Acid addition salt of 4-amino-2-halobenzonitrile compound and method for producing same

Abstract

Provided is a method for producing, in an industrially advantageous manner, an acid addition salt of an organic sulfonic acid and a 4-amino-2-halobenzonitrile compound.　An acid addition salt of an organic sulfonic acid and a 4-amino-2-halobenzonitrile compound represented by formula (2) is produced. A production method according to the present invention includes a separation step for, by using a method in which the solubility difference between acid addition salts of isomers in a solvent is used, separating, from acid addition salts of an organic sulfonic acid and an isomer mixture of compounds represented by formula (1) with at least a compound represented by formula (2) being included in the acid addition salts, an acid addition salt of the compound represented by formula (2) and the organic sulfonic acid. (In the formulas, X denotes a halogen atom, R1 denotes a substituent that is inert to the reaction, and n denotes an integer of 0-3.)

Description

Acid addition salts of 4-amino-2-halobenzonitrile compounds and their production method

[0001] The present invention relates to an acid addition salt of a 4-amino-2-halobenzonitrile compound with an organic sulfonic acid (an organic sulfonate salt of a 4-amino-2-halobenzonitrile compound), which is useful as an intermediate, a reagent, etc. for pharmaceuticals, and a method for producing the same.

[0002] 4-Amino-2-fluorobenzamide, an aromatic compound having an amino group, a fluorine atom, and an amide group as substituents, is known to be useful as an intermediate for pharmaceuticals, etc.

[0003] As a method for producing 4-amino-2-fluorobenzamide, Chinese Patent Application Publication No. 116332789 (Patent Document 1) discloses a method that involves an amination step in which one fluorine atom of the raw material 2,4-difluorobenzonitrile is converted to an amino group, a separation step in which isomers of the resulting amino-substituted product are separated, and an amidation step in which the cyano group of the resulting 4-amino-2-fluorobenzonitrile is converted to an amide group. The separation step is disclosed to be a method of performing distillation or a method of forming an acid addition salt of a mixture of isomers of the amino-substituted product with an acid and then separating the acid addition salt of 4-amino-2-fluorobenzonitrile and the acid by precipitation.

[0004] Chinese Patent Application Publication No. 116332789

[0005] However, in the examples of Patent Document 1, a halogen-containing solvent is used as the solvent, and gaseous hydrochloric acid gas (hydrogen chloride gas) which is difficult to handle is used, which is not industrially advantageous.

[0006] Therefore, an object of the present invention is to provide a method for industrially advantageously producing an acid addition salt of a 4-amino-2-halobenzonitrile compound and an organic sulfonic acid (an organic sulfonate salt of a 4-amino-2-halobenzonitrile compound).

[0007] Another object of the present invention is to provide a method for easily and efficiently producing an acid addition salt of a 4-amino-2-halobenzonitrile compound with an organic sulfonic acid.

[0008] A further object of the present invention is to provide a method for easily and efficiently producing a high-purity acid addition salt of a 4-amino-2-halobenzonitrile compound with an organic sulfonic acid.

[0009] As a result of intensive research to achieve the above-mentioned object, the present inventors have found that in a method for separating an acid addition salt of a 4-amino-2-halobenzonitrile compound and an acid from an isomer mixture of an aminohalobenzonitrile compound and an acid by utilizing the difference in solubility in a solvent between the isomers, by using an organic sulfonic acid as the acid, the difference in solubility in a solvent is significantly different from that of other acid addition salts, and the organic sulfonate salt of a 4-amino-2-halobenzonitrile compound can be produced industrially and advantageously. Furthermore, the present inventors have found that such a method can easily or efficiently produce an organic sulfonate salt of a 4-amino-2-halobenzonitrile compound, and can easily or efficiently produce a high-purity organic sulfonate salt of a 4-amino-2-halobenzonitrile compound. The present invention was completed based on these findings.

[0010] That is, the present invention may include the following aspects.

[0011] Aspect [1]: Formula (1) below

[0012]

[0013] (wherein X represents a halogen atom, R １ represents a substituent inert to the reaction, and n represents an integer of 0 to 3.

[0014] and an acid addition salt of an isomer mixture of an aminohalobenzonitrile compound represented by the following formula (2):

[0015]

[0016] (In the formula, X, R １ , n are the same as in formula (1) above).

[0017] and an organic sulfonic acid, utilizing the difference in solubility between isomeric acid addition salts in a solvent.

[0018] Aspect [2]: The method according to Aspect [1], wherein in the separation step, the method of separating isomers by utilizing the difference in solubility between the acid addition salts of the isomers in a solvent includes precipitation and / or extraction.

[0019] Aspect [3]: The method according to aspect [1] or [2], wherein in the separation step, the solvent contains an ester and / or an alcohol.

[0020] Aspect [4]: ​​The method according to any one of Aspects [1] to [3], which comprises a salt-forming step, as a pre-step before the separation step, of forming an acid addition salt by reacting an isomer mixture of the aminohalobenzonitrile compound represented by Formula (1) with the organic sulfonic acid, which contains at least the 4-amino-2-halobenzonitrile compound represented by Formula (2).

[0021] Aspect [5]: Formula (3) below

[0022]

[0023] (wherein, each X independently represents a halogen atom; R １ , n are the same as in formula (1) above).

[0024] and a 2,4-dihalobenzonitrile compound represented by the following formula (4):

[0025]

[0026] (In the formula, X, R １ , n are the same as in formula (3) above).

[0027] The method according to embodiment [4], further comprising an amination step of subjecting a dihalobenzonitrile compound represented by the following formula (I) to an amination reaction as a precursor to the salt formation step.

[0028] Aspect [6]: The method according to Aspect [4] or [5], wherein the reaction in the salt-forming step is carried out in the presence of a solvent, and the solvent used in the salt-forming step is the same as the solvent used in the separation step.

[0029] Aspect [7]: The method according to any one of aspects [1] to [6], wherein the organic sulfonic acid comprises an aromatic sulfonic acid.

[0030] Aspect [8]: The aromatic sulfonic acid is represented by the following formula (5):

[0031]

[0032] (wherein ring Z represents an arene ring; R ２ represents a substituent inert to the reaction, m represents an integer of 0 or more, and k represents an integer of 1 or more.

[0033] The method according to embodiment [7], wherein the sulfonic acid includes an arene ring-containing sulfonic acid represented by the formula:

[0034] Aspect [9]: In the formula (5), the ring Z is C ６－１４ is an arene ring, and R ２ is a linear or branched chain C １－３ The method according to embodiment [8], wherein m is an alkyl group, m is 0 or 1, and k is 1 or 2.

[0035] Aspect

[10] : The method according to any one of Aspects [1] to [9], wherein the ratio of sulfonic acid groups in the organic sulfonic acid is 0.8 to 1.2 moles per mole of the total amount of the isomeric mixture of aminohalobenzonitrile compounds represented by Formula (1).

[0036] Aspect

[11] : A method for producing an acid addition salt of the formula (6) below, comprising an amidation step of subjecting the acid addition salt produced by the method according to any one of aspects [1] to

[10] to a hydrolysis reaction:

[0037]

[0038] (In the formula, X, R １ , n are the same as those in formula (1) described in aspect [1].

[0039] The present invention relates to a method for producing a 4-amino-2-halobenzamide compound represented by the formula:

[0040] Aspect

[12] : Formula (2) below

[0041]

[0042] (In the formula, X, R １ , n are the same as those in formula (1) described in aspect [1].

[0043] and an acid addition salt of an organic sulfonic acid with a 4-amino-2-halobenzonitrile compound represented by the formula:

[0044] In the method of the present invention, an acid addition salt of a 4-amino-2-halobenzonitrile compound or a mixture of its isomers with an organic sulfonic acid (an organic sulfonate salt of a 4-amino-2-halobenzonitrile compound or a mixture of its isomers) can be separated from the resulting acid addition salt by utilizing the difference in solubility between the acid addition salts of the isomers in a solvent, thereby industrially advantageously producing the acid addition salt of the 4-amino-2-halobenzonitrile compound and an organic sulfonic acid. Furthermore, by selecting a specific solvent type as the solvent, the organic sulfonate salt of the target compound can be produced easily and efficiently (and, if necessary, with high purity).

