Method of producing aromatic amide derivative

Abstract

Provided is a method of producing an aromatic amide derivative represented by Formula (I), which method includes a process a containing reacting an aniline derivative represented by Formula (II) with a carboxylic acid derivative represented by Formula (III) in the presence of a base to obtain an imide compound represented by Formula (IV) and a process b containing hydrolyzing the imide compound represented by Formula (IV) to obtain the aromatic amide derivative represented by Formula (I): ##STR00001##
wherein R.sup.1 represents a C.sub.1-C.sub.4 haloalkyl group, etc.; each of R.sup.2 and R.sup.3 independently represents a hydrogen atom, a halogen atom, etc.; R.sup.4 represents a hydrogen atom, a C.sub.1-C.sub.4 alkyl group, etc.; each of X.sup.1 and X.sup.2 independently represents a halogen atom, a C.sub.1-C.sub.4 haloalkyl group, etc.; and Q represents a C.sub.1-C.sub.4 alkyl group, a phenyl group, a pyridyl group, etc.

Claims

1. A method of producing an aromatic amide derivative of the following Formula (I), comprising the following process a and process b: ##STR00026## in Formula (I), R.sup.1 represents a halogen atom; a C.sub.1-C.sub.4 haloalkyl group; or a C.sub.1-C.sub.4 haloalkyl group substituted by 1 to 8 substituents, which may be the same or different, selected from the group consisting of a C.sub.1-C.sub.4 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4 haloalkoxy group, a C.sub.1-C.sub.4 alkylthio group, a C.sub.1-C.sub.4 haloalkylthio group, a C.sub.1-C.sub.4 alkylamino group, a di-C.sub.1-C.sub.4 alkylamino group, a cyano group, and a nitro group; each of X.sup.1 and X.sup.2 independently represents a hydrogen atom, a halogen atom, a C.sub.1-C.sub.4 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.2-C.sub.4 alkenyl group, a C.sub.2-C.sub.4 haloalkenyl group, a C.sub.2-C.sub.4 alkynyl group, a C.sub.2-C.sub.4 haloalkynyl group, a C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4 haloalkoxy group, a C.sub.1-C.sub.4 alkylthio group, a C.sub.1-C.sub.4 haloalkylthio group, a C.sub.1-C.sub.4 alkylsulfinyl group, a C.sub.1-C.sub.4 haloalkylsulfinyl group, a C.sub.1-C.sub.4 alkylsulfonyl group, a C.sub.1-C.sub.4 haloalkylsulfonyl group, a C.sub.1-C.sub.4 alkylamino group, a di-C.sub.1-C.sub.4 alkylamino group, a cyano group, a nitro group, a C.sub.1-C.sub.4 alkylcarbonyl group, or a C.sub.1-C.sub.4 haloalkylcarbonyl group; each of R.sup.2 and R.sup.3 independently represents a hydrogen atom, a halogen atom, a C.sub.1-C.sub.4 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4 haloalkoxy group, a C.sub.1-C.sub.4 alkylthio group, a C.sub.1-C.sub.4 haloalkylthio group, a C.sub.1-C.sub.4 alkylsulfinyl group, a C.sub.1-C.sub.4 haloalkylsulfinyl group, a C.sub.1-C.sub.4 alkylsulfonyl group, a C.sub.1-C.sub.4 haloalkylsulfonyl group, a C.sub.1-C.sub.4 alkylamino group, a di-C.sub.1-C.sub.4 alkylamino group, a cyano group, or a nitro group; R.sup.4 represents: a hydrogen atom; a C.sub.1-C.sub.4 alkyl group; a C.sub.1-C.sub.4 haloalkyl group; a C.sub.1-C.sub.4 alkylcarbonyl group; a C.sub.1-C.sub.4 haloalkylcarbonyl group; a C.sub.1-C.sub.4 alkoxycarbonyl group; a C.sub.1-C.sub.4 haloalkoxycarbonyl group; a C.sub.1-C.sub.4 alkylsulfonyl group; a C.sub.1-C.sub.4 haloalkylsulfonyl group; or a C.sub.1-C.sub.4 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 alkylcarbonyl group, a C.sub.1-C.sub.4 haloalkylcarbonyl group, a C.sub.1-C.sub.4 