a methylene chain is formed at each methoxymethyl group of the compound A1, or a compound represented by chemical formula (A3) (sometimes referred to as "compound A3"), which is a trimer in which three molecules of compound A1 are similarly bonded together via a methylene chain. [ka] [ka]

[0011] As a method for synthesizing compound A1, for example, as shown in the following reaction formula, a method (hereinafter, sometimes referred to as "method for methoxylation of hydroxymethyl group") may be mentioned, 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). In the method for producing a crystal of compound A1 of the present invention, compound A1 used as a raw material is preferably compound A1 synthesized by reacting a phenol compound having a hydroxymethyl group represented by chemical formula (B) with methanol in the presence of an acid catalyst, which is the "method for methoxylation of a hydroxymethyl group." [ka] The method for producing compound A1 by the "hydroxymethyl group methoxylation method" of the above synthesis method will be described below. The method for synthesizing the phenol compound having a hydroxymethyl group (compound B) represented by chemical formula (B) used in the methoxylation method of the hydroxymethyl group 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 to react a trisphenol compound (compound C) represented by chemical formula (C) with formaldehyde in the presence of a basic catalyst to synthesize a phenol compound (compound B) having a hydroxymethyl group represented by chemical formula (B). [ka]

[0012] The amount of methanol used in the method for methoxylating a hydroxymethyl group according to the present invention is preferably in the range of 80 to 170 mol, more preferably in the range of 100 to 150 mol, and particularly preferably in the range of 110 to 140 mol, per mol of compound B. This methanol can also serve as a reaction solvent.

[0013] Specific examples of the acid catalyst used in the methoxylation method of the 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 tungstophosphoric acid and tungstosilicic 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 in the range of 1.0 to 2.0 mol, and particularly preferably in the range of 1.2 to 1.7 mol, relative to 1 mol of compound B. The reaction temperature in the method for methoxylation of a hydroxymethyl group 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 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 hydrogen carbonate, or potassium hydrogen carbonate.

[0014] (Compound A1 after water washing treatment) The compound A1 used as a raw material is preferably a 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 carried out by preparing a solution of compound A1 and an organic solvent that dissolves compound A1 and separates from water, and then washing the organic layer with water. Examples of the compound A1 to be washed with water include the compound A1 contained in the reaction solution after the synthesis reaction and the compound A1 that has been isolated once. When using a reaction solution containing compound A1 after the synthesis reaction, the solution is prepared by replacing the organic solvent used in the reaction, such as methanol, with an organic solvent that can dissolve compound A1 and separate from water. When using compound A1 that has already been extracted, the solution is prepared by mixing it with an organic solvent that can dissolve compound A1 and separate from water. Examples of organic solvents that can be used as organic solvents that dissolve Compound A1 and separate from water include aromatic hydrocarbon solvents having 7 to 9 carbon atoms, such as toluene and xylene, chain aliphatic ketone solvents having a total of 4 to 8 carbon atoms, such as methyl ethyl ketone, methyl isobutyl ketone, and methyl isoamyl ketone, and chain aliphatic carboxylic acid ester solvents having a total of 5 to 8 carbon atoms, 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, and 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 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 0.5 to 4.0 times by weight, even more preferably 0.8 to 3.0 times by weight, and particularly preferably 0.8 to 2.0 times by weight. The amount of water used in the water washing treatment can be adjusted appropriately in consideration of 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 depending on the amount of water-soluble impurities to be removed.

[0015] <Preparation of the solution used in the crystallization step of the present invention> Although not limited to the above-mentioned method of methoxylation of a hydroxymethyl group, a solution containing compound A1 and the organic solvent used in the crystallization step of the present invention can be prepared by solvent substitution from an organic solvent such as methanol used in the reaction of a reaction solution containing compound A1 synthesized by a known synthesis method to the organic solvent used in the crystallization step of the present invention. Furthermore, after the above-described water washing treatment, compound A1 can be subjected to solvent substitution with the organic solvent used in the crystallization step of the present invention, or dissolved in the organic solvent, to prepare a solution containing compound A1 and the organic solvent used in the crystallization step of the present invention, which is used in the crystallization step 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 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 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 out and substituting the solvent with the organic solvent used in the crystallization step of the present invention to prepare a solution 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, and is more preferably 70 kPa or less, and even more preferably 50 kPa or less. In preparing a solution containing compound A1 to be used in the crystallization step of the present invention, a method is preferred in which a solution of compound A1 and a chain aliphatic alcohol solvent having 3 to 4 carbon atoms is prepared, and then an aliphatic hydrocarbon solvent having 6 to 8 carbon atoms is added.

[0016] <Organic solvents used in the crystallization process> Specific examples of the chain aliphatic alcohol solvent having 3 to 4 carbon atoms, which is the organic solvent used in the crystallization step of the present invention, include n-propanol, isopropyl alcohol (IPA), n-butanol, sec-butanol, tert-butanol, and isobutanol. In the crystallization step of the present invention, it is preferable to use at least one solvent selected from n-propanol, isopropyl alcohol (IPA), n-butanol, sec-butanol, tert-butanol, and isobutanol, it is more preferable to use at least one solvent selected from n-propanol, isopropyl alcohol (IPA), n-butanol, and isobutanol, it is even more preferable to use at least one solvent selected from isopropyl alcohol (IPA) and n-butanol, and isopropyl alcohol (IPA) is particularly preferable. Among the aliphatic hydrocarbon solvents having 6 to 8 carbon atoms used in the crystallization step of the present invention, chain aliphatic hydrocarbon solvents having 6 to 8 carbon atoms are preferred, chain aliphatic hydrocarbon solvents having 6 or 8 carbon atoms are more preferred, and chain aliphatic hydrocarbon solvents having 8 carbon atoms are even more preferred. Specific examples of aliphatic hydrocarbon solvents having 6 to 8 carbon atoms include hexane, cyclohexane, heptane, cycloheptane, octane, cyclooctane, etc. In the crystallization step of the present invention, it is preferable to use at least one solvent selected from hexane, cyclohexane, heptane, cycloheptane, octane, and cyclooctane, more preferably at least one solvent selected from n-hexane, cyclohexane, n-heptane, n-octane, and isooctane (2,2,4-trimethylpentane), even more preferably at least one solvent selected from n-hexane, cyclohexane, n-octane, and isooctane, with isooctane being particularly preferred. In the crystallization step 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. The small amount means, for example, the amount of the organic solvent or water used in the above-mentioned reaction step or water washing step remaining after the step of removing them.

