Method for producing crystals from phenol compound having methoxymethyl group

Abstract

The present invention addresses the problem of providing a method with which it is possible to quickly form crystals at a crystallization step, and which is suitable for industrial mass production to enable efficient production of crystals from a compound A1. As a means for solving said problem, provided is a method for producing crystals from a phenol compound represented by chemical formula (A1) and having a methoxymethyl group, said method including a crystallization step for precipitating crystals from a solution containing a phenol compound represented by chemical formula (A1) and having a methoxymethyl group, a C3-4 chain aliphatic alcohol solvent, and a C6-8 aliphatic hydrocarbon solvent.

Description

Method for producing crystals of phenolic compounds having a methoxymethyl group

[0001] The present invention relates to a method for producing crystals of a phenolic compound having a methoxymethyl group. More 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.

[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] 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 is possible that 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 production 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 involves 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 to crystallize until isolation is possible, which indicates that the crystallization rate is extremely slow. These production methods are therefore 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.

[0005] As a result of intensive research to solve the above-mentioned problems, the present inventors have found that by employing a crystallization step using a specific solvent, crystallization can be carried out quickly, and crystals of compound A1 can be produced in high yield and efficiently in a 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 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. 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.

[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.

[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 crystals of Compound A1 obtained in Example 1. FIG. 3 is a chart showing a differential scanning calorimetry (DSC) analysis of the crystals of Compound A1 obtained in Example 2. FIG. 4 is a chart showing a differential scanning calorimetry (DSC) analysis of the crystals of 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 Comparative Example 1. FIG. 6 is a chart showing a differential scanning calorimetry (DSC) analysis of the crystals of Compound A1 obtained in Comparative Example 2. FIG. 7 is a chart showing a differential scanning calorimetry (DSC) analysis of the crystals of Compound A1 obtained in Comparative Example 3. FIG. 8 is a chart showing a differential scanning calorimetry (DSC) analysis of the crystals of Compound A1 obtained in Comparative Example 4. Fig. 1 shows a differential scanning calorimetry (DSC) analysis chart of the crystals of Compound A1 obtained in Comparative Example 5. Fig. 2 shows a differential scanning calorimetry (DSC) analysis chart of the crystals of Compound A1 obtained in Comparative Example 6. Fig. 3 shows a graph illustrating 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. Fig. 4 shows a differential scanning calorimetry (DSC) analysis chart of the crystals of Compound A1 obtained in Comparative Example 7.

[0009] The present invention will be described in detail below. <Method for producing crystals of a phenolic 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 represented by chemical formula (A1) of the present invention (compound A1) is characterized by 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.

[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 extracted by an isolation procedure after the synthesis reaction. There is no particular limitation on the form, and examples include solid, oily, lumpy, and powdery forms. Compound A1 preferably has a detection area ratio of compound A1 in the range of 75.0 area% to 100 area%, more preferably 80.0 area% to 100 area%, even more preferably 83.0 area% to 100 area%, and particularly preferably 85.0 area% to 100 area%, relative to the detection areas of all components detected by liquid chromatography analysis using a UV detector at a wavelength of 280 nm. 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 as a result of a reaction in which a methylene chain is formed between the methoxymethyl groups of each molecule of 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.

[0011] 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 crystals of compound A1 of the present invention, compound A1 used as a starting material is preferably compound A1 synthesized by the "hydroxymethyl group methoxylation method", which is the reaction of 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 compound A1 by the "hydroxymethyl group methoxylation method" of the above-mentioned synthesis method is described below. The synthesis method of 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).

[0012] 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.

[0013] 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.

[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 performed by preparing a solution of compound A1 and an organic solvent that dissolves compound A1 and separates it from water, and then washing the organic layer with water. Examples of compound A1 to be subjected to the water washing treatment include compound A1 contained in the reaction solution after the synthesis reaction and compound A1 that has been isolated once. When a reaction solution containing compound A1 after the synthesis reaction is used, a solution is prepared by solvent substitution from the organic solvent used in the reaction, such as methanol, with an organic solvent that can dissolve compound A1 and separate it from water. When a compound A1 that has been extracted once is used, a solution is prepared by mixing it with an organic solvent that can dissolve compound A1 and separate it 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, 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 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 can be washed once or multiple times in consideration of the amount of water-soluble impurities to be removed.

