Method for producing aminoarene amide derivatives

Abstract

To provide a method for efficiently and industrially advantageously producing aminoarene amide derivatives.SOLUTION: An aminoarene amide derivative represented by the formula (3) in the figure is produced from a compound represented by the formula (1) in the figure. The production method comprises: an amination step, in which a nitro group of the compound represented by the formula (1) is reduced to an amino group; and an amidation step, in which a cyano group of the compound represented by formula (1) is hydrolyzed and converted into an amide group. (In the formulas, Z represents an arene ring, X represents a halogen atom, n is an integer of 0 or more, R represents a substituent inert to the reaction, and m is an integer of 0 or more.)SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing aminoareneamide derivatives. [Background technology]

[0002] 4-Amino-2-fluorobenzamide, a monocyclic arene having an amino group, a fluorine atom, and an amide group as substituents, is known to be useful as a raw material or intermediate for pharmaceuticals.

[0003] As a method for producing such aminoareneamide derivatives, JP-T-2022-550367 (Patent Document 1) discloses a method in which 2-fluoro-4-nitrobenzoic acid, 1-propylphosphonic anhydride, and ammonia are reacted to obtain 2-fluoro-4-nitrobenzamide, and then the nitro group is reduced in the presence of iron.

[0004] As a method for producing the aminoareneamide derivative, China Patent Application Publication No. 114276266 (Patent Document 2) discloses a method in which the 4-position of 2,4-difluorobenzonitrile is substituted with a phthaloyl group, followed by reduction and hydrolysis of the cyano group. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special table 2022-550367 [Patent Document 2] China Patent Application Publication No. 114276266 Summary of the Invention [Problem to be solved by the invention]

[0006] However, the method of Patent Document 1 is not industrially advantageous because it uses expensive raw materials such as 2-fluoro-4-nitrobenzoic acid and includes a step of using iron, which may corrode a reactor. In addition, the method of Patent Document 2 has many reaction steps and is not efficient. Therefore, a method for producing aminoareneamide derivatives industrially and efficiently is not disclosed.

[0007] Therefore, an object of the present invention is to provide a method for producing aminoareneamide derivatives industrially advantageously and efficiently. [Means for solving the problem]

[0008] As a result of intensive research to achieve the above-mentioned object, the present inventors have found that an aminoareneamide derivative can be efficiently produced in high yield by a production method including a step of converting a nitro group of a nitroarenenitrile compound to an amino group by a reducing agent and a step of converting a cyano group to an amide group, and have completed the present invention.

[0009] That is, the present disclosure may include the following aspects.

[0010] Aspect [1]: A method for producing an aminoarene amide derivative represented by the following formula (3) from a compound represented by the following formula (1),

[0011] [ka]

[0012] (In the formula, Z represents an arene ring; X represents a halogen atom, n represents an integer of 0 or more, R represents a substituent that is inert to the reaction, and m represents an integer of 0 or more.

[0013] [ka]

[0014] (In the formula, Z, X, R, n, and m are each the same as in formula (1) above.)

[0015] A production method comprising the following amination step and the following amidation step:

[0016] An amination step of reducing the nitro group of the compound represented by formula (1) to an amino group. an amidation step in which the cyano group of the compound represented by formula (1) is hydrolyzed to convert it into an amide group;

[0017] Aspect [2]: The method according to embodiment [1], wherein the compound represented by formula (1) is subjected to an amination step and then to an amidation step.

[0018] Aspect [3]: In the formula (1), The method according to embodiment [1] or [2], wherein the arene ring Z represents a benzene ring.

[0019] Aspect [4]: The method according to any one of aspects [1] to [3], wherein the compound represented by formula (1) is represented by the following formula (1a):

[0020] [ka]

[0021] (In the formula, X, R, and m are the same as those in formula (1) above.)

[0022] Aspect [5]: X represents a fluorine atom; The method according to any one of the embodiments [1] to [4], wherein m is 0.

[0023] Aspect [6]: The method according to any one of aspects [1] to [5], wherein the amination step and the amidation step are carried out in one pot.

[0024] Aspect [7]: The method according to any one of the aspects [1] to [6], wherein in the amination step, a nitro group is reduced to an amino group in the presence of a heterogeneous catalyst.

[0025] Aspect [8]: The method according to any one of the embodiments [1] to [7], wherein in the amidation step, a cyano group is converted into an amide group under basic conditions in the presence of a peroxide.

