Method for producing aromatic heterocyclic compound

Abstract

To improve production efficiency of an aromatic heterocyclic compound having a phenolic hydroxyl group.SOLUTION: There is provided a method for producing an aromatic heterocyclic compound (A) having a phenolic hydroxyl group represented by the formula (A) which comprises the following steps (1) to (4). Step (1): a step of mixing an aromatic heterocyclic compound (B) having an ether structure represented by formula (B), Lewis acid, a thiol compound and a hydrophobic solvent (C) to obtain a reaction solution (P) containing the aromatic heterocyclic compound (A). Step(2): a step of mixing the reaction solution (P) obtained in the step (1) with a hydrophilic solvent (D) to obtain a mixed solution (Q). Step (3): a step of mixing the mixed solution (Q) obtained in the step (2) with water (E) to precipitate the aromatic heterocyclic compound (A), followed by obtaining a suspension (R) containing a precipitate of the aromatic heterocyclic compound (A). Step (4): a step of filtering the suspension (R) obtained in the step (3) to isolate the aromatic heterocyclic compound (A).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing an aromatic heterocyclic compound. [Background technology]

[0002] Patent Document 1 discloses a method for producing an aromatic heterocyclic compound having a phenolic hydroxy group by reacting an aromatic heterocyclic compound having an ether structure. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2015-193554 A Summary of the Invention [Problem to be solved by the invention]

[0004] In the production method disclosed in Patent Document 1, when the mixed liquid obtained after the reaction is filtered, the time required for filtration may be long. [Means for solving the problem]

[0005] The present invention includes the following inventions. [Invention 1] A method for producing an aromatic heterocyclic compound (A) having a phenolic hydroxyl group represented by formula (A), comprising the following steps (1) to (4): Step (1): A step of obtaining a reaction liquid (P) containing the aromatic heterocyclic compound (A) by mixing an aromatic heterocyclic compound (B) having an ether structure represented by formula (B), a Lewis acid, a thiol compound, and a hydrophobic solvent (C). Step (2): A step of obtaining a mixed solution (Q) by mixing the reaction liquid (P) obtained in the step (1) with a hydrophilic solvent (D). Step (3): A step of precipitating the aromatic heterocyclic compound (A) by mixing the mixed solution (Q) obtained in the step (2) with water (E) to obtain a suspension (R) containing a precipitate of the aromatic heterocyclic compound (A). Step (4): A step of isolating the aromatic heterocyclic compound (A) by filtering the suspension (R) obtained in the step (3).

[0006] [ka]

[0007] [In formula (A) and formula (B), Q 1 -CR 11 R 12 -, -S-, -NR 11 represents -, -CO- or -O-. Y 1 represents an aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent.

[0008] Z 1 and Z 2 each independently represents a hydrogen atom, an aliphatic hydrocarbon group or an alkoxy group having 1 to 20 carbon atoms, an alicyclic hydrocarbon group having 3 to 20 carbon atoms, a monovalent aromatic hydrocarbon group having 6 to 20 carbon atoms, a halogen atom, a cyano group, a nitro group, -NR 11 R 12 or -SR 11 represents Z 1 and Z 2 may be bonded to each other to form an aromatic ring or an aromatic heterocycle.

[0009] R 11 and R 12 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. R 1 and R 2 each independently represents an alkyl group. [Invention 2] Q in formula (B) and formula (A) 1The method for producing an aromatic heterocyclic compound according to [Invention 1], wherein

[0010] [Invention 3] The method for producing an aromatic heterocyclic compound according to [Invention 1] or [Invention 2], wherein the step (3) is a step of obtaining the suspension (R) by dropping the mixed solution (Q) into the water (E).

[0011] [Invention 4] The method for producing an aromatic heterocyclic compound according to any one of [Invention 1] to [Invention 3], wherein the hydrophilic solvent (D) is an alcohol.

[0012] [Invention 5] The method for producing an aromatic heterocyclic compound according to any one of [Invention 1] to [Invention 4], wherein a mass ratio (D / B) of an amount of the hydrophilic solvent (D) used to an amount of the aromatic heterocyclic compound (B) used is 3 or more and 12 or less. Effect of the Invention

[0013] According to the present invention, the time required for filtration when isolating an aromatic heterocyclic compound having a phenolic hydroxyl group can be shortened. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Hereinafter, one embodiment of the method for producing an aromatic heterocyclic compound will be described. The method for producing an aromatic heterocyclic compound of this embodiment includes steps (1) to (4). Step (1) is a step of mixing an aromatic heterocyclic compound having an ether structure, a Lewis acid, a thiol compound, and a hydrophobic solvent (C) to obtain a reaction liquid (P) containing an aromatic heterocyclic compound having a phenolic hydroxyl group.