[0017] In the crystallization step of the present invention, the amount of the chain aliphatic alcohol solvent having 3 to 4 carbon atoms used relative to Compound A1 can be appropriately adjusted in consideration of the solubility of Compound A1 in the chain aliphatic alcohol solvent having 3 to 4 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 4 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 4 carbon atoms used relative to the total amount of the chain aliphatic alcohol solvent having 3 to 4 carbon atoms and the aliphatic hydrocarbon solvent having 6 to 8 carbon atoms used is in the range of 0.5 to 0.95 times by weight, preferably in the range of 0.5 to 0.9 times by weight, more preferably in the range of 0.55 to 0.9 times by weight, and particularly preferably in the range of 0.55 to 0.8 times by weight. After the crystals are precipitated, an aliphatic hydrocarbon solvent having 6 to 8 carbon atoms may be further added to the crystallization solution. In such a case, the amount of the chain aliphatic alcohol solvent having 3 to 4 carbon atoms used is preferably 0.1 to 0.5 times by weight, and particularly preferably 0.1 to 0.4 times by weight, relative to the total amount of the chain aliphatic alcohol solvent having 3 to 4 carbon atoms and the aliphatic hydrocarbon solvent having 6 to 8 carbon atoms used.

[0018] (Crystallization process conditions) In the present invention, 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 the crystals, seed crystals do not have 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 the compound A1 to be precipitated. After the crystals are precipitated, it is preferable to cool the crystallization solution from the viewpoint of yield. 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 rate at which the crystallization solution is cooled, but it is preferably in the range of 3 to 15°C / h.

[0019] <Post-crystallization process> The crystals of compound A1 obtained in the crystallization step in the production method can be separated from the crystallization solution by filtration and recovered. In the present invention, it is preferable to further include a filtration step in which the crystals precipitated in the crystallization step are filtered out. During filtration, the separated crystals can be washed with an organic solvent, for example, the solvent used in the crystallization step. The crystals obtained by filtration can be dried to remove the solvent used. 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 for industrial use, reduced pressure is preferred. 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. [Example]

[0020] EXAMPLES The present invention will be specifically explained below with reference to examples and comparative examples, but the present invention is not limited to these examples and comparative examples. <Analysis method> 1. High-Performance Liquid Chromatography (HPLC) Analysis In the examples, the contents of impurities such as Compound A1, Compound A2, and Compound A3 were calculated from the area ratio of a high performance liquid chromatograph (HPLC) chart measured under the following conditions. Equipment: Shimadzu Corporation Prominence 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℃ Flow rate: 1mL / min. Mobile phase: (A) 0.2% acetic acid aqueous solution, (B) methanol Gradient conditions: (B) volume % 0-30min.,50%→100% 30-45min.,100% Sample injection volume: 20 μL Detection wavelength: 280 nm 2. Differential Scanning Calorimetry (DSC) The crystals were 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℃ / min. Measurement temperature range: 30 to 400°C Measurement atmosphere: Nitrogen 50mL / min. Sample amount: 4 to 5 mg

[0021] Example 1 A 5 L four-neck flask equipped with a stirrer, thermometer, and condenser was charged with 1731 g (54.11 mol) of methanol and 57.7 g (0.59 mol) of sulfuric acid and heated to 60° C. 192.4 g (0.40 mol) of a phenol 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 reduced pressure with heating, and 462.0 g of water and 462.0 g of butyl acetate were added and stirred, and the mixture was allowed to stand for 30 minutes, after which the aqueous layer was removed. The organic layer was then washed with water several times to obtain 816 g of an organic layer containing the washed compound A1. As a result of HPLC analysis of the obtained compound A1 by the above-mentioned method, the organic layer was found to contain 86.9 area % of compound A1, 5.6 area % of compound A2, and 0.6 area % of compound A3. A portion (263 g) of the obtained washed organic layer containing Compound A1 was transferred to a four-neck flask equipped with a stirrer, a thermometer, and a condenser. 177 g of the solvent in the organic layer was distilled off under heating and reduced pressure to obtain a distillation residue. The obtained distillation residue was analyzed by HPLC using the above method, and as a result, the contents of Compound A1 were 86.9 area %, Compound A2 were 5.6 area %, and Compound A3 were 0.6 area %. To prepare a crystallization solution of Compound A1 having the above composition, 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. This is shown as "0.7 times by weight crystallization solution" in the graph of Figure 1.) 1.4 g of crystals of Compound A1 were added as seed crystals, and the solution was 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 mixed over 2 hours, and the mixture was stirred at 15°C for 21 hours (the weight of IPA relative to the total weight of IPA and isooctane in the crystallization solution at this time was 0.4 times by weight. In the graph of Figure 1, this is indicated as "0.4 times by weight crystallization solution"). Furthermore, 120 g of isooctane was mixed over 4.5 hours and stirred at 15°C for 17 hours (the amount of IPA relative to the amounts of IPA and isooctane in the crystallization solution at this time was 0.2 times by weight. In the graph of Figure 1, this is indicated as "0.2 times by weight crystallization solution"). During the crystallization process, the supernatant was sampled and analyzed by liquid chromatography to determine the concentration of Compound A1 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 as the crystallization operation continued in the "0.7x weight crystallization solution." This is presumably due to the progress of crystal growth, and it became clear that crystallization was rapid. By adding isooctane, the concentration of compound A1 decreased, and it became clear that further crystals were being precipitated. . The precipitated crystals were filtered and dried to obtain 63.2 g of crystals of Compound A1 (yield 86.9%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 87.2 area %, Compound A2 for 5.7 area %, and Compound A3 for 0.7 area %. The crystals of Compound A1 obtained by differential scanning calorimetry (DSC) analysis showed that the onset temperature was 55.9°C, the top temperature of the endothermic peak was 68.2°C, and the heat of fusion based on the observed endothermic peak was 77.0 mJ / mg. The DSC analysis chart is shown in Figure 2.