[0045] In the present invention, an acid addition salt (2a) of a 4-amino-2-halobenzonitrile compound (2) and an organic sulfonic acid is produced in an industrially advantageous manner by separating an acid addition salt of a 4-amino-2-halobenzonitrile compound (2) represented by the formula (2) described below (hereinafter also referred to as "4-amino-2-halobenzonitrile compound (2)") and an organic sulfonic acid from an acid addition salt (1a) of an isomer mixture of an aminohalobenzonitrile compound represented by the formula (1) below (hereinafter also referred to as "aminohalobenzonitrile compound (1)") and an organic sulfonic acid through a separation step. A preferred embodiment may include an amination step in which a dihalobenzonitrile compound (4) represented by the formula (4) below (hereinafter also referred to as "dihalobenzonitrile compound (4)"), which may contain an isomer mixture, is subjected to an amination reaction to obtain an isomer mixture of aminohalobenzonitrile compound (1), and a salt formation step in which the obtained isomer mixture of aminohalobenzonitrile compound (1) is reacted with an organic sulfonic acid. The present invention may include at least the separation step.

[0046] To facilitate understanding of the invention, these steps are shown in the following scheme, where the organic sulfonic acid is organic monosulfonic acid A.

[0047]

[0048] (wherein, each X independently represents a halogen atom; R １ represents a substituent inert to the reaction, n represents an integer of 0 to 3, and A represents an organic monosulfonic acid.

[0049] [Amination Step] In the amination step, dihalobenzonitrile compound (4) containing at least a 2,4-dihalobenzonitrile compound represented by the following formula (3) (hereinafter also referred to as "2,4-dihalobenzonitrile compound (3)") is subjected to an amination reaction to convert one of the halogen atoms X to an amino group, thereby producing aminohalobenzonitrile compound (1) containing at least a 4-amino-2-halobenzonitrile compound (2).

[0050]

[0051] (wherein, each X independently represents a halogen atom; R １ represents a substituent inert to the reaction, and n represents an integer of 0 to 3.

[0052]

[0053] (wherein X represents a halogen atom, R １ , n is the same as in formula (3) above)

[0054] In the formulas (1), (2), (3) and (4), examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0055] Of these halogen atoms, a fluorine atom, a chlorine atom and a bromine atom are preferred, a fluorine atom and a chlorine atom are more preferred, and a fluorine atom is even more preferred.

[0056] In the formulas (3) and (4), the types of the two Xs may be different from each other, but it is preferable that they are the same.

[0057] In the formulas (1), (2), (3) and (4), the substituent R １ is not particularly limited as long as it is a group inert to the reaction, and examples thereof include a hydroxy group, a linear or branched alkyl group (e.g., a C group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group). １－６ alkyl groups, straight or branched alkoxy groups (e.g., methoxy groups, ethoxy groups, propoxy groups, etc.) １－６ alkoxy group, etc.), cycloalkyl group (e.g., cyclopropyl group, cyclobutyl group, cyclohexyl group, etc.) ３－１２ cycloalkyl groups, etc.).

[0058] These substituents R １ Among these, a linear or branched alkyl group, a linear or branched alkoxy group, and a cycloalkyl group are preferred, and a linear or branched alkyl group (for example, a linear or branched C １－６ alkyl group), and linear or branched C groups such as methyl and ethyl groups are more preferred. １－３ Alkyl groups are more preferred.

[0059] In the formulas (1), (2), (3) and (4), the substituent R １ The number of substitutions n in the substituent R may be an integer of 0 to 3, preferably an integer of 0 to 2, more preferably 0 or 1, and even more preferably 0. １ When the number of substitutions n is an integer of 2 or more, two or more substituents R １ The types may be different or the same.

[0060] In the formula (3), the substituent R １ The substitution position of may be any one of the 3-, 5- and / or 6-positions relative to the cyano group at the 1-position of the 2,4-dihalobenzonitrile compound (3).

[0061] Representative examples of the 2,4-dihalobenzonitrile compound (3) include 2,4-dihalobenzonitriles such as 2,4-difluorobenzonitrile, 2,4-dichlorobenzonitrile, and 2,4-dibromobenzonitrile.

[0062] In the formula (4), the substitution positions of the two halogen atoms X are not particularly limited as long as they include a combination of the 2- and 4-positions corresponding to the 2,4-dihalobenzonitrile compound (3). The substitution positions may include a combination of the 2- and 4-positions and a combination of any two of the 2-, 3-, 4-, 5-, and 6-positions (excluding the combination of the 2- and 4-positions) relative to the cyano group at the 1-position of the dihalobenzonitrile compound (4). The proportion of the 2,4-dihalobenzonitrile compound (3) in the dihalobenzonitrile compound (4) is, for example, 50% or more, preferably 60% or more (e.g., 70% or more), more preferably 80% or more (e.g., 90% or more), and most preferably 100% (i.e., the dihalobenzonitrile compound (4) contains only the 2,4-dihalobenzonitrile compound (3)).

[0063] In the formula (4), the substituent R １ The substitution position of may be different from the substitution position of the halogen atom X.

[0064] Representative dihalobenzonitrile compounds (4) include, for example, dihalobenzonitriles such as difluorobenzonitrile, dichlorobenzonitrile, and dibromobenzonitrile.

[0065] Examples of the aminating agent include ammonia, aqueous ammonia, and metal amide salts (e.g., alkali metal amides such as lithium amide, potassium amide, and sodium amide). Among these aminating agents, ammonia, aqueous ammonia, and alkali metal amides are preferred, ammonia and aqueous ammonia are more preferred, and aqueous ammonia is even more preferred.

[0066] These aminating agents can be used alone or in combination of two or more.

[0067] The proportion of the aminating agent relative to 1 mole of the dihalobenzonitrile compound (4) is, for example, 1 to 10 moles, preferably 2 to 8 moles, more preferably 3 to 7 moles, and even more preferably 4 to 6 moles. If the proportion of the aminating agent is too small, the yield may decrease.

[0068] In the amination step, the reaction of the dihalobenzonitrile compound (4) with an aminating agent may be carried out in the presence or absence of a solvent.

[0069] The solvent is preferably a polar solvent capable of dissolving the aminating agent, and for example, an aprotic polar organic solvent may be used.

[0070] Examples of aprotic polar organic solvents include sulfoxides (e.g., di-C such as dimethyl sulfoxide). １－６ alkyl sulfoxides, etc.), sulfones (e.g., cyclic sulfones such as sulfolane, etc.), amides [e.g., chain amides (e.g., N,N-diC amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc. １－６ Alkyl-C １－６ acylamides, etc.), cyclic amides (for example, N-methyl-2-pyrrolidone, etc.), ethers (for example, chain ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran, etc.), ketones (for example, acetone, methyl ethyl ketone, etc.), esters (for example, ethyl acetate, etc.), nitriles (for example, acetonitrile, etc.), etc.

[0071] These aprotic polar organic solvents can be used alone or in combination of two or more. Among these, sulfoxides are preferred, and diC １－６ Alkyl sulfoxides (e.g., diC １－４ Alkyl sulfoxides are more preferred, with dimethyl sulfoxide being even more preferred.

[0072] The proportion of the aprotic polar organic solvent may be any proportion that allows stirring of the reaction system, and is, for example, 50 to 500 parts by mass, preferably 100 to 400 parts by mass, more preferably 150 to 300 parts by mass, and even more preferably 200 to 250 parts by mass, relative to 100 parts by mass of the dihalobenzonitrile compound (4). If the proportion of the solvent is too low, stirring may become difficult, and if the proportion of the solvent is too high, the reaction may proceed slowly.

[0073] Furthermore, water may be added as the solvent in the form of an aqueous solution of the aminating agent.

[0074] The proportion of water as a solvent is, for example, 10 to 300 parts by mass, preferably 50 to 250 parts by mass, more preferably 100 to 200 parts by mass, and even more preferably 140 to 180 parts by mass, relative to 100 parts by mass of the dihalobenzonitrile compound (4).

[0075] The proportion of water as a solvent is, for example, 10 to 200 parts by mass, preferably 30 to 150 parts by mass, more preferably 40 to 100 parts by mass, and even more preferably 60 to 80 parts by mass, per 100 parts by mass of the organic solvent.

[0076] The reaction temperature is, for example, 50 to 180° C., preferably 70 to 150° C., more preferably 90 to 130° C., and more preferably 95 to 120° C. The reaction time is not particularly limited and is, for example, 2 to 40 hours, preferably 8 to 30 hours, more preferably 12 to 25 hours, and more preferably 15 to 21 hours.

[0077] The reaction may be carried out in air or an inert gas (e.g., nitrogen; a rare gas such as argon or helium), under atmospheric pressure or under pressure.

[0078] In the formula (2), the substituent R １ The substitution positions are the same as those in the formula (3).

[0079] Representative 4-amino-2-halobenzonitrile compounds (2) include 4-amino-2-halobenzonitriles such as 4-amino-2-fluorobenzonitrile, 4-amino-2-chlorobenzonitrile, and 4-amino-2-bromobenzonitrile.