[0015] Step (2) is a step of obtaining a mixed solution (Q) by mixing the reaction liquid (P) obtained in step (1) with a hydrophilic solvent (D). Step (3) is a step of obtaining a suspension (R) containing a precipitate of an aromatic heterocyclic compound having a phenolic hydroxyl group by mixing the mixed solution (Q) obtained in step (2) with water (E).

[0016] Step (4) is a step of isolating the aromatic heterocyclic compound having a phenolic hydroxyl group by filtering the suspension (R) obtained in step (3). [Process (1)] An example of step (1) will be described.

[0017] In step (1), for example, a reaction liquid (P) is obtained by mixing a mixed liquid (1A) and a mixed liquid (1B). The mixed liquid (1A) contains a Lewis acid and a thiol compound. The mixed liquid (1B) contains an aromatic heterocyclic compound having an ether structure and a hydrophobic solvent (C).

[0018] The method of mixing the mixed liquid (1A) and the mixed liquid (1B) is not particularly limited. For example, the mixed liquid (1A) and the mixed liquid (1B) may be mixed at once, the mixed liquid (1A) may be added dropwise to the mixed liquid (1B), or the mixed liquid (1B) may be added dropwise to the mixed liquid (1A). As a method of mixing the mixed liquid (1A) and the mixed liquid (1B), a method of adding the mixed liquid (1B) dropwise to the mixed liquid (1A) is preferable.

[0019] The rate at which the mixed solution (1B) is added is usually 0.08 to 2 mass% / min, preferably 0.15 to 2 mass% / min, based on the total amount of the mixed solution (1B). A preferred rate is one at which 80 mol% or more of the added aromatic heterocyclic compound having an ether structure is converted into an aromatic heterocyclic compound having a phenolic hydroxyl group within 1 minute, more preferably within 10 seconds.

[0020] The addition time is determined depending on the amount of the mixed liquid (1B) and the addition rate, and is usually 1 to 20 hours, preferably 1 to 8 hours. The mixing temperature is preferably from -15 to 120°C, more preferably from 0 to 100°C, and further preferably from 0 to 80°C.

[0021] The time for mixing after adding the mixed liquid (1B) to the mixed liquid (1A) is preferably 1 to 72 hours, more preferably 2 to 48 hours. The mixed solution (1A) and the mixed solution (1B) are mixed and reacted to produce an aromatic heterocyclic compound having a phenolic hydroxyl group.

[0022] <Lewis acid> The amount of the Lewis acid used is preferably 1 to 10 mol, more preferably 1 to 8 mol, and even more preferably 1 to 5 mol, per mol of the phenolic hydroxyl group of the aromatic heterocyclic compound.

[0023] Examples of the Lewis acid include aluminum chloride, boron tribromide, boron trifluoride diethyl ether complex, boron trichloride, titanium tetrachloride, and tin tetrachloride. Of these, aluminum chloride, boron trifluoride diethyl ether complex, titanium tetrachloride, and tin tetrachloride are preferred, and aluminum chloride is more preferred.

[0024] <Thiol compounds> The amount of the thiol compound used is preferably 1 to 10 mol, more preferably 1 to 8 mol, and even more preferably 1 to 5 mol, relative to 1 mol of the phenolic hydroxyl group of the aromatic heterocyclic compound, and is preferably 1 to 10 mol, more preferably 1 to 6 mol, and even more preferably 1 to 4 mol, relative to 1 mol of the Lewis acid.

[0025] Examples of the thiol compound include aromatic thiols such as benzenethiol, benzenedithiol, and phenylethanethiol, alkyl thiols such as ethanethiol, propanethiol, t-butanethiol, pentanethiol, hexanethiol, heptanethiol, octanethiol, nonanethiol, decanethiol, undecanethiol, dodecanethiol, hexadecanethiol, eicosanethiol, and hentriacontanethiol, and polyfunctional alkyl thiols such as ethanedithiol, propanedithiol, and ethanetrithiol. Preferred are alkyl thiols, and more preferred are compounds represented by formula (F) (hereinafter sometimes referred to as "compound (F)").

[0026] [ka]

[0027] [In the formula, R 0 represents an alkyl group having 1 to 31 carbon atoms, and a carbon atom contained in the alkyl group may be substituted with an oxygen atom or a sulfur atom.] R 0 is preferably an alkyl group having 6 to 31 carbon atoms, more preferably an alkyl group having 8 to 22 carbon atoms, and further preferably an alkyl group having 10 to 16 carbon atoms. Also, it is preferably an alkyl group that does not contain an oxygen atom or a sulfur atom. An alkyl group having 10 or more carbon atoms is preferred because it has no odor and is easy to handle.

[0028] R 0 Examples of the alkyl group include an ethyl group, a propyl group, a t-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a hexadecyl group, an eicosyl group, and a hentriacontyl group.

