Method for producing aromatic ketone

Abstract

A method for producing an aromatic ketone represented by formula (1), said method comprising a reaction step in which a compound represented by formula (2) is reacted in the presence of a sulfonic acid to obtain the aromatic ketone, wherein the sulfonic acid includes at least one sulfonic acid selected from the group consisting of C1-3 alkyl sulfonic acids and C1-3 fluoroalkyl sulfonic acids. (In formulas (1) and (2), R1 and R2 each independently represent a C1-6 hydrocarbon group.)

Description

Method for producing aromatic ketones

[0001] The present disclosure relates to a method for producing aromatic ketones.

[0002] Aromatic ketones are useful compounds as raw materials for pharmaceuticals, agricultural chemicals, and various chemical products. Known examples of aromatic ketones include apocynin (4'-hydroxy-3'-methoxyacetophenone). Patent Document 1 discloses a tear film stabilizer containing apocynin.

[0003] On the other hand, Non-Patent Document 1 discloses a method for producing aromatic ketones such as apocynin, in which an acetyl group is introduced into the 4-position of an aromatic ring using a phenol such as guaiacol (2-methoxyphenol) as a raw material.

[0004] International Publication No. 2022 / 065436

[0005] Boodida, S. et al. , Asian J. Chem. 2022, 34, 1245-1254.

[0006] However, when the present inventors examined the production method disclosed in Non-Patent Document 1, they found that there was room for improvement in the yield of the target aromatic ketone. An object of the present disclosure is to provide a method for producing an aromatic ketone that is excellent in the yield of the target product.

[0007] The present disclosure is configured as follows: [1] A method for producing an aromatic ketone represented by the following formula (1), comprising a reaction step of reacting a compound represented by the following formula (2) in the presence of a sulfonic acid to obtain the aromatic ketone, wherein the sulfonic acid comprises one or more sulfonic acids selected from the group consisting of alkylsulfonic acids having 1 to 3 carbon atoms and fluoroalkylsulfonic acids having 1 to 3 carbon atoms. (In formula (1) and formula (2), R １ and R ２each independently represents a hydrocarbon group having 1 to 6 carbon atoms.) [2] The method for producing an aromatic ketone according to [1], comprising a purification step of purifying the mixed solution obtained in the reaction step, wherein the purification step comprises a precipitation step A of precipitating the aromatic ketone, wherein the precipitation step A comprises: adding the mixed solution dropwise to an aqueous potassium hydroxide solution to precipitate the aromatic ketone; or adding an aqueous potassium hydroxide solution dropwise to the mixed solution to precipitate the aromatic ketone. [3] The method for producing an aromatic ketone according to [2], comprising a treatment step of treating the aromatic ketone obtained in the precipitation step A with activated carbon. [4] The method for producing an aromatic ketone according to [2] or [3], wherein the purification step comprises a recrystallization step of recrystallizing the aromatic ketone. [5] The method for producing an aromatic ketone according to any of [1] to [4], comprising an acylation step of acylating a hydroxyl group in a compound represented by the following formula (3) to obtain the compound represented by formula (2): (In formula (3), R １ represents a hydrocarbon group having 1 to 6 carbon atoms.) [6] The method for producing an aromatic ketone according to [5], wherein the acylation step is a step of reacting the compound represented by formula (3) with acetic anhydride in the presence of one or more selected from the group consisting of sulfonic acids and sulfuric acid, and the sulfonic acids include one or more sulfonic acids selected from the group consisting of alkylsulfonic acids having 1 to 3 carbon atoms and fluoroalkylsulfonic acids having 1 to 3 carbon atoms.

[0008] According to the present disclosure, a method for producing an aromatic ketone is provided that provides an excellent yield of the target product.

[0009] The present disclosure will be described in detail below, but is not limited to the following description. The expressions "XX or more and YY or less" and "XX to YY" that represent a numerical range mean a numerical range including the lower and upper limits, which are the endpoints, unless otherwise specified. When a numerical range is described in stages, the upper and lower limits of each numerical range can be combined in any way.

[0010] The present disclosure relates to a method for producing an aromatic ketone represented by the following formula (1), which includes a reaction step of reacting a compound represented by the following formula (2) in the presence of a sulfonic acid to obtain the aromatic ketone, wherein the sulfonic acid comprises one or more sulfonic acids selected from the group consisting of alkylsulfonic acids having 1 to 3 carbon atoms and fluoroalkylsulfonic acids having 1 to 3 carbon atoms. (In formula (1) and formula (2), R １ and R ２ each independently represents a hydrocarbon group having 1 to 6 carbon atoms.

[0011] The present inventors produced an aromatic ketone represented by the above formula (1) using the production method disclosed in Non-Patent Document 1, and found that the yield of the aromatic ketone represented by the above formula (1) was low. This is thought to be due to the structure of the raw material and the structure of the aromatic ketone represented by the above formula (1). In the production method disclosed in Non-Patent Document 1, the target product is thought to be obtained by Fries rearrangement. However, in this production method, the Fries rearrangement does not proceed sufficiently, and the yield of the target product is thought to be low.

[0012] As a result of extensive investigations, the present inventors have found that the method for producing an aromatic ketone according to the present disclosure can solve the above-mentioned problems. Specific features of the method are described below.

[0013] The method for producing an aromatic ketone according to the present disclosure is a method for producing an aromatic ketone represented by the following formula (1). In formula (1), R １ and R ２ each independently represents a hydrocarbon group having 1 to 6 carbon atoms (preferably 1 to 3, more preferably 1).

[0014] The hydrocarbon group is not particularly limited, and examples thereof include an alkyl group and a phenyl group, with an alkyl group being preferred. The alkyl group may be linear or branched. For example, R １ and R ２ When R is an alkyl group having one carbon atom, the aromatic ketone represented by the above formula (1) is apocynin. Apocynin is a compound useful as a raw material for pharmaceuticals, agricultural chemicals, and various chemical products.

