Method for producing crystals of phenol compound having methoxymethyl group
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- HONSHU CHEM INDAL
- Filing Date
- 2026-01-27
- Publication Date
- 2026-08-06
Smart Images
Figure JP2026002591_06082026_PF_FP_ABST
Abstract
Description
Method for producing crystals of a phenol compound having a methoxymethyl group
[0001] The present invention relates to a method for producing crystals of a phenol compound having a methoxymethyl group. Specifically, it relates to a method for producing crystals of the compound, including a crystallization step of a phenol compound having a methoxymethyl group (Compound A) represented by the chemical formula (A) described later.
[0002] Conventionally, 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 physical properties of photosensitive resins. As a phenol compound having a methoxymethyl group, a phenol compound having a methoxymethyl group represented by the chemical formula (A) (hereinafter sometimes referred to as Compound A) is known. As a conventionally known isolation method of Compound A, ethyl acetate is added to a reaction solution obtained by reacting a hexahydroxymethyl compound (Compound B, described later), which is a precursor of this compound, with methanol in the presence of sulfuric acid, followed by washing with water and then distilling off the solvent to obtain an oily substance (Patent Document 1). As another isolation method, Patent Document 2 describes that, similarly to the above, the hexahydroxymethyl compound (Compound B) is reacted with methanol in the presence of sulfuric acid, an anionic ion exchange resin is mixed with the reaction solution and stirred, then the ion exchange resin is removed, and the solvent is replaced with ethyl lactate to prepare an ethyl lactate solution of Compound A, and the solution is left at room temperature for 2 days to obtain crystals.
[0003] JP-A-07-017888 JP-A-2010-044143
[0004] The compound A obtained by the isolation method described in Patent Document 1 is an oily substance, making it difficult to handle in industrial production. Furthermore, although the synthesis reaction of compound A involves distillation off methanol, dissolution in ethyl acetate, and washing of the organic layer with water, the oily substance is the distillation residue after distillation off ethyl acetate, and therefore the isolation operation does not have a purification effect to remove by-products. Moreover, in the oily form of the distillation residue, compound A, which has a thermally crosslinkable methoxymethyl group, is difficult to reduce by distilling off the remaining solvent under severe heating conditions. In addition, variations in the degree of solvent distillation from one production to the next lead to variations in the content of the active ingredient as a crosslinking agent, making it difficult to handle in industrial production. In the manufacturing method described in Patent Document 2, compound A can be isolated as a crystal, but crystallization takes two days, and it is understood that the crystallization rate is extremely slow and the method is inefficient. This manufacturing method is not suitable for the industrial production of compound A. In view of the above-mentioned problems identified by the present inventors, the objective is to provide a method for producing compound A as a crystal in a manner suitable for industrial mass production.
[0005] As a result of diligent research to solve the above-mentioned problems, the inventors have found an efficient method for isolating a phenol compound having a methoxymethyl group represented by chemical formula (A) as crystals in an industrially suitable manner by employing a crystallization process using a specific solvent, and have completed 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 (A), comprising a crystallization step of precipitating crystals from a solution containing a phenol compound having a methoxymethyl group represented by chemical formula (A) and a chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms. 2. The manufacturing method according to 1, wherein the chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms is isopropyl alcohol or n-butanol. 3. The manufacturing method according to 1, wherein the crystallization step is either (1) a crystallization step in which crystals are precipitated from a solution containing a phenol compound having a methoxymethyl group represented by chemical formula (A) and a chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms, and then an aliphatic hydrocarbon solvent having 5 to 10 carbon atoms is mixed into the solution containing the crystals to precipitate further crystals, or (2) a crystallization step in which crystals are precipitated from a solution containing a phenol compound having a methoxymethyl group represented by chemical formula (A), a chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms, and an aliphatic hydrocarbon solvent having 5 to 10 carbon atoms. 4. The manufacturing method according to 3, wherein the aliphatic hydrocarbon solvent having 5 to 10 carbon atoms is a chain-like aliphatic hydrocarbon solvent having 5 to 10 carbon atoms. 5. The manufacturing method according to 3., wherein the chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms is isopropyl alcohol or n-butanol, and the aliphatic hydrocarbon solvent having 5 to 10 carbon atoms is isooctane.