[0029] <Compound (B)> Examples of aromatic heterocyclic compounds having an ether structure include compounds having a structure represented by carbon atom-oxygen atom-primary carbon atom of an aromatic heterocycle, carbon atom-oxygen atom-secondary carbon atom of an aromatic heterocycle, carbon atom-oxygen atom-tertiary carbon atom of an aromatic heterocycle, carbon atom-oxygen atom-quaternary carbon atom of an aromatic heterocycle, or carbon atom-oxygen atom-aromatic carbon atom of an aromatic heterocycle. Preferred are compounds having a structure represented by carbon atom-oxygen atom-primary carbon atom of an aromatic heterocycle, carbon atom-oxygen atom-secondary carbon atom of an aromatic heterocycle, or carbon atom-oxygen atom-tertiary carbon atom of an aromatic heterocycle, and more preferred are compounds having a structure represented by carbon atom-oxygen atom-primary carbon atom of an aromatic heterocycle, or carbon atom-oxygen atom-secondary carbon atom of an aromatic heterocycle.

[0030] An example of a group constituting a primary carbon is a methyl group. Examples of groups constituting a secondary carbon include an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, and an octyl group.

[0031] Examples of groups constituting a tertiary carbon include an isopropyl group and a sec-butyl group. Examples of groups constituting a quaternary carbon include a tert-butyl group. Examples of groups that constitute an aromatic carbon include a phenyl group, a naphthyl group, and a pyridyl group.

[0032] The aromatic heterocycle is preferably a compound having at least one structure represented by -NH-, -N<, -N=, -P<, -O- or -S-, more preferably a compound having at least one structure represented by -NH-, -N< or -N=, and even more preferably a compound having at least one structure represented by -N=.

[0033] The aromatic heterocyclic compound having an ether group is particularly preferably a compound represented by formula (B) (hereinafter sometimes referred to as "compound (B)" or aromatic heterocyclic compound (B)).

[0034] [ka]

[0035] [In the formula, Q 1 -CR 11 R 12 -, -S-, -NR 11 represents -, -CO- or -O-. Y 1 represents an aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent.

[0036] Z 1 and Z 2 each independently represents a hydrogen atom, an aliphatic hydrocarbon group or an alkoxy group having 1 to 20 carbon atoms, an alicyclic hydrocarbon group having 3 to 20 carbon atoms, a monovalent aromatic hydrocarbon group having 6 to 20 carbon atoms, a halogen atom, a cyano group, a nitro group, -NR 11 R 12 or -SR 11 represents Z 1 and Z 2 may be bonded to each other to form an aromatic ring or an aromatic heterocycle.

[0037] R 11 and R 12 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. R 1 and R 2 each independently represents an alkyl group. Q 1 is preferably -O- or -S-, and more preferably -S-.

[0038] Z 1 and Z 2 is preferably a hydrogen atom. R 1 and R 2are each independently preferably an alkyl group in which the carbon atom adjacent to the ether bond is a primary carbon, and an alkyl group in which the carbon atom adjacent to the ether bond is a secondary carbon, more preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group, further preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

[0039] Y 1 The substituents of the aromatic hydrocarbon group which may have a substituent and the aromatic heterocyclic group which may have a substituent, represented by the following formula (1), are halogen atoms, -R 3 , haloalkyl group, cyano group, nitro group, nitroso group, -SO2R 4 , -SOR 4 , -SR 4 , -OR 4 , carboxy group and -NR 11 R 5 Examples include: R 3 and R 4 each independently represents an alkyl group having 1 to 6 carbon atoms. A haloalkyl group represents an alkyl group having a halogen atom.

[0040] Y 1 is preferably represented by the formula (Y 1 -1) ~ formula (Y 1 -7).

[0041] [ka]

[0042] [Formula (Y 1 -1) ~ formula (Y 1 -7) Medium, Z 3 each independently represents a halogen atom, -R 3 , haloalkyl group, cyano group, nitro group, nitroso group, -SO2R 4 , -SOR 4 , -SR 4 , -OR 4 , a carboxy group or -NR 11 R 5Represents.

[0043] V 1 and V 2 are each independently -CO- or -NR 11 -, -SO2-, or a Group 16 element. W 1 ~W 6 each independently represents -CH= or -N=.

[0044] R 11 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. R 3 , R 4 and R 5 each independently represents an alkyl group having 1 to 6 carbon atoms. a represents an integer of 0 to 5.

[0045] b represents an integer of 0 to 3. c represents an integer of 0 to 2. When a or b is an integer of 2 or more, multiple Z 3 may be the same or different from each other.

[0046] * denotes a binding site.] R 1 , R 2 , R 3 , R 4 , R 5 , R 11 and R 12 Examples of the alkyl group having 1 to 6 carbon atoms represented by the formula (1) include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, etc. Preferably, they are each independently an alkyl group having 1 to 4 carbon atoms, more preferably, they are each independently an alkyl group having 1 to 2 carbon atoms, and even more preferably, they are each independently a methyl group.