[0015] <Preparation of Solution Used in the Crystallization Step of the Present Invention> Although not limited to the above-mentioned methoxylation method of the 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, Compound A1 that has undergone the above-mentioned water washing treatment can be washed and then solvent-substituted 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. Examples of solvent substitution methods 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 to maintain the solution state without drying, thereby performing solvent substitution 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, 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 solvent used in the crystallization step> 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, isobutanol, etc. 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 preferred. As the aliphatic hydrocarbon solvent having 6 to 8 carbon atoms to be used in the crystallization step of the present invention, a chain aliphatic hydrocarbon solvent having 6 to 8 carbon atoms is preferred, a chain aliphatic hydrocarbon solvent having 6 or 8 carbon atoms is more preferred, and a chain aliphatic hydrocarbon solvent having 8 carbon atoms is even more preferred. Specific examples of the aliphatic hydrocarbon solvent having 6 to 8 carbon atoms include hexane, cyclohexane, heptane, cycloheptane, octane, and cyclooctane. 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, it is more preferable to use at least one solvent selected from n-hexane, cyclohexane, n-heptane, n-octane, and isooctane (2,2,4-trimethylpentane), it is even more preferable to use at least one solvent selected from n-hexane, cyclohexane, n-octane, and isooctane, and isooctane is 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 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 aliphatic hydrocarbon solvent having 6 to 8 carbon atoms may be added to the crystallization solution. In such a case, 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 preferably in the range of 0.1 to 0.5 times by weight, particularly preferably 0.1 to 0.4 times by weight.

[0018] (Conditions for the Crystallization Step) 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 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 the 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 limitations on the rate at which the crystallization solution is cooled, but it is preferably in the range of 3 to 15°C / h.

[0019] <Steps after the Crystallization Step> 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. The present invention preferably further comprises 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, 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 comprises 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 when carried out industrially. 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.

[0020] 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 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. Apparatus: 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°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 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°C / min. Measurement temperature range: 30 to 400°C. Measurement atmosphere: Nitrogen 50 mL / min. Sample amount: 4 to 5 mg

[0021] 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. Methanol was removed by distillation under heating and reduced pressure, 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 to obtain 816 g of a washed organic layer containing compound A1. As a result of HPLC analysis of compound A1 in the obtained organic layer using the above-mentioned method, compound A1 was 86.9 area %, compound A2 was 5.6 area %, and compound A3 was 0.6 area %. A portion of the obtained organic layer containing the washed compound A1 (263 g) was transferred to 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 reduced pressure with heating to obtain a distillation residue. The HPLC analysis of the obtained distillation residue by the above method showed that the compound A1 was 86.9 area %, the compound A2 was 5.6 area %, and the compound A3 was 0.6 area %. To prepare a crystallized 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 crystallized solution was 0.7 times by weight. In the graph of FIG. 1, this is referred to as "0.7 times by weight crystallized solution"). 1.4 g of crystals of Compound A1 were added as seed crystals, cooled to 15°C over 1 hour, and stirred at 15°C for 20.5 hours, resulting in precipitation of crystals. Next, 44.5 g of isooctane was added over 2 hours and 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 referred to as "0.4 times by weight crystallization solution"). Furthermore, 120 g of isooctane was added over 4.5 hours and stirred at 15°C for 17 hours (the weight of IPA relative to the amount 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 referred to as "0.2 times by weight crystallization solution").During the crystallization process, the supernatant was sampled and analyzed for the concentration of Compound A1 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 while the crystallization operation was continued in the "0.7-fold crystallization solution." This was presumably due to the progression 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 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 above method, and the results were as follows: Compound A1 was 87.2 area %, Compound A2 was 5.7 area %, and Compound A3 was 0.7 area %. The obtained crystals of Compound A1 were analyzed by differential scanning calorimetry (DSC), and 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. Methanol was removed by distillation under heating and reduced pressure, 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. Thereafter, the organic layer was repeatedly washed with water several 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 by a distillation operation 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, compound A1 was 86.6 area%, compound A2 was 6.3 area%, and compound A3 was 0.7 area%. To prepare a crystallization 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. (At this time, the weight of IPA relative to the total weight of IPA and isooctane in the crystallization solution 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 (At this time, the weight of IPA relative to the total weight of IPA and isooctane in the crystallization solution was 0.14 times by weight). 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 subjected to HPLC analysis using the method described above, and the results showed that compound A1 was 86.9 area %, compound A2 was 6.2 area %, and compound A3 was 0.7 area %. The onset temperature of the obtained crystals of 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.