[0080] In the formula (1), the substitution position of the halogen atom X is not particularly limited and may be any of the 2-, 3-, 4-, 5-, and 6-positions relative to the cyano group at the 1-position of the aminohalobenzonitrile compound (1), but among these, the 2- or 4-position is preferred.

[0081] In the formula (1), the substitution position of the amino group is not particularly limited, and may be any of the 2-, 3-, 4-, 5-, and 6-positions relative to the cyano group at the 1-position of the aminohalobenzonitrile compound (1), and among these, the 2- or 4-position is preferred.

[0082] That is, the aminohalobenzonitrile compound (1) preferably contains at least a 4-amino-2-halobenzonitrile compound (2) and a 2-amino-4-halobenzonitrile compound, more preferably contains a 4-amino-2-halobenzonitrile compound (2) and a 2-amino-4-halobenzonitrile compound as main components, and particularly preferably contains only a 4-amino-2-halobenzonitrile compound (2) and a 2-amino-4-halobenzonitrile compound.

[0083] Furthermore, the organic sulfonate salt of 4-amino-2-halobenzonitrile compound (2) appears to have a significantly lower solubility in a solvent than other isomers such as the organic sulfonate salt of 2-amino-4-halobenzonitrile compound. In the separation step described below, this difference in solubility is utilized to obtain the acid addition salt of 4-amino-2-halobenzonitrile compound (2). Therefore, by having aminohalobenzonitrile compound (1) contain 4-amino-2-halobenzonitrile compound (2) and a 2-amino-4-halobenzonitrile compound as main components, the efficiency of separation of the acid addition salt can be improved.

[0084] In the formula (1), the substituent R １ The substitution position of may be different from the substitution positions of the halogen atom X and the amino group.

[0085] Representative examples of the aminohalobenzonitrile compound (1) include 4-amino-2-halobenzonitriles such as 4-amino-2-fluorobenzonitrile, 4-amino-2-chlorobenzonitrile, and 4-amino-2-bromobenzonitrile, and 2-amino-4-halobenzonitriles such as 2-amino-4-fluorobenzonitrile, 2-amino-4-chlorobenzonitrile, and 2-amino-4-bromobenzonitrile.

[0086] [Salt Formation Step] In the salt formation step, an isomer mixture of aminohalobenzonitrile compounds (1) containing at least 4-amino-2-halobenzonitrile compounds (2) is reacted with an organic sulfonic acid to form an acid addition salt of the isomer mixture (organic sulfonate salt of the mixture).

[0087] In the present invention, by selecting an organic sulfonic acid as the acid, the efficiency of separating the target acid addition salt of 4-amino-2-halobenzonitrile compound (2) from the acid addition salt of the isomer mixture in the separation step described below can be improved.

[0088] The organic sulfonic acid is not particularly limited as long as it has one or more sulfonic acid groups in the molecule, can form a salt with the 4-amino-2-halobenzonitrile compound (1), and can be separated from isomers. Examples include sulfonic acids that have no aromatic ring in the molecule and have an aliphatic hydrocarbon group (aliphatic sulfonic acids), and sulfonic acids that have at least one aromatic ring in the molecule (aromatic sulfonic acids).

[0089] These organic sulfonic acids may be used alone or in combination of two or more.

[0090] Examples of aliphatic sulfonic acids include alkanesulfonic acids (e.g., C alkane sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and dodecanesulfonic acid). １－１２ C alkane sulfonic acids, etc.), alkenyl sulfonic acids (e.g., vinyl sulfonic acid, butenyl sulfonic acid, etc. ２－１２ alkenylsulfonic acids, etc.), halogenated sulfonic acids (e.g., trihalo C such as trichloromethanesulfonic acid, tribromomethanesulfonic acid, trifluoromethanesulfonic acid, etc.１－６ Alkanesulfonic acids, etc.

[0091] These aliphatic sulfonic acids may be used alone or in combination of two or more.

[0092] Examples of the aromatic ring of the aromatic sulfonic acid include an aromatic heterocycle containing a nitrogen atom, an oxygen atom, or a sulfur atom as a ring-constituting atom, an arene ring, etc. These aromatic sulfonic acids can be used alone or in combination of two or more.

[0093] Examples of aromatic heterocycles include heterocycles containing at least one heteroatom, such as nitrogen-containing heterocycles (e.g., pyridine ring, quinoline ring, carbazole ring, imidazole ring, phthalimide ring, etc.) and nitrogen- and oxygen-containing heterocycles (e.g., oxazole ring, isoxazole ring, etc.).

[0094] The arene ring may be either a monocyclic arene ring (for example, a benzene ring) or a polycyclic arene ring (for example, a fused polycyclic arene ring, a ring assembly arene ring, etc.).

[0095] The fused polycyclic arene ring includes, for example, a fused bicyclic arene ring (e.g., a fused bicyclic C ring such as a naphthalene ring or an indene ring). １０－２０ arene ring, etc.), fused tricyclic arene ring (e.g., fused tricyclic C such as anthracene ring, phenanthrene ring, etc. １４－２０ arene rings, etc.

[0096] Examples of the ring-assembled arene ring include biarene rings (e.g., C 11111 such as biphenyl ring, phenylnaphthalene ring, and binaphthyl ring). １２－２０ Biarene ring, etc.

[0097] Among these aromatic rings, monocyclic arene rings (e.g., benzene ring, etc.), fused polycyclic arene rings (e.g., fused bicyclic C rings such as naphthalene ring and indene ring), １０－２０ Fused tricyclic rings such as arene rings, anthracene rings, and phenanthrene rings １４－２０arene rings, etc.), a monocyclic arene ring or a fused bicyclic arene ring is more preferred, a benzene ring or a naphthalene ring is more preferred, and a benzene ring is most preferred.

[0098] In the aromatic sulfonic acid, the aromatic ring and the sulfonic acid group may be bonded directly or via a linking group (such as an alkylene group), but a direct bond is preferred.

[0099] Examples of aromatic sulfonic acids in which the aromatic ring is an arene ring include compounds represented by the following formula (5).

[0100]

[0101] (wherein ring Z represents an arene ring; R ２ represents a substituent inert to the reaction, m represents an integer of 0 or more, and k represents an integer of 1 or more.

[0102] Examples of ring Z include arene rings such as monocyclic arene rings and polycyclic arene rings exemplified as the aromatic rings contained in the aromatic sulfonic acids.

[0103] Among these arene rings, C ６－２０ An arene ring is preferred, and C ６－１４ An arene ring is more preferred, and C ６－１２ An arene ring is more preferred, and C such as a benzene ring or a naphthalene ring is preferred. ６－１０ An arene ring is particularly preferred, and a benzene ring is most preferred.

[0104] Substituent R ２ is not particularly limited as long as it is a group inert to the reaction, and examples thereof include a hydroxy group, a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), a nitro group, a linear or branched alkyl group (e.g., a C group such as a methyl group, an ethyl group, or a propyl group), １－１２ alkyl groups, straight or branched alkoxy groups (e.g., methoxy groups, ethoxy groups, propoxy groups, etc.) １－１２ alkoxy group, etc.), cycloalkyl group (e.g., cyclopropyl group, cyclobutyl group, cyclohexyl group, etc.) ３－１４Among these, alkyl groups (for example, linear or branched C cycloalkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl groups) are preferred. １－６ alkyl groups, alkoxy groups (e.g., linear or branched C groups such as methoxy, ethoxy, propoxy, and isopropoxy groups); １－６ alkoxy group, etc.), cycloalkyl group (e.g., cyclobutyl group, cyclohexyl group, etc.) ３－１２ A cycloalkyl group is preferred, and a linear or branched C alkyl group such as a methyl group, an ethyl group, a propyl group, or a butyl group is preferred. １－４ Alkyl groups are more preferred, and linear or branched C groups such as methyl and ethyl groups are preferred. １－３ Alkyl groups are more preferred.

[0105] Substituent R ２ The number of substitutions m in the substituent R may be an integer of 0 or more, preferably an integer of 0 to 3, more preferably an integer of 0 to 2, even more preferably 0 or 1, and most preferably 1. ２ When the number of substitutions m is an integer of 2 or more, two or more substituents R ２ The types of the substituents R may be different or the same. ２ The substitution position of is not particularly limited, and when ring Z is a benzene ring and m is 1, the substitution position of the substituent R ２ is preferably in the para position relative to the sulfonic acid group.