[0047] Y 1 is preferred because it has excellent compound stability and is easy to synthesize. 2 -1) ~ formula (Y 2-7) is more preferable.

[0048] [ka]

[0049] [Formula (Y 2 -1) ~ formula (Y 2 -7) Medium, Z 3 , a, b, c and * have the same meanings as above. J 1 and J 2 are each independently -CO- or -NR 11 - or a Group 16 element.

[0050] L 1 each independently represents -CH= or -N=. L 1 is preferably -CH=. Y 1 More preferably, the formula (Y 3 -1) ~ formula (Y 3 -4).

[0051] [ka]

[0052] [Formula (Y 3 -1) ~ formula (Y 3 -4) Medium, Z 3 , a, b, c, J 1 , and * have the same meaning as above.] Z 3 -SO2R in 4 Examples of the sulfonyl group include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, an isobutylsulfonyl group, a sec-butylsulfonyl group, a tert-butylsulfonyl group, a pentylsulfonyl group, and a hexylsulfonyl group.

[0053] Z 3-SOR in 4 Examples of the sulfinyl group include a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, an isopropylsulfinyl group, a butylsulfinyl group, an isobutylsulfinyl group, a sec-butylsulfinyl group, a tert-butylsulfinyl group, a pentylsulfinyl group, and a hexylsulfinyl group.

[0054] Z 3 -SR in 4 Examples of the sulfanyl group include a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, an isopropylsulfanyl group, a butylsulfanyl group, an isobutylsulfanyl group, a sec-butylsulfanyl group, a tert-butylsulfanyl group, a pentylsulfanyl group, and a hexylsulfanyl group.

[0055] Z 3 -OR in 4 Examples of the aryloxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, and a hexyloxy group.

[0056] Z 3 -NR in 11 R 5 Examples of the alkylamino group include N-monoalkylamino groups such as an N-methylamino group, an N-ethylamino group, an N-propylamino group, an N-isopropylamino group, an N-butylamino group, an N-isobutylamino group, an N-sec-butylamino group, an N-tert-butylamino group, an N-pentylamino group, and an N-hexylamino group; and N,N-dialkylamino groups such as an N,N-dimethylamino group, an N-methyl-N-ethylamino group, an N,N-diethylamino group, an N,N-dipropylamino group, an N,N-diisopropylamino group, an N,N-dibutylamino group, an N,N-diisobutylamino group, an N,N-dipentylamino group, and an N,N-dihexylamino group.

[0057] Z 3is preferably a hydrogen atom, a halogen atom, a methyl group, an ethyl group, an isopropyl group, a sec-butyl group, a pentyl group, a hexyl group, a cyano group, a nitro group, a methylsulfonyl group, a carboxy group, a trifluoromethyl group, a methoxy group, a methylsulfanyl group, an N,N-dimethylamino group, or an N-methylamino group, more preferably a hydrogen atom, a halogen atom, a methyl group, an ethyl group, an isopropyl group, a sec-butyl group, a pentyl group, a hexyl group, a cyano group, a nitro group, or a trifluoromethyl group, and particularly preferably a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a sec-butyl group, a pentyl group, or a hexyl group.

[0058] V 1 and V 2 Examples of Group 16 elements represented by the formula include S, O, and Se. V 1 and V 2 are preferably each independently -S-, -NR 11 -or -O-. Specific examples of compound (B) include compounds (B-001) to (B-076) represented by the following formulae (B-001) to (B-076).

[0059] [ka] JPEG2025005782000008.jpg27170 JPEG2025005782000009.jpg27170 JPEG2025005782000010.jpg29170 JPEG2025005782000011.jpg30170 JPEG2025005782000012.jpg31170

[0060] [ka] JPEG2025005782000014.jpg29170 JPEG2025005782000015.jpg29170 JPEG2025005782000016.jpg33170

[0061] <Hydrophobic Solvent (C)> The hydrophobic solvent (C) mixed with the compound (B) is not particularly limited as long as it is inactive to Lewis acid, and examples thereof include aromatic solvents such as benzene, toluene, xylene, mesitylene, phenol, monochlorobenzene, and nitrobenzene, and halogen-containing solvents such as chloroform, dichloromethane, carbon tetrachloride, and trichloroethane. The hydrophobic solvent (C) is preferably a solvent in which the compound (B) is highly soluble. Preferred are toluene, xylene, monochlorobenzene, and mixed solvents thereof, and more preferably monochlorobenzene. The solvent may be used alone or in combination.

[0062] The amount of the hydrophobic solvent (C) used is preferably 1 or more and 20 or less, more preferably 4 or more and 8 or less, and even more preferably 6 or more and 8 or less, as expressed by the mass ratio (C / B) of the amount of the hydrophobic solvent (C) used to the amount of the compound (B) used.