[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, 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, 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 repeatedly washed with water several times 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 by a distillation operation under heating and reduced pressure, obtaining a distillation residue. HPLC analysis of the obtained distillation residue by the above method showed that Compound A1 was 86.4 area %, Compound A2 was 6.2 area %, and Compound A3 was 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. (At this time, the weight of IPA relative to the total weight of IPA and isooctane in the crystallized 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 crystallized solution was 0.20 times by weight). The precipitated crystals were filtered and dried, obtaining 311.4 g of crystals of Compound A1 (yield 82.9%). The obtained crystals of Compound A1 were subjected to HPLC analysis using the above method, and the results showed that Compound A1 was 86.5 area %, Compound A2 was 6.3 area %, and Compound A3 was 0.8 area %. Differential scanning calorimetry (DSC) analysis of the obtained crystals of Compound A1 showed an onset temperature of 51.8°C, an endothermic peak top temperature 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.

[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 in the range of 30 to 50°C, pressure in the range of 50 kPa or less), and 89.8 g of water and 89.8 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 127 g of a washed organic layer containing compound A1. As a result of HPLC analysis of the obtained organic layer by the above method, compound A1 was 86.4 area %, compound A2 was 5.6 area %, and compound A3 was 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, obtaining a distillation residue. As a result of HPLC analysis of the obtained distillation residue by the above method, compound A1 was 86.4 area %, compound A2 was 5.6 area %, and compound A3 was 0.6 area %. To prepare a crystallization solution 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. From this obtained IPA solution, 5.05 g was taken into a 100 mL test tube, 1.49 g of octane was added, and 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 octane in the crystallization solution was 0.60 times by weight). 0.0586 g of crystals of Compound A1 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 relative to the total weight of IPA and octane in the crystallization solution was 0.20 times by weight). The precipitated crystals were filtered and dried, yielding 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 were 87.2 area % of Compound A1, 6.4 area % of Compound A2, and 0.9 area % of Compound A3.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, 1.51 g of hexane was added, and 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 Compound A1 crystals (yield 72.5%). The obtained crystals of Compound A1 were subjected to HPLC analysis by the above method, and the results showed that Compound A1 was 87.4 area %, Compound A2 was 6.2 area %, and Compound A3 was 0.8 area %. Differential scanning calorimetry (DSC) analysis of the obtained crystals of Compound A1 showed 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: 5.00 g of the IPA solution containing Compound A1 obtained in Example 4 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. 7.37 g of cyclohexane was then added dropwise over 1 hour, and the mixture was cooled to 7°C over 0.5 hours. 11.07 g of cyclohexane was then 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, yielding 2.06 g of Compound A1 crystals (yield 63.8%). The obtained crystals of Compound A1 were subjected to HPLC analysis by the above method, and the results showed that Compound A1 was 88.5 area %, Compound A2 was 5.4 area %, and Compound A3 was 0.8 area %. Differential scanning calorimetry (DSC) analysis of the obtained crystals of Compound A1 showed an onset temperature of 61.4°C, an endothermic peak top temperature of 70.2°C, and a heat of fusion of 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 in the range of 30 to 50°C, pressure in the range of 50 kPa or less), and 89.8 g of water and 89.8 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 127 g of a washed organic layer containing compound A1. As a result of HPLC analysis of the obtained organic layer by the above method, the content of Compound A1 was 86.4 area %, the content of Compound A2 was 5.6 area %, and the content of Compound A3 was 0.6 area %. The obtained organic layer containing Compound A1 was subjected to a distillation operation under heating and reduced pressure to distill off 84.2 g of the solvent from the organic layer, thereby obtaining a distillation residue. As a result of HPLC analysis of the obtained distillation residue by the above method, the content of Compound A1 was 86.4 area %, the content of Compound A2 was 5.6 area %, and the content of Compound A3 was 0.6 area %. To prepare a crystallized solution containing Compound A1 having the above composition, 30.1 g of n-propanol was added to the obtained distillation residue at 47°C and dissolved. From the obtained n-propanol solution, 5.00 g was taken into a 100 mL test tube, 1.49 g of isooctane was added, and the mixture was cooled to 30°C while stirring with a stirrer (at this time, the weight of n-propanol relative to the total weight of n-propanol and isooctane in the crystallized solution was 0.60 times by weight). 