Acid addition salt of 4-amino-2-halogenated benzonitrile compound and preparation method thereof

Abstract

The present invention provides an industrially advantageous method for preparing an acid addition salt of a 4-amino-2-halobenzonitrile compound with an organic sulfonic acid. Specifically, an acid addition salt of a 4-amino-2-halobenzonitrile compound represented by formula (2) and an organic sulfonic acid is prepared. The present invention relates to a method for producing a compound represented by formula (1), the method comprising a separation step for separating an acid addition salt of a compound represented by formula (2) and an organic sulfonic acid from an acid addition salt of an organic sulfonic acid and an isomer mixture containing at least a compound represented by formula (2) and represented by formula (1) by using the solubility difference between acid addition salts of isomers in a solvent. (In the formula, X represents a halogen atom, R1 represents a reaction-inert substituent, and n represents an integer of 0-3. )

Description

TECHNICAL FIELD

[0001] The present application relates to an acid addition salt of a 4-amino-2-halogenophenylcarbonitrile compound and an organic sulfonic acid (an organic sulfonic acid salt of a 4-amino-2-halogenophenylcarbonitrile compound) and a production method thereof; the acid addition salt is useful as a pharmaceutical intermediate, a reagent, and the like. BACKGROUND

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

[0003] As a method for producing 4-amino-2-fluorobenzamide, Patent Application Publication No. 116332789 Specification (CN116332789A, Patent Document 1) discloses a method including an amination step of converting one fluorine atom in 2,4-difluorobenzonitrile as a raw material into an amino group, a separation step of separating isomers of the obtained amino-substituted compound, and an amidation step of converting the cyano group of the obtained 4-amino-2-fluorobenzonitrile into an amide group. As the separation step, a distillation method or a method of first forming an acid addition salt of an amino-substituted compound isomer mixture and an acid, and then separating the acid addition salt of 4-amino-2-fluorobenzonitrile and the acid by precipitation is disclosed. PRIOR ART DOCUMENTS PATENT DOCUMENTS

[0004] Patent Document 1: CN116332789A SUMMARY PROBLEMS TO BE SOLVED BY THE INVENTION

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

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

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

[0008] Another object of the present application is to provide a method for easily or efficiently producing a high-purity acid addition salt of a 4-amino-2-halogenophenylcarbonitrile compound and an organic sulfonic acid. MEANS FOR SOLVING PROBLEMS

[0009] The inventors of the present application conducted intensive studies to achieve the above object, and finally found that, in a method for separating an acid-addition salt of a 4-amino-2-halobenzonitrile compound with an acid from an isomer mixture of an aminohalobenzonitrile compound by utilizing a difference in solubility between the isomers in a solvent, using an organic sulfonic acid as the acid, an organic sulfonic acid salt of the 4-amino-2-halobenzonitrile compound, which is significantly different in solubility in a solvent from other acid-addition salts, can be industrially advantageously produced. Furthermore, the inventors of the present application found that such a method can easily or effectively produce an organic sulfonic acid salt of the 4-amino-2-halobenzonitrile compound, and can easily or effectively produce an organic sulfonic acid salt of the 4-amino-2-halobenzonitrile compound with high purity. The present application was completed on the basis of the above findings.

[0010] That is, the present application can include the following aspects and the like.

[0011] Item [1] A method for producing an acid-addition salt of a 4-amino-2-halobenzonitrile compound with an organic sulfonic acid, comprising:

[0012] a separation step in which an acid-addition salt of an isomer mixture of an aminohalobenzonitrile compound represented by the following formula (1)

[0013] [Chemical Formula 1]

[0014] (in the formula, X represents a halogen atom, R 1 represents a reaction-inert substituent group, and n represents an integer of 0 to 3, an acid-addition salt of an isomer mixture of an aminohalobenzonitrile compound represented by the following formula (1)

[0015] [Chemical Formula 2]

[0016] (in the formula, X, R 1 and n each have the same meanings as in formula (1). an acid-addition salt of a 4-amino-2-halobenzonitrile compound represented by the following formula (2)

[0017] Item [2] The method according to item [1], wherein, in the separation step, the separation utilizing a difference in solubility between the acid-addition salts of the isomers in a solvent includes precipitation and / or extraction.

[0018] Item [3] The method according to item [1] or [2], wherein, in the separation step, the solvent contains an ester and / or an alcohol.

[0019] [4]: the method according to any one of [1] to [3], which comprises a salt formation step as a pre-step of the separation step, wherein an isomer mixture of an amino halobenzonitrile compound represented by the formula (1) and containing at least a 4-amino-2-halobenzonitrile compound represented by the formula (2) is reacted with the organic sulfonic acid to form an acid addition salt.

[0020] [5]: the method according to [4],

[0021] which comprises an amination step as a pre-step of the salt formation step,

[0022] wherein a dihalobenzonitrile compound represented by the formula (4) and containing at least a 2,4-dihalobenzonitrile compound represented by the formula (3) is subjected to an amination reaction:

[0023] [Chem. 3]

[0024] (in the formulae, each X independently represents a halogen atom, and R 1 and n each have the same meanings as in the formula (1),

[0025] [Chem. 4]

[0026] (in the formulae, X, R 1 and n each have the same meanings as in the formula (3).

[0027] [6]: the method according to [4] or [5], wherein the reaction in the salt formation step is carried out in the presence of a solvent, and the solvent used in the salt formation step is the same as the solvent used in the separation step.

[0028] [7]: the method according to any one of [1] to [6], wherein the organic sulfonic acid comprises an aromatic sulfonic acid.

[0029] [8]: the method according to [7],

[0030] the aromatic sulfonic acid comprises an aromatic ring-containing sulfonic acid represented by the formula (5):

[0031] [Chem. 5]

[0032] (in the formulae, ring Z represents an aromatic ring, R 2 represents a reaction-inert substituent, m represents an integer of 0 or more, and k represents an integer of 1 or more.

[0033] Scheme [9]: The method according to Scheme [8], wherein, in the formula (5), ring Z represents C 6-14 aromatic ring, R 2 represents a linear or branched C 1-3 alkyl group, m represents 0 or 1, and k represents 1 or 2.

[0034] Scheme

[10] : The method according to any one of Schemes [1] to [9], wherein the proportion of sulfonic acid groups of the organic sulfonic acid is 0.8 to 1.2 mol relative to 1 mol of the total amount of the isomer mixture of the aminohalobenzonitrile compound represented by the formula (1).

[0035] Scheme

[11] : A method for producing a 4-amino-2-halobenzamide compound represented by the following formula (6) or an acid addition salt thereof,

[0036] [Chem. 6]

[0037] (in the formula, X, R 1 and n each have the same meanings as in the formula (1) described in Scheme [1], the method comprising:

[0038] an amidation step in which the acid addition salt produced by the method according to any one of Schemes [1] to

[10] is subjected to a hydrolysis reaction.

[0039] Scheme

[12] : An acid addition salt of a 4-amino-2-halobenzonitrile compound represented by the following formula (2) and an organic sulfonic acid:

[0040] [Chem. 7]

[0041] (in the formula,

[0042] X, R 1 and n each have the same meanings as in the formula (1) described in Scheme [1]. Effects of the Invention

[0043] The process of the present application allows the industrial production of the acid addition salt of the 4-amino-2-halogenophenylcarbonitrile compound and the organic sulfonic acid from the acid addition salt of the mixture of the 4-amino-2-halogenophenylcarbonitrile compound and its isomers and the organic sulfonic acid (the organic sulfonic acid salt of the mixture of the 4-amino-2-halogenophenylcarbonitrile compound and its isomers) advantageously by utilizing the solubility difference between the acid addition salts of the isomers in the solvent, to be used in the separation process. In addition, the organic sulfonic acid salt of the target compound can be easily or efficiently (and also at a high purity, if necessary) produced by selecting a specific solvent kind as the solvent or other means. DETAILED DESCRIPTION

[0044] According to the present application, the acid addition salt of the 4-amino-2-halogenophenylcarbonitrile compound (2) and the organic sulfonic acid (2a) can be industrially advantageously produced by a separation process of separating the acid addition salt of the 4-amino-2-halogenophenylcarbonitrile compound (2) and the organic sulfonic acid from the acid addition salt of the isomer mixture of the amino halogenophenylcarbonitrile compound represented by the following formula (1) (hereinafter, this compound can also be referred to as "amino halogenophenylcarbonitrile compound (1)") and the organic sulfonic acid (la). As a preferred mode, the present application can include an amination process in which an isomer mixture of the dihalogenophenylcarbonitrile compound represented by the following formula (4) (hereinafter, this compound can also be referred to as "dihalogenophenylcarbonitrile compound (4)") which can contain an isomer mixture is subjected to an amination reaction to obtain the isomer mixture of the amino halogenophenylcarbonitrile compound (1), and a salt formation process in which the obtained isomer mixture of the amino halogenophenylcarbonitrile compound (1) is reacted with the organic sulfonic acid. The present application at least includes the separation process.