[0106] The number k of sulfonic acid group substitutions may be an integer of 1 or more, preferably an integer of 1 to 3, more preferably 1 or 2, and more preferably 1 from the viewpoint of the purity of the resulting product.

[0107] Representative compounds represented by the formula (5) include, for example, benzene mono- or disulfonic acids which may have one or more (for example, 2 or 3) alkyl groups, such as benzenesulfonic acid and p-toluenesulfonic acid; and naphthalene mono- or disulfonic acids which may have one or more (for example, 2 or 3) alkyl groups, such as 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, and 2,6-naphthalenedisulfonic acid.

[0108] These aromatic sulfonic acids represented by the formula (5) may be used alone or in combination of two or more.

[0109] Among these organic sulfonic acids, aromatic sulfonic acids are preferred in terms of the efficiency of separation of the acid addition salt with the 4-amino-2-halobenzonitrile compound (2) and productivity, and aromatic sulfonic acids represented by the formula (5) are more preferred. In the formula (5), the ring Z is C ６－１４ Arene ring, R ２ is an alkyl group, m is an integer of 0 to 2, and k is an integer of 1 to 3. １－６ benzene mono- or disulfonic acids which may have an alkyl group; C 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, etc. １－６ Naphthalene mono- or disulfonic acids which may have an alkyl group are more preferred, and C 1 ... １－３ benzenemonosulfonic acids which may have an alkyl group; C １－３ Naphthalene monosulfonic acid which may have an alkyl group is particularly preferred, and C 6 hydroxybenzoates such as p-toluenesulfonic acid are particularly preferred. １－３ Benzene monosulfonic acid which may have an alkyl group is most preferred.

[0110] The proportion of the organic sulfonic acid (particularly the aromatic sulfonic acid represented by the formula (5)) is, for example, 0.1 to 3 moles, preferably 0.4 to 2 moles, more preferably 0.6 to 1.5 moles, and even more preferably 0.8 to 1.2 moles of sulfonic acid groups per mole of the total amount of the isomer mixture of aminohalobenzonitrile compound (1). If the proportion of sulfonic acid groups is too low, the yield of the target product may decrease, whereas if the proportion of sulfonic acid groups is too high, the purity of the target product may decrease.

[0111] The reaction to form an acid addition salt may be carried out in the presence or absence of a solvent, preferably in the presence of a solvent.

[0112] The solvent may be an organic solvent or an organic solvent containing water, for example, water may be contained in the form of a hydrate of an organic sulfonic acid.

[0113] Examples of organic solvents include aliphatic hydrocarbons, alicyclic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, sulfoxides, sulfones, amides, nitriles, esters, and alcohols, and these may be either polar or non-polar solvents.

[0114] Examples of aliphatic hydrocarbons include linear or branched C cyclohexane such as pentane, hexane, heptane, octane, nonane, and decane. ５－１５ Alkanes and the like.

[0115] Examples of alicyclic hydrocarbons include C cyclopentane, cyclohexane, cyclooctane, and the like. ５－１５ Cycloalkanes and the like.

[0116] Examples of aromatic hydrocarbons include mono- or di-C hydrocarbons such as benzene, toluene, and xylene. １－６ Alkylbenzenes and the like.

[0117] Examples of halogenated hydrocarbons include chlorinated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene.

[0118] Examples of ethers include chain ethers (such as diethyl ether) and cyclic ethers (such as tetrahydrofuran).

[0119] Examples of ketones include chain ketones (for example, linear or branched di-C ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diisobutyl ketone). １－１２ alkyl ketones, cyclic ketones (for example, cyclohexanone), and the like.

[0120] Examples of sulfoxides include dialkyl sulfoxides (e.g., di-C such as dimethyl sulfoxide). １－６ alkyl sulfoxides, etc.)

[0121] Examples of sulfones include cyclic sulfones such as sulfolane.

[0122] Examples of amides include N,N-dialkyl acyl amides (e.g., N,N-diC amides such as N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, and N,N-diethylacetamide). １－６ Alkyl-C １－６ and cyclic amides such as N-methyl-2-pyrrolidone.

[0123] Examples of nitriles include C nitriles such as acetonitrile and propionitrile. １－６ C alkyl nitriles, benzonitriles, etc. ６－１２ arene-nitrile and the like.

[0124] Examples of the esters include chain esters [for example, carboxylic acid esters (for example, alkanoic acid esters) such as formate esters, acetate esters, propionate esters, and butyrate esters; hydroxycarboxylic acid esters (for example, hydroxyalkanoic acid esters) such as lactate esters; ether esters (for example, C esters such as ethylene glycol monomethyl ether acetate and propylene glycol monomethyl ether acetate); ２－１０ Alkylene glycol mono C １－１０Alkyl Ether C １－１０ acylates, etc.)], cyclic esters (for example, three-membered ring lactones, four-membered ring lactones, five-membered ring lactones, six-membered ring lactones, etc.), and the like.

[0125] Examples of formic acid esters include alkyl formates (e.g., formic acid C such as methyl formate, ethyl formate, propyl formate, and butyl formate). １－６ alkyl, etc.).

[0126] Examples of acetate esters include alkyl acetate esters (e.g., acetate C such as methyl acetate, ethyl acetate, propyl acetate, and butyl acetate). １－６ alkyl, etc.).

[0127] Examples of propionic acid esters include propionic acid alkyl esters (e.g., propionic acid C esters such as methyl propionate, ethyl propionate, propyl propionate, and butyl propionate). １－６ alkyl, etc.).

[0128] Examples of butyrate esters include alkyl butyrate esters (e.g., butyrate C such as ethyl butyrate, isopropyl butyrate, and butyl butyrate). １－６ alkyl esters, etc.).

[0129] Examples of lactate esters include alkyl lactate esters (e.g., lactic acid C esters such as methyl lactate, ethyl lactate, and butyl lactate). １－６ alkyl esters, etc.).

[0130] Examples of cyclic esters include C esters such as β-propiolactone, γ-butyrolactone, δ-valerolactone, and ε-caprolactone. ２－１０ Cyclic esters and the like are included.

[0131] Examples of alcohols include linear or branched alcohols (e.g., linear or branched C alcohols such as methanol, ethanol, n-propanol, isopropanol (isopropyl alcohol), n-butanol, isobutanol, sec-butanol, tert-butanol, n-pentanol, isopentanol, 2-methylbutanol, sec-pentanol, and tert-pentanol). １－１２ alkanols, etc.), ether alcohols (e.g., 2-methoxyethanol, 2-methoxypropanol, 2-ethoxyethanol, propylene glycol monomethyl ether, etc. ２－１０ Alkylene glycol mono or di C １－１０ alkyl ethers, etc.

[0132] These organic solvents may be used alone or in combination of two or more.

[0133] Among these organic solvents, ethers, ketones, esters, and alcohols are preferred because they can be easily used as solvents for separating the target compound in the separation step described below, and esters [e.g., alkyl carboxylic acid esters such as alkyl acetate esters (e.g., alkyl alkanoates)] and alcohols (e.g., linear or branched alcohols) are more preferred, and acetate C such as methyl acetate, ethyl acetate, and propyl acetate are more preferred. １－６ Linear or branched C alkyl esters such as methanol, ethanol, n-propyl alcohol, and isopropyl alcohol １－６ Alkanols are more preferred, and acetates such as methyl acetate and ethyl acetate are preferred. １－３ C such as alkyl esters, methanol, ethanol, and isopropyl alcohol １－３ Alkanols are particularly preferred, with isopropyl alcohol being most preferred.

[0134] The proportion of the solvent may be any proportion that allows stirring of the reaction system, and is, for example, 50 to 500 parts by mass, preferably 100 to 400 parts by mass, more preferably 150 to 350 parts by mass, and even more preferably 200 to 300 parts by mass, relative to 100 parts by mass of the total amount of the isomer mixture of aminohalobenzonitrile compound (1). If the proportion of the solvent is too small, stirring may become difficult, and if the proportion of the solvent is too large, the reaction may proceed slowly.

[0135] The reaction temperature is, for example, 0 to 50° C., preferably 10 to 40° C., further preferably 15 to 35° C., and even more preferably 20 to 30° C. The reaction time is not particularly limited and is, for example, 0.5 to 5 hours, preferably 1 to 2 hours.

[0136] The reaction may be carried out in air or an inert gas (e.g., nitrogen; a rare gas such as argon or helium), under atmospheric pressure or under pressure.

[0137] [Separation Step] In the separation step, the acid addition salt of 4-amino-2-halobenzonitrile compound (2) with an organic sulfonic acid (organic sulfonate of the target compound) is separated from the acid addition salt of an isomer mixture of aminohalobenzonitrile compound (1) with an organic sulfonic acid (a mixture containing an organic sulfonate of the target compound and an organic sulfonate of another isomer) by utilizing the difference in solubility between the acid addition salts of the mixture in a solvent.