alkoxycarbonyl group, a C.sub.1-C.sub.4 haloalkoxycarbonyl group, a C.sub.1-C.sub.4 alkylsulfonyl group, or a C.sub.1-C.sub.4 haloalkylsulfonyl group, substituted by 1 to 9 substituents, which may be the same or different, selected from the group consisting of a C.sub.1-C.sub.4 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4 haloalkoxy group, a C.sub.1-C.sub.4 alkylthio group, a C.sub.1-C.sub.4 haloalkylthio group, a C.sub.1-C.sub.4 alkylsulfonyl group, a C.sub.1-C.sub.4 haloalkylsulfonyl group, a C.sub.1-C.sub.4 alkylamino group, a di-C.sub.1-C.sub.4 alkylamino group, a C.sub.1-C.sub.4 alkylcarbonyl group, a C.sub.1-C.sub.4 alkoxycarbonyl group, a di-C.sub.1-C.sub.4 alkylaminocarbonyl group, a cyano group, and a nitro group; and Q represents: a C.sub.1-C.sub.4 alkyl group; a C.sub.1-C.sub.4 haloalkyl group; a C.sub.1-C.sub.4 alkylaminocarbonyl group; a C.sub.1-C.sub.4 haloalkylaminocarbonyl group; a di-C.sub.1-C.sub.4 alkylaminocarbonyl group; a di-C.sub.1-C.sub.4 haloalkylaminocarbonyl group; a phenyl group; a heterocyclic group; a C.sub.1-C.sub.4 alkyl group or a C.sub.1-C.sub.4 haloalkyl group, substituted by 1 to 9 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C.sub.1-C.sub.4 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4 haloalkoxy group, a C.sub.1-C.sub.4 alkylthio group, a C.sub.1-C.sub.4 haloalkylthio group, a C.sub.1-C.sub.4 alkylamino group, a di-C.sub.1-C.sub.4 alkylamino group, a cyano group, and a nitro group; a phenyl group substituted by 1 to 5 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C.sub.1-C.sub.4 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4 haloalkoxy group, a C.sub.1-C.sub.4 alkylthio group, a C.sub.1-C.sub.4 haloalkylthio group, a C.sub.1-C.sub.4 alkylamino group, a di-C.sub.1-C.sub.4 alkylamino group, a cyano group, and a nitro group; or a heterocyclic group substituted by 1 to 4 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C.sub.1-C.sub.4 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4 haloalkoxy group, a C.sub.1-C.sub.4 alkylthio group, a C.sub.1-C.sub.4 haloalkylthio group, a C.sub.1-C.sub.4 alkylamino group, a di-C.sub.1-C.sub.4 alkylamino group, a cyano group, and a nitro group; wherein the heterocyclic group is a pyridyl group, a pyridyl-N-oxide group, a pyrimidyl group, a pyridazyl group, a pyrazyl group, a furyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a triazolyl group, a pyrrolyl group, a pyrazolyl group, or a tetrazolyl group; and wherein the process a comprises reacting an aniline derivative of the following Formula (II) with a carboxylic acid derivative of the following Formula (III), in the presence of a base, to thereby obtain an imide compound of the following Formula (IV): ##STR00027## in Formula (II), R.sup.1, X.sup.1, and X.sup.2 are the same as R.sup.1, X.sup.1, and X.sup.2 in Formula (I), ##STR00028## in Formula (III), X.sup.3 represents a halogen atom or a C.sub.1-C.sub.4 alkoxy group, and R.sup.2, R.sup.3, R.sup.4, and Q are the same as R.sup.2, R.sup.3, R.sup.4, and Q in Formula (I), ##STR00029## in Formula (IV), R.sup.1, X.sup.1, X.sup.2, R.sup.2, R.sup.3, R.sup.4, and Q are the same as R.sup.1, X.sup.1, X.sup.2, R.sup.2, R.sup.3, R.sup.4, and Q in Formula (I), and two of R.sup.2, R.sup.3, R.sup.4 and Q may be the same or different at each occurrence, respectively; and the process b comprises hydrolyzing the imide compound of Formula (IV), to thereby obtain the aromatic amide derivative of Formula (I).