[0045] To help understand the present application, when the organic sulfonic acid is an organic monosulfonic acid A, these processes are shown in the following scheme:

[0046] [Chem. 8]

[0047] (In the formulae, X each independently represents a halogen atom, R 1 represents a reaction-inert substituent, n represents an integer of 0 to 3, and A represents an organic monosulfonic acid.)

[0048] [Amination process] In the amination step, an amination reaction is performed on a dihalonitrile compound (4) containing at least a 2,4-dihalobenzonitrile compound represented by the following formula (3) (hereinafter, this compound can be referred to as "2,4-dihalobenzonitrile compound (3)"), to convert one halogen atom X into an amino group, thereby producing an amino halobenzonitrile compound (1) containing at least a 4-amino-2-halobenzonitrile compound (2).

[0049] [Chem. 9]

[0050] (In the formula, X each independently represents a halogen atom, R 1 represents a non-reactive substituent, and n represents an integer of 0 to 3,

[0051] [Chem. 10]

[0052] (In the formula, X represents a halogen atom, and R 1 and n each have the same meanings as in formula (3).

[0053] In formulae (1), (2), (3), and (4), examples of the halogen atom represented by X can include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0054] Among these halogen atoms, a fluorine atom, a chlorine atom, or a bromine atom is preferred, a fluorine atom or a chlorine atom is more preferred, and a fluorine atom is further preferred.

[0055] In formulae (3) and (4), the kinds of the two atoms X can be different from each other, but are preferably the same.

[0056] In formulae (1), (2), (3), and (4), the substituent R 1 There is no particular limitation, and it can be any non-reactive group. Examples of the substituent can include a hydroxyl group, a linear or branched alkyl group (e.g., C 1-6 alkyl 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, and a t-butyl group), a linear or branched alkoxy group (e.g., C 1-6 alkoxy group such as a methoxy group, an ethoxy group, and a propoxy group), and a cycloalkyl group (e.g., C 3-12 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, and a cyclohexyl group).

[0057] Among these substituents R 1In the present specification, preferably, a straight-chain or branched alkyl group, a straight-chain or branched alkoxy group, or a cycloalkyl group, more preferably a straight-chain or branched alkyl group (for example, a straight-chain or branched C 1-6 alkyl group), further preferably a straight-chain or branched C 1-3 alkyl group (for example, a straight-chain or branched C

[0058] In formulae (1), (2), (3), and (4), the number (the number of substitutions) n of the substituent group R 1 is an integer of 0 to 3, preferably an integer of 0 to 2, more preferably 0 or 1, further preferably 0. When the number n of the substituent group R 1 is 2 or more, the kinds of the two or more substituent groups R 1 may be different from each other or the same.

[0059] In formula (3), the substitution position of the substituent group R 1 may be any of the 3-position, the 5-position, and / or the 6-position with respect to the 1-position cyano group in the 2,4-dihalobenzonitrile compound (3).

[0060] Representative examples of the 2,4-dihalobenzonitrile compound (3) can include 2,4-dihalobenzonitriles such as 2,4-difluorobenzonitrile, 2,4-dichlorobenzonitrile, and 2,4-dibromobenzonitrile.

[0061] In formula (4), the substitution position of the two halogen atoms X is not particularly limited and can be any position including a combination of the 2-position and the 4-position corresponding to the 2,4-dihalobenzonitrile compound (3). With respect to the 1-position cyano group of the dihalobenzonitrile compound (4), the substitution position can include a combination of the 2-position and the 4-position, as well as a combination of any two positions of the 2-position, the 3-position, the 4-position, the 5-position, and the 6-position (excluding the combination of the 2-position and the 4-position). In the dihalobenzonitrile compound (4), the proportion of the 2,4-dihalobenzonitrile compound (3) is, for example, not less than 50%, preferably not less than 60% (for example, not less than 70%), more preferably not less than 80% (for example, not less than 90%), most preferably 100% (i.e., the dihalobenzonitrile compound (4) contains only the 2,4-dihalobenzonitrile compound (3)).

[0062] In formula (4), the substitution position of the substituent group R 1 may be any position different from the substitution position of the halogen atom X.

[0063] Representative examples of the dihalobenzonitrile compound (4) can include dihalobenzonitriles such as difluorobenzonitrile, dichlorobenzonitrile, and dibromobenzonitrile.

[0064] As the aminating agent, for example, ammonia, aqueous ammonia, and an amino alkali metal salt (e.g., an amino lithium salt, an amino potassium salt, and an amino sodium salt) can be mentioned. Among these aminating agents, ammonia, aqueous ammonia, or an amino alkali metal salt is preferred, and ammonia or aqueous ammonia is more preferred, and aqueous ammonia is further preferred.

[0065] These aminating agents can be used alone or in combination of two or more.

[0066] The ratio of the aminating agent to 1 mol of the dihalobenzonitrile compound (4) is, for example, 1 to 10 mol, preferably 2 to 8 mol, more preferably 3 to 7 mol, and further preferably 4 to 6 mol. Too low a ratio of the aminating agent can result in a low yield.

[0067] In the amination step, the reaction of the dihalobenzonitrile compound (4) with the aminating agent can be carried out in the presence or absence of a solvent.

[0068] As the solvent, a polar solvent capable of dissolving the aminating agent is preferred. For example, an aprotic polar organic solvent can be used.

[0069] Examples of the aprotic polar organic solvent can include: a sulfoxide (e.g., a diC 1-6 alkyl sulf oxide such as dimethyl sulfoxide), a sulfone (e.g., a cyclic sulfone such as sulfolane), an amide [e.g., a chain amide (e.g., N,N-diC 1-6 alkyl-C 1-6 ylamide such as N,N-dimethylformamide and N,N-dimethylacetamide) and a cyclic amide (e.g., N-methyl-2-pyrrolidone)], an ether (e.g., a chain ether such as diethyl ether and a cyclic ether such as tetrahydrofuran), a ketone (e.g., acetone and methyl ethyl ketone), an ester (e.g., ethyl acetate), and a nitrile (e.g., acetonitrile).

[0070] These aprotic polar organic solvents can be used alone or in combination of two or more. Among these, a sulfoxide is preferred, a diC 1-6 alkyl sulf oxide (e.g., a diC 1-4 alkyl sulf oxide) is more preferred, and dimethyl sulfoxide is further preferred.

[0071] The ratio of the aprotic polar organic solvent should ensure that the reaction system can be stirred. The ratio of the aprotic polar organic solvent to 100 parts by mass of the dihalobenzonitrile compound (4) 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 further preferably 200 to 250 parts by mass. Too low a ratio of the solvent can make it difficult to stir the reaction system. Too high a ratio of the solvent can slow down the reaction.

[0072] In addition, as the solvent, water can be added in the form of an aqueous solution of the aminating agent.

[0073] The ratio of water as the solvent to 100 parts by mass of the dihalogenated benzo nitrile compound (4) is, for example, 10 to 300 parts by mass, preferably 50 to 250 parts by mass, more preferably 100 to 200 parts by mass, further preferably 140 to 180 parts by mass.

[0074] The ratio of water as the solvent to 100 parts by mass of the organic 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, further preferably 60 to 80 parts by mass.

[0075] The reaction temperature is, for example, 50 to 180°C, preferably 70 to 150°C, more preferably 90 to 130°C, further 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, further preferably 15 to 21 hours.

[0076] The reaction can be performed in air or in a non-reactive gas (for example, nitrogen; and rare gases such as argon and helium). The reaction can be performed under normal pressure or ordinary pressure, or under pressurization.

[0077] In formula (2), the substitution position of the substituent group R 1 is the same as that in formula (3).

[0078] Representative examples of the 4-amino-2-halogenated benzonitrile compound (2) can include 4-amino-2-halogenated benzonitriles such as 4-amino-2-fluorobenzonitrile, 4-amino-2-chlorobenzonitrile, and 4-amino-2-bromobenzonitrile.