[0026] In this specification and the claims, the term "nitro group of the compound represented by formula (1)" is used to mean not only the nitro group of the compound represented by formula (1) itself, but also the nitro group derived from the compound represented by formula (1) [the nitro group of the product obtained by subjecting the compound represented by formula (1) to an amidation step].

[0027] In this specification and the claims, the term "cyano group of the compound represented by formula (1)" is used to mean not only the cyano group of the compound represented by formula (1) itself, but also a cyano group derived from the compound represented by formula (1) [i.e., a cyano group of the product obtained by subjecting the compound represented by formula (1) to an amination step]. Effect of the Invention

[0028] In the method of the present invention, aminoareneamide derivatives (3) can be produced efficiently and industrially advantageously by simply subjecting nitroarenenitrile compound (1) to an amination step (reduction step) and an amidation step (hydrolysis step). In addition, aminoareneamide derivatives (3) can be produced with high purity and yield. Furthermore, the reaction can be carried out in one pot without isolating the reaction intermediate, and aminoareneamide derivatives can be obtained in high yield with a simple reaction procedure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] In the present invention, the nitroarenenitrile compound represented by the formula (1) is used as a raw material, and the aminoareneamide derivative represented by the formula (3) is produced by subjecting the compound to an amination (reduction) step and an amidation (hydrolysis) step.

[0030] [Aminoarene amide derivatives (3)] In the aminoarene amide derivative represented by the above formula (3) [aminoarene amide derivative (3)], examples of the arene ring (aromatic hydrocarbon ring) represented by ring Z include monocyclic arene rings such as a benzene ring, and fused polycyclic arene rings.

[0031] Examples of the fused polycyclic arene ring include a fused bicyclic arene ring, a fused tricyclic arene ring, and a fused tetracyclic arene ring. Examples of the fused bicyclic arene ring include a naphthalene ring and an indene ring. Examples of the fused tricyclic arene ring include an anthracene ring and a phenanthrene ring. Examples of the fused tetracyclic arene ring include a pyrene ring.

[0032] Of these arene rings, C 6-10 An arene ring is preferred, and a benzene ring is more preferred.

[0033] The group X (halogen atom) includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among 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.

[0034] In the formula (3), the substituent for R (non-reactive group or non-polymerizable substituent) may be any group other than a nitro group, a cyano group, an amino group, or an amido group, and examples thereof include a hydrocarbon group, an alkoxy group, a cycloalkyloxy group, an aryloxy group, and an aralkyloxy group.

[0035] Examples of the hydrocarbon group include an alkyl group, a cycloalkyl group, an aryl group, and an aralkyl group. Examples of the alkyl group include a linear or branched C alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a s-butyl group, and a t-butyl group. 1-6Examples of the cycloalkyl group include a C alkyl group such as a cyclopentyl group and a cyclohexyl group. 5-10 Examples of the aryl group include C aryl groups such as phenyl and naphthyl groups. 6-14 Examples of the aralkyl group include C aryl groups such as benzyl groups and phenethyl groups. 6-10 Aryl-C 1-6 Alkyl groups and the like.

[0036] Examples of the alkoxy group include linear or branched C alkoxy groups such as methoxy, ethoxy, propoxy, and butoxy groups. 1-6 Examples of the alkyl group include an alkoxy group.

[0037] These substituents may be used alone or in combination of two or more. Among these, alkyl groups are preferred, and linear or branched C groups such as methyl and ethyl groups are preferred. 1-3 Alkyl groups are particularly preferred.

[0038] The number of substitutions n of the group X may be an integer of 0 or more, and is preferably an integer of 0 to 2, more preferably 0 or 1, and even more preferably 1.

[0039] The number m of the substituents R may be an integer of 0 or more, and is preferably an integer of 0 to 3, more preferably an integer of 0 to 2, even more preferably 0 or 1, and most preferably 0.

[0040] When n and / or m are 1 or more, the substitution position of the group X and / or the substituent R is not particularly limited, and the group X and / or the substituent R may be substituted at any position other than the substitution positions of the amino group and the amido group of the ring Z. When multiple groups X and / or multiple substituents R are substituted, the types of the groups X and / or the substituents R may be the same or different from each other.

[0041] A preferred aminoareneamide derivative (3) can be represented by the following formula (3a): A representative example of the following formula (3a) is 4-amino-2-fluorobenzamide.