[0063] <Mixed liquid (1A)> The mixing temperature is preferably from -20 to 120°C, more preferably from 0 to 100°C, and even more preferably from 0 to 80°C.

[0064] The mixing is preferably carried out until the Lewis acid is dissolved. The Lewis acid and the thiol compound may be mixed in a solvent. The solvent is not particularly limited as long as it is inactive against Lewis acid, but it is preferably the same as the hydrophobic solvent (C). Specific examples include the same as the hydrophobic solvent (C). The solvent may be used alone or in combination. These solvents are preferred because they have high solubility for Lewis acid and are easy to handle.

[0065] The amount of the solvent is preferably 1 to 10 parts by mass, more preferably 2 to 8 parts by mass, relative to 1 part by mass of the Lewis acid, and is preferably an amount that completely dissolves the Lewis acid. <Mixed liquid (1B)> The mixing temperature is preferably from -20 to 120°C, more preferably from 0 to 100°C, and even more preferably from 0 to 80°C.

[0066] The mixing is preferably carried out until the aromatic heterocyclic compound having an ether structure is dissolved. The water content of the solvent used in the mixed solution (1A) and the mixed solution (1B) is preferably 0.03% by weight or less. If the water content is 0.03% by weight or less, the activity of the Lewis acid is not decreased, which is preferable. If the water content of the solvent is higher than 0.03% by weight, it is preferable to dehydrate the solvent using a means such as dehydration reflux.

[0067] <Compound (A)> By reacting compound (B) with a Lewis acid in step (1), an aromatic heterocyclic compound having a phenolic hydroxyl group can be obtained. Examples of aromatic heterocyclic compounds having a phenolic hydroxyl group include a compound represented by formula (A) (hereinafter sometimes referred to as "compound (A)" or "aromatic heterocyclic compound (A)").

[0068] [ka]

[0069] [In the formula, Q 1 And, Y 1 has the same meaning as above.] An aromatic heterocyclic compound having a phenolic hydroxyl group can be used as a raw material for the liquid crystal compound described in JP-A-2010-31223 and the like.

[0070] In step (1), a by-product may be generated as a result of a side reaction. When an aromatic heterocyclic compound having an ether structure is reacted with a Lewis acid, a by-product may be generated due to a side reaction between the ether structure and the aromatic heterocyclic structure of the aromatic heterocyclic compound having an ether structure, and such a side reaction may decrease the yield of the aromatic heterocyclic compound having a phenolic hydroxyl group.

[0071] For example, the reaction of compound (B) with a Lewis acid may produce compound (A) and a by-product, a compound represented by formula (G) (hereinafter sometimes referred to as “compound (G)”).

[0072] [ka]

[0073] [In the formula, Z 1 , Z 2 , Q 1 and Y 1 has the same meaning as above.] Compound (G) has low solubility, and therefore it may be difficult to purify and remove it. According to the production method of this embodiment, it is possible to reduce the production of by-products such as compound (G). Therefore, it is possible to obtain an aromatic heterocyclic compound having a phenolic hydroxyl group such as compound (A) in high yield.

[0074] [Process (2)] An example of step (2) will be described. In the step (2), the reaction liquid (P) after completion of the reaction is mixed with a hydrophilic solvent (D) to obtain a mixed solution (Q) in which the precipitate in the reaction liquid (P) is dissolved.

[0075] The method of mixing the reaction liquid (P) and the hydrophilic solvent (D) in the step (2) is not particularly limited. For example, the reaction liquid (P) and the hydrophilic solvent (D) may be mixed at once, the reaction liquid (P) may be dropped into the hydrophilic solvent (D), or the hydrophilic solvent (D) may be dropped into the reaction liquid (P). As a method of mixing the reaction liquid (P) and the hydrophilic solvent (D), a method of dropping the hydrophilic solvent (D) into the reaction liquid (P) is preferable.

[0076] <Hydrophilic solvent (D)> Examples of the hydrophilic solvent (D) include aprotic polar solvents and alcohols. Examples of aprotic polar solvents include dimethyl sulfoxide, N-methylpyrrolidinone, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0077] The alcohol may, for example, be a lower alcohol having a carbon number of 1 to 4. Specific examples include methanol, ethanol, n-propyl alcohol, isopropyl alcohol, and ethylene glycol.

[0078] These solvents may be used alone or in combination. The hydrophilic solvent (D) is preferably dimethylsulfoxide, N-methylpyrrolidinone, N,N-dimethylformamide, or methanol, and more preferably methanol.

[0079] The amount of the hydrophilic solvent (D) used is preferably 1 or more and 20 or less, more preferably 3 or more and 12 or less, and even more preferably 8 or more and 9 or less, as expressed by the mass ratio (D / B) of the amount of the hydrophilic solvent (D) used to the amount of the compound (B) used.