[0079] In formula (1), the substitution position of the halogen atom X is not particularly limited, and can be any of the 2-position, 3-position, 4-position, 5-position, or 6-position relative to the 1-position cyano group in the amino halogenated benzonitrile compound (1). Of these, the 2-position or 4-position is preferred.

[0080] In formula (1), the substitution position of the amino group is not particularly limited, and can be any of the 2-position, 3-position, 4-position, 5-position, or 6-position relative to the 1-position cyano group in the amino halogenated benzonitrile compound (1). Of these, the 2-position or 4-position is preferred.

[0081] Specifically, the amino halogenated benzonitrile compound (1) preferably contains at least the 4-amino-2-halogenated benzonitrile compound (2) and the 2-amino-4-halogenated benzonitrile compound, more preferably contains the 4-amino-2-halogenated benzonitrile compound (2) and the 2-amino-4-halogenated benzonitrile compound as the main components, and particularly preferably contains only the 4-amino-2-halogenated benzonitrile compound (2) and the 2-amino-4-halogenated benzonitrile compound.

[0082] The organic sulfonic acid salt of the 4-amino-2-halobenzonitrile compound (2) appears to have a significantly lower solubility in a solvent than other isomers such as the organic sulfonic acid salt of the 2-amino-4-halobenzonitrile compound. In the separation process described later, the acid addition salt of the 4-amino-2-halobenzonitrile compound (2) is obtained by utilizing the difference in solubility described above, and thus the amino halobenzonitrile compound (1) containing the 4-amino-2-halobenzonitrile compound (2) and the 2-amino-4-halobenzonitrile compound as main components can improve the separation efficiency of the acid addition salt.

[0083] In formula (1), the substitution position of the substituent group R 1 may be any position other than the substitution position of the halogen atom X and the amino group.

[0084] Representative examples of the amino halobenzonitrile compound (1) can 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.

[0085] [Salt formation process] In the salt formation process, an isomer mixture of the amino halobenzonitrile compound (1) containing at least the 4-amino-2-halobenzonitrile compound (2) is reacted with an organic sulfonic acid to form an acid addition salt of the isomer mixture (i.e., an organic sulfonic acid salt of the mixture).

[0086] In the present application, by selecting an organic sulfonic acid as the acid or the like, the efficiency of separating the acid addition salt of the target 4-amino-2-halobenzonitrile compound (2) from the acid addition salt of the isomer mixture in the separation process described later can be improved.

[0087] The organic sulfonic acid is not particularly limited, as long as it contains one or more sulfonic acid groups in the molecule, can form a salt with the 4-amino-2-halobenzonitrile compound (1), and allows isomer separation. Examples of the organic sulfonic acid can include: a sulfonic acid (aliphatic sulfonic acid) that does not contain an aromatic ring in the molecule and contains an aliphatic hydrocarbon group, and a sulfonic acid (aromatic sulfonic acid) that contains at least one aromatic ring in the molecule.

[0088] These organic sulfonic acids can be used alone or in combination of two or more.

[0089] As the aliphatic sulfonic acid, for example, an alkane sulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid, and dodecanesulfonic acid, and the like C 1-12 alkene sulfonic acid (e.g., vinylsulfonic acid and butenylsulfonic acid, and the like C 2-12alkane sulfonic acid), and a halogenated sulfonic acid (e.g., trichloromethane sulfonic acid, tribromomethane sulfonic acid, and trifluoromethane sulfonic acid, and the like trihalogenated C 1-6 alkane sulfonic acid).

[0090] These aliphatic sulfonic acids can be used alone or in combination of two or more.

[0091] Examples of the aromatic ring of the aromatic sulfonic acid can include: an aromatic heterocycle containing any one of a nitrogen atom, an oxygen atom, and a sulfur atom as a constituent atom of the ring, and an arene ring. These aromatic sulfonic acids can be used alone or in combination of two or more.

[0092] As the aromatic heterocycle, for example, a heterocycle containing at least one heteroatom, such as a nitrogen-containing heterocycle (e.g., a pyridine ring, a quinoline ring, a carbazole ring, an imidazole ring, and a phthalimide ring), and a nitrogen- and oxygen-containing heterocycle (e.g., a pyrrole ring, an indole ring, a benzoxazole ring, a benzimidazole ring, and a benzothiazole ring) can be given. a pyrrole ring, an indole ring, a benzoxazole ring, a benzimidazole ring, and a benzothiazole ring). a pyrrole ring, an indole ring, a benzoxazole ring, a benzimidazole ring, and a benzothiazole ring).

[0093] The arene ring can be a monocyclic arene ring (e.g., a benzene ring) or a polycyclic arene ring (e.g., a fused polycyclic arene ring, and an arene ring of a ring assembly or a ring collection).

[0094] Examples of the fused polycyclic arene ring can include: a fused bicyclic arene ring (e.g., a fused bicyclic C 10-20 an arene ring such as a naphthalene ring and an indene ring), and a fused tricyclic arene ring (e.g., a fused tricyclic C 14-20 an arene ring such as an anthracene ring and a phenanthrene ring).

[0095] As the arene ring of the ring collection, for example, a biarene ring (e.g., a C 12-20 a biarene ring such as a biphenyl ring, a phenylnaphthalene ring, and a binaphthalene ring) can be given.

[0096] Among these aromatic rings, a monocyclic arene ring (e.g., a benzene ring), a fused polycyclic arene ring (e.g., a naphthalene ring and an indene ring, and the like fused bicyclic C 10-20 an arene ring, and an anthracene ring and a phenanthrene ring, and the like fused tricyclic C 14-20 an arene ring), a monocyclic arene ring or a fused bicyclic arene ring, a benzene ring or a naphthalene ring, and most preferably a benzene ring.

[0097] In the aromatic sulfonic acid, the aromatic ring and the sulfonic acid group can be bonded directly or through a linking group (e.g., an alkylene group), but direct bonding is preferred.

[0098] Examples of the aromatic sulfonic acid in which the aromatic ring is an arene ring can include: a compound represented by the following formula (5) :

[0099] [Chemical Formula 11]

[0100] (in the formula, n is an integer of 1 or more, and R represents a hydrogen atom or a substituent group). Ring Z represents an aromatic ring. R 2 Substituents indicating inert reactivity m represents an integer greater than or equal to 0, and k represents an integer greater than or equal to 1.

[0101] As ring Z, as an aromatic ring in aromatic sulfonic acids, examples include: aromatic rings, such as monocyclic aromatic rings and polycyclic aromatic rings.

[0102] Among these aromatic rings, C is preferred. 6-20 Aromatic rings, more preferably C 6-14 Aromatic rings, further preferred C 6-12 Aromatic rings, especially C4 are preferred. 6-10 Aromatic rings, such as benzene rings and naphthalene rings, are preferred, with benzene rings being the most preferred.

[0103] Substituent R 2 There are no particular restrictions; it can be any reactive group. Substituent R 2 Examples may include: hydroxyl groups, halogen atoms (e.g., fluorine, chlorine, bromine, and iodine atoms), nitro groups, straight-chain or branched alkyl groups (e.g., C14, 2 ... 1-12 Alkyl groups, such as methyl, ethyl, and propyl; straight-chain or branched alkoxy groups (e.g., C14); 1-12 Alkoxy groups, such as methoxy, ethoxy, and propoxy, and cycloalkyl groups (e.g., C14, C24, C15, C26, C16, C2 ... 3-14 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclohexyl. Preferably, the alkyl group (e.g., straight-chain or branched C4) is used. 1-6 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl; alkoxy groups (e.g., straight-chain or branched C-aryl groups). 1-6 Alkyl groups, such as methoxy, ethoxy, propoxy, and isopropoxy, or cycloalkyl groups (e.g., C14, C24, C34, C4 ... 3-12 Cycloalkyl groups (such as cyclobutyl and cyclohexyl), more preferably straight-chain or branched C4 groups. 1-4 Alkyl groups, such as methyl, ethyl, propyl, and butyl, more preferably straight-chain or branched C-chains. 1-3 Alkyl groups, such as methyl and ethyl.

[0104] Substituent R 2 The number (substitution number) m is an integer of 0 or more, preferably an integer from 0 to 3, more preferably an integer from 0 to 2, further preferably 0 or 1, and most preferably 1. When the substituent R 2 When the number m is an integer greater than or equal to 2, there are more than 2 substituents R 2 The types can be different from each other, or they can be the same. Furthermore, the substituent R... 2 There are no specific restrictions on the substitution position. When ring Z represents a benzene ring and m represents 1, the substituent R... 2 Preferably, it is located at the para position of the sulfonic acid group.