[0007] The present invention's method for producing crystals of compound A is extremely useful because it allows for the more efficient production of compound A in crystalline form compared to conventional methods for producing compound A.
[0008] The present invention will now be described in detail. The present invention provides a method for producing crystals of a phenol compound having a methoxymethyl group represented by chemical formula (A) (compound A), characterized by comprising a crystallization step of precipitating crystals from a solution containing compound A and a chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms.
[0009] <Phenol compound having a methoxymethyl group represented by chemical formula (A)> The method for synthesizing the phenol compound having a methoxymethyl group represented by chemical formula (A) (compound A) according to the present invention is not particularly limited and can be synthesized by conventionally known methods. It may be a substance that has been isolated once after the synthesis reaction. There are no particular restrictions on the form, and it may be solid, oily, lumpy, or powdery. For example, as shown in the reaction formula below, there is a method for synthesizing the phenol compound having a methoxymethyl group represented by chemical formula (A) by reacting a phenol compound having a hydroxymethyl group represented by chemical formula (B) (hereinafter sometimes referred to as compound B) with methanol in the presence of an acid catalyst (hereinafter sometimes referred to as the "hydroxymethyl group methoxylation method"). In the method for producing crystals of compound A of the present invention, it is preferable that compound A provided as a raw material is compound A synthesized by the "hydroxymethyl group methoxylation method," which involves reacting a phenol compound having a hydroxymethyl group represented by chemical formula (B) with methanol in the presence of an acid catalyst. A method for producing compound A by the "methoxymethyl group methoxylation method" of the above synthesis method will be described below. The method for synthesizing the phenol compound having a hydroxymethyl group represented by chemical formula (B) (compound B), which is used in the methoxymethyl group methoxylation method, is not particularly limited and can be synthesized by conventionally known methods. As an example of a method for synthesizing compound B, one can react a trisphenol compound represented by chemical formula (C) (compound C) with formaldehyde in the presence of a basic catalyst to synthesize a phenol compound having a hydroxymethyl group represented by chemical formula (B).
[0010] In the methoxylation method of the hydroxymethyl group according to the present invention, the amount of methanol used is preferably in the range of 80 to 800 moles, and more preferably in the range of 100 to 700 moles, per mole of compound B. This methanol can also serve as the reaction solvent.
[0011] Specifically, examples of acid catalysts used in the methoxylation method of hydroxymethyl groups according to the present invention include sulfuric acid, hydrochloric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, cation exchange resin (acid type), oxalic acid, phosphotungstic acid, or heteropoly acids such as silotungstic acid, and it is preferable to use at least one of these compounds. Among these, the use of sulfuric acid is particularly preferable. The amount of acid catalyst used is preferably in the range of 0.2 to 2.0 moles, more preferably in the range of 0.2 to 1.5 moles, and particularly preferably in the range of 0.3 to 1.0 moles, per mole of compound B. The reaction temperature in the methoxylation method of hydroxymethyl groups according to the present invention is preferably in the range of 30 to 62°C, more preferably in the range of 45 to 62°C, and particularly preferably in the range of 58 to 62°C. After the reaction is complete, it is preferable to neutralize the acid catalyst used in the reaction by mixing it with a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate.