[0080] [Process (3)] An example of step (3) will be described. In step (3), the compound (A) can be precipitated by mixing the mixed solution (Q) with water (E). In step (3), a suspension (R) containing a precipitate of the compound (A) can be obtained.

[0081] The method of mixing the mixed solution (Q) and water (E) in the step (3) is not particularly limited. For example, the mixed solution (Q) and water (E) may be mixed all at once, the mixed solution (Q) may be added dropwise to the water (E), or the water (E) may be added dropwise to the mixed solution (Q). As a method of mixing the mixed solution (Q) and water (E), a method of adding the mixed solution (Q) dropwise to the water (E) is preferable.

[0082] In step (3), seed crystals may be added, that is, in step (3), the mixed solution (Q) may be added dropwise to water (E) to which previously prepared crystals of compound (A) have been added. The amount of seed crystals added is not particularly limited, but is, for example, from 1 wt % to 20 wt %, and preferably from 5 wt % to 15 wt %, based on the compound (B).

[0083] <Water(E)> The water (E) is not particularly limited, but distilled water, pure water, ultrapure water, purified water, etc. can be used.

[0084] The amount of water (E) used is preferably 1 or more and 20 or less, more preferably 2 or more and 10 or less, and even more preferably 4 or more and 5 or less, in terms of the mass ratio (E / B) of the amount of water (E) used to the amount of compound (B) used.

[0085] The temperature of the water (E) is preferably 5°C or higher and 70°C or lower, more preferably 10°C or higher and 55°C or lower, and even more preferably 40°C or higher and 55°C or lower. [Process (4)] An example of step (4) will be described.

[0086] In step (4), the suspension (R) obtained in step (3) is filtered to isolate the aromatic heterocyclic compound (A) as a solid. The method of filtration is not particularly limited, but for example, suction filtration can be used.

[0087] The suspension (R) obtained in step (3) is preferably cooled before filtering in step (4). For example, the suspension (R) is preferably cooled to room temperature. An example of room temperature is 20°C or higher and 30°C or lower.

[0088] In step (4), filtration may be performed multiple times. For example, the suspension (R) may be filtered to obtain a solid, which may then be mixed with water, and the resulting mixture may then be filtered. The solid matter obtained by filtration in step (4) is preferably washed and dried after filtration.

[0089] <Effects of this embodiment> According to the production method of this embodiment, the aromatic heterocyclic compound (A) can be produced in a high yield. According to the production method of this embodiment, the filterability when isolating the aromatic heterocyclic compound (A) can be improved. Specifically, the time required for filtration can be shortened. This can improve the production efficiency of the aromatic heterocyclic compound (A). EXAMPLES

[0090] The method for producing an aromatic heterocyclic compound will be described in more detail with reference to the following examples. Note that the method for producing an aromatic heterocyclic compound is not limited to the configurations described in the examples.

[0091] The aromatic heterocyclic compounds (A) shown in Examples 1 to 15, Comparative Example 1 and Comparative Example 2 in Table 1 were produced. Example 1 Compound (A-055), which is an aromatic heterocyclic compound (A), was synthesized from compound (B-055), which is an aromatic heterocyclic compound (B), according to the following scheme.

[0092] [ka]

[0093] Specifically, compound (A-055) was obtained according to the following steps (1) to (4). <Process (1)> A 1L separable flask equipped with a Dimroth condenser and a thermometer was filled with nitrogen and 95g of aluminum chloride (5.0 molar ratio to B-055) was dissolved in 145g of dodecanethiol (5.0 molar ratio to B-055) at 70°C. After confirming that the aluminum chloride had dissolved, a suspension of 51g of compound (B-055) and 306g of monochlorobenzene (6.0 mass ratio to B-055) was added dropwise over 3 hours or more. After the addition, the reaction was terminated by keeping the mixture warm for 3 hours or more.

[0094] <Process (2)> After the reaction was completed, 408 g of methanol (mass ratio of 8.0 to B-055) was added dropwise to the suspension to dissolve the precipitate.

[0095] <Process (3)> A 2L separable flask equipped with a Dimroth condenser and a thermometer was filled with 255g of pure water (5.0 mass ratio to B-055) and kept at 10°C. A solution of the compound dissolved in methanol was then added dropwise to precipitate crystals of the compound (A-055). The mixture was then cooled to 25°C.

[0096] <Process (4)> The time required for filtration was measured when a filter paper (No. 5A) was laid on a Buchner funnel, the suspension was poured in, and suction filtration was performed. After the initial filtration, the mixture was immersed in 306 g of monochlorobenzene (6.0 mass ratio to B-055) and filtered, and then immersed in a mixed solvent of 153 g of methanol (3.0 mass ratio to B-055) and 153 g of pure water (3.0 mass ratio to B-055) and filtered. The obtained wet mass was placed in a 1 L separable flask together with 510 g of pure water (10.0 mass ratio to B-055) and stirred at 60 ° C for 0.5 hours. The suspension was then filtered using a Buchner funnel with filter paper (No. 5A) laid in it in the same manner as above. The mixture was then immersed in 102 g of pure water (2.0 mass ratio to B-055) and filtered to obtain a wet mass. The wet product was dried under reduced pressure at 70°C to obtain 40.5 g of the target compound (A-055).