[0105] The number (the number of substitutions) k of the sulfonic acid group is an integer of 1 or more, preferably an integer of 1 to 3, and more preferably 1 or 2. The value of k is more preferably 1 in terms of the purity of the resulting product.

[0106] Representative examples of the compound represented by formula (5) can include: benzenemono- or disulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid, which can have one or more (e.g., two or three) alkyl groups; and naphthalene mono- or disulfonic acids such as 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, and 2,6-naphthalenedisulfonic acid, which can have one or more (e.g., two or three) alkyl groups.

[0107] These aromatic sulfonic acids represented by formula (5) can be used alone or in combination with two or more.

[0108] Among these organic sulfonic acids, aromatic sulfonic acids are preferred in terms of the separation efficiency of the acid-addition salt formed with the 4-amino-2-halobenzonitrile compound (2) and the yield, etc.; more preferred are aromatic sulfonic acids represented by formula (5); further preferred are aromatic sulfonic acids represented by formula (5) in which ring Z represents C 6-14 an aromatic hydrocarbon ring, R 2 represents an alkyl group, m represents an integer of 0 to 2, and k represents an integer of 1 to 3; more further preferred are benzenemono- or disulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid, which can have C 1-6 alkyl groups; naphthalene mono- or disulfonic acids such as 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, and 1,5-naphthalenedisulfonic acid, which can have C 1-6 alkyl groups; particularly preferred are benzenemono- or disulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid, which can have C 1-3 alkyl groups; naphthalene mono- or disulfonic acids such as 1-naphthalenesulfonic acid and 2-naphthalenesulfonic acid, which can have C 1-3 alkyl groups; particularly preferred are benzenemono- or disulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid, which can have C 1-3 alkyl groups.

[0109] As for the proportion of the organic sulfonic acid (particularly, the aromatic sulfonic acid represented by formula (5)), the sulfonic acid group of the organic sulfonic acid is, for example, 0.1 to 3 mol, preferably 0.4 to 2 mol, more preferably 0.6 to 1.5 mol, and further preferably 0.8 to 1.2 mol, relative to 1 mol of the total amount of the isomer mixture of the aminohalobenzonitrile compound (1). Too low a proportion of the sulfonic acid group can decrease the yield of the target product. Too high a proportion of the sulfonic acid group can decrease the purity of the target product.

[0110] The reaction of forming the acid-addition salt can be performed in the presence or absence of a solvent, but is preferably performed in the presence of a solvent.

[0111] The solvent can be an organic solvent or an aqueous organic solvent. For example, water can be present in the form of a hydrate of the organic sulfonic acid.

[0112] As the organic solvent, for example, aliphatic hydrocarbons, alicyclic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, sulfoxides, sulfones, amides, nitriles, esters, and alcohols can be cited. These solvents can be polar solvents or nonpolar solvents.

[0113] Examples of the aliphatic hydrocarbons can include: straight-chain or branched-chain C 5-15 Alkanes such as pentane, hexane, heptane, octane, nonane, and decane.

[0114] Examples of the alicyclic hydrocarbons can include: C 5-15 Naphthenes such as cyclopentane, cyclohexane, and cyclooctane.

[0115] Examples of the aromatic hydrocarbons can include: benzene, and mono- or di-C 1-6 Alkylbenzenes such as toluene and xylene.

[0116] Examples of the halogenated hydrocarbons can include: chlorinated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene.

[0117] Examples of the ethers can include: chain ethers (for example, diethyl ether) and cyclic ethers (for example, tetrahydrofuran).

[0118] Examples of the ketones can include: chain ketones (for example, straight-chain or branched-chain di-C 1-12 Alkyl ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diisobutyl ketone) and cyclic ketones (for example, cyclohexanone).

[0119] Examples of the sulfoxides can include: dialkyl sulfoxides (for example, di-C 1-6 Alkyl sulfoxides such as dimethyl sulfoxide.

[0120] Examples of the sulfones can include: cyclic sulfones such as sulfolane.

[0121] Examples of the amides can include: chain amides such as N,N-dialkyl amides (for example, N,N-dimethylformamide, N,N-dimethylacetamide, and N,N-diethylacetamide) and cyclic amides such as N-methyl-2-pyrrolidone. 1-6 Alkyl-C 1-6 Acyl amides such as N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, and N,N-diethylacetamide) and cyclic amides such as N-methyl-2-pyrrolidone.

[0122] Examples of the nitriles can include: C 1-6 Alkyl nitriles such as acetonitrile and propionitrile, and C 6-12 Aromatic nitriles such as benzonitrile.

[0123] Examples of the esters can include: chain esters [for example, carboxylic acid esters (for example, alkanoic acid esters) such as formate, acetate, propionate, and butyrate; hydroxy carboxylic acid esters (for example, hydroxy alkanoic acid esters) such as lactate; and ether esters (for example, C 2-10 Alkylene glycol mono-C 1-10 Alkyl ethers C1-10 acylates [e.g., ethylene glycol monomethyl ether acetate and propylene glycol monomethyl ether acetate], and cyclic esters (e.g., triatomic ring lactone, tetraatomic ring lactone, pentaatomic ring lactone, and hexaatomic ring lactone).

[0124] Examples of formates can include: alkyl formates (e.g., C 1-6 alkyl esters [e.g., methyl formate, ethyl formate, propyl formate, and butyl formate].

[0125] Examples of acetates can include: alkyl acetates (e.g., C 1-6 alkyl esters [e.g., methyl acetate, ethyl acetate, propyl acetate, and butyl acetate].

[0126] Examples of propionates can include: alkyl propionates (e.g., C 1-6 alkyl esters [e.g., methyl propionate, ethyl propionate, propyl propionate, and butyl propionate].

[0127] Examples of butyrates can include: alkyl butyrates (e.g., C 1-6 alkyl esters [e.g., ethyl butyrate, isopropyl butyrate, and butyl butyrate].

[0128] Examples of lactates can include: alkyl lactates (e.g., C 1-6 alkyl esters [e.g., methyl lactate, ethyl lactate, and butyl lactate].

[0129] Examples of cyclic esters can include: C 2-10 cyclic esters [e.g., β-propiolactone, γ-butyrolactone, δ-valerolactone, and ε-caprolactone].

[0130] Examples of alcohols can include: straight-chain or branched alcohols (e.g., straight-chain or branched C 1-12 alkanols [e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, t-butanol, n-pentanol, isopentanol, 2-methylbutanol, sec-pentanol, and t-pentanol], and ether alcohols [e.g., C 2-10 alkylene glycol mono- or di-C 1-10 alkyl ethers [e.g., 2-methoxyethanol, 2-methoxypropanol, 2-ethoxyethanol, and propylene glycol monomethyl ether].

[0131] These organic solvents can be used alone or in combination of two or more.

[0132] Among these organic solvents, in terms of ease of use as a solvent for isolating a target compound in a later-described isolation step, ethers, ketones, esters, or alcohols are preferable, esters [e.g., alkyl carboxylates (e.g., alkyl alkanoates), such as alkyl acetates] or alcohols (e.g., straight-chain or branched alcohols) are more preferable, and C 1-6 alkyl esters [e.g., methyl acetate, ethyl acetate, and propyl acetate] or straight-chain or branched C1-6 alkyl esters (e.g., methyl acetate and ethyl acetate), or C 1-3 alkyl esters (e.g., methyl acetate and ethyl acetate), or C 1-3 alkyl esters (e.g., methyl acetate and ethyl acetate), or C

[0133] The proportion of the solvent should ensure that the reaction system can be stirred. The proportion of the solvent relative to the total amount of the isomer mixture of the amino halobenzonitrile compound (1) 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 further preferably 200 to 300 parts by mass. Too low a proportion of the solvent can make stirring of the reaction system difficult. Too high a proportion of the solvent can slow the reaction.

[0134] The reaction temperature is, for example, 0 to 50°C, preferably 10 to 40°C, more preferably 15 to 35°C, and further 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.

[0135] The reaction can be performed in air or in a non-reactive gas (e.g., nitrogen; and noble gases such as argon and helium). The reaction can be performed under normal pressure or ordinary pressure, or under pressurization.