[0012] As compound A used in the crystallization step of the present invention, for example, compound A obtained by the above-described reaction and other conventionally known reactions, compound A obtained from a reaction solution containing compound A by the above-described post-treatment operation, or separation operation such as concentration, reprecipitation, or column separation, crystals of compound A obtained through the crystallization step of the present invention, or crystals of compound A that have not undergone the crystallization step of the present invention can be used. There are no particular restrictions on the form, and it can be solid, oily, lumpy, or powdery. Compound A may include, for example, reaction intermediates produced during the synthesis reaction of compound A, by-products, and raw materials used. A composition of compound A containing these can also be used in the crystallization step. In such cases, the compound A used in the crystallization step preferably has a detection peak area of 75 area % or more, more preferably 78 area % or more, even more preferably 80 area % or more, and particularly preferably 82 area % or more, relative to the total area of detection peaks of all components detected by high-performance liquid chromatography analysis with a UV detector at a wavelength of 280 nm. According to the present invention, compared to crystallization methods using other crystallization solvents, even when the detection peak area of compound A relative to the total detection peak area of all components detected by high-performance liquid chromatography analysis of compound A using a 280 nm UV detector is relatively low, the crystallization of compound A can be achieved. Therefore, the present invention has high process tolerance for producing compound A as crystals and is extremely useful.
[0013] (Compound A after water washing treatment) The compound A used as a raw material is preferably compound A that has undergone water washing treatment in order to remove the catalyst used in the synthesis reaction, water-soluble impurities generated during the deactivation of the catalyst (such as salts produced by neutralization of the acid catalyst), and metal components contained in the raw materials used or the base used in neutralization. This water washing treatment can be carried out by preparing a solution of compound A and an organic solvent that dissolves compound A and separates it from water, and washing the organic layer with water. Examples of compound A to which water washing treatment is applied include compound A contained in the reaction solution after the synthesis reaction, and compound A that has been isolated once. When using a reaction solution containing compound A after the synthesis reaction, the solvent is replaced from the organic solvent used in the reaction, such as methanol, to an organic solvent that can be used to dissolve compound A and separate it from water, in order to prepare the solution. When using compound A that has been isolated once, the solution is prepared by mixing it with an organic solvent that can be used to dissolve compound A and separate it from water. Organic solvents that can be used to dissolve compound A and separate it from water include, for example, aromatic hydrocarbon solvents having 7 to 9 carbon atoms such as toluene and xylene, linear aliphatic ketone solvents having 4 to 8 total carbon atoms such as methyl ethyl ketone, methyl isobutyl ketone, and methyl isoamyl ketone, and linear aliphatic carboxylic acid ester solvents having 5 to 8 total 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 linear aliphatic ketone solvents having 4 to 8 total carbon atoms and linear aliphatic carboxylic acid ester solvents having 5 to 8 total carbon atoms, 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 A can be adjusted as appropriate in view of the solubility of compound A in the organic solvent used, but is preferably in the range of 0.5 to 5.0 times by weight, more preferably in the range of 0.5 to 4.0 times by weight, even more preferably in the range of 0.8 to 3.0 times by weight, and particularly preferably in the range of 0.8 to 2.0 times by weight. The amount of water used during the washing treatment can be adjusted as appropriate in view 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 relative to the weight of the organic layer to be washed, more preferably in the range of 0.5 to 2.5 times by weight, even more preferably in the range of 0.5 to 2.0 times by weight, and particularly preferably in the range of 0.5 to 1.5 times by weight. The number of times the organic layer is washed can be one or more times, in view of the amount of water-soluble impurities to be removed.
[0014] <Preparation of the solution used in the crystallization step of the present invention> Although not limited to the hydroxymethyl group methoxylation method described above, a solution containing compound A 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 A synthesized by a known synthesis method to an organic solvent used in the crystallization step of the present invention. Alternatively, compound A that has undergone the water washing treatment described above can be washed and then solvent-substituted with the organic solvent used in the crystallization step of the present invention, or dissolved in that organic solvent, to prepare a solution containing compound A and the organic solvent used in the crystallization step of the present invention. Methods for solvent substitution include: distilling off the organic solvent used in the reaction step to obtain a distillation residue containing compound A, and then mixing it with a chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms used in the crystallization step of the present invention to prepare a solution containing compound A used in the crystallization step of the present invention; or repeatedly distilling off the organic solvent used in the reaction step from the reaction solution and mixing it with a chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms used in the crystallization step of the present invention, thereby maintaining a solution state without drying and performing solvent substitution with a chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms to prepare a solution containing compound A used in the crystallization step of the present invention. When distilling off the organic solvent, it is preferable to perform the distillation under heating and reduced pressure or under 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 in the range of 25 to 55°C, and even more preferably in the range of 30 to 50°C. The pressure is preferably under reduced pressure, more preferably 70 kPa or less, and even more preferably 50 kPa or less. The temperature at which the solution is prepared is preferably in the range of 25 to 60°C, more preferably in the range of 25 to 55°C, and even more preferably in the range of 30 to 50°C.