[0015] (Reaction Step) The method for producing an aromatic ketone includes a reaction step of reacting a compound represented by the following formula (2) in the presence of a sulfonic acid to obtain an aromatic ketone represented by the above formula (1). In formula (2), R １ and R ２ R each independently represents a hydrocarbon group having 1 to 6 carbon atoms (preferably 1 to 3, more preferably 1). １ and R ２ The formula (1) can be used as described in the explanation section.

[0016] The sulfonic acid includes one or more sulfonic acids selected from the group consisting of alkylsulfonic acids having 1 to 3 carbon atoms and fluoroalkylsulfonic acids having 1 to 3 carbon atoms. By reacting the compound represented by formula (2) in the presence of such a sulfonic acid, the Fries rearrangement proceeds efficiently, and the aromatic ketone represented by formula (1) is obtained in good yield. Examples of alkylsulfonic acids having 1 to 3 carbon atoms include methanesulfonic acid, ethanesulfonic acid, 1-propanesulfonic acid, and 2-propanesulfonic acid. Of these, methanesulfonic acid is preferred. Examples of fluoroalkylsulfonic acids having 1 to 3 carbon atoms include trifluoromethanesulfonic acid, difluoromethanesulfonic acid, monofluoromethanesulfonic acid, 2,2,2-trifluoroethanesulfonic acid, and heptafluoropropanesulfonic acid. Of these, trifluoromethanesulfonic acid is preferred.

[0017] Among the above, trifluoromethanesulfonic acid is particularly preferred. The use of trifluoromethanesulfonic acid improves the regioselectivity of the reaction and suppresses the production of by-products. Furthermore, the coloring of the resulting aromatic ketone is reduced. Furthermore, since trifluoromethanesulfonic acid is particularly excellent in reactivity, the amount of sulfonic acid used can be reduced.

[0018] The amount of sulfonic acid at the start of the reaction step is not particularly limited, but is preferably 100 to 2000 mL, and more preferably 500 to 1500 mL, per 100 g of the compound represented by formula (2). Furthermore, when the sulfonic acid includes trifluoromethanesulfonic acid, the amount of trifluoromethanesulfonic acid at the start of the reaction step is not particularly limited, but is preferably 1 to 20 molar parts, more preferably 1 to 10 molar parts, and even more preferably 1 to 5 molar parts, per 1 molar part of the compound represented by formula (2).

[0019] A solvent may be used in the reaction step. The reaction step may be a step of reacting a compound represented by formula (2) in a solvent in the presence of a sulfonic acid to obtain an aromatic ketone represented by formula (1). While the sulfonic acid is preferably used as the solvent, other solvents may also be used. Examples of other solvents include, but are not limited to, one or more solvents selected from the group consisting of dichloroethane, tetrachloroethane, toluene, chlorobenzene, and acetonitrile. Of these, one or more solvents selected from the group consisting of dichloroethane, toluene, and chlorobenzene are preferred. The amount of other solvent is also not particularly limited, but may be 100 to 2500 mL, 150 to 1000 mL, or 200 to 800 mL per 100 g of the compound represented by formula (2). It is particularly preferred to use the sulfonic acid as the solvent without using any other solvent. In this case, the compound represented by formula (2) reacts with the sulfonic acid, resulting in so-called neat reaction conditions. Under such reaction conditions, the reaction efficiency is likely to be improved.

[0020] The temperature in the reaction step is not particularly limited, but is preferably 40 to 70°C, more preferably 40 to 60°C. The time for the reaction step is not particularly limited, but may be, for example, 1 to 24 hours, preferably 3 to 7 hours, more preferably 3 to 6 hours. The pressure in the reaction step is not particularly limited, but may be, for example, 1.0 x 10 ４ ~1.0 x 10 ６ Pa, and 5.0×10 ４ ~5.0 x 10 ５Pa is preferable. Particularly preferable is 1.0×10 ５ The reaction atmosphere in the reaction step is not particularly limited, but is preferably an inert gas atmosphere such as nitrogen gas. When the sulfonic acid includes trifluoromethanesulfonic acid, the temperature in the reaction step can be 0 to 40°C, preferably 0 to 30°C, since trifluoromethanesulfonic acid has particularly excellent reactivity. The reaction time can be 10 minutes to 3 hours, preferably 10 minutes to 1 hour.

[0021] The compound represented by the above formula (2) may be a commercially available product, or a compound obtained by the acylation step described below may be used.

[0022] According to the method for producing an aromatic ketone of the present disclosure, the aromatic ketone represented by the above formula (1) can be obtained in high yield. The yield of the aromatic ketone may be, for example, 50.0 to 100.0%, preferably 60.0 to 100.0%, more preferably 63.0 to 100.0%, and even more preferably 65.0 to 100.0%. The yield of the aromatic ketone is measured as the isolated yield or HPLC yield. In the case of the HPLC yield, HPLC is measured under the conditions described in the purity column below.

[0023] <Purification Step> The method for producing the aromatic ketone represented by formula (1) preferably includes a purification step of purifying the mixed solution obtained in the reaction step. By including the purification step, the aromatic ketone represented by formula (1) can be obtained with high purity. As the purification step, a known purification step can be used, but it is preferred that the purification step includes the following precipitation step A or the following recrystallization step.

[0024] (Precipitation Step A) The purification step preferably includes a precipitation step A in which the aromatic ketone represented by formula (1) is precipitated. The precipitation step A is not particularly limited as long as it can precipitate the aromatic ketone, but is preferably a step in which the mixed solution obtained in the reaction step is dropped into an alkaline aqueous solution to precipitate the aromatic ketone represented by formula (1), or a step in which an alkaline aqueous solution is dropped into the mixed solution obtained in the reaction step to precipitate the aromatic ketone represented by formula (1). In the precipitation step A, hydroxide ions contained in the alkaline aqueous solution are neutralized with the acid derived from the sulfonic acid used in the reaction step. Therefore, heat of neutralization is generated. From the viewpoint of making it easier to control the temperature of the mixed solution in the precipitation step A, the precipitation step A is preferably a step in which the mixed solution obtained in the reaction step is dropped into an alkaline aqueous solution to precipitate the aromatic ketone represented by formula (1).