[0136] [Separation Process] In the separation process, the 4-amino-2-halobenzonitrile compound (2) and the acid addition salt of the organic sulfonic acid (the organic sulfonic acid salt of the target compound) are separated from the acid addition salt of the organic sulfonic acid (the mixture of the organic sulfonic acid salt of the target compound and the organic sulfonic acid salt of the other isomer) of the isomer mixture of the amino halobenzonitrile compound (1) by using the difference in solubility in the solvent.

[0137] Examples of the separation method using the difference in solubility in the solvent can include precipitation (or crystallization), solvent extraction (or elution), and combinations thereof.

[0138] These methods can be used alone or in combination with one or more conventional separation means selected from washing, concentration, solid-liquid separation (e.g., filtration, centrifugation, and decantation), column chromatography, and the like.

[0139] The organic sulfonic acid salt of the target compound can be obtained in liquid form or in solid form. In terms of productivity, it is preferable to obtain the organic sulfonic acid salt in solid form.

[0140] The precipitation (or crystallization) can be performed by a conventional method. In the precipitation (or crystallization) process, the organic sulfonic acid salt of the target compound is separated from the mixture by precipitating the organic sulfonic acid salt of the target compound from the precipitation solvent (the crystallization solvent) as a solid product while dissolving the organic sulfonic acid salts of other isomers in the precipitation solvent (the crystallization solvent).

[0141] Examples of the precipitation (or crystallization) method can include cooling crystallization, poor solvent crystallization, concentration crystallization, reprecipitation, and combinations thereof. Among them, cooling crystallization is preferred.

[0142] The solvent extraction (or elution) can be performed by a conventional method. In the solvent extraction (or elution) process, the isomer mixture containing the organic sulfonic acid salt of the target compound is concentrated or dried and solidified, and then the organic sulfonic acid salts of other isomers are extracted into a liquid phase by using an extraction solvent (an elution solvent), thereby separating the organic sulfonic acid salt of the target compound from the mixture.

[0143] The precipitation solvent (the crystallization solvent) and the extraction solvent (the elution solvent) at least contain an organic solvent, and can contain water. For example, in the salt formation step, water can be added as a hydrate of the organic sulfonic acid.

[0144] Examples of the organic solvent can include the organic solvents exemplified in the salt formation step.

[0145] These organic solvents can be used alone or in combination of two or more.

[0146] Among these organic solvents, ethers, ketones, esters, or alcohols are preferred, and in terms of productivity, esters [e.g., alkyl carboxylates (e.g., alkane carboxylates) such as alkyl acetates], or alcohols (e.g., linear or branched alcohols) are more preferred, and further, acetic acid C 1-6 alkyl esters (e.g., methyl acetate, ethyl acetate, and propyl acetate), or linear or branched C 1-6 alkyl esters (e.g., methyl acetate, ethyl acetate, and propyl acetate), or linear or branched C 1-3 alkyl esters (e.g., methyl acetate, ethyl acetate, and propyl acetate), or linear or branched C 1-3 alkyl esters (e.g., methyl acetate, ethyl acetate, and propyl acetate), or linear or branched C

[0147] Among these organic solvents, from the viewpoint of product purity, alcohols are preferred, and methanol, ethanol, n-propanol, or isopropanol is more preferred, and isopropanol is most preferred.

[0148] In the precipitation (or crystallization) process, the precipitation solvent (the crystallization solvent) can be different from the reaction solvent used in the salt formation 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 directly used as the precipitation solvent (the crystallization solvent), thereby improving the productivity.

[0149] The concentration of the acid addition salt in the solution subjected to the precipitation (or crystallization) process, particularly the cooling crystallization process, is, for example, 5 to 80% by mass, preferably 10 to 65% by mass, more preferably 30 to 60% by mass, and further preferably 40 to 55% by mass. A too low concentration of the acid addition salt can result in a low yield. A too high concentration of the acid addition salt can make it difficult to maintain the uniformity of agitation and the temperature gradient in the crystallization tank.

[0150] The cooling temperature is not particularly limited as long as the organic sulfonic acid salt of the target compound can be precipitated. The cooling temperature is, for example, -20°C to 25°C, preferably -10°C to 20°C, more preferably -5°C to 10°C, and further preferably 0°C to 5°C.

[0151] The cooling rate is not particularly limited for the cooling crystallization, and is, for example, 0.01 to 8°C / minute, preferably 0.05 to 5°C / minute, more preferably 0.1 to 2°C / minute, and further preferably 0.5 to 1°C / minute. A too high cooling rate can lower the purity of the target product. A too low cooling rate can lower the productivity.

[0152] After the precipitation (or crystallization), further solid-liquid separation (for example, filtration, centrifugation, and decantation) is performed, and the separated organic sulfonic acid salt of the target compound can be obtained.

[0153] The precipitation (or crystallization) operation can be performed once or repeatedly. If repeated, the precipitated solvent (the antediluvian solvent) after the solid-liquid separation can be concentrated, and further subjected to precipitation (for example, cooling crystallization), and the organic sulfonic acid salt of the target compound can be collected.

[0154] The obtained organic sulfonic acid salt of the target compound can be purified by one or more of conventional methods, including washing with the precipitating solvent or the like, distillation, sublimation, column chromatography, and the like.

[0155] In the extraction (or elution) process, the reaction solvent used in the salt formation process is concentrated or dried and solidified, and the extraction solvent can be the same as or different from the reaction solvent.

[0156] The proportion 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 further preferably 15 to 30 parts by mass, relative to 100 parts by mass of the isomer mixture containing the organic sulfonic acid salt of the target compound.

[0157] The concentration of the isomer mixture containing the organic sulfonic acid salt of the target compound after the concentration or drying and solidification is, for example, not less than 70% by mass, preferably not less than 85% by mass, more preferably not less than 95% by mass, and further preferably not less than 99% by mass. A too low concentration of the mixture can result in a low yield.

[0158] The temperature of the solvent extraction (or elution) is not particularly limited, and is a temperature at which the organic sulfonic acid salt of the other isomer is extracted (or eluted) into the liquid phase with the extraction solvent. The temperature is, for example, 0 to 50°C, preferably 5 to 45°C, more preferably 10 to 40°C, and further preferably 20 to 35°C.

[0159] After the extraction (or elution), further solid-liquid separation (for example, filtration, centrifugation, and decantation) is performed, and the organic sulfonic acid salt of the separated target compound is obtained.

[0160] The solvent extraction (or elution) operation can be performed once or repeatedly. If repeated, the extraction solvent after the solid-liquid separation can be concentrated or dried and solidified, and the solid phase can be recovered, and then the solid phase can be further subjected to extraction (or elution). In the case of performing extraction (or elution) repeatedly, the types of the solvents used can be the same or different.

[0161] The obtained organic sulfonic acid salt of the target compound can be purified by one or more of conventional methods, including washing with an extraction solvent or the like, distillation, sublimation, column chromatography, and the like.

[0162] The precipitation (or crystallization) and the solvent extraction (or elution) can be used alone or in combination.

[0163] Among these separation methods, the precipitation (or crystallization) is preferred from the viewpoint of improving productivity by continuously performing the salt formation step and the separation step using the reaction solvent as the precipitation solvent.

[0164] [Acid addition salt of a 4-amino-2-halobenzonitrile compound and an organic sulfonic acid] The present application includes an acid addition salt of a 4-amino-2-halobenzonitrile compound (2) represented by the following formula (2) and an organic sulfonic acid:

[0165] [Chemical 12]

[0166] (In the formula, X represents a halogen atom, R 1 represents a reaction-inert substituent, and n represents an integer of 0 to 3.

[0167] In the formula (2), as the halogen atom X, the substituent R 1 and the integer n, the same as the halogen atom X, the substituent R 1 and the integer n shown in the above separation step are included as preferred modes.

[0168] Representative examples of the compound represented by formula (2) can include: 4-amino-2-fluorobenzonitrile, 4-amino-2-chlorobenzonitrile, and 4-amino-2-bromobenzonitrile.

[0169] As the organic sulfonic acid, the same as shown in the salt formation step is included, preferably, and is preferably an aromatic sulfonic acid represented by formula (5).