[0015] <Crystallization Solvent> (Cylindrical Aliphatic Alcohol Solvent Having 3 to 5 Carbon atoms) Among the chain-like aliphatic alcohol solvents having 3 to 5 carbon atoms used in the crystallization step of the present invention, chain-like aliphatic alcohol solvents having 3 or 4 carbon atoms are preferred, and among these, it is even more preferable to use at least one solvent selected from n-propanol, isopropyl alcohol (IPA), n-butanol, and isobutanol, with isopropyl alcohol (IPA) or n-butanol being particularly preferred. Specifically, examples of chain-like aliphatic alcohol solvents having 3 to 5 carbon atoms include n-propanol, isopropyl alcohol (IPA), n-butanol, sec-butanol, tert-butanol, isobutanol, n-pentyl alcohol, n-amyl alcohol, sec-amyl alcohol, isoamyl alcohol, and tert-amyl alcohol. In the crystallization step of the present invention, it is preferable to use at least one solvent selected from these compounds, more preferably at least one solvent selected from n-propanol, isopropyl alcohol (IPA), n-butanol, isobutanol, n-amyl alcohol and isoamyl alcohol, even more preferably at least one solvent selected from n-propanol, isopropyl alcohol (IPA), n-butanol and isobutanol, and isopropyl alcohol (IPA) or n-butanol is particularly preferred. The amount of the chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms used in the crystallization step of the present invention can be appropriately adjusted in view of the solubility of compound A in the chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms used, but it is preferably in the range of 0.8 to 3.0 weight times the weight of compound A, more preferably in the range of 0.9 to 2.5 weight times, even more preferably in the range of 0.9 to 2.0 weight times, and particularly preferably in the range of 1.0 to 2.0 weight times. The amount of chain-like aliphatic alcohol solvent with 3 to 5 carbon atoms used can be adjusted by the amount added, or by removing it from the system by distillation.
[0016] (Aliphatic hydrocarbon solvent having 5 to 10 carbon atoms) In the crystallization step of the present invention, an aliphatic hydrocarbon solvent having 5 to 10 carbon atoms can be used in combination. The aliphatic hydrocarbon solvent having 5 to 10 carbon atoms acts as a poor solvent for compound A. Embodiments of its use include (1) an embodiment in which crystals are precipitated from a solution containing compound A and a chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms, and then the aliphatic hydrocarbon solvent having 5 to 10 carbon atoms is mixed into the solution containing the crystals to precipitate further crystals (Embodiment 1), and (2) an embodiment in which crystals are precipitated from a solution containing compound A, a chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms, and an aliphatic hydrocarbon solvent having 5 to 10 carbon atoms (Embodiment 2). In the case of embodiment 2, the method for preparing the solution containing compound A, a chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms, and an aliphatic hydrocarbon solvent having 5 to 10 carbon atoms is preferably a solution prepared by first preparing a solution with compound A and a chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms, and then mixing in the aliphatic hydrocarbon solvent having 5 to 10 carbon atoms. When using the aliphatic hydrocarbon solvent having 5 to 10 carbon atoms in combination, the mixing method may be to mix all at once, or to mix continuously or intermittently over a period of 0.1 to 5.0 hours, but continuous or intermittent mixing is preferred.