0.0580 g of crystals of Compound A1 were added as seed crystals, and the mixture was cooled to 20°C over 1 hour. Then, 7.85 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 n-propanol relative to the total weight of n-propanol and isooctane in the crystallization solution was 0.20 times). 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 subjected to HPLC analysis by the above method, and the results showed that Compound A1 was 88.4 area %, Compound A2 was 5.6 area %, and Compound A3 was 1.0 area %. Differential scanning calorimetry (DSC) analysis of the obtained crystals of Compound A1 showed an onset temperature of 58.5°C, an endothermic peak top temperature of 68.7°C, and a heat of fusion of 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, 1.52 g of octane was added, and 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. Thereafter, 7.60 g of octane was added dropwise over 1 hour, and the mixture was cooled to 7°C over 2 hours. Thereafter, the mixture was 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 Compound A1 crystals (yield 71.7%). The obtained crystals of Compound A1 were subjected to HPLC analysis by the above method, and the results showed that Compound A1 was 87.9 area %, Compound A2 was 6.0 area %, and Compound A3 was 0.9 area %. Differential scanning calorimetry (DSC) analysis of the obtained crystals of Compound A1 showed 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 5.00 g of the n-propanol solution containing Compound A1 obtained in Example 7 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. 7.55 g of hexane 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 hexane in the crystallization solution). The precipitated crystals were filtered and dried to obtain 2.00 g of Compound A1 crystals (yield 61.8%). The obtained crystals of Compound A1 were subjected to HPLC analysis by the above method, and the results showed that Compound A1 was 87.8 area %, Compound A2 was 6.1 area %, and Compound A3 was 0.9 area %. Differential scanning calorimetry (DSC) analysis of the obtained crystals of Compound A1 showed an onset temperature of 53.8°C, an endothermic peak top temperature of 68.5°C, and a heat of fusion of 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, 1.66 g of cyclohexane was added, and 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. Then, 8.38 g of cyclohexane was 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 Compound A1 crystals (yield 36.7%). The obtained crystals of Compound A1 were subjected to HPLC analysis by the above method, and the results showed that Compound A1 was 92.8 area %, Compound A2 was 3.2 area %, and Compound A3 was 0.4 area %. Differential scanning calorimetry (DSC) analysis of the obtained crystals of Compound A1 showed an onset temperature of 64.6°C, an endothermic peak top temperature of 71.7°C, and a heat of fusion of 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 in the range of 30 to 50°C, pressure in the range of 50 kPa or less), and 89.8 g of water and 89.8 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 127 g of a washed organic layer containing compound A1. As a result of HPLC analysis of the obtained organic layer by the above method, the content of compound A1 was 86.4 area %, the content of compound A2 was 5.6 area %, and the content of compound A3 was 0.6 area %. The obtained organic layer containing compound A1 was subjected to a distillation operation under heating and reduced pressure to distill off 84.2 g of the solvent from the organic layer, thereby obtaining a distillation residue. As a result of HPLC analysis of the obtained distillation residue by the above method, the content of compound A1 was 86.4 area %, the content of compound A2 was 5.6 area %, and the content of compound A3 was 0.6 area %. To prepare a crystallization solution containing compound A1 having the above composition, 30.1 g of n-butanol was added to the obtained distillation residue at 47°C and dissolved. From the obtained n-butanol solution, 5.05 g was taken into a 100 mL test tube, 1.50 g of isooctane 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 isooctane in the crystallization solution was 0.60 times by weight). 0.0573 g of crystals of Compound A1 were added as seed crystals, and the mixture was cooled to 20°C over 1 hour. Then, 7.50 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 (the weight of n-butanol relative to the total weight of n-butanol and isooctane in the crystallization solution at this time was 0.20 times by weight). 