[0138] Examples of separation methods that utilize differences in solubility in a solvent include precipitation (or crystallization), solvent extraction (or elution), and combinations of these.

[0139] These methods may be used alone or in combination with one or more conventional separation means selected from washing, concentration, solid-liquid separation (filtration, centrifugation, decantation, etc.), column chromatography, etc.

[0140] The organic sulfonate of the target compound may be obtained in either a liquid phase or a solid phase, but from the viewpoint of productivity, it is preferable to obtain it in a solid phase.

[0141] The precipitation (or crystallization) may be carried out by conventional means, in which the organic sulfonate of the target compound is precipitated as a solid product from a precipitation solvent (crystallization solvent), and the organic sulfonate of the other isomer is dissolved in the precipitation solvent (crystallization solvent), thereby separating the organic sulfonate of the target compound from the mixture.

[0142] Examples of the precipitation (or crystallization) method include cooling crystallization, poor solvent crystallization, concentration crystallization, reprecipitation, and combinations of these. Of these, cooling crystallization is preferred.

[0143] The solvent extraction (or elution) may be carried out by a conventional means. In the solvent extraction (or elution), an isomer mixture containing the organic sulfonate of the target compound is concentrated or dried, and then an extraction solvent (elution solvent) is used to extract the organic sulfonate of the other isomer into a liquid phase, thereby separating the organic sulfonate of the target compound from the mixture.

[0144] The precipitation solvent (crystallization solvent) and the extraction solvent (dissolution solvent) may contain at least an organic solvent and may also contain water, for example, water that has been added in the form of a hydrate of an organic sulfonic acid in the salt formation step.

[0145] Examples of the organic solvent include the organic solvents exemplified in the salt-forming step.

[0146] These organic solvents may be used alone or in combination of two or more.

[0147] Among these organic solvents, ethers, ketones, esters, and alcohols are preferred, and from the viewpoint of productivity, esters [e.g., alkyl esters of carboxylic acids such as alkyl acetates (e.g., alkyl alkanoates)] and alcohols (e.g., linear or branched alcohols) are more preferred, and acetate C such as methyl acetate, ethyl acetate, and propyl acetate are more preferred. １－６ Linear or branched C alkyl esters such as methanol, ethanol, n-propyl alcohol, and isopropyl alcohol １－６ Alcohol (C １－６Alkanols, etc.) are more preferred, and acetic acid C such as methyl acetate and ethyl acetate is preferred. １－３ C such as alkyl esters, methanol, ethanol, and isopropyl alcohol １－３ Alcohol (C １－３ Alkanols, etc. are particularly preferred, with isopropyl alcohol being most preferred.

[0148] Of these organic solvents, from the viewpoint of purity of the product, alcohols are preferred, methanol, ethanol, n-propyl alcohol and isopropyl alcohol are more preferred, and isopropyl alcohol is most preferred.

[0149] In the precipitation (or crystallization) step, the precipitation solvent (crystallization solvent) may be different from the reaction solvent used in the salt-forming step, but is preferably the same as the reaction solvent. If the precipitation solvent is the same as the reaction solvent, the reaction solvent can be used as the precipitation solvent (crystallization solvent) as is, thereby improving productivity.

[0150] The concentration of the acid addition salt in the solution subjected to the precipitation (or crystallization) method (particularly cooling crystallization) is, for example, 5 to 80% by mass, preferably 10 to 65% by mass, more preferably 30 to 60% by mass, and even more preferably 40 to 55% by mass. If the concentration of the acid addition salt is too low, the yield may decrease, whereas if the concentration of the acid addition salt is too high, the stirring uniformity and temperature gradient in the crystallization tank may not be maintained.

[0151] The cooling temperature is not particularly limited as long as it is a temperature at which an organic sulfonate salt of the target compound precipitates, and may be, for example, −20° C. to 25° C., preferably −10° C. to 20° C., more preferably −5° C. to 10° C., and even more preferably 0 to 5° C.

[0152] For cooling crystallization, the cooling rate is not particularly limited and is, for example, 0.01 to 8°C / min, preferably 0.05 to 5°C / min, further preferably 0.1 to 2°C / min, and even more preferably 0.5 to 1°C / min. If the cooling rate is too fast, the purity of the target product may be reduced, whereas if the cooling rate is too slow, productivity may be reduced.

[0153] After precipitation (or crystallization), solid-liquid separation (filtration, centrifugation, decantation, etc.) can be carried out to obtain the separated organic sulfonate of the target compound.

[0154] The precipitation (or crystallization) operation may be performed once or may be repeated multiple times. When the precipitation (or crystallization) operation is repeated multiple times, the precipitation solvent (crystallization solvent) after solid-liquid separation may be concentrated and further precipitated (for example, by cooling crystallization) to recover the organic sulfonate of the target compound.

[0155] The obtained organic sulfonate salt of the target compound may be purified by one or more conventional methods selected from washing with the above-mentioned deposition solvent, distillation, sublimation, column chromatography, and the like.

[0156] In the extraction (or elution) step, the reaction solvent used in the salt formation step is concentrated or dried up, and therefore the extraction solvent may be the same as or different from the reaction solvent.

[0157] The ratio of the extraction solvent is, for example, 1 to 50 parts by mass, preferably 5 to 40 parts by mass, more preferably 10 to 35 parts by mass, and even more preferably 15 to 30 parts by mass, relative to 100 parts by mass of the isomer mixture containing the organic sulfonate of the target compound.

[0158] The concentration of the isomer mixture containing the organic sulfonate salt of the target compound after concentration or drying is, for example, 70% by mass or more, preferably 85% by mass or more, more preferably 95% by mass or more, and even more preferably 99% by mass or more. If the concentration of the salt mixture is too low, the yield may decrease.

[0159] The solvent extraction (or elution) temperature is not particularly limited as long as it is a temperature at which the organic sulfonate salt of the other isomer is extracted (or eluted) into the liquid phase by the extraction solvent, and is, for example, 0 to 50°C, preferably 5 to 45°C, more preferably 10 to 40°C, and even more preferably 20 to 35°C.

[0160] After the extraction (or elution), solid-liquid separation (filtration, centrifugation, decantation, etc.) can be carried out to obtain the separated organic sulfonate salt of the target compound.

[0161] The solvent extraction (or elution) operation may be performed once or may be repeated multiple times. When repeated multiple times, the extraction solvent after solid-liquid separation may be concentrated or dried to recover the solid phase, and then further extraction (or elution) may be performed. When extraction (or elution) is performed multiple times, the types of solvents may be the same or different.

[0162] The obtained organic sulfonate salt of the target compound may be purified by one or more conventional methods selected from washing with the above-mentioned extraction solvent, distillation, sublimation, column chromatography, and the like.

[0163] Precipitation (or crystallization) and solvent extraction (or elution) may be used alone or in combination.

[0164] Of these separation methods, precipitation (or crystallization) is preferred because it allows the salt formation step and the separation step to be carried out continuously using the reaction solvent as a precipitation solvent, thereby improving productivity.

[0165] [Acid Addition Salt of 4-Amino-2-Halobenzonitrile Compound and Organic Sulfonic Acid] The present invention includes an acid addition salt of a 4-amino-2-halobenzonitrile compound (2) represented by the following formula (2) and an organic sulfonic acid.

[0166]

[0167] (wherein X represents a halogen atom, R １ represents a substituent inert to the reaction, and n represents an integer of 0 to 3.

[0168] In the formula (2), the halogen atom of X and the substituent R １ and the integer n is the halogen atom of X shown in the separation step above, including the preferred embodiment, R １ and the integer n are the same as those in the above formula (1).

[0169] Representative examples of the compound represented by the formula (2) include 4-amino-2-fluorobenzonitrile, 4-amino-2-chlorobenzonitrile, and 4-amino-2-bromobenzonitrile.

[0170] The organic sulfonic acid, including preferred embodiments thereof, is the same as that shown in the salt-forming step, and aromatic sulfonic acids represented by the formula (5) are preferred.

[0171] Representative combinations of the acid addition salts of the 4-amino-2-halobenzonitrile compound (2) and organic sulfonic acids include, for example, acid addition salts of the 4-amino-2-halobenzonitrile compound (2) and aromatic sulfonic acids represented by the formula (5), and acid addition salts of the 4-amino-2-fluorobenzonitrile and at least one selected from benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, and 2,6-naphthalenedisulfonic acid. １－６ C optionally having an alkyl group ６－１０ and acid addition salts with arene mono- or disulfonic acids.