[0025] The alkaline aqueous solution is not particularly limited, and for example, a sodium hydroxide aqueous solution or a potassium hydroxide aqueous solution can be used. Among these, a potassium hydroxide aqueous solution is preferred. When a potassium hydroxide aqueous solution is used, precipitation of a gel-like substance does not occur in the precipitation step A, and the precipitation step A can be carried out suitably. When a sodium hydroxide aqueous solution is used, precipitation of a gel-like substance may occur in the precipitation step A.

[0026] The alkali concentration of the alkaline aqueous solution is not particularly limited and may be 5 to 10 M (mol / L), preferably 7 to 9 M. The alkaline aqueous solution preferably contains an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran or cyclopentyl methyl ether, or a ketone solvent such as acetone or methyl isobutyl ketone. It is more preferable that the alkaline aqueous solution contains one or more selected from the group consisting of alcohol solvents and ketone solvents, and preferably contains an alcohol solvent or a ketone solvent. The alcohol solvent is more preferably ethanol. Furthermore, the ketone solvent is more preferably acetone. The inclusion of an ethanol solvent or a ketone solvent makes it easier for the aromatic ketone to precipitate and for impurities to dissolve. As a result, it becomes easier to obtain an aromatic ketone represented by formula (1) with higher purity. The content of the alcohol solvent in the alkaline aqueous solution is not particularly limited and may be 100 to 1,000 mL, 150 to 750 mL, or 200 to 500 mL per 100 g of the aromatic ketone represented by formula (1). The content of the ketone solvent in the alkaline aqueous solution is not particularly limited, but may be 10 to 150 mL, 20 to 140 mL, or 30 to 130 mL per 100 g of the aromatic ketone represented by formula (1).

[0027] The temperature of the precipitation step A is not particularly limited, but may be, for example, 10 to 30°C. By setting the temperature within this range, the aromatic ketone is more likely to precipitate and impurities are more likely to dissolve. As a result, the aromatic ketone represented by formula (1) with higher purity is more likely to be obtained. The temperature of the precipitation step A refers to the temperature of the alkaline aqueous solution, for example, when the precipitation step A is a step of dropping the mixed solution obtained in the reaction step into an alkaline aqueous solution to precipitate the aromatic ketone represented by formula (1). Furthermore, when the precipitation step A is a step of dropping the alkaline aqueous solution into the mixed solution obtained in the reaction step to precipitate the aromatic ketone represented by formula (1), the temperature refers to the temperature of the mixed solution. The duration of the precipitation step A is not particularly limited, but may be, for example, 10 minutes to 3 hours, and preferably 30 minutes to 1 hour. Within the above range, the temperature of the precipitation step can be easily adjusted to the above range. The atmosphere in the precipitation step A is not particularly limited, but an inert gas atmosphere such as nitrogen gas is preferred.

[0028] (Recrystallization Step) The purification step preferably includes a recrystallization step of recrystallizing the aromatic ketone represented by formula (1). By including the recrystallization step, a highly pure aromatic ketone represented by formula (1) can be obtained. The recrystallization step is not particularly limited, but preferably includes a step of dissolving the aromatic ketone represented by formula (1) in a solvent to obtain a solution, and a precipitation step B of precipitating the aromatic ketone represented by formula (1) from the solution. By including such steps, crystals of the aromatic ketone represented by formula (1) can be obtained by the recrystallization step. The solvent is not particularly limited, but a mixed solution of ethanol / ion-exchanged water or a mixed solution of acetone / ion-exchanged water is preferred. The ratio of the mixed solution is not particularly limited as long as it can suitably recrystallize the aromatic ketone represented by formula (1). In the case of a mixed solution of ethanol / ion-exchanged water, the volume ratio of ethanol / ion-exchanged water is preferably 4 / 6 to 9 / 1, and more preferably 6 / 4 to 8 / 2. The volume ratio of acetone / ion-exchanged water is preferably 1 / 9 to 8 / 2, and more preferably 2 / 8 to 7 / 3.

[0029] In the step of obtaining a solution, the temperature of the solution is preferably 50 to 70°C, more preferably 55 to 65°C. When a mixed solution of acetone / ion-exchanged water is used, the temperature of the solution may be 40 to 60°C, or may be 45 to 55°C. By setting the temperature of the solution within the above range, the aromatic ketone is more easily precipitated in the precipitation step B. In the step of obtaining a solution, the aromatic ketone represented by formula (1) is preferably the aromatic ketone represented by formula (1) precipitated in the above precipitation step A.

[0030] The precipitation step B of precipitating the aromatic ketone represented by formula (1) from the solution is preferably a step of lowering the temperature of the solution to precipitate the aromatic ketone represented by formula (1). For example, the temperature of the solution is preferably lowered to 3 to 30°C, more preferably to 3 to 15°C, and even more preferably to 3 to 10°C. Within the above range, the aromatic ketone represented by formula (1) is likely to precipitate.

[0031] Furthermore, it is preferable that the recrystallization step further includes an aging step in which the crystals of the aromatic ketone represented by formula (1) are aged. By including the aging step, the yield of the aromatic ketone represented by formula (1) is likely to be improved. The aging step can be carried out, for example, by stirring the solution (slurry) at the reduced temperature for a desired period of time after the precipitation step B. The time for the aging step is not particularly limited, but may be, for example, 0.1 to 2 hours, and preferably 0.5 to 1 hour. It is also preferable that the temperature of the solution in the aging step is equal to or lower than the temperature of the solution in the precipitation step B. For example, the temperature of the solution in the aging step may be 0 to 10°C, or 0 to 8°C.

[0032] The aromatic ketone represented by formula (1) obtained in the precipitation step A or the recrystallization step can be isolated through a known process, for example, a filtration step of filtering out the aromatic ketone, a washing step of washing the aromatic ketone, and a drying step of drying the aromatic ketone.