[0017] Aliphatic hydrocarbon solvents having 5 to 10 carbon atoms include linear aliphatic hydrocarbon solvents having 5 to 10 carbon atoms and cyclic aliphatic hydrocarbon solvents having 5 to 10 carbon atoms. Among these aliphatic hydrocarbon solvents having 5 to 10 carbon atoms, linear aliphatic hydrocarbon solvents having 5 to 10 carbon atoms are preferred, linear aliphatic hydrocarbon solvents having 6 to 8 carbon atoms are more preferred, linear aliphatic hydrocarbon solvents having 7 or 8 carbon atoms are even more preferred, and linear aliphatic hydrocarbon solvents having 8 carbon atoms are particularly preferred. Specific examples of linear aliphatic hydrocarbon solvents having 5 to 10 carbon atoms include hexane, heptane, octane, nonane, and decane. In the crystallization step of the present invention, it is preferable to use at least one solvent selected from these compounds, more preferably at least one solvent selected from n-hexane, n-heptane, n-octane, isooctane (2,2,4-trimethylpentane), n-nonane, and n-decane, even more preferably at least one solvent selected from n-hexane, n-heptane, n-octane, and isooctane, with isooctane being particularly preferred. Specific examples of cyclic aliphatic hydrocarbon solvents having 5 to 10 carbon atoms include cyclopentane, cyclohexane, cycloheptane, and cyclooctane. In the crystallization step of the present invention, it is preferable to use at least one solvent selected from these compounds, more preferably at least one solvent selected from cyclopentane, cyclohexane, and cycloheptane, even more preferably at least one solvent selected from cyclopentane and cyclohexane, with cyclohexane being particularly preferred. The amount of aliphatic hydrocarbon solvent having 5 to 10 carbon atoms used is preferably in the range of 1.0 to 5.0 times by weight, more preferably in the range of 1.2 to 4.0 times by weight, even more preferably in the range of 1.5 to 3.5 times by weight, and particularly preferably in the range of 1.5 to 3.0 times by weight, compared to the amount of linear aliphatic alcohol solvent having 3 to 5 carbon atoms used.
[0018] (Other crystallization solvents) In the crystallization step of the present invention, as long as the effects of the present invention are not impaired, a solution containing compound A and a chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms, or a solution containing compound A, a chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms, and an aliphatic hydrocarbon solvent having 5 to 10 carbon atoms may further contain other organic solvents. Examples of other organic solvents that may further contain include chain-like aliphatic ketone solvents having a total of 4 to 7 carbon atoms, cyclic aliphatic ketone solvents having a total of 5 to 8 carbon atoms, and chain-like aliphatic carboxylic acid ester solvents having a total of 6 to 8 carbon atoms. These other organic solvents can be contained in an amount of 0.3 to 3.0 times the weight of the chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms used, and more preferably in an amount of 0.5 to 2.5 times the weight. Specific examples of linear aliphatic ketone solvents having a total of 4 to 7 carbon atoms include methyl ethyl ketone (4 total carbon atoms), diethyl ketone, 2-pentanone, isopropyl methyl ketone (5 total carbon atoms), methyl isobutyl ketone (6 total carbon atoms), isoamyl methyl ketone, 2-heptanone (7 total carbon atoms), and methyl hexyl ketone (8 total carbon atoms). Among these, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone, isoamyl methyl ketone, or 2-heptanone are preferred, methyl isobutyl ketone or 2-heptanone are more preferred, and methyl isobutyl ketone is particularly preferred. Specific examples of cyclic aliphatic ketone solvents having a total of 5 to 8 carbon atoms include cyclopentanone and cyclohexanone, with cyclic aliphatic ketone solvents having a total of 5 or 6 carbon atoms being preferred, and cyclopentanone or cyclohexanone being more preferred. Specific examples of linear aliphatic carboxylic acid ester solvents having a total of 6 to 8 carbon atoms include butyl acetate (n-butyl acetate, isobutyl acetate, sec-butyl acetate, t-butyl acetate), pentyl acetate (n-pentyl acetate (also known as amyl acetate), isoamyl acetate, etc.), and hexyl acetate (n-hexyl acetate, etc.). Among these, butyl acetate or pentyl acetate is preferred, butyl acetate is more preferred, and n-butyl acetate is particularly preferred among butyl acetates.Furthermore, in the crystallization step of the present invention, organic solvents and water used in the aforementioned reaction step and washing step may remain in the product after the step to remove them, resulting in a small amount being present. This small amount is acceptable as long as it does not impair the effects of the present invention.