[0172] These acid addition salts of 4-amino-2-halobenzonitrile compounds with organic sulfonic acids are useful as intermediates for pharmaceuticals, reagents, etc.

[0173] [Amidation Step] In the present invention, the separation step may be followed by an amidation step of producing a 4-amino-2-halobenzamide compound represented by the following formula (6) (hereinafter also simply referred to as "4-amino-2-halobenzamide compound (6)") or an organic sulfonate salt thereof:

[0174] The amidation step is shown in the following scheme:

[0175]

[0176] (In the formula, X, R １ , n is the same as in the formula (2) above, including preferred embodiments.

[0177] In the amidation step, the compounds represented by the formulas (2) and (6) may be in the form of an organic sulfonate salt. From the viewpoint of productivity, it is preferable to subject the 4-amino-2-halobenzonitrile compound (2) to the amidation reaction as a salt.

[0178] In the amidation step, the 4-amino-2-halobenzamide compound (6) represented by the formula (6) or an organic sulfonate thereof is produced by subjecting the 4-amino-2-halobenzonitrile compound (2) or an organic sulfonate thereof to a hydrolysis reaction.

[0179] Representative examples of the 4-amino-2-halobenzamide compound (6) include 4-amino-2-halobenzamides such as 4-amino-2-fluorobenzamide, 4-amino-2-chlorobenzamide, and 4-amino-2-bromobenzamide.

[0180] The hydrolysis reaction may be carried out in the presence of a base or an acid, and is preferably carried out in the presence of a base.

[0181] Examples of the base used in the hydrolysis reaction include alkali metal hydroxides (e.g., lithium hydroxide, potassium hydroxide, sodium hydroxide, etc.), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, etc.), ammonia (aqueous ammonia), etc. These bases may be used alone or in combination of two or more.

[0182] Of these, alkali metal hydroxides are preferred, sodium hydroxide and potassium hydroxide are more preferred, and sodium hydroxide is even more preferred.

[0183] The proportion of the base in the hydrolysis reaction is, for example, 0.3 to 10 moles, preferably 0.5 to 6 moles, more preferably 0.8 to 3 moles, and more preferably 0.9 to 1.5 moles, relative to 1 mole of the 4-amino-2-halobenzonitrile compound (2). The proportion of the base is, for example, 1 to 8 equivalents, preferably 1.05 to 5 equivalents, more preferably 1.1 to 2 equivalents, and more preferably 1.2 to 1.3 equivalents, relative to 1 equivalent of the 4-amino-2-halobenzonitrile compound (2). If the proportion of the base is too low, the reaction rate may be slow, whereas if the proportion is too high, there is a risk of large amounts of impurities being produced as by-products.

[0184] The hydrolysis reaction is preferably carried out under basic conditions in the presence of a peroxide, from the viewpoint of improving the yield of the target product by stopping the progress of hydrolysis at the stage of amide group formation. The peroxide may be an inorganic peroxide or an organic peroxide.

[0185] Examples of inorganic peroxides include hydrogen peroxide, alkali metal peroxides (e.g., sodium peroxide, lithium peroxide, etc.), alkaline earth metal peroxides (e.g., magnesium peroxide, calcium peroxide, etc.), and persulfates (e.g., ammonium persulfate, potassium persulfate, etc.).

[0186] Examples of organic peroxides include peracids (for example, peracetic acid, perbenzoic acid, perchlorobenzoic acid, etc.), and hydroperoxides (for example, t-butyl hydroperoxide, t-amyl hydroperoxide, cumene hydroperoxide, etc.).

[0187] These peroxides can be used alone or in combination of two or more. Among these, inorganic peroxides are preferred, and hydrogen peroxide is more preferred.

[0188] The proportion of the peroxide is, for example, 0.1 to 10 moles, preferably 1 to 5 moles, and more preferably 1.5 to 2.5 moles, relative to 1 mole of the acid addition salt of the 4-amino-2-halobenzonitrile compound (2) and an organic sulfonic acid. If the proportion of the peroxide is too small, the yield may decrease, whereas if it is too large, the hydrolysis reaction may proceed further, resulting in the production of a carboxylic acid.

[0189] The reaction may be carried out in the presence of a solvent, which may be an organic solvent containing water as at least one reactant.

[0190] Examples of the organic solvent include polar solvents (for example, protic polar solvents, aprotic polar solvents, etc.).

[0191] Examples of the protic polar solvent include alcohols (C such as methanol, ethanol, isopropyl alcohol, hexanol, and decanol). １－１２ alkyl alcohols, etc.

[0192] Examples of aprotic polar solvents include alkyl halides (e.g., dichloromethane), amides (e.g., chain amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and cyclic amides such as N-methyl-2-pyrrolidone), nitriles (e.g., acetonitrile and propionitrile), sulfoxides (e.g., di-C such as dimethyl sulfoxide), １－６ alkyl sulfoxides, etc.), sulfones (e.g., cyclic sulfones such as sulfolane, etc.), ethers (e.g., chain ethers such as diethyl ether and diisopropyl ether, cyclic ethers such as tetrahydrofuran, etc.), ketones (e.g., acetone and methyl ethyl ketone), esters (e.g., ethyl acetate, etc.), etc.

[0193] These organic solvents can be used alone or in combination of two or more. When two or more types are used in combination, the combination is preferably a mixed solvent of a protic polar solvent and an aprotic polar solvent, more preferably a mixed solvent of an alcohol and a sulfoxide, and C １－３ Alkyl alcohol and diC １－３ A mixed solvent of alkyl sulfoxides (for example, a mixed solvent of methanol and dimethyl sulfoxide) is more preferred.

[0194] The proportion of the organic solvent is, for example, 50 to 1,000 parts by mass, preferably 100 to 500 parts by mass, more preferably 150 to 300 parts by mass, and even more preferably 200 to 250 parts by mass, relative to 100 parts by mass of the acid addition salt of 4-amino-2-halobenzonitrile compound (2) and organic sulfonic acid.

[0195] The proportion of the protic polar solvent is, for example, 10 to 1,000 parts by mass, preferably 50 to 800 parts by mass, further preferably 100 to 650 parts by mass, further preferably 150 to 500 parts by mass, and most preferably 180 to 220 parts by mass, relative to 100 parts by mass of the acid addition salt of 4-amino-2-halobenzonitrile compound (2) and organic sulfonic acid. If the proportion of the protic polar solvent is too low, the yield may decrease, whereas if the proportion is too high, the yield may also decrease.

[0196] The proportion of the protic polar solvent is, for example, 200 to 2000 parts by mass, preferably 400 to 1500 parts by mass, more preferably 600 to 1300 parts by mass, and even more preferably 800 to 1000 parts by mass, relative to 100 parts by mass of the aprotic polar solvent. If the proportion of the protic polar solvent is too low, the yield may decrease, and if it is too high, the yield may also decrease.

[0197] The proportion of the aprotic polar solvent is, for example, 5 to 100 parts by mass, preferably 10 to 80 parts by mass, more preferably 15 to 60 parts by mass, and even more preferably 20 to 40 parts by mass, relative to 100 parts by mass of the acid addition salt of 4-amino-2-halobenzonitrile compound (2) and organic sulfonic acid.

[0198] The proportion of water is preferably 0.1 to 20 moles, more preferably 1 to 15 moles, and even more preferably 6 to 10 moles, per mole of the acid addition salt of 4-amino-2-halobenzonitrile compound (2) and an organic sulfonic acid. The proportion of water is, for example, 10 to 100 parts by mass, preferably 20 to 80 parts by mass, more preferably 25 to 60 parts by mass, and even more preferably 30 to 50 parts by mass, per 100 parts by mass of the acid addition salt of 4-amino-2-halobenzonitrile compound (2) and an organic sulfonic acid. If the proportion of water is too low, the progress of the hydrolysis reaction may be slowed, and if the proportion of water is too high, the yield may be reduced.

[0199] The proportion of water is, for example, 1 to 200 parts by mass, preferably 5 to 100 parts by mass, more preferably 8 to 50 parts by mass, and even more preferably 10 to 20 parts by mass, relative to 100 parts by mass of the total of the organic solvents. If the proportion of water is too low, the progress of the hydrolysis reaction may be slowed, whereas if it is too high, the yield may be reduced.

[0200] The water may be contained in the form of an aqueous solution of the peroxide and / or the base, or may be contained as a mixed solvent of water and an organic solvent.