[0022] <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. Thereafter, the reaction solution was cooled and neutralized by adding an aqueous sodium hydroxide solution and an aqueous phosphoric acid solution. The methanol was removed by distillation under reduced pressure with heating, 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, after which the aqueous layer was removed. The organic layer was then washed with water several times to obtain an organic layer containing the washed compound A1. 106.8 g of the solvent in the organic layer was distilled off from the flask by distillation under heating and reduced pressure to obtain a distillation residue. The distillation residue thus obtained was analyzed by HPLC using the method described above, and as a result, the contents of Compound A1 were 86.6 area %, Compound A2 were 6.3 area %, and Compound A3 were 0.7 area %. To prepare a crystallized solution of Compound A1 having the above composition, 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 crystallized solution at this time was 0.59 times by weight). 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. Thereafter, 103.9 g of isooctane was added dropwise over 2.5 hours, and the mixture was 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 0.14 times). The precipitated crystals were filtered and dried to obtain 48.9 g of crystals of compound A1 (yield 82.2%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and as a result, Compound A1 was 86.9 area %, Compound A2 was 6.2 area %, and Compound A3 was 0.7 area %. The DSC analysis of the obtained crystals of Compound A1 showed that the onset temperature 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.

[0023] 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, a thermometer, and a 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. Thereafter, the reaction solution was cooled and neutralized by adding an aqueous sodium hydroxide solution and an aqueous phosphoric acid solution. The methanol was removed by distillation under reduced pressure with heating, 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, after which the aqueous layer was removed. The organic layer was then washed with water several times to obtain an organic layer containing the washed compound A1. 790.9 g of the solvent in the organic layer was distilled off from the flask by distillation under heating and reduced pressure to obtain a distillation residue. The obtained distillation residue was analyzed by HPLC using the above method, and as a result, the contents of Compound A1 were 86.4 area %, Compound A2 were 6.2 area %, and Compound A3 were 0.7 area %. To prepare a crystallized solution of Compound A1 having the above composition, 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. (The weight of IPA relative to the total weight of IPA and isooctane in the crystallized solution at this time was 0.60 times by weight.) 6.4 g of crystals of Compound A1 were added as seed crystals, and the solution was cooled to 15 ° C. over 3 hours. Thereafter, 711.7 g of isooctane was added dropwise over 1 hour, and the mixture was 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). The precipitated crystals were filtered and dried to obtain 311.4 g of crystals of Compound A1 (yield 82.9%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 86.5 area %, Compound A2 for 6.3 area %, and Compound A3 for 0.8 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 51.8°C, the top temperature of the endothermic peak was 68.1°C, and the heat of fusion based on the observed endothermic peak was 67.4 mJ / mg. The DSC analysis chart is shown in Figure 4.

[0024] Example 4 336.6 g (10.50 mol) of methanol and 11.2 g (0.11 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. 39.0 g (0.08 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: 30 to 50°C, pressure: 50 kPa or less), and 89.8 g of water and 89.8 g of butyl acetate were added and stirred, and the mixture was allowed to stand for 30 minutes, after which the aqueous layer was removed. The organic layer was then washed with water several times to obtain 127 g of an organic layer containing the washed compound A1. The organic layer obtained was analyzed by HPLC using the above method, and as a result, the contents of Compound A1 were 86.4 area %, Compound A2 were 5.6 area %, and Compound A3 were 0.6 area %. The obtained organic layer containing Compound A1 was distilled under heating and reduced pressure to remove 84.2 g of the solvent from the organic layer, thereby obtaining a distillation residue. The obtained distillation residue was analyzed by HPLC using the above method, and as a result, the contents of Compound A1 were 86.4 area %, Compound A2 were 5.6 area %, and Compound A3 were 0.6 area %. To prepare a crystallization liquid containing Compound A1 having the above composition, 30.1 g of isopropyl alcohol (IPA) was added to the obtained distillation residue at 47°C and dissolved. 5.05 g of the resulting IPA solution was dispensed into a 100 mL test tube, and 1.49 g of octane was added. The mixture was cooled to 30°C while stirring with a stirrer (at this time, the weight of IPA was 0.60 times the total weight of IPA and octane in the crystallization solution). 0.0586 g of Compound A1 crystals were added as seed crystals, and the mixture was cooled to 20°C over 1 hour. 7.39 g of octane was then added dropwise over 1 hour, and the mixture was cooled to 7°C over 2 hours. The mixture was then stirred for 16 hours (at this time, the weight of IPA was 0.20 times the total weight of IPA and octane in the crystallization solution). The precipitated crystals were filtered and dried to obtain 2.38 g of crystals of Compound A1 (yield 73.0%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 87.2 area %, Compound A2 for 6.4 area %, and Compound A3 for 0.9 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC) to find that the onset temperature was 57.2°C, the top temperature of the endothermic peak was 68.4°C, and the heat of fusion based on the observed endothermic peak was 71.1 mJ / mg.