2. The method of producing an aromatic amide derivative according to claim 1, wherein each of X.sup.1 and X.sup.2 in Formulae (I), (II) and (IV) independently represents a hydrogen atom, a halogen atom, a C.sub.1-C.sub.4 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4 haloalkoxy group, a C.sub.1-C.sub.4 alkylthio group, a C.sub.1-C.sub.4 haloalkylthio group, a C.sub.1-C.sub.4 alkylsulfonyl group, or a C.sub.1-C.sub.4 haloalkylsulfonyl group; each of R.sup.2 and R.sup.3 in Formulae (I), (III) and (IV) independently represents a hydrogen atom, a halogen atom, a C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4 haloalkoxy group, a C.sub.1-C.sub.4 alkylthio group, a C.sub.1-C.sub.4 haloalkylthio group, a C.sub.1-C.sub.4 alkylsulfonyl group, a C.sub.1-C.sub.4 haloalkylsulfonyl group, a C.sub.1-C.sub.4 alkylamino group, a di-C.sub.1-C.sub.4 alkylamino group, a cyano group, or a nitro group; and R.sup.4 in Formulae (I), (III) and (IV) represents: a hydrogen atom; a C.sub.1-C.sub.4 alkyl group; a C.sub.1-C.sub.4 haloalkyl group; a C.sub.1-C.sub.4 alkylcarbonyl group; a C.sub.1-C.sub.4 haloalkylcarbonyl group; a C.sub.1-C.sub.4 alkoxycarbonyl group; a C.sub.1-C.sub.4 haloalkoxycarbonyl group; a C.sub.1-C.sub.4 alkylsulfonyl group; a C.sub.1-C.sub.4 haloalkylsulfonyl group; or a C.sub.1-C.sub.4 alkyl group or a C.sub.1-C.sub.4 haloalkyl group, substituted by 1 to 9 substituents, which may be the same or different, selected from the group consisting of a C.sub.1-C.sub.4 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4 haloalkoxy group, a C.sub.1-C.sub.4 alkylthio group, a C.sub.1-C.sub.4 haloalkylthio group, a C.sub.1-C.sub.4 alkylsulfonyl group, a C.sub.1-C.sub.4 haloalkylsulfonyl group, a C.sub.1-C.sub.4 alkylamino group, a di-C.sub.1-C.sub.4 alkylamino group, a C.sub.1-C.sub.4 alkylcarbonyl group, a C.sub.1-C.sub.4 alkoxycarbonyl group, a di-C.sub.1-C.sub.4 alkylaminocarbonyl group, a cyano group, and a nitro group.

3. The method of producing an aromatic amide derivative according to claim 2, wherein R.sup.2 in Formulae (I), (III) and (IV) represents a hydrogen atom, a halogen atom, a C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4 haloalkoxy group, a C.sub.1-C.sub.4 alkylthio group, a C.sub.1-C.sub.4 haloalkylthio group, a C.sub.1-C.sub.4 alkylsulfonyl group, a C.sub.1-C.sub.4 haloalkylsulfonyl group, a C.sub.1-C.sub.4 alkylamino group, a di-C.sub.1-C.sub.4 alkylamino group, a cyano group, or a nitro group; R.sup.3 in Formulae (I), (III) and (IV) represents a hydrogen atom, a halogen atom, a C.sub.1-C.sub.4 alkoxy group, a cyano group, or a nitro group; and Q in Formulae (I), (III) and (IV) represents: a C.sub.1-C.sub.4 alkylaminocarbonyl group; a C.sub.1-C.sub.4 haloalkylaminocarbonyl group; a di-C.sub.1-C.sub.4 alkylaminocarbonyl group; a di-C.sub.1-C.sub.4 haloalkylaminocarbonyl group; a phenyl group; a heterocyclic group; a phenyl group substituted by 1 to 5 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C.sub.1-C.sub.4 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4 haloalkoxy group, a C.sub.1-C.sub.4 alkylthio group, a C.sub.1-C.sub.4 haloalkylthio group, a C.sub.1-C.sub.4 alkylamino group, a di-C.sub.1-C.sub.4 alkylamino group, a cyano group, and a nitro group; or a heterocyclic group substituted by 1 to 4 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C.sub.1-C.sub.4 alkyl group, a C.sub.1-C.sub.4 haloalkyl group, a C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4 haloalkoxy group, a C.sub.1-C.sub.4 alkylthio group, a C.sub.1-C.sub.4 haloalkylthio group, a C.sub.1-C.sub.4 alkylamino group, a di-C.sub.1-C.sub.4 alkylamino group, a cyano group, and a nitro group.