[0201] The reaction temperature is, for example, 10 to 100°C, preferably 20 to 80°C, more preferably 30 to 60°C, and even more preferably 40 to 50°C.

[0202] The reaction time is not particularly limited and is, for example, 1 to 10 hours, preferably 1.5 to 5 hours, and more preferably 2 to 3 hours.

[0203] The reaction may be carried out in air or an inert gas (e.g., nitrogen; a rare gas such as argon or helium); the reaction may be carried out under atmospheric pressure or under increased pressure. After completion of the reaction, the reaction product may be separated and purified by a conventional separation and purification means such as neutralization, washing, extraction or elution, concentration, filtration, reprecipitation, centrifugation, precipitation or crystallization, or column chromatography, or a combination of these. By neutralization or the like, the 4-amino-2-halobenzamide compound (6) in the form of an organic sulfonate may be obtained as a liberated 4-amino-2-halobenzamide compound (6).

[0204] The method of the present invention for producing an acid addition salt of 4-amino-2-halobenzonitrile compound (2) and an organic sulfonic acid is sufficient as long as it includes at least a separation step, and may further include a salt-forming step as a step preceding the separation step, or may include an amination step as a step preceding the salt-forming step.

[0205] The present invention will be described in more detail below based on examples, but the present invention is not limited to these examples. Evaluation methods are shown below.

[0206] [ １ H-NMR] JEOL Ltd.'s "JNM-ECZ400 (400 MHz)" or JEOL Ltd.'s "JNM-ECA600 (600 MHz)" was used, and chloroform-d (CDCl) was used as a heavy solvent. ３ ), and tetramethylsilane (TMS) was used as a standard substance.

[0207] [HPLC] Using a "High-Pressure Gradient HPLC System / Detector SPD-M20A" manufactured by Shimadzu Corporation, a sample was dissolved in a mixed solvent (volume ratio 2 / 3) of 0.1% by mass formic acid water and 15% by volume acetonitrile-containing methanol solution and measured, and the composition ratio (molar ratio) was calculated based on the HPLC area percentage ratio. The purity of the sample can be calculated based on this composition ratio.

[0208] [Melting Point] The melting point was measured using a melting point measuring device (Buchi "535") in accordance with JIS K 4101 (1993) [5.1 Visual Observation Method].

[0209] Synthesis Example 1 Synthesis of crude 4-amino-2-fluorobenzonitrile [mixture of 4A2FBN (4-amino-2-fluorobenzonitrile) and 2A4FBN (2-amino-4-fluorobenzonitrile)]

[0210]

[0211] A 2 L SUS autoclave was charged with 242.6 g of dimethyl sulfoxide, 112.3 g (0.8087 mol) of 2,4-difluorobenzonitrile (DFBN), and 245.9 g of 28 mass % aqueous ammonia (5.0 molar ratio relative to DFBN), and the mixture was heated to 100°C and reacted for 18 hours.

[0212] After the reaction was completed, 587.7 g of the reaction solution obtained, water, and ethyl acetate were placed in a 1 L flask under a nitrogen atmosphere, stirred, and subjected to liquid separation and extraction. 315.7 g of a yellow solution containing crude 4A2FBN and ethyl acetate (crude 4A2FBN-ethyl acetate solution) was obtained as an organic layer (composition ratio: 4A2FBN / 2A4FBN=58 / 42, yield of 4A2FBN: 57.6% relative to DFBN).

[0213] Example 1 Purification of Crude 4A2FBN (using p-toluenesulfonic acid as the organic sulfonic acid, and isopropyl alcohol as the reaction solvent and precipitation solvent) A 500 mL flask was charged with 315.7 g of the crude 4A2FBN-ethyl acetate solution obtained in Synthesis Example 1, and the solvent was removed by concentration under reduced pressure. 272.5 g of isopropyl alcohol and 153.8 g of p-toluenesulfonic acid monohydrate (1.0 molar ratio (to DFBN)) were then charged, and the mixture was reacted at 20 to 30°C for 1 hour.

[0214] After completion of the reaction, the resulting solution was cooled from 28°C to 5°C at a cooling rate of about 0.8°C / min over about 30 minutes, and the precipitated solid was filtered, washed with ethyl acetate, and dried under reduced pressure to obtain 170.9 g of a salt of 4A2FBN and p-toluenesulfonic acid as a white solid (composition ratio: 4A2FBN / 2A4FBN=99 / 1, yield of 4A2FBN: 53.4% ​​relative to DFBN).

[0215] １ H-NMR (DMSO-d ６ ): δ (ppm) 2.29 (s, 3H), 6.41-6.46 (m, 2H), 7.13 (d, J = 7.6, 2H), 7.38-7.42 (m, 1H), 7.49 (d, J = 8.0, 2H), 8.56 (br s, 3H) Melting point: 219°C

[0216] Example 2 Purification of Crude 4A2FBN (using p-toluenesulfonic acid as organic sulfonic acid, and methanol as reaction solvent and precipitation solvent) A 500 mL flask was charged with 315.7 g of the crude 4A2FBN-ethyl acetate solution obtained in Synthesis Example 1, and the solvent was removed by concentration under reduced pressure. 272.5 g of methanol and 153.8 g of p-toluenesulfonic acid monohydrate (1.0 molar ratio (to DFBN)) were then charged, and the mixture was reacted at 20 to 30° C. for 1 hour.

[0217] After the reaction was completed, the resulting solution was cooled from 28°C to 5°C at a cooling rate of about 0.8°C / min over about 30 minutes, and the precipitated solid was filtered, washed with methanol, and dried under reduced pressure to obtain 145.3 g of a salt of 4A2FBN and p-toluenesulfonic acid as a white solid (composition ratio: 4A2FBN / 2A4FBN = 98 / 2, yield of 4A2FBN: 45.4% relative to DFBN). Melting point: 219°C

[0218] Example 3 Purification of Crude 4A2FBN (using p-toluenesulfonic acid as organic sulfonic acid, and ethyl acetate as reaction solvent and precipitation solvent) A 500 mL flask was charged with 315.7 g of the crude 4A2FBN-ethyl acetate solution obtained in Synthesis Example 1 and 153.8 g of p-toluenesulfonic acid monohydrate (1.0 molar ratio relative to DFBN), and the mixture was reacted at 20 to 30° C. for 1 hour.

[0219] ​After the reaction was completed, the resulting solution was cooled from 28°C to 5°C at a cooling rate of about 0.8°C / min over about 30 minutes, and the precipitated solid was filtered, washed with ethyl acetate, and dried under reduced pressure to obtain 162.65 g of a salt of 4A2FBN and p-toluenesulfonic acid as a white solid (composition ratio: 4A2FBN / 2A4FBN=91 / 9, yield of 4A2FBN: 50.8% relative to DFBN). Melting point: 219°C

[0220] Example 4 Purification of Crude 4A2FBN (Use of 2-naphthalenesulfonic Acid as Organic Sulfonic Acid, and Isopropyl Alcohol as Reaction Solvent and Precipitation Solvent) A 500 mL flask was charged with 315.7 g of the crude 4A2FBN-ethyl acetate solution obtained in Synthesis Example 1, and the solvent was removed by concentration under reduced pressure. 272.5 g of isopropyl alcohol and 168.4 g of 2-naphthalenesulfonic acid (1.0 molar ratio relative to DFBN) were then charged, and the mixture was reacted at 20 to 30° C. for 1 hour.

[0221] After completion of the reaction, the resulting solution was cooled from 28°C to 5°C at a cooling rate of about 0.8°C / min over about 30 minutes, and the precipitated solid was filtered, washed with isopropyl alcohol, and dried under reduced pressure to obtain 167.5 g of a salt of 4A2FBN and 2-naphthalenesulfonic acid as a white solid (composition ratio: 4A2FBN / 2A4FBN=99 / 1, yield of 4A2FBN: 52.3% relative to DFBN).

[0222] Example 5 Purification of Crude 4A2FBN (1,5-Naphthalenedisulfonic Acid Used as Organic Sulfonic Acid, and Isopropyl Alcohol Used as Reaction Solvent and Precipitation Solvent) A 500 mL flask was charged with 315.7 g of the obtained crude 4A2FBN-ethyl acetate solution, and the solvent was removed by concentration under reduced pressure. 272.5 g of isopropyl alcohol and 145.7 g of 1,5-naphthalenedisulfonic acid (0.5 molar ratio relative to DFBN) were then charged into the flask, and the mixture was reacted at 20 to 30° C. for 1 hour.