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 subjected to HPLC analysis using the method described above, and the results were as follows: Compound A1 was 87.5 area %, Compound A2 was 6.2 area %, and Compound A3 was 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 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, 1.48 g of octane 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 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. Thereafter, 7.52 g of octane was added dropwise over 1 hour, and the mixture was cooled to 7°C over 2 hours. Thereafter, the mixture was 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 Compound A1 crystals (yield 70.4%). The obtained crystals of Compound A1 were subjected to HPLC analysis by the above method, and the results showed that Compound A1 was 87.7 area %, Compound A2 was 6.1 area %, and Compound A3 was 0.8 area %. Differential scanning calorimetry (DSC) analysis of the obtained crystals of Compound A1 showed an onset temperature of 58.1°C, an endothermic peak top temperature of 67.6°C, and a heat of fusion of 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 was 0.60 times the total weight of n-butanol and hexane 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. Thereafter, 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 was 0.20 times the total weight of n-butanol and hexane in the crystallization solution). The precipitated crystals were filtered and dried to obtain 2.39 g of Compound A1 crystals (yield 73.1%). The obtained crystals of Compound A1 were subjected to HPLC analysis by the above-mentioned method, and the results showed that Compound A1 was 88.3 area %, Compound A2 was 5.7 area %, and Compound A3 was 0.8 area %. Differential scanning calorimetry (DSC) analysis of the obtained crystals of Compound A1 showed that the onset temperature was 57.5°C, the endothermic peak top temperature 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, 1.51 g of cyclohexane 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 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 Compound A1 crystals (yield 62.7%). The obtained crystals of Compound A1 were subjected to HPLC analysis by the above method, and the results showed that Compound A1 was 88.9 area %, Compound A2 was 5.2 area %, and Compound A3 was 0.9 area %. Differential scanning calorimetry (DSC) analysis of the obtained crystals of Compound A1 showed an onset temperature of 60.6°C, an endothermic peak top temperature of 69.7°C, and a heat of fusion of 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 in the range of 30 to 50°C, pressure in the range of 50 kPa or less), and 89.8 g of water and 89.8 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 to obtain 127 g of an organic layer containing washed compound A1. As a result of HPLC analysis of the obtained organic layer by the above method, the content of compound A1 was 86.4 area %, the content of compound A2 was 5.6 area %, and the content of compound A3 was 0.6 area %. The obtained organic layer containing compound A1 was subjected to a distillation operation under heating and reduced pressure to distill off 84.2 g of the solvent from the organic layer, thereby obtaining a distillation residue. As a result of HPLC analysis of the obtained distillation residue by the above method, the content of compound A1 was 86.4 area %, the content of compound A2 was 5.6 area %, and the content of compound A3 was 0.6 area %. To prepare a crystallization solution 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 taken into a 100 mL test tube, 1.60 g of isooctane 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 isooctane in the crystallization solution was 0.60 times by weight). 0.0569 g of crystals of Compound A1 were added as seed crystals, and the mixture was cooled to 20°C over 1 hour. 7.40 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 (the weight of isobutanol relative to the total weight of isobutanol and isooctane in the crystallization solution at this time was 0.20 times by weight). 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 subjected to HPLC analysis by the above method, and the results showed that Compound A1 was 87.0 area %, Compound A2 was 6.5 area %, and Compound A3 was 0.9 area %. Differential scanning calorimetry (DSC) analysis of the obtained crystals of Compound A1 showed an onset temperature of 53.9°C, an endothermic peak top temperature of 67.1°C, and a heat of fusion of 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 Compound A1 crystals (yield 72.2%). The obtained crystals of Compound A1 were subjected to HPLC analysis by the above method, and the results showed that Compound A1 was 87.2 area %, Compound A2 was 6.3 area %, and Compound A3 was 0.9 area %. Differential scanning calorimetry (DSC) analysis of the obtained crystals of Compound A1 showed an onset temperature of 53.6°C, an endothermic peak top temperature of 67.9°C, and a heat of fusion of 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 Compound A1 crystals (yield 64.6%). The obtained crystals of Compound A1 were subjected to HPLC analysis by the above method, and the results showed that Compound A1 was 87.5 area %, Compound A2 was 6.1 area %, and Compound A3 was 0.9 area %. Differential scanning calorimetry (DSC) analysis of the obtained crystals of Compound A1 showed an onset temperature of 55.3°C, an endothermic peak top temperature of 68.1°C, and a heat of fusion of 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 Compound A1 crystals (yield 55.7%). The obtained crystals of Compound A1 were subjected to HPLC analysis by the above method, and the results showed that Compound A1 was 91.1 area %, Compound A2 was 4.1 area %, and Compound A3 was 0.6 area %. Differential scanning calorimetry (DSC) analysis of the obtained crystals of Compound A1 showed an onset temperature of 63.2°C, an endothermic peak top temperature of 70.9°C, and a heat of fusion of 73.8 mJ / mg.