[0019] <Conditions for the Crystallization Process> In the crystallization process of the present invention, the temperature for precipitating crystals is preferably in the range of 5 to 45°C, more preferably in the range of 5 to 40°C, even more preferably in the range of 5 to 35°C, and particularly preferably in the range of 10 to 30°C. When precipitating crystals, it is not necessary to use seed crystals, but it is preferable to use seed crystals. The amount of seed crystal used is preferably in the range of 0.001 to 0.1 times the weight of compound A to be precipitated. After precipitating 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. The rate at which the crystallization solution is cooled is preferably in the range of 3 to 15°C / h.
[0020] <Post-crystallization step> The crystals of compound A obtained by the crystallization step of the present invention 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 off. During filtration, an organic solvent, for example, the organic solvent used in the crystallization step, can be used to wash the filtered crystals. The used solvent can be removed from the crystals obtained by filtration by drying. In the present invention, it is preferable to further include a drying step in which the crystals filtered off in the filtration step are dried. The drying step can preferably be carried out at a temperature in the range of 25 to 50°C, more preferably in the range of 25 to 45°C, and even more preferably in the range of 25 to 40°C. The pressure during drying can be atmospheric pressure or reduced pressure, but in the case of industrial implementation, reduced pressure is preferable. Specifically, reduced pressure of 10 kPa or less is more preferable, and reduced pressure of 5 kPa or less is even more preferable. Furthermore, in order to suppress oxidation, deterioration, discoloration, etc., caused by oxygen in the present invention, it is preferable to carry out each of the above-mentioned steps, such as reaction, neutralization, washing, crystallization, filtration, distillation, drying, packaging, melting, and cooling, under an inert gas atmosphere such as nitrogen or argon, or under an atmosphere with a lower oxygen level than air.
[0021] The present invention will be specifically described below with reference to examples, comparative examples, and synthesis examples, but the present invention is not limited to these examples and comparative examples. <Analysis Method> 1. High-Performance Liquid Chromatography (HPLC) Analysis The content of compound A in the examples was calculated from the area ratio of the high-performance liquid chromatography (HPLC) chart measured under the following conditions. Apparatus: Prominence manufactured by Shimadzu Corporation Pump: LC-20AT Column oven: CTO-20A Detector: SPD-20A Column: Shim-Pack CLC-ODS (inner diameter 6 mm, length 150 mm) Oven temperature: 50°C Flow rate: 1 mL / min. Mobile phase: (A) 0.2 vol% aqueous acetic acid solution (B) methanol gradient conditions: (B) vol% 0-40 min., 70% → 100% 40-45 min. 100% Sample injection volume: 20 μL Detection wavelength: 280 nm
[0022] <Comparative Example 1> 1500 g (46.86 mol) of methanol and 20.65 g (0.211 mol) of sulfuric acid were added to a 3 L four-necked flask equipped with a stirrer, thermometer, and condenser, and heated to 60°C. 50 g (0.083 mol) of a phenol compound having a hydroxymethyl group represented by chemical formula (B) (compound B) was added and stirred at 60°C for 2 hours. The reaction mixture was then cooled and neutralized by adding aqueous sodium hydroxide solution and aqueous phosphoric acid solution. Methanol was removed by distillation under reduced heat, and 75.0 g of water and 85.0 g of methyl isobutyl ketone (MIBK) were added and stirred. After standing for 30 minutes, the separated aqueous layer was removed. The organic layer was then washed with water multiple times to obtain an organic layer containing the washed compound A. The concentration of compound A in the obtained organic layer was 89.7 area % as a result of the above HPLC analysis. The solvent MIBK was completely distilled off from the flask by distillation under reduced heat to obtain the distillation residue. 56.5 g of methanol was added to the distillation residue obtained at 55°C to obtain a crystallization solution with methanol as the solvent. When the crystallization solution was then cooled to 45°C, no crystals precipitated. Furthermore, when 28.5 g of water was added, oil-out occurred in the crystallization solution, and no crystals of compound A formed, making isolation impossible.