[0025] <Example 5> From the IPA solution containing compound A1 obtained in Example 4, 4.98 g was dispensed into a 100 mL test tube, and 1.51 g of hexane was added. The mixture was cooled to 30°C while stirring with a stirrer (at this time, the weight of IPA relative to the total weight of IPA and hexane in the crystallization solution was 0.60 times by weight). 0.0549 g of compound A1 crystals were added as seed crystals, and the mixture was cooled to 20°C over 1 hour. Then, 7.39 g of hexane was added dropwise over 1 hour, and the mixture was cooled to 7°C over 2 hours. The mixture was then stirred for 16 hours (at this time, the weight of IPA relative to the total weight of IPA and hexane in the crystallization solution was 0.20 times by weight). The precipitated crystals were filtered and dried to obtain 2.33 g of crystals of Compound A1 (yield 72.5%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 87.4 area %, Compound A2 for 6.2 area %, and Compound A3 for 0.8 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC) to find that the onset temperature was 56.4°C, the top temperature of the endothermic peak was 68.7°C, and the heat of fusion based on the observed endothermic peak was 68.8 mJ / mg.

[0026] Example 6 From the IPA solution containing Compound A1 obtained in Example 4, 5.00 g was dispensed into a 100 mL test tube, and 1.48 g of cyclohexane was added. The mixture was cooled to 30°C while stirring with a stirrer (at this time, the weight of IPA relative to the total weight of IPA and cyclohexane in the crystallization solution was 0.60 times by weight). 0.0545 g of Compound A1 crystals were added as seed crystals, and the mixture was cooled to 10°C over 2 hours. Then, 7.37 g of cyclohexane was added dropwise over 1 hour, and the mixture was cooled to 7°C over 0.5 hours. Then, 11.07 g of cyclohexane was added dropwise over 1 hour, and the mixture was stirred for 16 hours (at this time, the weight of IPA relative to the total weight of IPA and cyclohexane in the crystallization solution was 0.10 times by weight). The precipitated crystals were filtered and dried to obtain 2.06 g of crystals of Compound A1 (yield 63.8%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 88.5 area %, Compound A2 for 5.4 area %, and Compound A3 for 0.8 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 61.4°C, the top temperature of the endothermic peak was 70.2°C, and the heat of fusion was 70.7 mJ / mg.

[0027] Example 7 336.6 g (10.50 mol) of methanol and 11.2 g (0.11 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. 39.0 g (0.08 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: 30 to 50°C, pressure: 50 kPa or less), and 89.8 g of water and 89.8 g of butyl acetate were added and stirred, and the mixture was allowed to stand for 30 minutes, after which the aqueous layer was removed. The organic layer was then washed with water several times to obtain 127 g of an organic layer containing the washed compound A1. The organic layer obtained was analyzed by HPLC using the above method, and as a result, the contents of Compound A1 were 86.4 area %, Compound A2 were 5.6 area %, and Compound A3 were 0.6 area %. The obtained organic layer containing Compound A1 was distilled under heating and reduced pressure to remove 84.2 g of the solvent from the organic layer, thereby obtaining a distillation residue. The obtained distillation residue was analyzed by HPLC using the above method, and as a result, the contents of Compound A1 were 86.4 area %, Compound A2 were 5.6 area %, and Compound A3 were 0.6 area %. To prepare a crystallization liquid containing Compound A1 having the above composition, 30.1 g of n-propanol was added to the obtained distillation residue at 47° C. to dissolve it. 5.00 g of the resulting n-propanol solution was dispensed into a 100 mL test tube, and 1.49 g of isooctane was added. The mixture was cooled to 30°C while stirring with a stirrer (at this time, the weight of n-propanol was 0.60 times the total weight of n-propanol and isooctane in the crystallization solution). 0.0580 g of Compound A1 crystals were added as seed crystals, and the mixture was cooled to 20°C over 1 hour. 7.85 g of isooctane was then added dropwise over 1 hour, and the mixture was cooled to 7°C over 2 hours. The mixture was then stirred for 16 hours (at this time, the weight of n-propanol was 0.20 times the total weight of n-propanol and isooctane in the crystallization solution). The precipitated crystals were filtered and dried to obtain 1.89 g of crystals of Compound A1 (yield 58.4%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 88.4 area %, Compound A2 for 5.6 area %, and Compound A3 for 1.0 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 58.5°C, the top temperature of the endothermic peak was 68.7°C, and the heat of fusion was 74.3 mJ / mg.

[0028] Example 8 From the n-propanol solution containing Compound A1 obtained in Example 7, 5.08 g was dispensed into a 100 mL test tube, and 1.52 g of octane was added. The mixture was cooled to 30°C while stirring with a stirrer (at this time, the weight of n-propanol was 0.60 times the total weight of n-propanol and octane in the crystallization solution). 0.0599 g of Compound A1 crystals were added as seed crystals, and the mixture was cooled to 20°C over 1 hour. Then, 7.60 g of octane was added dropwise over 1 hour, and the mixture was cooled to 7°C over 2 hours. The mixture was then stirred for 16 hours (at this time, the weight of n-propanol was 0.20 times the total weight of n-propanol and octane in the crystallization solution). The precipitated crystals were filtered and dried to obtain 2.34 g of crystals of Compound A1 (yield 71.7%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 87.9 area %, Compound A2 for 6.0 area %, and Compound A3 for 0.9 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC) to find that the onset temperature was 59.4°C, the top temperature of the endothermic peak was 68.6°C, and the heat of fusion based on the observed endothermic peak was 64.4 mJ / mg.