[0042] [ka]

[0043] (In the formula, X, R, and m are the same as those in the formula (1), including preferred embodiments.)

[0044] The aminoareneamide derivative (3) obtained by the production method of the present invention has a high purity, and the purity measured by HPLC (high performance liquid chromatography) (HPLC purity) can be selected from, for example, about 95% or more, preferably 96% or more, more preferably 97% or more, and even more preferably 98% or more.

[0045] In the following description, a method for producing the target compound by carrying out an amination step followed by an amidation step will be described.

[0046] [Amination process] In the amination step, as shown in the reaction formula below, a nitroarene nitrile compound represented by the formula (1) [nitroarene nitrile compound (1)] is reacted with a reducing agent to produce an aminoarene nitrile compound represented by the formula (2) below [aminoarene nitrile compound (2)].

[0047] [ka]

[0048] (In the formula, X, n, R, and m are the same as those in the formula (1) above, including preferred embodiments.)

[0049] A preferred nitroarenenitrile compound (1) may be a compound represented by the following formula (1a): A representative example of the compound represented by the formula (1a) is 2-fluoro-4-nitrobenzonitrile.

[0050] [ka]

[0051] (In the formula, X, R, and m are the same as those in the formula (1), including preferred embodiments.)

[0052] The method of reducing the nitro group in the formula (1) to convert it to an amino group is not particularly limited, and examples thereof include a metal reduction method using a metal component and an acid component, and a catalytic reduction (hydrogenation) method. In the reduction treatment by catalytic hydrogenation, a reducing agent may be used in the presence of a catalyst. Among these methods, a catalytic reduction method that does not corrode a reactor or the like is preferred, and a catalytic reduction method in the presence of a heterogeneous catalyst that allows simple post-treatment is more preferred.

[0053] Examples of hydrogenation catalysts include osmium catalysts (e.g., osmium on carbon, etc.); palladium catalysts (e.g., palladium, palladium on carbon, etc.); nickel catalysts (e.g., Raney nickel catalyst, etc.); platinum catalysts such as platinum catalysts (e.g., platinum on carbon, platinum black, platinum oxide (Adams catalyst), etc.), rhodium catalysts, and ruthenium catalysts (ruthenium on carbon, ruthenium oxide, ruthenium black, etc.); and rhenium catalysts. These hydrogenation catalysts can be used alone or in combination of two or more. Among these, heterogeneous catalysts are preferred, and palladium catalysts such as palladium on carbon supported on carbon are more preferred.

[0054] The proportion of the hydrogenation catalyst, calculated as metal, relative to 100 parts by mass of the nitroarenenitrile compound (1), is, for example, 0.01 to 10 parts by mass, preferably 0.03 to 5 parts by mass, more preferably 0.05 to 1 part by mass, and even more preferably 0.1 to 0.5 parts by mass.

[0055] The reducing agent may be, for example, hydrogen gas, a hydrogen source such as hydrazine, etc. Among these, hydrogen gas is preferred.

[0056] The reduction reaction may be carried out in the presence of a base. Examples of the base include alkali metal carbonates (e.g., potassium carbonate, sodium carbonate, etc.), alkali metal hydroxides (e.g., potassium hydroxide, sodium hydroxide, etc.), and alkali metal alkoxides (e.g., sodium methoxide, sodium-t-butoxide, etc.). These bases can be used alone or in combination of two or more. Among these, alkali metal hydroxides are preferred, potassium hydroxide and sodium hydroxide are more preferred, and sodium hydroxide is even more preferred.

[0057] The ratio of the base is, for example, 0.01 to 0.1 mol, preferably 0.015 to 0.05 mol, and more preferably 0.02 to 0.035 mol, relative to 1 mol of the nitro group. If the ratio of the base is too low, the yield may decrease, whereas if the ratio is too high, the yield may decrease.

[0058] The reaction may be carried out in the presence of a reaction solvent. The reaction solvent may be a solvent that is not reduced by a reducing agent, and examples of the reaction solvent include nonpolar solvents, aprotic polar solvents, and protic polar solvents.

[0059] Examples of non-polar solvents include saturated hydrocarbons (e.g., aliphatic hydrocarbons such as hexane, aromatic hydrocarbons such as toluene, benzene, and xylene), and ethers (diethyl ether, dioxane, and the like).