[0097] Example 2 Compound (A-055) was obtained in the same manner as in Example 1, except that the temperature in step (3) of Example 1 was changed from 10°C to 20°C.

[0098] Example 3 Compound (A-055) was obtained in the same manner as in Example 1, except that the temperature in step (3) of Example 1 was changed from 10°C to 40°C.

[0099] Example 4 Compound (A-055) was obtained in the same manner as in Example 1, except that the temperature in step (3) of Example 1 was changed from 10°C to 55°C.

[0100] Example 5 Compound (A-055) was obtained in the same manner as in Example 4, except that 2.6 g (5 wt % based on B-055) of compound (A-055) was added together with 255 g of pure water in step (3) of Example 4.

[0101] Example 6 Compound (A-055) was obtained in the same manner as in Example 4, except that 7.7 g (15 wt % based on B-055) of compound (A-055) was added together with 255 g of pure water in step (3) of Example 4.

[0102] Example 7 Compound (A-055) was obtained in the same manner as in Example 4, except that in step (1) of Example 4, 204 g of monochlorobenzene (4.0 mass ratio with respect to B-055) was added instead of 306 g of monochlorobenzene (6.0 mass ratio with respect to B-055).

[0103] Example 8 Compound (A-055) was obtained in the same manner as in Example 4, except that in step (1) of Example 4, 408 g of monochlorobenzene (8.0 mass ratio with respect to B-055) was added instead of 306 g of monochlorobenzene (6.0 mass ratio with respect to B-055).

[0104] Example 9 Compound (A-055) was obtained in the same manner as in Example 4, except that 153 g of methanol (3.0 mass ratio to B-055) was added in place of 408 g of methanol (8.0 mass ratio to B-055) in step (2) of Example 4.

[0105] Example 10 Compound (A-055) was obtained in the same manner as in Example 4, except that 459 g of methanol (9.0 mass ratio to B-055) was added in place of 408 g of methanol (8.0 mass ratio to B-055) in step (2) of Example 4.

[0106] Example 11 Compound (A-055) was obtained in the same manner as in Example 4, except that in step (3) of Example 4, 204 g of pure water (4.0 mass ratio to B-055) was added instead of 255 g of pure water (5.0 mass ratio to B-055).

[0107] Example 12 Compound (A-055) was obtained in the same manner as in Example 4, except that 408 g of N-methylpyrrolidinone (8.0 mass ratio with respect to B-055) was added instead of 408 g of methanol (8.0 mass ratio with respect to B-055) in step (2) of Example 4.

[0108] Example 13 Compound (A-055) was obtained in the same manner as in Example 4, except that 408 g of N,N-dimethylformamide (8.0 mass ratio with respect to B-055) was added in place of 408 g of methanol (8.0 mass ratio with respect to B-055) in step (2) of Example 4.

[0109] Example 14 Compound (A-055) was obtained in the same manner as in Example 4, except that 408 g of dimethyl sulfoxide (8.0 mass ratio to B-055) was added instead of 408 g of methanol (8.0 mass ratio to B-055) in step (2) of Example 4.

[0110] Example 15 Compound (A-036), which is an aromatic heterocyclic compound (A), was synthesized from compound (B-036), which is an aromatic heterocyclic compound (B), according to the following scheme. Specifically, compound (A-036) was obtained according to the following steps (1) to (4).

[0111] [ka]

[0112] <Process (1)> A 1L separable flask equipped with a Dimroth condenser and a thermometer was filled with nitrogen and 95g of aluminum chloride (5.0 molar ratio to B-036) was dissolved in 145g of dodecanethiol (5.0 molar ratio to B-036) at 70°C. After confirming that the aluminum chloride had dissolved, a suspension of 45g of compound (B-036) and 267g of monochlorobenzene (6.0 mass ratio to B-036) was added dropwise over 3 hours or more. After the addition, the reaction was terminated by keeping the mixture warm for 3 hours or more.

[0113] <Process (2)> After the reaction was completed, 357 g of methanol (mass ratio of 8.0 with respect to B-036) was added dropwise to the suspension to dissolve the precipitate.

[0114] <Process (3)> A 2L separable flask equipped with a Dimroth condenser and a thermometer was filled with 178g of pure water (5.0 mass ratio to B-036) and kept at 55°C. A solution of the compound dissolved in methanol was then added dropwise to precipitate crystals of the compound (A-036). The mixture was then cooled to 25°C.