[0033] (Treatment Step) The method for producing an aromatic ketone represented by formula (1) preferably includes a treatment step of treating the aromatic ketone represented by formula (1) obtained in the precipitation step A with activated carbon. In the production method of the present disclosure, the product may be slightly brown. This is thought to be due to the influence of trace amounts of by-products. Even in such cases, the treatment step can change the color of the product to the color of the aromatic ketone represented by formula (1). For example, if the aromatic ketone represented by formula (1) is brown, the treatment step can change the color of the product to white. The activated carbon used is not particularly limited, and powdered activated carbon, granular activated carbon, etc. can be used, but powdered activated carbon is preferred. Examples of activated carbon include steam activated carbon and zinc chloride carbon, with zinc chloride carbon being preferred. Commercially available zinc chloride carbon can be used, but preferred are, for example, Tokusei Shirasagi (manufactured by Osaka Gas Chemicals Co., Ltd.) and activated carbon, powder (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.).

[0034] The treatment step may be, for example, a step of dissolving the aromatic ketone represented by formula (1) obtained in the precipitation step A in a solvent to obtain a solution, and then adding powdered activated carbon to the solution and stirring the mixture. The method of obtaining a solution by dissolving in a solvent can be the step of dissolving the aromatic ketone represented by formula (1) in a solvent to obtain a solution, as described in the section explaining the recrystallization step. The type and amount of the solvent are also the same. The amount of activated carbon is not particularly limited, but can be 1 to 30 parts by mass, 2 to 20 parts by mass, or 5 to 15 parts by mass per 100 parts by mass of the aromatic ketone represented by formula (1).

[0035] The temperature in the treatment step is not particularly limited, but is preferably 40 to 80° C., and more preferably 50 to 70° C. When a mixed solution of acetone / ion-exchanged water is used, the temperature of the solution is preferably 40 to 70° C., and more preferably 40 to 60° C. The time for the treatment step is not particularly limited, but may be, for example, 1 minute to 2 hours, and is preferably 5 minutes to 1 hour.

[0036] By carrying out the purification process as described above, a highly pure aromatic ketone represented by formula (1) can be obtained. For example, when the aromatic ketone is in powder form, the purity of the aromatic ketone may be 98.0 to 100.0%, preferably 99.0 to 100.0%, more preferably 99.5 to 100.0%, and even more preferably 99.9 to 100.0%. The purity of the aromatic ketone is measured using HPLC purity. That is, the above percentages indicate area %. Specifically, the measurement is carried out under the following conditions:

[0037] Measuring equipment: LC-2010CHT (manufactured by Shimadzu Corporation) Column: L-column 2 ODS, 4.6 x 150 mm, S-5 μm Mobile phase A: H ３ P.O. ４ / H ２ O (1 / 1000, v / w) Mobile phase B: Acetonitrile Flow Rate: 1.0 mL / min Column temperature: 25°C Detection: 220 nm Injection Volume: 10 μL Analytical Time: 30 min Gradient Program: 0 min... A; 95%, B; 5% 15 min... A; 10%, B; 90% 20 min... A; 10%, B; 90% 22 min... A; 95%, B; 5% 30 min... A; 95%, B; 5% Diluent: Water / acetonitrile (3 / 7)

[0038] (Acylation Step) The method for producing the aromatic ketone represented by formula (1) preferably includes an acylation step of acylating a hydroxyl group in a compound represented by the following formula (3) to obtain a compound represented by formula (2). In formula (3), R １ represents a hydrocarbon group having 1 to 6 carbon atoms (preferably 1 to 3, more preferably 1). １The formula (1) can be used as described in the explanation section.

[0039] As described above, the compound represented by formula (2) can be obtained by the acylation step. Although known acylation steps can be used, a step in which the compound represented by formula (3) is reacted with acetic anhydride in the presence of one or more selected from the group consisting of sulfonic acid and sulfuric acid is preferred. The acylation step is preferably a step in which the compound represented by formula (3) is reacted with acetic anhydride in the presence of sulfonic acid or sulfuric acid, and more preferably a step in which the compound represented by formula (3) is reacted with acetic anhydride in the presence of sulfonic acid. Furthermore, the sulfonic acid preferably contains one or more sulfonic acids selected from the group consisting of alkylsulfonic acids having 1 to 3 carbon atoms and fluoroalkylsulfonic acids having 1 to 3 carbon atoms. As the sulfonic acid, those described in the description of the reaction step above can be used.

[0040] A solvent may be used in the acylation step. The acylation step may be a step in which a hydroxyl group in a compound represented by the above formula (3) is acylated in a solvent to obtain a compound represented by formula (2). While it is preferable to use the above sulfonic acid as the solvent, other solvents may also be used. As other solvents, those described in the description of the reaction step may be used. Furthermore, like the reaction step, the acylation step may be carried out under so-called neat reaction conditions.

[0041] Furthermore, the acylation step may be a step prior to the reaction step, or may be a step performed simultaneously with the reaction step. For example, the reaction step may be performed sequentially after the completion of the acylation step. That is, after the acylation step is completed, the reaction step may be performed in the same reaction vessel. For example, the materials for the acylation step may be placed in a reaction vessel, the acylation step may be performed, and then the materials for the reaction step may be added to the reaction vessel and the reaction step may be performed. That is, the production method of the present disclosure may be a so-called one-pot reaction. Furthermore, the acylation step may be performed simultaneously with the reaction step. When the acylation step is a step performed in the presence of sulfonic acid, in the production method of the present disclosure, some of the materials used in the reaction step and the materials used in the acylation step are the same. Therefore, the acylation step can be performed simultaneously with the reaction step. When the acylation step is performed simultaneously with the reaction step, it is preferable to obtain the aromatic ketone represented by the above formula (1) by reacting, for example, a compound represented by the above formula (3) with acetic anhydride and sulfonic acid.

[0042] The amount of acetic anhydride at the start of the acylation step is not particularly limited, and is preferably 100 to 150 parts by mole, more preferably 100 to 130 parts by mole, and even more preferably 100 to 120 parts by mole, relative to 100 parts by mole of the compound represented by formula (3).