[0060] Examples of the aprotic polar solvent include cyclic ethers such as tetrahydrofuran, nitriles such as acetonitrile, and halogenated hydrocarbons such as dichloromethane.

[0061] Examples of the protic polar solvent include linear or branched C 11 alkyl alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, s-butanol, t-butanol, hexanol, heptanol, octanol, decanol, and lauryl alcohol. 1-12 alkanols, etc.); aliphatic polyhydric alcohols (e.g., ethylene glycol, propylene glycol, etc. C 2-4 Di-C such as alkylene glycol and diethylene glycol 2-4 alkylene glycol, water, etc.

[0062] These reaction solvents can be used alone or in combination of two or more kinds.

[0063] Among these reaction solvents, protic polar solvents are preferred, and linear or branched C 1-12 Alkanols are more preferred, linear or branched C 1-6 Alkanols are more preferred, linear or branched C 1-3 Alkanols are most preferred.

[0064] The proportion of the protic polar solvent may be any proportion that allows the reaction system to be stirred, and is, for example, 10 to 1,000 parts by mass, preferably 100 to 800 parts by mass, more preferably 300 to 650 parts by mass, and even more preferably 500 to 600 parts by mass, relative to 100 parts by mass of the nitroarenenitrile compound (1).

[0065] Water may be added as a solvent in the form of an aqueous solution of the base.

[0066] The reaction temperature is, for example, 30 to 150°C, preferably 40 to 100°C, further preferably 45 to 80°C, and further preferably 50 to 70°C.

[0067] The reaction may be carried out under normal pressure or under pressure, but is preferably carried out under pressure. The reaction pressure is, for example, 0.01 to 10 MPa, preferably 0.05 to 5 MPa, more preferably 0.1 to 2 MPa, and more preferably 0.3 to 1 MPa. The reaction pressure may be the pressure of hydrogen gas, which is a reducing agent.

[0068] In any reduction treatment, after completion of the reaction, the reaction product may be separated and purified by a conventional separation and purification means such as washing, extraction, concentration, filtration, reprecipitation, centrifugation, crystallization, recrystallization, column chromatography, or a combination of these.

[0069] The production method of the present invention may be a one-pot method in which the reaction product obtained in the amination step is directly subjected to the subsequent amidation step without being separated, purified, and isolated. In the one-pot method, amination is preferably carried out by catalytic reduction using a heterogeneous catalyst from the viewpoint of productivity, etc.

[0070] The resulting aminoarenenitrile compound (2) may be a compound represented by the following formula (2):

[0071] [ka]

[0072] (In the formula, Z, X, n, R, and m are the same as those in the formula (1), including preferred embodiments.)

[0073] A preferred aminoarenenitrile compound (2) may be a compound represented by the following formula (2a): A representative example of the compound represented by the following formula (2a) is 4-amino-2-fluorobenzonitrile.

[0074] [ka]

[0075] (In the formula, X, R, and m are the same as those in the formula (1), including preferred embodiments.)

[0076] [Amidation process] In the amidation step, as shown in the following reaction formula, the cyano group of the aminoarenenitrile compound (2) is hydrolyzed to generate an amide group, thereby producing an aminoareneamide derivative (3).

[0077] [ka]

[0078] (In the formula, X, n, R, and m are the same as those in the formula (1) above, including preferred embodiments.)

[0079] 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.

[0080] Examples of the base include alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, etc.), and alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.). These bases may be used alone or in combination of two or more. Among these, alkali metal hydroxides are preferred, sodium hydroxide and potassium hydroxide are more preferred, and sodium hydroxide is even more preferred.

[0081] The ratio of the base is preferably 0.01 to 1 mol, more preferably 0.1 to 0.5 mol, and even more preferably 0.2 to 0.3 mol, per mol of the cyano group of the nitroarenenitrile compound (1). If the ratio of the base is too small, the reaction rate may be slow, whereas if the ratio is too large, a large amount of impurities may be produced as by-products.

[0082] The hydrolysis reaction can be carried out in the presence of a peroxide, which may be an inorganic peroxide or an organic peroxide.

[0083] Examples of inorganic peroxides include hydrogen peroxide, alkali metal peroxides (eg, sodium peroxide, etc.), alkaline earth metal peroxides (eg, lithium peroxide, etc.), and persulfates (eg, ammonium persulfate, potassium persulfate, etc.).