[0170] Representative examples of the combination of the acid addition salt of the 4-amino-2-halogenobenzonitrile compound (2) and the organic sulfonic acid are: the acid addition salt of the 4-amino-2-halogenobenzonitrile compound (2) and the aromatic sulfonic acid represented by formula (5), which can include: the acid addition salt of the 4-amino-2-halogenobenzonitrile and the aromatic sulfonic acid which can have C 1-6 alkyl group 6-10 the acid addition salt of the aryl mono- or di-sulfonic acid, such as the acid addition salt of 4-amino-2-fluorobenzonitrile and at least one acid selected from the group consisting of benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, and 2,6-naphthalenedisulfonic acid.

[0171] These acid addition salts of the 4-amino-2-halogenobenzonitrile compound and the organic sulfonic acid can be used as pharmaceutical intermediates, reagents, and the like.

[0172] [Amidation step] In the present application, as the step after the separation step, an amidation step of preparing a 4-amino-2-halogenobenzamide compound represented by the following formula (6) (hereinafter, this compound can be simply referred to as "4-amino-2-halogenobenzamide compound (6)") or an organic sulfonic acid salt thereof can be included.

[0173] The amidation step is shown in the following flowchart:

[0174] [Chemical 13]

[0175] (In the formula, X, R 1 and n are the same as the meanings in formula (2) (including the preferred modes).

[0176] In the amidation step, the compounds represented by formulae (2) and (6) can be in the form of an organic sulfonic acid salt. From the viewpoint of productivity, it is preferable to perform the amidation reaction of the 4-amino-2-halogenobenzonitrile compound (2) in the form of a salt.

[0177] In the amidation step, the 4-amino-2-halogenobenzonitrile compound (2) or the organic sulfonic acid salt thereof is subjected to a hydrolysis reaction to produce the 4-amino-2-halogenobenzamide compound (6) represented by formula (6) or the organic sulfonic acid salt thereof.

[0178] Representative examples of the 4-amino-2-halobenzamide compound (6) can include: 4-amino-2-halobenzamides such as 4-amino-2-fluorobenzamide, 4-amino-2-chlorobenzamide, and 4-amino-2-bromobenzamide.

[0179] The hydrolysis reaction can be performed in the presence of a base or an acid. Among them, the hydrolysis reaction is preferably performed in the presence of a base.

[0180] Examples of the base in the hydrolysis reaction can include: alkali metal hydroxides (e.g., lithium hydroxide, potassium hydroxide, and sodium hydroxide), alkaline earth metal hydroxides (e.g., magnesium hydroxide and calcium hydroxide), and ammonia (ammonia water). These bases can be used alone or in combination with two or more.

[0181] Among them, the alkali metal hydroxide is preferred, and sodium hydroxide or potassium hydroxide is more preferred, and sodium hydroxide is further preferred.

[0182] In the hydrolysis reaction, the ratio of the base to 1 mol of the 4-amino-2-halobenzonitrile compound (2) is, for example, 0.3 to 10 mol, preferably 0.5 to 6 mol, more preferably 0.8 to 3 mol, and further preferably 0.9 to 1.5 mol. The ratio of the base to 1 equivalent of the 4-amino-2-halobenzonitrile compound (2) is, for example, 1 to 8 equivalents, preferably 1.05 to 5 equivalents, more preferably 1.1 to 2 equivalents, and further preferably 1.2 to 1.3 equivalents. Too low a ratio of the base can slow the reaction rate. Too high a ratio of the base can produce many impurity by-products.

[0183] In order to improve the yield of the target product by stopping the hydrolysis at the amide group formation stage, the hydrolysis reaction is preferably performed in the presence of a base and in the presence of a peroxide. The peroxide can be an inorganic peroxide or an organic peroxide.

[0184] Examples of the inorganic peroxide can include: hydrogen peroxide, alkali metal peroxides (e.g., sodium peroxide and lithium peroxide), alkaline earth metal peroxides (e.g., magnesium peroxide and calcium peroxide), and persulfates (e.g., ammonium persulfate and potassium persulfate).

[0185] Examples of the organic peroxide can include: peracids (e.g., peracetic acid, perbenzoic acid, and perchlorobenzoic acid), and hydroperoxides (e.g., tert-butyl hydroperoxide, tert-amyl hydroperoxide, and cumene hydroperoxide).

[0186] These peroxides can be used alone or in combination with two or more. Among them, the inorganic peroxide is preferred, and hydrogen peroxide is more preferred.

[0187] The proportion of peroxide relative to 1 mol of the acid addition salt of 4-amino-2-halobenzonitrile compound (2) and organic sulfonic acid is, for example, 0.1 to 10 mol, preferably 1 to 5 mol, more preferably 1.5 to 2.5 mol. A low proportion of peroxide may result in a low yield. A high proportion of peroxide may cause further hydrolysis, potentially leading to the formation of carboxylic acids.

[0188] The reaction can be carried out in the presence of a solvent. This solvent can be an organic solvent containing at least water as a reactant component.

[0189] Examples of organic solvents may include polar solvents (e.g., protic polar solvents and aprotic polar solvents).

[0190] Examples of protic polar solvents may include: alcohols (e.g., C145-C ... 1-12 Alkyl alcohols, such as methanol, ethanol, isopropanol, hexanol, and decanol.

[0191] Examples of aprotic polar solvents may 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), and sulfoxides (e.g., dicarbonyl halides). 1-6 Alkyl sulfoxides, such as dimethyl sulfoxide, sulfones (e.g., cyclic sulfones, such as sulfolane), ethers (e.g., chain ethers, such as diethyl ether and diisopropyl ether, and cyclic ethers, such as tetrahydrofuran), ketones (e.g., acetone and methyl ethyl ketone), and esters (e.g., ethyl acetate).

[0192] These organic solvents can be used alone or in combination of two or more. When using a combination of two or more, a mixture of protic polar solvents and aprotic polar solvents is preferred, a mixture of alcohols and sulfoxides is more preferred, and C is even more preferred. 1-3 Alkyl alcohols and diC 1-3 Mixed solvents of alkyl sulfoxides (e.g., a mixture of methanol and dimethyl sulfoxide).

[0193] The proportion of organic solvent is, for example, 50 to 1000 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, 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.

[0194] The ratio of the protic polar solvent to 100 parts by mass of the acid-addition salt of the 4-amino-2-halogenocyanophenyl compound (2) with the organic sulfonic acid is, for example, 10 to 1000 parts by mass, preferably 50 to 800 parts by mass, more preferably 100 to 650 parts by mass, further preferably 150 to 500 parts by mass, and most preferably 180 to 220 parts by mass. A ratio of the protic polar solvent that is too low can result in a low yield. A ratio that is too high can also result in a low yield.

[0195] The ratio of the protic polar solvent to 100 parts by mass of the aprotic 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 further preferably 800 to 1000 parts by mass. A ratio of the protic polar solvent that is too low can result in a low yield. A ratio that is too high can also result in a low yield.

[0196] The ratio of the aprotic polar solvent to 100 parts by mass of the acid-addition salt of the 4-amino-2-halogenocyanophenyl compound (2) with the organic sulfonic acid 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 further preferably 20 to 40 parts by mass.

[0197] The ratio of water to 1 mole of the acid-addition salt of the 4-amino-2-halogenocyanophenyl compound (2) with the organic sulfonic acid is preferably 0.1 to 20 moles, more preferably 1 to 15 moles, and further preferably 6 to 10 moles. The ratio of water to 100 parts by mass of the acid-addition salt of the 4-amino-2-halogenocyanophenyl compound (2) with the organic sulfonic acid 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 further preferably 30 to 50 parts by mass. A ratio of water that is too low can result in a slow hydrolysis reaction. A ratio that is too high can result in a low yield.

[0198] The ratio of water to 100 parts by mass of the total amount of the organic solvent 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 further preferably 10 to 20 parts by mass. A ratio of water that is too low can result in a slow hydrolysis reaction. A ratio that is too high can result in a low yield.

[0199] The water can be contained in the form of an aqueous solution of a peroxide and / or an alkali, or can be contained as a mixed solvent of water and the organic solvent.

[0200] The reaction temperature is, for example, 10 to 100°C, preferably 20 to 80°C, more preferably 30 to 60°C, and further preferably 40 to 50°C.

[0201] The reaction time is not particularly limited and can be, for example, 1 to 10 hours, preferably 1.5 to 5 hours, and more preferably 2 to 3 hours.