[0043] When the acylation step is a step of reacting the compound represented by the above formula (3) with acetic anhydride in the presence of sulfuric acid, the amount of sulfuric acid at the start of the acylation step is not particularly limited, and is preferably 1 to 10 molar parts, more preferably 2 to 8 molar parts, and even more preferably 3 to 7 molar parts, relative to 100 molar parts of the compound represented by the above formula (3).

[0044] The temperature of the acylation step is not particularly limited, but may be 20 to 70°C, preferably 20 to 60°C, and more preferably 20 to 40°C. When the acylation step is carried out simultaneously with the reaction step, the temperature may be set at the temperature described in the above-mentioned section describing the reaction step. The time for the acylation step is not particularly limited, but is preferably, for example, 10 minutes to 1 hour. When the acylation step is carried out simultaneously with the reaction step, the time may be set at the time described in the above-mentioned section describing the reaction step. The pressure in the acylation step is not particularly limited, but may be, for example, 1.0 x 10 ４ ~1.0 x 10 ６ Pa, and 5.0×10 ４ ~5.0 x 10 ５ Pa is preferable. Particularly preferable is 1.0×10 ５ The reaction atmosphere in the acylation step is not particularly limited, but an inert gas atmosphere such as nitrogen gas is preferred.

[0045] The present disclosure will be described in more detail below using examples. The present disclosure is not limited to these examples. In addition, hereinafter, the term "parts" refers to "parts by mass" unless otherwise specified.

[0046] Example 1 To 1 molar part of isolated and purified 2-methoxyphenyl acetate, methanesulfonic acid (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added so that the concentration was 1,000 mL per 100 g of 2-methoxyphenyl acetate. The reaction was then carried out for 5 hours at 50°C under a nitrogen stream. The solution after the reaction was analyzed using HPLC, and the yield was measured. As a result, the yield of apocynin was 69.4%. Additionally, the compound represented by the following formula (C) (yield: 17.8%) and guaiacol (yield: 9.91%) were obtained as by-products.

[0047] Example 2 Apocynin was synthesized and the yield was measured in the same manner as in Example 1, except that 1.5 molar parts of acetic acid (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was further added dropwise to the mixed solution of 2-methoxyphenyl acetate and methanesulfonic acid. As a result, the yield of apocynin was 75.0%. In addition, the compound represented by the above formula (C) (yield: 18.9%) and guaiacol (yield: 3.00%) were obtained as by-products.

[0048] Comparative Example 1 Apocynin was produced using the method described in Non-Patent Document 1. The reaction scheme is shown below. In the reaction scheme, Ac ２ O represents acetic anhydride, AcOH represents acetic acid, Me represents a methyl group, and Ac represents an acetyl group. The solution after the reaction was analyzed using HPLC, and the yield was measured. The yield of apocynin obtained was 29.4%. In addition, the compound represented by formula (A) above (yield: 4.63%) and the compound represented by formula (B) above (2-methoxyphenyl acetate, yield: 27.3%) were obtained as by-products. Thus, the yield of apocynin was low, and a large amount of by-products was produced. In addition, the yield of guaiacol was 16.7%, and a large amount of the raw material guaiacol remained.

[0049] Comparative Example 2 To 1 molar part of guaiacol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.), 1.5 molar parts of acetic acid (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were added, and polyphosphoric acid (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added so that the total volume was 1000 mL per 100 g of guaiacol. The reaction was then carried out at 90°C for 1 hour under a nitrogen stream. The solution after the reaction was analyzed using HPLC, and the yield was measured. As a result, the yield of apocynin was 39.1%. Furthermore, a compound represented by the following formula (C) (yield: 5.00%) was obtained as a by-product. As such, the yield of apocynin was low, and a large amount of by-products was generated. The raw material guaiacol was almost completely consumed, and the yield of guaiacol was 0.13%. The reaction formula is shown below. In the reaction formula, AcOH represents acetic acid. Furthermore, Me represents a methyl group. Furthermore, 10 v / w indicates that the amount of polyphosphoric acid per 1 g of substrate is 10 mL.

[0050] Comparative Examples 3 and 4 Apocynin was synthesized in the same manner as in Comparative Example 2, except that phosphoric acid (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) and sulfuric acid (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were used instead of polyphosphoric acid. As a result, apocynin was not produced.

[0051] Example 3 To 1 molar part of guaiacol, 1.1 molar parts of acetic anhydride (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) and 0.1 molar parts of sulfuric acid (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were added. The mixture was then stirred for 30 minutes at 25°C under a nitrogen stream. The post-reaction solution at this point was analyzed using HPLC, and the yield was measured. As a result, apocynin was not produced. On the other hand, the compound represented by formula (B) above (2-methoxyphenyl acetate) was obtained in a yield of 96.8%. Subsequently, methanesulfonic acid (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added to a concentration of 1000 mL per 100 g of guaiacol. The reaction was then carried out for 3 hours at 50°C under a nitrogen stream. The post-reaction solution was analyzed using HPLC, and the yield was measured. As a result, the yield of apocynin was 73.2%. Furthermore, as by-products, the compound represented by the above formula (B) (yield: 0.40%) and the compound represented by the above formula (C) (yield: 18.2%) were obtained.

[0052] [Example 4] Methanesulfonic acid (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added to 1 molar part of guaiacol so that the total volume was 1000 mL per 100 g of guaiacol. 1.1 molar parts of acetic anhydride (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was then added dropwise. The mixture was then stirred at 25°C for 45 minutes under a nitrogen stream. The reaction was then carried out at 50°C for 3 hours under a nitrogen stream. The solution after the reaction was analyzed using HPLC, and the yield was measured. As a result, the yield of apocynin was 74.7%. Furthermore, as by-products, the compound represented by the above formula (B) (yield: 0.20%) and the compound represented by the above formula (C) (yield: 18.3%) were obtained.

[0053] Example 5 Apocynin was synthesized and the yield was measured in the same manner as in Example 4, except that the stirring at 25°C for 45 minutes was not performed. As a result, the yield of apocynin was 73.1%. In addition, the compound represented by the above formula (B) (yield: 0.31%) and the compound represented by the above formula (C) (yield: 18.5%) were obtained as by-products.