[0084] Examples of organic peroxides include peracids (eg, peracetic acid, perbenzoic acid, perchlorobenzoic acid, etc.), and hydroperoxides (eg, t-butyl hydroperoxide, t-amyl hydroperoxide, cumene hydroperoxide, etc.).

[0085] These peroxides can be used alone or in combination of two or more kinds. Among these, inorganic peroxides are preferred, and hydrogen peroxide is more preferred.

[0086] In addition, it is preferable to carry out the reaction 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 formation of an amide group.

[0087] The ratio of the peroxide is preferably 0.1 to 10 mol, more preferably 1 to 5 mol, and even more preferably 1.5 to 2.5 mol, relative to 1 mol of the cyano group of the nitroarenenitrile compound (1). If the ratio of the peroxide is too low, the yield may decrease, whereas if the ratio is too high, hydrolysis may proceed and a carboxylic acid may be produced.

[0088] The reaction may be carried out in the presence of a solvent, which may be water and / or an organic solvent, preferably a solvent containing at least water, more preferably a mixed solvent of water and an organic solvent.

[0089] Examples of the organic solvent include polar solvents (for example, protic polar solvents, aprotic polar solvents, etc.) These organic solvents can be used alone or in combination of two or more kinds.

[0090] Examples of protic polar solvents include C 2 O, C 1 O, ... 1-12 Alkanols are included.

[0091] Examples of aprotic polar solvents include alkyl halides such as dichloromethane, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, nitriles such as acetonitrile and propionitrile, and sulfoxides such as dimethyl sulfoxide.

[0092] As a combination of mixed solvents consisting of these organic solvents, a mixed solvent consisting of a protic polar solvent and an aprotic polar solvent is preferable. 1-6 A mixed solvent of alkanols and sulfoxides is more preferred, and C 1-3 Alkanols and DiC 1-3 A mixed solvent of alkyl sulfoxides is more preferred.

[0093] When the production method of the present invention is a one-pot method, the protic polar solvent can be the polar solvent added in the amination step, or a new protic polar solvent can be added in the amidation step. On the other hand, when the reaction product obtained in the amination step is separated, purified, and isolated, it is preferable to add a protic polar solvent in the amidation step.

[0094] The proportion of the protic polar solvent is, for example, 10 to 1000 parts by mass, preferably 100 to 800 parts by mass, more preferably 300 to 650 parts by mass, and even more preferably 500 to 600 parts by mass, relative to 100 parts by mass of the nitroarenenitrile compound (1).

[0095] The ratio of the protic polar solvent is, for example, 200 to 2000 parts by mass, preferably 500 to 1500 parts by mass, more preferably 700 to 1300 parts by mass, and more preferably 900 to 1100 parts by mass, relative to 100 parts by mass of the aprotic polar solvent. If the ratio of the protic polar solvent is too low, the yield may decrease, whereas if the ratio is too high, the yield may decrease.

[0096] The proportion of the aprotic polar solvent is, for example, 10 to 100 parts by mass, preferably 20 to 80 parts by mass, more preferably 30 to 70 parts by mass, and still more preferably 45 to 60 parts by mass, relative to 100 parts by mass of the nitroarenenitrile compound (1).

[0097] The proportion of water is preferably 0.1 to 20 mol, more preferably 1 to 15 mol, and more preferably 6 to 10 mol, relative to 1 mol of cyano group in the nitroarenenitrile compound (1). The proportion of water is, for example, 10 to 1000 parts by mass, preferably 30 to 500 parts by mass, further 50 to 150 parts by mass, and more preferably 80 to 100 parts by mass, relative to 100 parts by mass of the nitroarenenitrile compound (1).

[0098] 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 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 hydrolysis may be slowed, whereas if it is too high, the yield may be reduced.

[0099] The water as a solvent may be added in the form of an aqueous solution of the peroxide and the base.

[0100] The reaction temperature is, for example, 10 to 100°C, preferably 20 to 80°C, further preferably 30 to 60°C, and further preferably 40 to 50°C.

[0101] The reaction may be carried out in air or in an inert gas (e.g., nitrogen; or a rare gas such as argon or helium). The reaction may be carried out under normal pressure or under pressure. After completion of the reaction, the reaction product may be separated and purified by a conventional separation and purification means such as washing, extraction, concentration, filtration, reprecipitation, centrifugation, crystallization, recrystallization, or column chromatography, or a combination of these.