[0023] <Synthesis Example 1> 350 g (10.92 mol) of methanol and 4.0 g (0.041 mol) of sulfuric acid were added to a 1 L four-necked flask equipped with a stirrer, thermometer, and condenser, and heated to 60°C. 50 g (0.083 mol) of a phenol compound having a hydroxymethyl group represented by chemical formula (B) (compound B) was added and stirred at 60°C for 16 hours. The reaction mixture was then cooled and neutralized by adding aqueous sodium hydroxide solution and aqueous phosphoric acid solution. Methanol was removed by distillation under reduced heat, 100.0 g of water and 125.0 g of n-butyl acetate were added, and the mixture was stirred for 30 minutes. After standing, the separated aqueous layer was removed. The organic layer was then washed with water multiple times to obtain an organic layer containing the washed compound A. The concentration of compound A in the obtained organic layer was 84.6 area % as a result of the above HPLC analysis. 75 g of the solvent n-butyl acetate was distilled off the flask by distillation under reduced heat to obtain a concentrated solution. 300 g of n-hexane was added to the concentrated solution obtained at 50°C and cooled to room temperature (the weight ratio of n-butyl acetate to n-hexane in the crystallization solution at this time was 1:6). The crystallization solution was left to stand at room temperature overnight, and the precipitated crystals were filtered off and dried to obtain a powder of compound A crystals.
[0024] <Example 1> 350 g (10.92 mol) of methanol and 4.0 g (0.041 mol) of sulfuric acid were added to a 1 L four-necked flask equipped with a stirrer, thermometer, and condenser, and heated to 60°C. 50 g (0.083 mol) of a phenol compound having a hydroxymethyl group represented by chemical formula (B) (compound B) was added and stirred at 60°C for 16 hours. The reaction mixture was then cooled and neutralized by adding aqueous sodium hydroxide solution and aqueous phosphoric acid solution. Methanol was removed by distillation under reduced heat, 100.0 g of water and 125.0 g of n-butyl acetate were added, and the mixture was stirred for 30 minutes. After standing, the separated aqueous layer was removed. The organic layer was then washed with water multiple times to obtain an organic layer containing the washed compound A. HPLC analysis of the obtained organic layer showed that compound A accounted for 83.3 area %. 115 g of the solvent n-butyl acetate was distilled off the flask by distillation under reduced heat to obtain the distillation residue. To the obtained distillation residue at 50°C, 50 g of isopropyl alcohol (IPA) was added to prepare an IPA solution. Subsequently, 52 g of solvent was distilled off by vacuum distillation, and another 50 g of IPA was added to replace the solvent. To the obtained IPA solution, 0.5 g of the crystals of compound A obtained in Synthesis Example 1 were added as seed crystals, and the mixture was cooled to 25°C over 3 hours. The mixture was then stirred at 25°C for 12.5 hours to precipitate crystals. Subsequently, 100 g of isooctane was mixed over 2 hours, and further crystals precipitated during the 2-hour stirring process (the weight ratio of IPA to isooctane in the crystallization solution at this time was 1:2). The precipitated crystals were filtered off and dried in a rotary evaporator to obtain 42.4 g of compound A crystalline powder (yield 75%). HPLC analysis of the obtained crystals showed that compound A accounted for 82.9 area%. Analysis of the solvent content in the obtained crystals using headspace gas chromatography revealed that IPA was 0.34% by weight and isooctane was 0.1% by weight.