[0054] Example 6 Apocynin was synthesized and the yield was measured in the same manner as in Example 1, except that trifluoromethanesulfonic acid was used instead of methanesulfonic acid and the reaction was carried out at 25°C for 0.5 hours. As a result, the yield of apocynin was 79.0%. In addition, a compound represented by formula (C) (yield: 18.4%) was obtained as a by-product.

[0055] Example 7 Apocynin was synthesized and the yield was measured in the same manner as in Example 1, except that the amount of methanesulfonic acid was 5 molar parts, dichloromethane (500 mL per 100 g of 2-methoxyphenyl acetate) was further added as a solvent, and the reaction was carried out at 50° C. for 24 hours. The yield is shown in Table 1.

[0056] [Examples 8 to 14, Comparative Examples 5 to 6] Apocynin was synthesized and the yield was measured in the same manner as in Example 7, except that the type of solvent used, the type and amount of acid, and the reaction conditions were changed as shown in Table 1. The yields are shown in Table 1. In the table, DCE represents dichloroethane, PhCl represents chlorobenzene, MeCN represents acetonitrile, MsOH represents methanesulfonic acid, TfOH represents trifluoromethanesulfonic acid, and p-TsOH.H ２ O represents paratoluenesulfonic acid, (±)-CSA represents (±)-camphorsulfonic acid, and formula (C) represents a compound represented by formula (C). In the reaction conditions column, 0-25 indicates that the reaction was carried out according to the following procedure.

[0057] A mixed solution of 2-methoxyphenyl acetate and a solvent was prepared, and the acid was added little by little while maintaining the temperature at 0° C. After the acid addition was completed, the temperature was raised to 25° C. and the reaction was carried out for the time shown in Table 1.

[0058] Example 15 Isolation of apocynin crystals was carried out according to the following procedure. The post-reaction solution of Example 5 was added dropwise to an 8M aqueous potassium hydroxide solution containing ethanol. Here, the amount of ethanol contained in the 8M aqueous potassium hydroxide solution was 200 mL per 100 g of guaiacol (raw material), and the amount of the 8M aqueous potassium hydroxide solution was 2000 mL per 100 g of guaiacol (raw material). Crystals precipitated during the dropwise addition. After the dropwise addition, the mixture was stirred and aged until the crystals had grown sufficiently, and then filtered. The obtained crystals were analyzed using HPLC to measure the purity of the crystals and the amount of by-products in the crystals. As a result, the purity of apocynin was 98.6 area%. Furthermore, the amount of the by-product, the compound represented by formula (C), was 0.61 area%. The isolation yield of the obtained crystals was 61.3%.

[0059] Example 16: Apocynin crystals were isolated in the same manner as in Example 15, except that the post-reaction solution of Example 5 was added dropwise to a 6 M aqueous sodium hydroxide solution containing ethanol, and the purity of the crystals and the amount of by-products in the crystals were measured. The amounts of ethanol and 6 M aqueous sodium hydroxide contained in the 6 M aqueous sodium hydroxide solution were the same as in Example 15. As a result, the purity of apocynin was 99.0 area%. Furthermore, the amount of the by-product, the compound represented by formula (C), was 0.54 area%. The isolation yield of the obtained crystals was 62.6%. During the dropwise addition, precipitation of a gel-like substance occurred, temporarily making stirring difficult, but the gel-like substance gradually dissolved as the dropwise addition to the reaction solution proceeded. Therefore, the gel-like substance was presumed to be a salt generated by neutralization.

[0060] [Reference Example 1] Apocynin crystals were isolated in the same manner as in Example 15, except that the post-reaction solution of Example 5 was added dropwise to ion-exchanged water containing ethanol, and the purity of the crystals and the amount of by-products in the crystals were measured. The amount of ethanol contained in the ion-exchanged water was 100 mL per 100 g of the raw material guaiacol, and the amount of ion-exchanged water containing ethanol was 2000 mL per 100 g of the raw material guaiacol. As a result, the purity of apocynin was 98.9 area%. In addition, the amount of the by-product, the compound represented by formula (C), was 0.26 area%. The isolation yield of the obtained crystals was 46.6%. When neutralization was not performed, crystallization of the target product did not proceed very well. This is presumably due to, for example, methanesulfonic acid in the crystallization solution acting as a good solvent and inhibiting crystallization of the target product, or the low pH of the crystallization solution.

[0061] Example 17: To further purify the apocynin obtained in Example 15, recrystallization was performed. 1.0 g of the apocynin obtained in Example 15 and 2 mL of a mixed solution of ethanol / ion-exchanged water (volume ratio 7 / 3) were weighed out to obtain a mixed solution. Subsequently, the mixed solution was heated to 60°C under a nitrogen stream to dissolve the apocynin. The color of the mixed solution at this time was red. Subsequently, 0.1 g of activated carbon (trade name: Tokusei Shirasagi, manufactured by Osaka Gas Chemicals Co., Ltd.) was added, and the mixture was stirred for 15 minutes while maintaining the temperature at 60°C to perform activated carbon treatment. The stirred mixture was filtered to remove the activated carbon. The filtered activated carbon was washed with 1 mL of a mixed solution of ethanol / ion-exchanged water (volume ratio 7 / 3). Subsequently, the filtrate was heated to 60°C, and 3.3 mL of ion-exchanged water was added dropwise. At this point, apocynin had not crystallized. The color of the mixed solution at this time was yellow. The filtrate was further cooled to 25°C, whereupon apocynin crystallized to give a slurry. The slurry was stirred at 25°C for 0.5 hours, followed by stirring at 5°C for 1 hour to mature the crystals. The resulting crystals were collected by filtration and washed with 3 mL of a pre-cooled mixed solution of ethanol / ion-exchanged water (volume ratio 1 / 4). After washing, the crystals were dried under reduced pressure at 50°C for 18 hours to give apocynin. The yield of apocynin was 90.8%, and the HPLC purity of apocynin was 99.9 area%. The resulting apocynin was white.