[0102] The production method of the present invention may include an amination step and an amidation step, and may be the first method in which the amidation step is performed after the amination step, or the second method in which the amination step is performed after the amidation step. Among these, the first method is preferred in terms of improving the yield. The second method is similar to the first method except that the nitroarenenitrile compound (1) is used as the starting material for the amidation step, and the reaction conditions can be selected from those described above. EXAMPLES

[0103] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. Evaluation methods are shown below.

[0104] [ 1 H-NMR] Measurements were performed using a JEOL Ltd. "JNM-ECZ400 (400 MHz)" or a JEOL Ltd. "JNM-ECA600 (600 MHz)" with chloroform-d (CDCl3) as the deuterated solvent and tetramethylsilane (TMS) as the standard substance.

[0105] [purity] The HPLC purity was measured using HPLC (Shimadzu Corporation, "High Pressure Gradient HPLC System / Detector SPD-M20A").

[0106] [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 inspection method].

[0107] [Example 1] (Synthesis of 4-amino-2-fluorobenzamide)

[0108] [ka]

[0109] In a 2L stainless steel autoclave, 727.8g of methanol, 134.9g (0.8087mol) of 2-fluoro-4-nitrobenzonitrile (FNBN), 2.9g (0.025mol ratio) of 28% by mass aqueous sodium hydroxide solution, and 3.4g of 5% by mass palladium carbon were charged, and then the temperature was raised to 60°C. Hydrogen was added to the reaction vessel, and the mixture was reacted for 5 to 6 hours while pressurizing at 0.8MPa, to obtain 838.0g of reaction liquid. The residue was removed by pressure filtration, and 853.4g of reaction filtrate was obtained.

[0110] The resulting reaction filtrate was desolvated under reduced pressure at 50°C under a nitrogen atmosphere to obtain 250.6 g of a concentrated solution. 323.5 g of water was poured into the resulting concentrated solution, which was then cooled to 0-5°C and stirred for 1 hour. The resulting crystals were filtered, washed with water, and dried to obtain 97.3 g of 4-amino-2-fluorobenzonitrile (4A2FBN) as a yellow solid (HPLC purity: 99.5%, yield: 88.4% relative to FNBN).

[0111] In a nitrogen atmosphere, 97.3 g (0.7148 mol) of 4-amino-2-fluorobenzonitrile (4A2FBN), 714.8 g of methanol, 67.9 g of dimethyl sulfoxide, and 25.5 g (0.25 mol ratio) of 28% by mass sodium hydroxide aqueous solution were charged into a 2L flask, and the temperature was raised to 40-45°C. 138.9 g (2.00 mol ratio) of 35% by mass hydrogen peroxide solution was dropped into the reaction vessel. After the dropwise addition was completed, the reaction was carried out at a temperature of 40-45°C for 3 hours, and 1044.4 g of reaction liquid was obtained. The obtained reaction liquid was adjusted to pH 7-8 with 36% by mass hydrochloric acid, and the solvent was removed under reduced pressure at 50°C to obtain 330.5 g of a concentrated liquid. 571.8 g of water was poured into the obtained concentrated liquid, cooled to 0-5°C, and stirred for 1 hour. The resulting crystals were filtered, washed with water, and dried to give 97.1 g of 4-amino-2-fluorobenzamide (AFBAD) as a yellow solid (HPLC purity: 98.4%, yield: 86.7 mol% relative to 4A2FBN, overall yield: 76.6% relative to FNBN).

[0112] 1H-NMR (DMSO-d6): δ(ppm)5.94(s,2H), 6.25-6.29(dd,J 8.8 2.0,1H), 6.37-6.39(dd,J 8.8 2.0 1H), 6.99(br s,1H), 7.17(br s,1H), 7.48(t,J 8.8,1H)

[0113] Melting point: 148℃

[0114] [Example 2] (One-pot synthesis of 4-amino-2-fluorobenzamide)

[0115] [ka]

[0116] 727.8g of methanol, 134.9g (0.8087mol) of 2-fluoro-4-nitrobenzonitrile (FNBN), 2.9g (0.025mol ratio) of 28% by mass aqueous sodium hydroxide solution, and 3.4g of 5% by mass palladium carbon were charged into a 2L capacity stainless steel autoclave, and the temperature was raised to 60°C. Hydrogen was added to the reaction vessel, and the reaction was carried out for 5 to 6 hours while pressurizing at 0.8MPa. The residue was removed by pressure filtration, and 853.4g of reaction filtrate was obtained.