[0223] After completion of the reaction, the resulting solution was cooled from 28°C to 5°C at a cooling rate of about 0.8°C / min over about 30 minutes, and the precipitated solid was filtered, washed with isopropyl alcohol, and dried under reduced pressure to obtain 169.5 g of a salt of 4A2FBN and 1,5-naphthalenedisulfonic acid as a white solid (composition ratio: 4A2FBN / 2A4FBN=77 / 23, yield of 4A2FBN: 52.9% relative to DFBN).

[0224] Example 6: Synthesis of 4A2FBAD (4-amino-2-fluorobenzamide)

[0225]

[0226] Under a nitrogen atmosphere, a 2-L flask was charged with 170.9 g (0.4319 mol) of the acid addition salt of 4A2FBN and p-toluenesulfonic acid obtained in Example 1, 336.0 g of methanol, 41.0 g of dimethyl sulfoxide, and 77.0 g of a 28% by mass aqueous solution of sodium hydroxide (1.25 molar ratio (relative to the acid addition salt)), and the temperature was then raised to 40 to 45°C. 83.9 g of a 35% by mass aqueous solution of hydrogen peroxide (2.00 molar ratio (relative to the acid addition salt)) was added dropwise to the reaction vessel. After completion of the dropwise addition, the mixture was reacted at 40 to 45°C for 3 hours, yielding 647.2 g of a reaction liquid. The resulting reaction liquid was adjusted to a pH of 7 with 36% by mass hydrochloric acid, and the solvent was removed under reduced pressure at 50°C to yield 220.3 g of a concentrated liquid. 427.6 g of water was poured into the resulting concentrated liquid, which was then cooled to 0 to 5°C and stirred for 1 hour. The resulting solid was filtered, washed with water, and dried to give 47.1 g of 4A2FBAD as a light brown solid (HPLC purity: 99.0%, theoretical yield: 70.0% relative to the acid addition salt, overall yield: 37.4% relative to DFBN). Melting point: 148°C

[0227] Reference Example 1 Purification of Crude 4A2FBN (Use of Benzoic Acid as Acid, and Ethyl Acetate as Reaction Solvent and Precipitation Solvent) A 500 mL flask was charged with 315.7 g of the crude 4A2FBN-ethyl acetate solution obtained in Synthesis Example 1 and 98.8 g of benzoic acid (1.0 molar ratio relative to DFBN), and the mixture was reacted at 20 to 30° C. for 1 hour.

[0228] After the reaction was completed, the solution was cooled from 28°C to 5°C at a cooling rate of about 0.8°C / min over about 30 minutes, but no solid precipitated, and the benzoate of 4A2FBN and the benzoate of 2A4FBN could not be separated.

[0229] Reference Example 2 Purification of Crude 4A2FBN (using Hydrochloric Acid as Acid, and Ethyl Acetate as Reaction Solvent and Precipitation Solvent) A 500 mL flask was charged with 315.7 g of the crude 4A2FBN-ethyl acetate solution obtained in Synthesis Example 1 and 82.0 g of 36 mass % hydrochloric acid (1.0 molar ratio relative to DFBN), and the mixture was reacted at 20 to 30° C. for 1 hour.

[0230] After the reaction was completed, the solution was cooled from 28°C to 5°C at a cooling rate of about 0.8°C / min over about 30 minutes, but no solid precipitated, and the hydrochloride of 4A2FBN and the hydrochloride of 2A4FBN could not be separated.

[0231] Reference Example 3 Purification of Crude 4A2FBN (Using Sulfuric Acid as Acid, and Isopropyl Alcohol as Reaction Solvent and Precipitation Solvent) A 500 mL flask was charged with 315.7 g of the crude 4A2FBN-ethyl acetate solution obtained in Synthesis Example 1, and the solvent was removed by concentration under reduced pressure. Then, 272.5 g of isopropyl alcohol and 158.7 g of 50% by mass sulfuric acid (1.0 molar ratio relative to DFBN) were charged, and the mixture was reacted at 20 to 30° C. for 1 hour.

[0232] After completion of the reaction, the solution was cooled from 28°C to 5°C at a cooling rate of approximately 0.8°C / min over approximately 30 minutes, and the precipitated solid was filtered, washed with isopropyl alcohol, and dried under reduced pressure to obtain 90.4 g of 4A2FBN sulfate as a white solid (composition ratio: 4A2FBN / 2A4FBN=53 / 47, yield of 4A2FBN: 28.2% relative to DFBN).

[0233] Reference Example 4 Purification of Crude 4A2FBN (Sublimation Purification) A 500 mL flask was charged with 315.7 g of the crude 4A2FBN-ethyl acetate solution obtained in Synthesis Example 1, and the solvent was removed by concentration under reduced pressure. An attempt was made to purify the impurity 2A4FBN (isomer) by sublimation under conditions of a temperature of 105°C and a pressure (gauge pressure) of -100 kPa; however, the sublimated crystals inside the apparatus clogged the apparatus, making it inoperable.

[0234] Reference Example 5 Purification of Crude 4A2FBN (Using Toluene as Precipitation Solvent) A 1000 mL flask was charged with 315.7 g of the crude 4A2FBN-ethyl acetate solution obtained in Synthesis Example 1, and the solvent was removed by concentration under reduced pressure. 380.8 g of toluene was then charged, and the mixture was stirred at 20 to 30° C. for 1 hour and then allowed to stand.

[0235] Thereafter, the precipitated solid was filtered, washed with ethyl acetate, and dried under reduced pressure to obtain 24.2 g of 4A2FBN as a white solid (composition ratio: 4A2FBN / 2A4FBN=99 / 1, yield of 4A2FBN: 21.6% relative to DFBN). Melting point: 56° C.

[0236] The acid addition salts obtained by the production method of the present invention can be used as intermediates for pharmaceuticals, raw materials for reagents, etc.

Claims

1. The following formula (1) (wherein X represents a halogen atom, R １ represents a substituent inert to the reaction, and n represents an integer of 0 to 3), and an acid addition salt of an isomer mixture of an aminohalobenzonitrile compound represented by the following formula (2): (In the formula, X, R １ , n are the same as in formula (1) above), and an acid addition salt of the 4-amino-2-halobenzonitrile compound represented by the formula (1) above, and an organic sulfonic acid, the method comprising a separation step of separating an acid addition salt of the 4-amino-2-halobenzonitrile compound represented by the formula (1) above, and an organic sulfonic acid by utilizing the difference in solubility between the acid addition salts of isomers in a solvent.

2. The method according to claim 1, wherein in the separation step, the separation method utilizing the difference in solubility between the acid addition salts of the isomers in a solvent comprises precipitation and / or extraction.

3. The method according to claim 1 or 2, wherein in the separation step, the solvent contains an ester and / or an alcohol.

4. The method according to claim 1, which comprises a salt-forming step of reacting an isomer mixture of the 4-amino-2-halobenzonitrile compound represented by formula (2) and the aminohalobenzonitrile compound represented by formula (1) with the organic sulfonic acid to form an acid addition salt.

5. The following formula (3) (wherein, each X independently represents a halogen atom; R １ and n are the same as in the formula (1) above), and (In the formula, X, R １ 5. The method according to claim 4, further comprising an amination step of subjecting a dihalobenzonitrile compound represented by the formula (3):

6. The method according to claim 4, wherein the reaction in the salt-forming step is carried out in the presence of a solvent, and the solvent used in the salt-forming step is the same as the solvent used in the separation step.

7. The method of any one of claims 1, 2 and 4-6, wherein the organic sulfonic acid comprises an aromatic sulfonic acid.

8. The aromatic sulfonic acid is represented by the following formula (5): (wherein ring Z represents an arene ring; R ２ represents a substituent inert to the reaction, m represents an integer of 0 or more, and k represents an integer of 1 or more.

9. In the formula (5), ring Z is C ６－１４ is an arene ring, and R ２ is a linear or branched chain C １－３ 9. The method according to claim 8, wherein m is 0 or 1 and k is 1 or 2, and the alkyl group is an alkyl group.

10. The method according to any one of claims 1, 2, and 4 to 6, wherein the ratio of sulfonic acid groups in the organic sulfonic acid is 0.8 to 1.2 moles per mole of the total amount of the isomeric mixture of aminohalobenzonitrile compounds represented by formula (1).

11. A method for producing an acid addition salt of a compound represented by the following formula (6), which comprises an amidation step of subjecting the acid addition salt produced by the method according to any one of claims 1 to 6 to a hydrolysis reaction: (In the formula, X, R １ and n are the same as in formula (1) of claim 1, or an acid addition salt thereof.

12. The following formula (2) (wherein X represents a halogen atom, R １ represents a substituent inert to the reaction, and n represents an integer of 0 to 3) with an organic sulfonic acid.

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