[0029] Example 9 From the n-propanol solution containing Compound A1 obtained in Example 7, 5.00 g was dispensed into a 100 mL test tube, and 1.49 g of hexane was added. The mixture was cooled to 30°C while stirring with a stirrer (at this time, the weight of n-propanol was 0.60 times the total weight of n-propanol and hexane in the crystallization solution). 0.0550 g of Compound A1 crystals were added as seed crystals, and the mixture was cooled to 20°C over 1 hour. Then, 7.55 g of hexane was added dropwise over 1 hour, and the mixture was cooled to 7°C over 2 hours. The mixture was then stirred for 16 hours (at this time, the weight of n-propanol was 0.20 times the total weight of n-propanol and hexane in the crystallization solution). The precipitated crystals were filtered and dried to obtain 2.00 g of crystals of Compound A1 (yield 61.8%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 87.8 area %, Compound A2 for 6.1 area %, and Compound A3 for 0.9 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 53.8°C, the top temperature of the endothermic peak was 68.5°C, and the heat of fusion was 69.2 mJ / mg.

[0030] Example 10 From the n-propanol solution containing Compound A1 obtained in Example 7, 5.55 g was dispensed into a 100 mL test tube, and 1.66 g of cyclohexane was added. The mixture was cooled to 30°C while stirring with a stirrer (at this time, the weight of n-propanol was 0.60 times the total weight of n-propanol and cyclohexane in the crystallization solution). 0.0594 g of Compound A1 crystals were added as seed crystals, and the mixture was cooled to 15°C over 1.5 hours. 8.38 g of cyclohexane was then added dropwise over 1 hour. The mixture was then cooled to 7°C over 1.5 hours and stirred for 16 hours (at this time, the weight of n-propanol was 0.20 times the total weight of n-propanol and cyclohexane in the crystallization solution). The precipitated crystals were filtered and dried to obtain 1.32 g of crystals of Compound A1 (yield 36.7%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 92.8 area %, Compound A2 for 3.2 area %, and Compound A3 for 0.4 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 64.6°C, the top temperature of the endothermic peak was 71.7°C, and the heat of fusion was 81.4 mJ / mg.

[0031] Example 11 336.6 g (10.50 mol) of methanol and 11.2 g (0.11 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. 39.0 g (0.08 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: 30 to 50°C, pressure: 50 kPa or less), and 89.8 g of water and 89.8 g of butyl acetate were added and stirred, and the mixture was allowed to stand for 30 minutes, after which the aqueous layer was removed. The organic layer was then washed with water several times to obtain 127 g of an organic layer containing the washed compound A1. The organic layer obtained was analyzed by HPLC using the above method, and as a result, the contents of Compound A1 were 86.4 area %, Compound A2 were 5.6 area %, and Compound A3 were 0.6 area %. The obtained organic layer containing Compound A1 was distilled under heating and reduced pressure to remove 84.2 g of the solvent from the organic layer, thereby obtaining a distillation residue. The obtained distillation residue was analyzed by HPLC using the above method, and as a result, the contents of Compound A1 were 86.4 area %, Compound A2 were 5.6 area %, and Compound A3 were 0.6 area %. To prepare a crystallization liquid containing Compound A1 having the above composition, 30.1 g of n-butanol was added to the obtained distillation residue at 47° C. to dissolve it. 5.05 g of the resulting n-butanol solution was dispensed into a 100 mL test tube, and 1.50 g of isooctane was added. The mixture was cooled to 30°C while stirring with a stirrer (at this time, the weight of n-butanol was 0.60 times the total weight of n-butanol and isooctane in the crystallization solution). 0.0573 g of Compound A1 crystals were added as seed crystals, and the mixture was cooled to 20°C over 1 hour. 7.50 g of isooctane was then added dropwise over 1 hour, and the mixture was cooled to 7°C over 2 hours. The mixture was then stirred for 16 hours (at this time, the weight of n-butanol was 0.20 times the total weight of n-butanol and isooctane in the crystallization solution). The precipitated crystals were filtered and dried to obtain 2.46 g of crystals of Compound A1 (yield 75.0%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 87.5 area %, Compound A2 for 6.2 area %, and Compound A3 for 0.9 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 57.2°C, the top temperature of the endothermic peak was 67.3°C, and the heat of fusion was 71.2 mJ / mg.

[0032] Example 12 From the n-butanol solution containing compound A1 obtained in Example 11, 5.05 g was dispensed into a 100 mL test tube, and 1.48 g of octane was added. The mixture was cooled to 30 ° C. while stirring with a stirrer (at this time, the weight of n-butanol was 0.60 times the total weight of n-butanol and octane in the crystallization solution). 0.0558 g of compound A1 crystals were added as seed crystals, and the mixture was cooled to 20 ° C. over 1 hour. Then, 7.52 g of octane was added dropwise over 1 hour, and the mixture was cooled to 7 ° C. over 2 hours. The mixture was then stirred for 16 hours (at this time, the weight of n-butanol was 0.20 times the total weight of n-butanol and octane in the crystallization solution). The precipitated crystals were filtered and dried to obtain 2.31 g of crystals of Compound A1 (yield 70.4%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and as a result, Compound A1 was 87.7 area %, Compound A2 was 6.1 area %, and Compound A3 was 0.8 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 58.1°C, the top temperature of the endothermic peak was 67.6°C, and the heat of fusion was 70.9 mJ / mg.