[0117] In a nitrogen atmosphere, 853.4 g of the reaction filtrate, 76.8 g of dimethyl sulfoxide, and 28.9 g of 28% by mass sodium hydroxide aqueous solution (0.25 mol ratio) were charged into a 2L flask, and the temperature was raised to 40-45°C. 157.2 g of 35% by mass hydrogen peroxide solution (2.00 mol ratio) was added dropwise to the reaction vessel. After the dropwise addition was completed, the reaction was carried out at a temperature of 40-45°C for 3 hours, and 1116.3 g of a reaction liquid was obtained. The resulting reaction liquid was adjusted to pH 7-8 with 36% by mass hydrochloric acid, and the solvent was removed under reduced pressure at 50°C to obtain 330.5 g of a concentrated liquid. 647.0 g of water was poured into the obtained concentrated liquid, cooled to 0-5°C, and stirred for 1 hour. The resulting crystals were filtered, washed with water, and dried to give 106.3 g of 4-amino-2-fluorobenzamide (AFBAD) as a yellow solid (HPLC purity: 100%, consistent yield: 85.2% relative to FNBN).

[0118] 1 H-NMR (DMSO-d6): δ(ppm)5.94(s,2H), 6.25-6.29(dd,J 8.8 2.0,1H), 6.37-6.39(dd,J 8.8 2.0 1H), 6.99(br s,1H), 7.17(br s,1H), 7.48(t,J 8.8,1H)

[0119] Melting point: 148℃

[0120] [Comparative Example 1] (Synthesis of 4-amino-2-fluorobenzamide) A 2L flask was charged with 566.1g of dimethylacetamide and 149.8g of potassium phthalimide (1.00 mol ratio), and then dehydrated under reduced pressure. Under a nitrogen stream, 112.5g (0.8087mol) of 2,4-difluorobenzonitrile (DFBN) was charged and heated to 100°C. The reaction was carried out for 21 hours, and 828.4g of reaction liquid was obtained. 452.9g of water was dropped into the reaction liquid obtained, and the resulting crystals were filtered and washed with water to obtain 334.0g of crude product. The crude product obtained and 849.1g of methanol were charged into a 2L flask, and the mixture was stirred for 1 hour, filtered, washed with methanol, and dried to obtain 164.2g of 4-[(1,3-dioxo-1,3-dihydro-2H-indol-2-yl)methyl]-3-fluorobenzonitrile (phthalimide compound) as a white solid.

[0121] Under a nitrogen stream, 1641.9 g of methanol and 164.2 g (0.6168 mol) of phthalimide were charged into a 5 L flask, and then 63.7 g of hydrazine monohydrate (2.00 mol ratio) was added dropwise. The reaction was continued for 17 hours, yielding 1776.8 g of reaction liquid. The reaction liquid was cooled to 5°C or less and stirred for 30 minutes. The residue was removed by vacuum filtration, yielding 1805.2 g of filtrate and washings. The obtained filtrate and washings were concentrated under reduced pressure, and 622.7 g of water and 622.7 g of toluene were added to the concentrated liquid, followed by stirring for 1 hour. The resulting crystals were filtered, and 38.5 g of 4-amino-2-fluorobenzonitrile (4A2FBN) was obtained as a slightly yellowish white solid (HPLC purity: 98.9%, yield: 34.6% relative to DFBN).

[0122] In a nitrogen atmosphere, 38.5g (0.2828mol) of 4A2FBN, 303.5g of methanol, 27.2g of dimethyl sulfoxide, and 10.1g of 28% by mass sodium hydroxide aqueous solution (0.25mol ratio) were charged into a 2L flask, and the temperature was raised to 40-45°C. 55.0g (2.0mol ratio) of 35% by mass hydrogen peroxide solution was added dropwise to the reaction liquid. After the dropwise addition was completed, the reaction was carried out for 3 hours, and 1866.1g of reaction liquid was obtained. The solvent was removed from the obtained reaction liquid under normal pressure to obtain 525.4g of a concentrated liquid. 226.5g of water was poured into the obtained concentrated liquid, which was cooled to 0-5°C and stirred for 1 hour. The resulting crystals were filtered, washed with water, and dried to give 36.7 g of AFBAD as a yellow solid (HPLC purity: 100%, yield: 85.2% vs. 4A2FBN, overall yield: 29.5% vs. DFBN).