[0025] <Example 2> 350 g (10.92 mol) of methanol and 4 g (0.041 mol) of sulfuric acid were added to a 1 L four-necked flask equipped with a stirrer, thermometer, and condenser, and heated to 60°C. 50 g (0.083 mol) of a phenol compound having a hydroxymethyl group represented by chemical formula (B) (compound B) was added and stirred at 60°C for 16 hours. The reaction mixture was then cooled and neutralized by adding aqueous sodium hydroxide solution and aqueous phosphoric acid solution. Methanol was removed by distillation under reduced heat, 100.0 g of water and 125.0 g of n-butyl acetate were added, and the mixture was stirred for 30 minutes. After standing, the separated aqueous layer was removed. The organic layer was then washed with water multiple times to obtain an organic layer containing the washed compound A. HPLC analysis of the obtained organic layer showed that compound A accounted for 83.3 area %. 115 g of the solvent n-butyl acetate was distilled off the flask by distillation under reduced heat to obtain the distillation residue. An n-butanol solution was prepared by adding 50 g of n-butanol to the distillation residue obtained at 50°C. Subsequently, 52 g of solvent was distilled off by vacuum distillation, and another 50 g of n-butanol was added to replace the solvent. To the obtained n-butanol solution, 0.5 g of the crystals of compound A obtained in Synthesis Example 1 were added as seed crystals, and the mixture was cooled to 25°C over 3 hours. The mixture was then stirred at 25°C for 12.5 hours to precipitate crystals. Subsequently, 100 g of isooctane was mixed over 2 hours and stirred for 2 hours. A further 25 g of isooctane was then mixed and stirred for 10 minutes to precipitate more crystals (the weight ratio of n-butanol to isooctane in the crystallization solution at this time was 1:2.5). The precipitated crystals were filtered off and dried in a rotary evaporator to obtain 42.4 g of powdered compound A crystals (yield 72%). HPLC analysis of the obtained crystals showed that compound A accounted for 82.9 area%. Analysis of the solvent content in the obtained crystals using headspace gas chromatography revealed that n-butanol was 0.48% by weight and isooctane was 0.01% by weight.
[0026] According to the present invention, it has become clear that not only can compound A be obtained in crystalline form, but crystallization proceeds rapidly, and crystals of compound A can be produced in high yield.
Claims
1. A method for producing crystals of a phenol compound having a methoxymethyl group represented by chemical formula (A), comprising a crystallization step of precipitating crystals from a solution containing a phenol compound having a methoxymethyl group represented by chemical formula (A) and a chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms.
2. The manufacturing method according to claim 1, wherein the chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms is isopropyl alcohol or n-butanol.
3. The manufacturing method according to claim 1, wherein the crystallization step is either (1) a crystallization step in which crystals are precipitated from a solution containing a phenol compound having a methoxymethyl group represented by chemical formula (A) and a chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms, and then an aliphatic hydrocarbon solvent having 5 to 10 carbon atoms is mixed into the solution containing the crystals to precipitate further crystals, or (2) a crystallization step in which crystals are precipitated from a solution containing a phenol compound having a methoxymethyl group represented by chemical formula (A), a chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms, and an aliphatic hydrocarbon solvent having 5 to 10 carbon atoms.
4. The manufacturing method according to claim 3, wherein the aliphatic hydrocarbon solvent having 5 to 10 carbon atoms is a chain-like aliphatic hydrocarbon solvent having 5 to 10 carbon atoms.
5. The manufacturing method according to claim 3, wherein the chain-like aliphatic alcohol solvent having 3 to 5 carbon atoms is isopropyl alcohol or n-butanol, and the aliphatic hydrocarbon solvent having 5 to 10 carbon atoms is isooctane.