[0033] Example 13 From the n-butanol solution containing compound A1 obtained in Example 11, 5.03 g was dispensed into a 100 mL test tube, 1.55 g of hexane was added, and the mixture was cooled to 30 ° C. while stirring with a stirrer (at this time, the weight of n-butanol relative to the total weight of n-butanol and hexane in the crystallization solution was 0.60 times by weight). 0.0554 g of compound A1 crystals were added as seed crystals, and the mixture was cooled to 20 ° C. over 1 hour. Then, 7.48 g of hexane was added dropwise over 1 hour, and the mixture was cooled to 7 ° C. over 2 hours. The mixture was then stirred for 16 hours (at this time, the weight of n-butanol relative to the total weight of n-butanol and hexane in the crystallization solution was 0.20 times by weight). The precipitated crystals were filtered and dried to obtain 2.39 g of crystals of Compound A1 (yield 73.1%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 88.3 area %, Compound A2 for 5.7 area %, and Compound A3 for 0.8 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 57.5°C, the top temperature of the endothermic peak was 68.8°C, and the heat of fusion was 72.2 mJ / mg.

[0034] Example 14 From the n-butanol solution containing Compound A1 obtained in Example 11, 5.03 g was dispensed into a 100 mL test tube, and 1.51 g of cyclohexane was added. The mixture was cooled to 30 ° C. while stirring with a stirrer (at this time, the weight of n-butanol was 0.60 times the total weight of n-butanol and cyclohexane in the crystallization solution). 0.0558 g of Compound A1 crystals were added as seed crystals, and the mixture was cooled to 10 ° C. over 2 hours. Then, 7.56 g of cyclohexane was added dropwise over 1 hour, and the mixture was cooled to 7 ° C. over 0.5 hours. Then, 11.00 g of cyclohexane was added dropwise over 1 hour, and the mixture was stirred for 16 hours (at this time, the weight of n-butanol was 0.10 times the total weight of n-butanol and cyclohexane in the crystallization solution). The precipitated crystals were filtered and dried to obtain 2.05 g of crystals of Compound A1 (yield 62.7%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 88.9 area %, Compound A2 for 5.2 area %, and Compound A3 for 0.9 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 60.6°C, the top temperature of the endothermic peak was 69.7°C, and the heat of fusion was 71.6 mJ / mg.

[0035] Example 15 336.6 g (10.50 mol) of methanol and 11.2 g (0.11 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. 39.0 g (0.08 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: 30 to 50°C, pressure: 50 kPa or less), and 89.8 g of water and 89.8 g of butyl acetate were added and stirred, and the mixture was allowed to stand for 30 minutes, after which the aqueous layer was removed. The organic layer was then washed with water several times to obtain 127 g of an organic layer containing the washed compound A1. The organic layer obtained was analyzed by HPLC using the above method, and as a result, the contents of Compound A1 were 86.4 area %, Compound A2 were 5.6 area %, and Compound A3 were 0.6 area %. The obtained organic layer containing Compound A1 was distilled under heating and reduced pressure to remove 84.2 g of the solvent from the organic layer, thereby obtaining a distillation residue. The obtained distillation residue was analyzed by HPLC using the above method, and as a result, the contents of Compound A1 were 86.4 area %, Compound A2 were 5.6 area %, and Compound A3 were 0.6 area %. To prepare a crystallization liquid containing Compound A1 having the above composition, 30.1 g of isobutanol was added to the obtained distillation residue at 47°C and dissolved. From the obtained isobutanol solution containing Compound A1, 5.06 g was dispensed into a 100 mL test tube, and 1.60 g of isooctane was added. The mixture was cooled to 30°C while stirring with a stirrer (at this time, the weight of isobutanol was 0.60 times the total weight of isobutanol and isooctane in the crystallization solution). 0.0569 g of Compound A1 crystals were added as seed crystals, and the mixture was cooled to 20°C over 1 hour. Then, 7.40 g of isooctane was added dropwise over 1 hour, and the mixture was cooled to 7°C over 2 hours. The mixture was then stirred for 16 hours (at this time, the weight of isobutanol was 0.20 times the total weight of isobutanol and isooctane in the crystallization solution). The precipitated crystals were filtered and dried to obtain 2.36 g of crystals of Compound A1 (yield 72.6%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 87.0 area %, Compound A2 for 6.5 area %, and Compound A3 for 0.9 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 53.9°C, the top temperature of the endothermic peak was 67.1°C, and the heat of fusion was 67.8 mJ / mg.

[0036] Example 16 From the isobutanol solution containing Compound A1 obtained in Example 15, 5.02 g was dispensed into a 100 mL test tube, and 1.47 g of octane was added. The mixture was cooled to 30°C while stirring with a stirrer (at this time, the weight of isobutanol was 0.60 times the total weight of isobutanol and octane in the crystallization solution). 0.0554 g of Compound A1 crystals were added as seed crystals, and the mixture was cooled to 20°C over 1 hour. Then, 7.31 g of octane was added dropwise over 1 hour, and the mixture was cooled to 7°C over 2 hours. The mixture was then stirred for 16 hours (at this time, the weight of isobutanol was 0.20 times the total weight of isobutanol and octane in the crystallization solution). The precipitated crystals were filtered and dried to obtain 2.33 g of crystals of Compound A1 (yield 72.2%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 87.2 area %, Compound A2 for 6.3 area %, and Compound A3 for 0.9 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 53.6°C, the top temperature of the endothermic peak was 67.9°C, and the heat of fusion was 64.5 mJ / mg.

[0037] Example 17 From the isobutanol solution containing Compound A1 obtained in Example 15, 5.01 g was dispensed into a 100 mL test tube, 1.50 g of hexane was added, and the mixture was cooled to 30°C while stirring with a stirrer (at this time, the weight of isobutanol relative to the total weight of isobutanol and hexane in the crystallization solution was 0.60 times by weight). 0.0551 g of Compound A1 crystals were added as seed crystals, and the mixture was cooled to 20°C over 1 hour. Then, 7.38 g of hexane was added dropwise over 1 hour, and the mixture was cooled to 7°C over 2 hours. The mixture was then stirred for 16 hours (at this time, the weight of isobutanol relative to the total weight of isobutanol and hexane in the crystallization solution was 0.20 times by weight). The precipitated crystals were filtered and dried to obtain 2.08 g of crystals of Compound A1 (yield 64.6%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 87.5 area %, Compound A2 for 6.1 area %, and Compound A3 for 0.9 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 55.3°C, the top temperature of the endothermic peak was 68.1°C, and the heat of fusion was 67.8 mJ / mg.