4. The method of producing an aromatic amide derivative according to claim 2, wherein R.sup.2 in Formulae (I), (III) and (IV) represents a hydrogen atom, a halogen atom, a C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4 alkylamino group, a di-C.sub.1-C.sub.4 alkylamino group, a cyano group, or a nitro group; and R.sup.4 in Formulae (I), (III) and (IV) represents a hydrogen atom, a C.sub.1-C.sub.4 alkyl group, or a C.sub.1-C.sub.4 haloalkyl group.

5. The method of producing an aromatic amide derivative according to claim 3, wherein R.sup.2 in Formulae (I), (III) and (IV) represents a hydrogen atom, a halogen atom, or a C.sub.1-C.sub.4 alkoxy group; R.sup.3 in Formulae (I), (III) and (IV) represents a hydrogen atom, a halogen atom, or a cyano group; and Q in Formulae (I), (III) and (IV) represents: a di-C.sub.1-C.sub.4 alkylaminocarbonyl group; a phenyl group; a heterocyclic group; a phenyl group substituted by 1 to 5 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a cyano group, a nitro group, and a C.sub.1-C.sub.4 haloalkyl group; or a heterocyclic group substituted by 1 to 4 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a cyano group, a nitro group, and a C.sub.1-C.sub.4 haloalkyl group.

6. The method of producing an aromatic amide derivative according to claim 5, wherein R.sup.2 in Formulae (I), (III) and (IV) represents a hydrogen atom or a halogen atom; R.sup.4 in Formulae (I), (III) and (IV) represents a hydrogen atom or a C.sub.1-C.sub.4 alkyl group; and Q in Formulae (I), (III) and (IV) represents: a phenyl group; a pyridyl group; a phenyl group substituted by 1 to 5 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a cyano group, and a nitro group; or a pyridyl group substituted by 1 to 4 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a cyano group, a nitro group, and a C.sub.1-C.sub.4 haloalkyl group.

7. The method of producing an aromatic amide derivative according to claim 1, wherein the method further comprises the following process c, process d, and process e, wherein: the process c comprises obtaining a carboxylic acid compound of the following Formula (V) produced together with the aromatic amide derivative of Formula (I) in the process b, and halogenating or esterifying the carboxylic acid compound, to thereby obtain a carboxylic acid derivative reproducing compound of the following Formula (IIIa): ##STR00030## in Formula (V), R.sup.2, R.sup.3, R.sup.4 and Q are the same as R.sup.2, R.sup.3, R.sup.4 and Q in Formula (III); ##STR00031## in Formula (IIIa), R.sup.2, R.sup.3, R.sup.4 and Q are the same as R.sup.2, R.sup.3, R.sup.4 and Q in Formula (V) and X.sup.3 in Formula (IIIa) is the same as X.sup.3 in Formula (III); the process d comprises allowing the carboxylic acid derivative reproducing compound obtained in the process c and the aniline derivative of Formula (II) to react with each other in the presence of a base to obtain the imide compound of Formula (IV); and the process e comprises hydrolyzing the imide compound of Formula (IV) obtained in the process d to obtain the aromatic amide derivative of Formula (I).