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

[0040]

[0041]

[0042]

[0043]

[0044] 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 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 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 5). 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 5). 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 5). 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 5. By adding water to the methanol solution of Compound A1 and the water and methanol solution to change the ratio of methanol to water, the concentration of Compound A1 in the supernatant decreased, but 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.

[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 (approximately 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 using the method described above, and were found to contain 90.9 area% of compound A1, 2.9 area% of compound A2, and 0.3 area% of compound A3. Differential scanning calorimetry (DSC) analysis of the obtained crystals of 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 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 (approximately 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 using the method described above, revealing that they contained 90.8 area% of compound A1, 2.9 area% of compound A2, and 0.3 area% of compound A3. Differential scanning calorimetry (DSC) analysis of the obtained crystals of 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 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 (approximately 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 using the method described above, revealing that they contained 93.3 area% of Compound A1, 2.0 area% of Compound A2, and 0.2 area% of Compound A3. Differential scanning calorimetry (DSC) analysis of the obtained crystals of 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 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 by the same method. The obtained distillation residue was analyzed by HPLC using the above method, and the results showed that Compound A1 was 86.4 area %, Compound A2 was 6.2 area %, and Compound A3 was 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 above method, and the results showed that Compound A1 was 94.3 area %, Compound A2 was 0.9 area %, and Compound A3 was 0.1 area %. 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 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 crystals. The precipitated crystals were filtered and dried. The yield of Compound A1 crystals was 15%. The obtained Compound A1 crystals were subjected to HPLC analysis using the method described above, resulting in 94.4 area % of Compound A1, 1.6 area % of Compound A2, and 0.2 area % of Compound A3. Differential scanning calorimetry (DSC) analysis of the obtained Compound A1 crystals 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 10.

[0050] Comparative Example 7: A portion (330 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. 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 11). 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 11, 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 11, 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 11. 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 during the crystallization procedure while the solvent ratio was kept the same, revealing that crystal growth was not rapid. The precipitated crystals were filtered and dried to obtain 29.9 g of Compound A1 crystals (yield 32.8%). The obtained Compound A1 crystals were subjected to HPLC analysis using the method described above, and the results showed that Compound A1 was 86.5 area %, Compound A2 was 4.5 area %, and Compound A3 was 0.8 area %. Differential scanning calorimetry (DSC) analysis of the obtained Compound A1 crystals showed an onset temperature of 63.7°C, a top temperature of the endothermic peak of 69.2°C, and a heat of fusion based on the observed endothermic peak of 71.4 mJ / mg.The DSC analysis chart is shown in FIG.

[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, 1.98 g of ethylbenzene was added, and 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 Compound A1 crystals 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 also to be inefficient, due to the fact that attempted crystallization 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 a long period of time was required to obtain the crystals. On the other hand, it was found that crystallization proceeded rapidly in all of the crystallization methods for producing crystals of Compound A1 in Examples 1 to 18. It was also found that Compound A1 could be obtained in a high yield of 36.7 to 86.9%, and in crystals with easy-to-handle properties. Therefore, it was found that crystals of Compound A1 could be produced efficiently, 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.

2. The method for producing crystals 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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