[0038] Example 18 From the isobutanol solution containing Compound A1 obtained in Example 15, 5.03 g was dispensed into a 100 mL test tube, and 1.46 g of cyclohexane was added. The mixture was cooled to 30°C while stirring with a stirrer (at this time, the weight of isobutanol relative to the total weight of isobutanol and cyclohexane in the crystallization solution was 0.60 times by weight). 0.0550 g of Compound A1 crystals were added as seed crystals, and the mixture was cooled to 15°C over 1.5 hours. Then, 7.39 g of cyclohexane was added dropwise over 1 hour, and the mixture was cooled to 7°C over 1.5 hours. The mixture was then stirred for 16 hours (at this time, the weight of isobutanol relative to the total weight of isobutanol and cyclohexane in the crystallization solution was 0.10 times by weight). The precipitated crystals were filtered and dried to obtain 1.80 g of crystals of Compound A1 (yield 55.7%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 91.1 area %, Compound A2 for 4.1 area %, and Compound A3 for 0.6 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 63.2°C, the top temperature of the endothermic peak was 70.9°C, and the heat of fusion was 73.8 mJ / mg.

[0039] Tables 1 to 4 show the HPLC analysis results of the crystallization solutions and the obtained crystals in Examples 1 to 18, as well as the DSC analysis results and yields of the obtained crystals.

[0040] [Table 1]

[0041] [Table 2]

[0042] [Table 3]

[0043] [Table 4]

[0044] <Comparative Example 1> A portion (202 g) of the washed organic layer containing Compound A1 obtained in Example 1 was placed in a four-neck flask equipped with a stirrer, a thermometer, and a condenser. 118 g of the solvent in the organic layer was distilled off by distillation under heating and reduced pressure to obtain a distillation residue. To prepare a crystallized solution of compound A1 having the above composition, 117.9 g of methanol was added to the distillation residue at 40° C. Subsequently, the solution was cooled to 15° C. over 3 hours, and 1.4 g of crystals of compound A1 were added as seed crystals, followed by stirring at 15° C. for 19 hours (referred to as "1.0 weight-fold crystallized solution" in the graph of FIG. 5). Thereafter, 27.0 g of water was added dropwise over 2.5 hours, and the mixture was stirred at 15°C for 20.5 hours (the weight of methanol relative to the total weight of methanol and water in the crystallization solution at this time was 0.8 times by weight. In the graph of Figure 5, this is indicated as "0.8 times by weight crystallization solution"). Further, 43.3 g of water was added dropwise over 5 hours, and the mixture was stirred at 15°C for 18 hours (the weight of methanol relative to the total weight of methanol and water in the crystallization solution at this time was 0.6 times by weight. In the graph of Figure 5, this is indicated as "0.6 times by weight crystallization solution"). Subsequently, 54.1 g of water was added dropwise over 2.5 hours, causing oiling out of the crystallization solution, and a highly viscous oil appeared (the weight of methanol relative to the total weight of methanol and water in the crystallization solution at this time was 0.45 times). Compound A1 could not be isolated from this crystallized solution. During the crystallization process, the supernatant was sampled and analyzed by liquid chromatography to determine the concentration of Compound A1 over time. The results are shown in Figure 5. In the methanol solution and the water / methanol solution of compound A1, adding water to change the ratio of methanol to water reduced the concentration of compound A1 in the supernatant, but oiling out occurred and compound A1 could not be precipitated as crystals. On the other hand, it was also found that the concentration of compound A1 hardly decreased during the crystallization procedure when the solvent ratio was kept the same.

[0045] <Comparative Example 2> The crystals of compound A1 obtained in Example 1 were 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 (about 4°C) for 3 days, resulting in the precipitation of crystals. The precipitated crystals were filtered and dried. The obtained crystals of compound A1 were subjected to HPLC analysis by the above method, and as a result, it was revealed that the crystals contained 90.9 area % of compound A1, 2.9 area % of compound A2, and 0.3 area % of compound A3. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 65.4°C, the top 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 6.

[0046] <Comparative Example 3> The crystals of compound A1 obtained in Example 1 were 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 (about 4°C) for 3 days, resulting in the precipitation of crystals. The precipitated crystals were filtered and dried. The obtained crystals of compound A1 were subjected to HPLC analysis by the above method, and as a result, it was revealed that the crystals contained 90.8 area % of compound A1, 2.9 area % of compound A2, and 0.3 area % of compound A3. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 67.2°C, the top 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 7.

[0047] <Comparative Example 4> The crystals of compound A1 obtained in Example 1 were 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 (about 4°C) for 3 days, resulting in the precipitation of crystals. The precipitated crystals were filtered and dried. The obtained crystals of compound A1 were subjected to HPLC analysis by the above method, and as a result, it was revealed that the crystals contained 93.3 area % of compound A1, 2.0 area % of compound A2, and 0.2 area % of compound A3. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 68.7°C, the top 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 8.

[0048] <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 in the same manner. The obtained distillation residue was analyzed by HPLC using the above method, and as a result, the contents of Compound A1 were 86.4 area %, Compound A2 were 6.2 area %, and Compound A3 were 0.7 area %. To prepare a crystallized solution of 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 crystals precipitated. The precipitated crystals were filtered and dried. The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the contents were 94.3 area % of Compound A1, 0.9 area % of Compound A2, and 0.1 area % of Compound A3. The obtained crystals of Compound A1 were 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 9.