[0062] [Example 18] Apocynin was recrystallized in the same manner as in Example 17, except that activated carbon treatment was not performed. As a result, the yield of apocynin was 92.2%, and the HPLC purity of apocynin was 99.9 area%. The obtained apocynin was slightly brown. The yield of apocynin was higher than in Example 17, but this is thought to be due to the fact that activated carbon treatment in Example 17 resulted in equipment adhesion loss.

[0063] Example 19 Based on the results of the above study, the synthesis method was scaled up to confirm its validity. (Synthesis Example of Apocynin) 50.0 g of guaiacol (Fujifilm Wako Pure Chemical Industries, Ltd.) and 500 mL of methanesulfonic acid (Fujifilm Wako Pure Chemical Industries, Ltd.) were weighed into a four-neck flask to obtain a mixed solution. Subsequently, the mixed solution was cooled to 20°C under a nitrogen stream. Furthermore, while maintaining the mixed solution at 20-30°C, 45.2 g of acetic anhydride (Fujifilm Wako Pure Chemical Industries, Ltd.) was added dropwise under a nitrogen stream. The resulting mixed solution was heated to 50°C and reacted at 50°C for 4 hours under a nitrogen stream to obtain a mixed solution after the reaction.

[0064] 832 mL of ion-exchanged water was weighed into another four-neck flask, and 449 g of potassium hydroxide (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added little by little while stirring under cooling to prepare an aqueous potassium hydroxide solution. At this time, the temperature of the aqueous solution was adjusted to 50°C or less. Next, 100 mL of ethanol was added to the aqueous solution to obtain an aqueous ethanol solution. The obtained aqueous ethanol solution was cooled to 10°C under a nitrogen stream. Thereafter, the entire amount of the mixture after the above reaction was added dropwise to the aqueous ethanol solution under a nitrogen stream. Crystals precipitated during the dropwise addition. At this time, the temperature of the aqueous solution was adjusted to 10 to 30°C.

[0065] After completion of the dropwise addition, the resulting slurry was stirred for 1 hour at 20 to 30°C under a nitrogen stream. After stirring, the crystals precipitated in the slurry were collected by filtration. Subsequently, the crystals were washed with 100 mL of a mixed solution of ethanol / ion-exchanged water (volume ratio 1 / 10). Washing with 100 mL of this mixed solution was carried out once more. Furthermore, the crystals were washed with 100 mL of ion-exchanged water. Washing with 100 mL of ion-exchanged water was carried out once more. The resulting crystals were dried under reduced pressure at 50°C for 15 hours to obtain apocynin. The yield of apocynin was 63.8%, and the HPLC purity of apocynin was 98.3 area%.

[0066] (Example of Recrystallization of Apocynin) 42.0 g of apocynin obtained in the above Synthesis Example and 82 mL of a mixed solution of ethanol / ion-exchanged water (volume ratio 7 / 3) were weighed into a four-neck flask to obtain a mixed solution. Subsequently, the mixed solution was heated to 60 ° C under a nitrogen stream to dissolve apocynin. Subsequently, 4.2 g of activated carbon (trade name: Tokusei Shirasagi, manufactured by Osaka Gas Chemicals Co., Ltd.) was added to the four-neck flask and stirred for 15 minutes while maintaining the temperature at 60 ° C. After stirring, the mixed solution was filtered to remove the activated carbon. Furthermore, the filtered activated carbon was washed with 42 mL of a mixed solution of ethanol / ion-exchanged water (volume ratio 7 / 3). Subsequently, the filtrate was heated to 60 ° C., and 139 mL of ion-exchanged water was added dropwise. At this point, apocynin had not crystallized. Furthermore, when the filtrate was cooled to 25 ° C., apocynin crystallized, and a slurry was obtained. The slurry was stirred at 25°C for 0.5 hours, followed by stirring at 5°C for 1 hour to mature the crystals. The resulting crystals were collected by filtration and washed with 126 mL of a pre-cooled mixed solution of ethanol and ion-exchanged water (volume ratio 1 / 4). After washing, the crystals were dried under reduced pressure at 50°C for 18 hours to obtain apocynin. The recrystallization yield was 92.6%, and the HPLC purity was 99.9 area%.

[0067] Example 20: 3.50 g of guaiacol (Fujifilm Wako Pure Chemical Industries, Ltd.) and 138 mg of concentrated sulfuric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) were added to a four-neck flask to obtain a mixed solution. The mixed solution was then cooled to 20°C under a nitrogen stream. Furthermore, while maintaining the mixed solution at 20-40°C, 3.16 g of acetic anhydride (Fujifilm Wako Pure Chemical Industries, Ltd.) was added dropwise, and the mixture was stirred at room temperature (25°C) for 15 minutes. The post-reaction solution at this point was analyzed using HPLC, and the yield was measured. As a result, apocynin was not produced. Meanwhile, 2-methoxyphenyl acetate was obtained in a yield of 98.7%. The resulting mixed solution was then cooled to 5°C. Furthermore, while maintaining the mixed solution at 5-15°C, 16.9 g of trifluoromethanesulfonic acid (Fujifilm Wako Pure Chemical Industries, Ltd.) was added dropwise. The resulting mixture was heated to 25°C and reacted at 25°C for 3.5 hours under a nitrogen stream to obtain a reacted solution. The reacted solution was cooled, and 17.5 mL of ion-exchanged water was added dropwise while maintaining the temperature at 10 to 30°C. Furthermore, 1.75 mL of ethanol was added dropwise. Thereafter, an 8 M aqueous potassium hydroxide solution was added dropwise while maintaining the temperature at 10 to 30°C. Crystals precipitated during the dropwise addition.

[0068] After the dropwise addition was completed, the resulting slurry was stirred for 1 hour at 20 to 30°C under a nitrogen stream. After stirring, the crystals precipitated in the slurry were collected by filtration. Subsequently, the crystals were washed with 7 mL of a mixed solution of ethanol / ion-exchanged water (volume ratio 1 / 20). Washing with 7 mL of this mixed solution was carried out once more. Furthermore, the crystals were washed with 7 mL of ion-exchanged water. Washing with 7 mL of ion-exchanged water was carried out once more. The obtained crystals were dried under reduced pressure at 50°C for 15 hours to obtain apocynin. The yield of apocynin was 67.4%, and the HPLC purity of apocynin was 99.3 area%. The obtained apocynin was white.