[0115] <Process (4)> The time required for filtration was measured when a filter paper (No. 5A) was laid on a Buchner funnel, the suspension was poured in, and suction filtration was performed. After the initial filtration, the mixture was immersed in 267 g of monochlorobenzene (6.0 mass ratio to B-036) and filtered, and then immersed in a mixed solvent of 134 g of methanol (3.0 mass ratio to B-036) and 134 g of pure water (3.0 mass ratio to B-036) and filtered. The obtained wet mass was placed in a 1 L separable flask together with 446 g of pure water (10.0 mass ratio to B-036) and stirred at 60 ° C for 0.5 hours. The suspension was then filtered using a Buchner funnel with filter paper (No. 5A) laid in it in the same manner as above. The mixture was then immersed in 89 g of pure water (2.0 mass ratio to B-036) and filtered to obtain a wet mass. The wet product was dried under reduced pressure at 70°C to obtain 38.5 g of the target compound (A-036).

[0116] Comparative Example 1 Compound (A-055) was obtained in the same manner as in Example 4, except that in step (2) of Example 4, 408 g of methanol (8.0 mass ratio to B-055) was replaced with no methanol.

[0117] Comparative Example 2 Compound (A-055) was obtained in the same manner as in Comparative Example 1, except that in step (3) of Comparative Example 1, 255 g of pure water (mass ratio of 5.0 to B-055) was replaced with no pure water.

[0118] [Table 1]

[0119] <Yield> It was confirmed that in all of Examples 1 to 15, compound (A) was obtained in a yield of 80% or more based on compound (B).

[0120] <Evaluation of filterability> The filterability in Examples 1 to 15 and Comparative Examples 1 and 2 was evaluated according to the following evaluation criteria. The filterability was evaluated based on the time required for the first filtration through the Buchner funnel in step (4). The results are shown in Table 1.

[0121] Filterability evaluation criteria ◎ (Excellent): Filtration time is less than 15 minutes. ○ (Acceptable): Filtration time is between 15 and 120 minutes. × (Not acceptable): Filtration time is 120 minutes or more.

[0122] As shown in Table 1, excellent filterability was confirmed in Examples 3 to 11 and 15. That is, it was confirmed that the production efficiency of the aromatic heterocyclic compound (A) having a phenolic hydroxyl group was particularly improved. In addition, in Examples 1, 2, and 12 to 14, the filterability was evaluated as acceptable, so it was confirmed that the production efficiency of the aromatic heterocyclic compound (A) was improved.

Claims

1. A method for producing an aromatic heterocyclic compound (A) having a phenolic hydroxyl group represented by formula (A), comprising the following steps (1) to (4): Step (1): A step of obtaining a reaction liquid (P) containing the aromatic heterocyclic compound (A) by mixing an aromatic heterocyclic compound (B) having an ether structure represented by formula (B), a Lewis acid, a thiol compound, and a hydrophobic solvent (C). Step (2): A step of obtaining a mixed solution (Q) by mixing the reaction liquid (P) obtained in the step (1) with a hydrophilic solvent (D). Step (3): A step of precipitating the aromatic heterocyclic compound (A) by mixing the mixed solution (Q) obtained in the step (2) with water (E) to obtain a suspension (R) containing a precipitate of the aromatic heterocyclic compound (A). Step (4): A step of isolating the aromatic heterocyclic compound (A) by filtering the suspension (R) obtained in the step (3). 【Chemistry 1】 [In formula (A) and formula (B), Q １ is -CR １１ R １２ -, -S-, -NR １１ It represents --, --CO-- or --O--. Y １ represents an aromatic hydrocarbon group which may have a substituent or an aromatic heterocyclic group which may have a substituent. Z １ and Z ２ each independently represents a hydrogen atom, an aliphatic hydrocarbon group or an alkoxy group having 1 to 20 carbon atoms, an alicyclic hydrocarbon group having 3 to 20 carbon atoms, a monovalent aromatic hydrocarbon group having 6 to 20 carbon atoms, a halogen atom, a cyano group, a nitro group, -NR １１ R １２ Or -SR １１ represents Z １ and Z ２ may be bonded to each other to form an aromatic ring or an aromatic heterocycle. R １１ and R １２ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. R １ and R ２ each independently represents an alkyl group.

2. Q in formula (B) and formula (A) １ is -S- A method for producing the aromatic heterocyclic compound according to claim 1.

3. The step (3) is a step of obtaining the suspension (R) by dropping the mixed solution (Q) into the water (E). A method for producing the aromatic heterocyclic compound according to claim 1 or 2.

4. The hydrophilic solvent (D) is an alcohol. A method for producing the aromatic heterocyclic compound according to claim 1 or 2.

5. The mass ratio (D / B) of the amount of the hydrophilic solvent (D) to the amount of the aromatic heterocyclic compound (B) is 3 or more and 12 or less. A method for producing the aromatic heterocyclic compound according to claim 1 or 2.

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