[0123] [Comparative Example 2] (Synthesis of 4-amino-2-fluorobenzamide) 242.6 g of dimethyl sulfoxide, 112.5 g (0.8087 mol) of 2,4-difluorobenzonitrile (DFBN), and 245.9 g (5.00 mol ratio) of 28% by mass ammonia water were charged into a 1 L capacity stainless steel autoclave, and then the temperature was raised to 100°C.

[0124] After the temperature was raised, the mixture was reacted for 18 hours and cooled to 30°C or less. 592.6g of reaction liquid was obtained. The resulting reaction liquid was desolvated under reduced pressure at 120°C to obtain 167.0g of a concentrated liquid. 240.2g of methanol was added dropwise to the resulting concentrated liquid at 60-70°C, and the residue was removed by filtration under reduced pressure to obtain 392.3g of 4-amino-2-fluorobenzonitrile (4A2FBN) / methanol filtrate and washings (yield: 56.3% based on DFBN).

[0125] Under a nitrogen stream, 392.3 g (0.4553 mol) of the methanol filtrate and 57.9 g of dimethyl sulfoxide were charged into a 1 L flask, and then a 28% by mass aqueous sodium hydroxide solution was added dropwise to adjust the pH to 12-13. The reaction liquid was heated to 40°C, and 148.8 g (3.36 mol ratio) of 35% by mass aqueous hydrogen peroxide was added dropwise. After the dropwise addition was completed, the reaction was continued for 3 hours to obtain 630.7 g of a reaction liquid. The resulting reaction liquid was desolvated under reduced pressure at 120°C to obtain 230.3 g of a concentrated liquid. 758.1 g of water was poured into the resulting concentrated liquid at 60-70°C, cooled to 0-5°C, and stirred for 1 hour. The resulting crystals were filtered and washed with water to obtain 235.5 g of a crude product.

[0126] A 5L flask was charged with 1837.9g ​​of toluene and a toluene suspension of 235.5g of the crude product, and then the mixture was dehydrated using a Dean-Stark tube and gradually cooled to 60-65°C. After stirring for 1 hour, the resulting crystals were filtered, washed with toluene, and dried to obtain 47.3g of AFBAD as a yellow solid (HPLC purity: 99.5%, yield: 67.1% vs. 4A2FBN / methanol filtrate, total yield: 37.8% vs. DFBN). [Industrial Applicability]

[0127] In the method of the present invention, aminoareneamide derivatives can be efficiently produced from nitroarenenitrile compounds as raw materials. Such aminoareneamide derivatives can be used as reagents or raw materials for physiologically or pharmacologically active compounds, and for example, 4-amino-2-fluorobenzamide, which is a monocyclic arene, is useful as a raw material or reagent for pharmaceuticals.

Claims

1. A method for producing an aminoarene amide derivative represented by the following formula (3) from a compound represented by the following formula (1), 【Chemistry 1】 (In the formula, Z represents an arene ring; X represents a halogen atom; n represents an integer of 0 or more; R represents a substituent inactive to the reaction, and m represents an integer of 0 or more. 【Chemistry 2】 (In the formula, Z, X, R, n, and m are each the same as in formula (1).) A production method comprising the following amination step and the following amidation step: an amination step of reducing the nitro group of the compound represented by formula (1) to an amino group; An amidation step in which the cyano group of the compound represented by formula (1) is hydrolyzed to convert it into an amide group.

2. The method according to claim 1, wherein the compound represented by formula (1) is subjected to an amination step and then to an amidation step.

3. In the formula (1), 3. The process according to claim 1, wherein the arene ring Z is a benzene ring.

4. The method according to claim 1 or 2, wherein the compound represented by formula (1) is a compound represented by the following formula (1a): 【Chemistry 3】 (In the formula, X, R, and m are the same as those in formula (1)).

5. X represents a fluorine atom; The process according to claim 1 or 2, wherein m is 0.

6. The method according to claim 1 or 2, wherein the amination step and the amidation step are carried out in one pot.

7. 3. The process according to claim 1, wherein in the amination step, the nitro group is reduced to an amino group in the presence of a heterogeneous catalyst.

8. 3. The method according to claim 1, wherein in the amidation step, the cyano group is converted to an amide group under basic conditions in the presence of a peroxide.

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