[0049] <Comparative Example 6> A portion of the washed organic layer containing Compound A1 obtained in Example 1 was transferred into a polypropylene screw tube and sealed with a lid. The screw tube was cooled in a refrigerator (about 4°C) for 2 weeks, and crystals were precipitated. The precipitated crystals were filtered and dried. The yield of the crystals of Compound A1 was 15%. The obtained crystals of Compound A1 were analyzed by HPLC using the method described above, and the results showed that Compound A1 accounted for 94.4 area %, Compound A2 for 1.6 area %, and Compound A3 for 0.2 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and the onset temperature was 71.1°C, the top 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 10.

[0050] <Comparative Example 7> A portion (330 g) of the washed organic layer containing Compound A1 obtained in Example 1 was placed in a four-necked flask equipped with a stirrer, a thermometer, and a condenser. 106.8 g of the solvent from the organic layer was distilled off under heating and reduced pressure to obtain a concentrated solution. To the concentrated solution at 55°C, 49.8 g of cyclohexane was added (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. In the graph of Figure 11, this is indicated as "0.7 times by weight crystallization solution"). Subsequently, the solution was cooled to 35°C, 0.1 g of crystals of compound A1 was added as seed crystals, and the solution was 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 (the weight of butyl acetate relative to the total weight of butyl acetate and cyclohexane in the crystallization solution at this time was 0.5 times by weight. In the graph of Figure 11, this is indicated as "0.5 times by weight crystallization solution"). Further, 133 g of cyclohexane was added dropwise over 1.5 hours, and the mixture was stirred at 15°C for 22 hours (the weight of butyl acetate relative to the total weight of butyl acetate and cyclohexane in the crystallization solution at this time was 0.3 times by weight. In the graph of Figure 11, this is indicated as "0.3 times by weight crystallization solution"). During the crystallization process, the supernatant was sampled and analyzed by liquid chromatography to determine the concentration of Compound A1 over time. The results are shown in Figure 11. In a solution of compound A1 in butyl acetate and cyclohexane, by changing the ratio of butyl acetate to cyclohexane, the concentration of compound A1 in the supernatant decreased, and crystals precipitated from the crystallization solution. On the other hand, while the solvent ratio remained the same, the concentration of compound A1 did not decrease significantly during the crystallization operation, and it became clear that crystal growth was not rapid. The precipitated crystals were filtered and dried to obtain 29.9 g of crystals of compound A1 (yield 32.8%). The obtained crystals of Compound A1 were analyzed by HPLC using the method described above. As a result, Compound A1 was found to be 86 0.5 area %, Compound A2 was 4.5 area %, and Compound A3 was 0.8 area %. The obtained crystals of Compound A1 were 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 12.

[0051] <Comparative Example 8> From the IPA solution containing Compound A1 obtained in Example 4, 7.06 g was dispensed into a 100 mL test tube, and 1.98 g of ethylbenzene was added. The mixture was cooled to 30°C while stirring with a stirrer (at this time, the weight of IPA relative to the total weight of IPA and ethylbenzene in the crystallization solution was 0.60 times by weight). 0.07 g of Compound A1 crystals were added as seed crystals, and the mixture was cooled to 15°C over 3 hours. After stirring for 16 hours, 8.83 g of ethylbenzene was added dropwise over 4 hours, resulting in the crystals dissolving (at this time, the weight of IPA relative to the total weight of IPA and ethylbenzene in the crystallization solution was 0.20 times by weight). It was not possible to isolate crystals of compound A1 from this crystallization solution.

[0052] <Comparative Example 9> From the n-butanol solution containing Compound A1 obtained in Example 11, 17.30 g was dispensed into a 100 mL test tube, 4.77 g of ethylbenzene was added, and the mixture was cooled to 30°C while stirring with a stirrer (at this time, the weight of n-butanol was 0.60 times the total weight of n-butanol and ethylbenzene in the crystallization solution). 0.19 g of Compound A1 crystals were added as seed crystals, and the mixture was cooled to 15°C over 3 hours. Thereafter, 23.72 g of ethylbenzene was added dropwise over 1 hour, and the crystals dissolved (at this time, the weight of n-butanol was 0.20 times the total weight of n-butanol and ethylbenzene in the crystallization solution). It was not possible to isolate crystals of compound A1 from this crystallization solution.

[0053] The crystallization methods for producing crystals of Compound A1 in Comparative Examples 1 to 9 were found to be unsuitable for industrial production and to be inefficient because attempts to crystallize them failed, the crystallization required a long period of time, and the yield of the obtained crystals was low. The highest yield among Comparative Examples 1 to 9 was 32.8% in Comparative Example 7, but it was revealed that crystallization was not rapid and it took a long time to obtain the crystals. On the other hand, it was revealed that crystallization proceeded rapidly in all of the crystallization methods for compound A1 in Examples 1 to 18. It was also revealed that compound A1 could be obtained in a high yield of 36.7 to 86.9% and in crystals that were easy to handle. Therefore, it was revealed that crystals of compound A1 could be efficiently produced in a manner suitable for industrial mass production.

Claims

1. A method for producing crystals of a phenol compound having a methoxymethyl group represented by chemical formula (A1), comprising a crystallization step of precipitating crystals from a solution containing a phenol compound having a methoxymethyl group represented by chemical formula (A1), a chain aliphatic alcohol solvent having 3 to 4 carbon atoms, and an aliphatic hydrocarbon solvent having 6 to 8 carbon atoms. 【Chemical 1】

2. The method for producing a crystal according to claim 1, wherein the chain aliphatic alcohol solvent having 3 to 4 carbon atoms is at least one selected from n-propanol, isopropyl alcohol, n-butanol, and isobutanol, and the aliphatic hydrocarbon solvent having 6 to 8 carbon atoms is at least one selected from hexane, cyclohexane, octane, and isooctane.

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