[0202] The reaction can be carried out in air or in an inactive gas (for example, nitrogen; and rare gases such as argon and helium). The reaction can be carried out under normal pressure or ordinary pressure, or under pressurization. After completion of the reaction, the reaction product can be isolated and purified by a conventional separation-purification means (for example, neutralization, washing, extraction or elution, concentration, filtration, reprecipitation, centrifugal separation, precipitation or crystallization, and column chromatography) or a combination of these means. By means of neutralization or the like, the 4-amino-2-halobenzamide compound (6) in the form of an organic sulfonic acid salt can be converted into the free 4-amino-2-halobenzamide compound (6).

[0203] The production method of the acid addition salt of the 4-amino-2-halobenzonitrile compound (2) with an organic sulfonic acid according to the present application includes at least a separation step, and can include a salt formation step as a preceding step of the separation step, and / or can include an amination step as a preceding step of the salt formation step. Examples

[0204] The present application is explained in more detail below based on examples, but the scope of the present application is not limited thereto. The evaluation methods are shown below.

[0205] [ 1 H-NMR] H-NMR was measured using "JNM-ECZ400 (400 MHz)" manufactured by JEOL Ltd. or "JNM-ECA600 (600 MHz)" manufactured by JEOL Ltd., and chloroform-d (CDCl3) was used as a deuterated solvent and tetramethylsilane (TMS) was used as a standard substance. 1 H-NMR was measured using "JNM-ECZ400 (400 MHz)" manufactured by JEOL Ltd. or "JNM-ECA600 (600 MHz)" manufactured by JEOL Ltd., and chloroform-d (CDCl3) was used as a deuterated solvent and tetramethylsilane (TMS) was used as a standard substance.

[0206] [HPLC] HPLC area was measured using "High Performance Gradient HPLC System / Detector SPD-M20A" manufactured by Shimadzu Corporation, with a sample dissolved in a mixed solvent (volume ratio: 2 / 3) of 0.1 mass% aqueous formic acid and a methanol solution containing 15% by volume of acetonitrile. The composition ratio (molar ratio) was calculated based on the ratio of the HPLC area percentage. Based on the composition ratio, the purity of the sample can be calculated.

[0207] [Melting Point] The melting point was measured using a melting point measuring apparatus ("535" manufactured by BUCHI Co., Ltd.) according to Japanese Industrial Standard (JIS) K 4101 (1993) [5.1 Method according to visual observation].

[0208] [Synthesis Example 1] Synthesis of crude 4-amino-2-fluorobenzonitrile [a mixture of 4A2FBN (4-amino-2-fluorobenzonitrile) and 2A4FBN (2-amino-4-fluorobenzonitrile)]

[0209] [Chemical 14]

[0210] In a 2L autoclave made of SUS, 242.6g of dimethyl sulfoxide, 112.3g (0.8087mol) of 2,4-difluorobenzonitrile (DFBN) and 245.9g (5.0 molar ratio (relative to DFBN)) of 28 mass% ammonia water were charged, the mixture was heated to 100°C, and reacted for 18 hours.

[0211] After completion of the reaction, under a nitrogen atmosphere, a 1L flask was charged with 587.7g of the obtained reaction solution, water and ethyl acetate, the mixture was stirred and subjected to liquid-liquid extraction. As the organic layer, 315.7g of a yellow solution containing crude 4A2FBN and ethyl acetate (crude 4A2FBN-ethyl acetate solution) was obtained (composition ratio: 4A2FBN / 2A4FBN = 58 / 42, yield of 4A2FBN: 57.6% of DFBN).

[0212] [Example 1] Purification of crude 4A2FBN (using p-toluenesulfonic acid as an organic sulfonic acid, using isopropyl alcohol as a reaction solvent and a precipitation solvent) A 500mL flask was charged with the crude 4A2FBN-ethyl acetate solution 315.7g obtained in Synthesis Example 1, and concentrated under reduced pressure to remove the solvent, then isopropyl alcohol 272.5g and p-toluenesulfonic acid monohydrate 153.8g (molar ratio of 1.0 relative to DFBN) were charged to the flask, and then the resulting mixture was reacted at 20 to 30°C for 1 hour.

[0213] 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 / minute over about 30 minutes. The precipitated solid was separated by filtration, the separated solid was washed with ethyl acetate, and the washed product was dried under reduced pressure to obtain 170.9g of a white solid containing a salt of 4A2FBN and p-toluenesulfonic acid (composition ratio: 4A2FBN / 2A4FBN = 99 / 1, yield of 4A2FBN: 53.4% of DFBN).

[0214] 1 H-NMR (DMSO-d6): 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

[0215] [Example 2] Purification of crude 4A2FBN (using p-toluenesulfonic acid as an organic sulfonic acid, using methanol as a reaction solvent and a precipitation solvent) Into a 500 mL flask was charged with the crude 4A2FBN-ethyl acetate solution 315.7 g obtained in Synthesis Example 1, and concentrated under reduced pressure to remove the solvent, then methanol 272.5 g and p-toluenesulfonic acid monohydrate 153.8 g (molar ratio of 1.0 with respect to DFBN) were charged into the flask, and the resulting mixture was reacted at 20-30°C for 1 hour.

[0216] 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 / minute for about 30 minutes. The precipitated solid was separated by filtration, the separated solid was washed with methanol, and the washed product was dried under reduced pressure to obtain 145.3 g of a white solid containing a salt of 4A2FBN with p-toluenesulfonic acid (composition ratio: 4A2FBN / 2A4FBN = 98 / 2, yield of 4A2FBN: 45.4% of DFBN). Melting point: 219°C

[0217] [Example 3] Purification of crude 4A2FBN (using p-toluenesulfonic acid as an organic sulfonic acid, using ethyl acetate as a reaction solvent and a precipitation solvent) Into a 500 mL flask was charged with the crude 4A2FBN-ethyl acetate solution 315.7 g obtained in Synthesis Example 1, and p-toluenesulfonic acid monohydrate 153.8 g (molar ratio of 1.0 with respect to DFBN), and the resulting mixture was reacted at 20-30°C for 1 hour.

[0218] 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 / minute for about 30 minutes. The precipitated solid was separated by filtration, the separated solid was washed with ethyl acetate, and the washed product was dried under reduced pressure to obtain 162.65 g of a white solid containing a salt of 4A2FBN with p-toluenesulfonic acid (composition ratio: 4A2FBN / 2A4FBN = 91 / 9, yield of 4A2FBN: 50.8% of DFBN). Melting point: 219°C

[0219] [Example 4] Purification of crude 4A2FBN (using 2-naphthalenesulfonic acid as an organic sulfonic acid, using isopropanol as a reaction solvent and a precipitation solvent) A 500 mL flask was charged with the crude 4A2FBN-ethyl acetate solution 315.7 g obtained in Synthesis Example 1, and concentrated under reduced pressure to remove the solvent, then isopropyl alcohol 272.5 g and 2-naphthalenesulfonic acid 168.4 g (molar ratio of 1.0 relative to DFBN) were charged to the flask, and the resulting mixture was allowed to react at 20 to 30°C for 1 hour.

[0220] 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 / minute over about 30 minutes. The precipitated solid was isolated by filtration, the isolated solid was washed with isopropyl alcohol, and the washed product was dried under reduced pressure to obtain 167.5 g of a white solid containing a salt of 4A2FBN and 2-naphthalenesulfonic acid (composition ratio: 4A2FBN / 2A4FBN = 99 / 1, yield of 4A2FBN: 52.3% of DFBN).

[0221] [Example 5] Purification of crude 4A2FBN (using 1,5-naphthalenedisulfonic acid as an organic sulfonic acid, and using isopropyl alcohol as a reaction solvent and a precipitation solvent) A 500 mL flask was charged with the crude 4A2FBN-ethyl acetate solution 315.7 g obtained in Synthesis Example 1, and concentrated under reduced pressure to remove the solvent, then isopropyl alcohol 272.5 g and 1,5-naphthalenedisulfonic acid 145.7 g (molar ratio of 0.5 relative to DFBN) were charged to the flask, and the resulting mixture was allowed to react at 20 to 30°C for 1 hour.

[0222] 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 / minute over about 30 minutes. The precipitated solid was isolated by filtration, the isolated solid was washed with isopropyl alcohol, and the washed product was dried under reduced pressure to obtain 169.5 g of a white solid containing a salt of 4A2FBN and 1,5-naphthalenedisulfonic acid (composition ratio: 4A2FBN / 2A4FBN = 77 / 23, yield of 4A2FBN: 52.9% of DFBN).