[0069] Example 21 (Synthesis Example of Apocynin) 1200 g of guaiacol (Fujifilm Wako Pure Chemical Industries, Ltd.) and 47.4 g of concentrated sulfuric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) were added to a four-neck flask to obtain a mixed solution. The mixed solution was then cooled to 24°C under a nitrogen stream. Furthermore, while maintaining the mixed solution at 24-29°C, 1085 g of acetic anhydride (Fujifilm Wako Pure Chemical Industries, Ltd.) was added dropwise, and the mixture was stirred at room temperature (25°C) for 20 minutes. The resulting mixed solution was then cooled to 3°C. Furthermore, while maintaining the mixed solution at 3-25°C, 5800 g of trifluoromethanesulfonic acid (Fujifilm Wako Pure Chemical Industries, Ltd.) was added dropwise. The resulting mixed solution was heated to 22-24°C and allowed to react for 1 hour at 22-24°C under a nitrogen stream to obtain a post-reaction solution.

[0070] Into another four-neck flask, 3000 mL of 8 M aqueous potassium hydroxide solution, 18000 mL of ion-exchanged water, and 600 mL of acetone were weighed and cooled to 22°C to prepare an aqueous potassium hydroxide solution. Subsequently, the entire amount of the solution after the reaction was added dropwise to the aqueous potassium hydroxide solution. At this time, the temperature of the aqueous solution was adjusted to 21 to 25°C. Furthermore, the four-neck flask containing the solution after the reaction was washed with 600 mL of acetone. The obtained washing liquid was added to the aqueous potassium hydroxide solution, and then 3000 mL of 8 M aqueous potassium hydroxide solution was added dropwise. At this time, the temperature of the aqueous solution was adjusted to 24 to 28°C.

[0071] After the dropwise addition was completed, the resulting slurry was stirred under a nitrogen stream at about 25°C for 6 hours. After stirring, the crystals precipitated in the slurry were collected by filtration. Subsequently, the crystals were washed with 4800 mL of ion-exchanged water. The resulting crystals were dried under reduced pressure at 50°C for 9.5 hours to obtain apocynin. The yield of apocynin was 64.1%, and the HPLC purity of apocynin was 98.1 area%.

[0072] (Example of Recrystallization of Apocynin) 1,000 g of apocynin obtained in the above Synthesis Example, 1,315 mL of acetone, and 600 mL of ion-exchanged water were weighed into a four-neck flask to obtain a mixed solution. Subsequently, the mixed solution was heated to 51°C under a nitrogen stream to dissolve the apocynin. Subsequently, 50 g of activated carbon (trade name: activated carbon, powder, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was added to the four-neck flask. Furthermore, the container containing the weighed activated carbon was washed with 86 mL of acetone. The resulting washings were added to the four-neck flask and stirred for 30 minutes while maintaining the temperature at 48-55°C. The stirred mixed solution was filtered to remove the activated carbon. Furthermore, the filtered activated carbon was washed with 1,000 mL of a mixed solution of acetone / ion-exchanged water (volume ratio 7 / 3). Subsequently, the filtrate was maintained at 46-48°C, and 10 L of ion-exchanged water was added dropwise. The resulting slurry was cooled to 6°C and then stirred at 0 to 6°C for 10 hours to mature the crystals. The resulting crystals were collected by filtration and washed with 3,300 mL of a pre-cooled mixed solution of acetone and ion-exchanged water (volume ratio 1 / 10). After washing, the crystals were dried under reduced pressure at 50°C for 7 hours to obtain apocynin. The recrystallization yield was 89.1%, and the HPLC purity was 99.4 area%. The resulting apocynin was white.

Claims

A method for producing an aromatic ketone represented by the following formula (1): The method for producing an aromatic ketone includes a reaction step of reacting a compound represented by the following formula (2) in the presence of a sulfonic acid to obtain the aromatic ketone, The method for producing an aromatic ketone, wherein the sulfonic acid comprises one or more sulfonic acids selected from the group consisting of alkylsulfonic acids having 1 to 3 carbon atoms and fluoroalkylsulfonic acids having 1 to 3 carbon atoms. (In formula (1) and formula (2), R １ and R ２ each independently represents a hydrocarbon group having 1 to 6 carbon atoms. 　 the method for producing an aromatic ketone includes a purification step of purifying the mixed solution obtained in the reaction step, the purification step includes a precipitation step A of precipitating the aromatic ketone, The deposition step A comprises: a step of adding the mixed solution dropwise to an aqueous potassium hydroxide solution to precipitate the aromatic ketone; or adding an aqueous potassium hydroxide solution dropwise to the mixture to precipitate the aromatic ketone The method for producing an aromatic ketone according to claim 1, wherein 　 3. The method for producing an aromatic ketone according to claim 2, further comprising a treatment step of treating the aromatic ketone obtained in the precipitation step A with activated carbon. 　 The method for producing an aromatic ketone according to claim 2 or 3, wherein the purification step comprises a recrystallization step of recrystallizing the aromatic ketone. 　 The method for producing an aromatic ketone according to any one of claims 1 to 4, comprising an acylation step of acylating a hydroxyl group in a compound represented by the following formula (3) to obtain a compound represented by the formula (2): (In formula (3), R １ represents a hydrocarbon group having 1 to 6 carbon atoms.) the acylation step is a step of reacting the compound represented by formula (3) with acetic anhydride in the presence of one or more selected from the group consisting of sulfonic acid and sulfuric acid, 6. The method for producing an aromatic ketone according to claim 5, wherein the sulfonic acid comprises one or more sulfonic acids selected from the group consisting of alkylsulfonic acids having 1 to 3 carbon atoms and fluoroalkylsulfonic acids having 1 to 3 carbon atoms.

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