[0223] [Example 6] Synthesis of 4A2FBAD (4-amino-2-fluorobenzamide)

[0224] [Chemical 15]

[0225] A 2L flask was charged with the acid-addition salt of 4A2FBN with p-toluenesulfonic acid 170.9 g (0.4319 mol) obtained in Example 1, methanol 336.0 g, dimethyl sulfoxide 41.0 g, and a 28 mass% aqueous sodium hydroxide solution 77.0 g (molar ratio relative to the acid-addition salt: 1.25) under a nitrogen atmosphere, and the mixture was then heated to 40 to 45°C. To the reaction vessel was added dropwise a 35 mass% hydrogen peroxide solution 83.9 g (molar ratio relative to the acid-addition salt: 2.00). After the completion of the dropwise addition, the resulting mixture was allowed to react at 40 to 45°C for 3 hours, and a reaction liquid 647.2 g was obtained. The pH of the resulting reaction liquid was adjusted to 7 with a 36 mass% hydrochloric acid, and the resulting mixture was then subjected to desolvation under reduced pressure at 50°C to obtain a concentrated liquid 220.3 g. To the resulting concentrated liquid was poured 427.6 g of water, and the resulting mixture was cooled to 0 to 5°C and stirred for 1 hour. The resulting solid was separated by filtration, and the separated product was washed with water, and the washed product was dried to obtain 47.1 g of a light brown solid containing 4A2FBAD (purity: 99.0% by HPLC, theoretical yield: 70.0% of the acid-addition salt, stable yield: 37.4% of DFBN). Melting point: 148°C

[0226] [Reference Example 1] Purification of crude 4A2FBN (using benzoic acid as the acid and using ethyl acetate as the reaction solvent and the precipitation solvent) A 500 mL flask was charged with the crude 4A2FBN-ethyl acetate solution 315.7 g obtained in Synthesis Example 1 and benzoic acid 98.8 g (molar ratio relative to DFBN: 1.0), and the resulting mixture was then allowed to react at 20 to 30°C for 1 hour.

[0227] After the completion of the reaction, the resulting solution was cooled from 28°C to 5°C at a cooling rate of about 0.8°C / minute over about 30 minutes, but no solid precipitated. Thus, it was not possible to separate the benzoic acid salts of 4A2FBN and 2A4FBN.

[0228] [Reference Example 2] Purification of crude 4A2FBN (using hydrochloric acid as the acid and using ethyl acetate as the reaction solvent and the precipitation solvent) A 500 mL flask was charged with the crude 4A2FBN-ethyl acetate solution 315.7 g obtained in Synthesis Example 1 and a 36 mass% hydrochloric acid 82.0 g (molar ratio relative to DFBN: 1.0), and the resulting mixture was then allowed to react at 20 to 30°C for 1 hour.

[0229] 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 / minute over about 30 minutes, but no solid precipitated. Thus, it was not possible to isolate the hydrochloride salt of 4A2FBN and the hydrochloride salt of 2A4FBN.

[0230] [Reference Example 3] Purification of crude 4A2FBN (using sulfuric acid as the acid and using isopropanol as the reaction solvent and the precipitation solvent) A 500 mL flask was charged with the crude 4A2FBN-ethyl acetate solution 315.7 g obtained in Synthesis Example 1, and the solvent was removed under reduced pressure, then isopropanol 272.5 g and 50 mass% sulfuric acid 158.7 g (molar ratio of 1.0 relative to DFBN) were charged to the flask, and the resulting mixture was allowed to react at 20 to 30°C for 1 hour.

[0231] After completion of the reaction, the solution was cooled from 28°C to 5°C at a cooling rate of about 0.8°C / minute over about 30 minutes. The precipitated solid was isolated by filtration, the isolated solid was washed with isopropanol, and the washed product was dried under reduced pressure to obtain 90.4 g of a white solid containing 4A2FBN monosulfate (composition ratio: 4A2FBN / 2A4FBN = 53 / 47, yield of 4A2FBN: 28.2% of DFBN).

[0232] [Reference Example 4] Purification of crude 4A2FBN (purification by sublimation) A 500 mL flask was charged with the crude 4A2FBN-ethyl acetate solution 315.7 g obtained in Synthesis Example 1, and the solvent was removed under reduced pressure, then an attempt was made to purify the resulting concentrate by sublimation of the impurity 2A4FBN (isomer) at a temperature of 105°C and a pressure (gauge pressure) of -100 KPa. However, the device was clogged by the crystals sublimated within the device, resulting in failure to operate.

[0233] [Reference Example 5] Purification of crude 4A2FBN (using toluene as the precipitation solvent) A 1000 mL flask was charged with the crude 4A2FBN-ethyl acetate solution 315.7 g obtained in Synthesis Example 1, and the solvent was removed under reduced pressure, then toluene 380.8 g was charged to the flask. The resulting mixture was stirred at 20 to 30°C for 1 hour, and then allowed to stand.

[0234] Subsequently, the precipitated solid was separated by filtration, the separated solid was washed with ethyl acetate, and the washed product was dried under reduced pressure to obtain 24.2 g of a white solid containing 4A2FBN (composition ratio: 4A2FBN / 2A4FBN = 99 / 1, yield of 4A2FBN: 21.6% of DFBN). Melting point: 56°C Industrial applicability

[0235] The acid addition salt obtained by the production method of the present application can be used as a raw material of a pharmaceutical intermediate, a reagent, etc.

Claims

A method for preparing an acid addition salt of a 1,4-amino-2-halobenzonitrile compound and an organic sulfonic acid, comprising a separation step, wherein, By utilizing the solubility difference between the acid addition salts of isomers in solvents, the acid addition salt of 4-amino-2-halobenzonitrile compound and organic sulfonic acid, represented by formula (2), can be separated from the acid addition salt of an organic sulfonic acid and a mixture of isomers of amino-halobenzonitrile compound represented by formula (1). In the formula, X represents a halogen atom. R 1 Substituents indicating reactive inertness, and n represents an integer from 0 to 3. In the formula, X, R 1 and n each have the same meaning as in equation (1).

2. The method according to claim 1, wherein, In the separation process, the separation using the solubility difference between the acid addition salts of the isomers in the solvent includes precipitation and / or extraction.

3. The method according to claim 1 or 2, wherein, In the separation process, the solvent comprises esters and / or alcohols.

4. The method according to claim 1, further comprising a salt formation step, wherein, An acid addition salt is formed by reacting a mixture of isomers of a 4-amino-2-halobenzonitrile compound represented by formula (2) and an amino-halobenzonitrile compound represented by formula (1) with the organic sulfonic acid.

5. The method according to claim 4, comprising an amination step as a pre-process of the salt formation step, wherein the amination step is performed by amination of a 2,4-dihalobenzonitrile compound containing at least the following formula (3) and a dihalobenzonitrile compound represented by the following formula (4): In the formula, X represents each halogen atom independently, and R 1 and n each have the same meaning as in equation (1). In the formula, X, R 1 and n each have the same meaning as in equation (3).

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

7. The method according to any one of claims 1, 2, and 4 to 6, wherein, The organic sulfonic acid includes aromatic sulfonic acids.

8. The method according to claim 7, wherein, The aromatic sulfonic acid comprises an aromatic cyclic sulfonic acid represented by the following formula (5): In the formula, Ring Z represents an aromatic ring. R 2 Substituents indicating inert reactivity m represents an integer greater than or equal to 0, and k represents an integer greater than or equal to 1.

9. The method according to claim 8, wherein, In equation (5), ring Z represents C 6-14 Aromatic ring, R 2 C represents a straight chain or a branch chain. 1-3 Alkyl, m represents 0 or 1, k represents 1 or 2.

10. The method according to any one of claims 1, 2, and 4 to 6, wherein, The proportion of sulfonic acid groups in the organic sulfonic acid is 0.8 to 1.2 mol relative to the total amount of 1 mol of the mixture of isomers of the amino halobenzonitrile compound represented by formula (1).

11. A method for preparing 4-amino-2-halobenzamide compounds represented by the following formula (6) or their acid addition salts: In the formula, X, R 1 And n each have the same meaning as in equation (1) of claim 1. The method includes an amidation step, wherein... The acid addition salt prepared by any one of claims 1 to 6 is subjected to a hydrolysis reaction.

12. The acid addition salt of the 4-amino-2-halobenzonitrile compound represented by the following formula (2) with an organic sulfonic acid: In the formula, X represents a halogen atom. R 1 Substituents indicating reactive inertness, and n represents an integer from 0 to 3.

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