8. The method of producing an aromatic amide derivative according to claim 7, wherein R.sup.2 in Formulae (III), (V) and (IIIa) represents a hydrogen atom, a halogen atom, a C.sub.1-C.sub.4 alkoxy group, a C.sub.1-C.sub.4 alkylamino group, a di-C.sub.1-C.sub.4 alkylamino group, a cyano group, or a nitro group; R.sup.3 in Formulae (III), (V) and (IIIa) represents a hydrogen atom or a halogen atom; R.sup.4 in Formulae (III), (V) and (IIIa) represents a hydrogen atom, a C.sub.1-C.sub.4 alkyl group, or a C.sub.1-C.sub.4 haloalkyl group; and Q in Formulae (III), (V) and (IIIa) represents: a di-C.sub.1-C.sub.4 alkylaminocarbonyl group; a phenyl group; a heterocyclic group; a phenyl group substituted by 1 to 5 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a cyano group, a nitro group, and a C.sub.1-C.sub.4 haloalkyl group; or a heterocyclic group substituted by 1 to 4 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a cyano group, a nitro group, and a C.sub.1-C.sub.4 haloalkyl group; wherein the heterocyclic group is a pyridyl group, a pyridyl-N-oxide group, a pyrimidyl group, a pyridazyl group, a pyrazyl group, a furyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a triazolyl group, a pyrrolyl group, a pyrazolyl group, or a tetrazolyl group.

9. The method of producing an aromatic amide derivative according to claim 7, wherein R.sup.2 in Formulae (III), (V) and (IIIa) represents a hydrogen atom or a halogen atom; R.sup.4 in Formulae (III), (V) and (IIIa) represents a hydrogen atom or a C.sub.1-C.sub.4 alkyl group; and Q in Formulae (III), (V) and (IIIa) represents: a di-C.sub.1-C.sub.4 alkylaminocarbonyl group; a phenyl group; a pyridyl group; a phenyl group substituted by 1 to 5 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a cyano group, and a nitro group; or a pyridyl group substituted by 1 to 4 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C.sub.1-C.sub.4 haloalkyl group.

Description

EXAMPLES

(1) Hereinafter, the present invention is further explained in more detail with reference to Examples; however it should be construed that the invention is by no means limited thereto.

(2) Note that the chemical shift values of .sup.1H-NMR are expressed in ppm unit at the lower magnetic field side on the basis of tetramethylsilane, s means a singlet, d means a doublet, t means a triplet, m means a multiplet, and brs means a broad singlet. Further, unless otherwise specifically stated, parts and % are expressed in terms of mass basis.

Reference Example 1

Synthesis of N-[2-fluoro-3-[benzoyl(methyl)amino]benzoyl]-3-[benzoyl(methyl)amino]-N-[2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)phenyl]-2-fluorobenzamide (Compound No.: 1-123)

(3) 1.00 g of 2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)aniline, 0.89 g of triethylamine, 0.03 g of N,N-dimethyl-4-aminopyridine, and 1.57 g of 2-fluoro-3-(N-methylbenzamide)benzoyl chloride were added to 4.00 g of 1,3-dimethyl-2-imidazolidinon, and the mixture was stirred at room temperature for 1 hour. The resulting reaction solution was extracted with ethyl acetate, washed with saturated brine, and the organic phase was dried over magnesium sulfate. After filtering off the magnesium sulfate, the solution was concentrated and purified by silica gel chromatography to obtain 2.20 g of the aimed imide compound (Compound No.: 1-123) (isolation yield: 97%) as a white solid.

(4) The .sup.1H-NMR chemical shift values of the obtained imide compound are shown below.

(5) .sup.1H-NMR (DMSO-d.sub.6, 70 C.) ppm: 8.44 (s, 1H), 7.99 (s, 1H), 7.60-7.57 (m, 2H), 7.51 (brs, 2H), 7.30-7.18 (m, 12H), 3.12 (s, 6H)

(6) MS (M+H).sup.+=918, 920

Reference Example 2

Synthesis of N-[2-fluoro-3-[benzoyl(methyl)amino]benzoyl]-3-[benzoyl(methyl)amino]-N-[2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)phenyl]-2-fluorobenzamide (Compound No.: 1-123)

(7) 2.16 g of the aimed imide compound (Compound No. 1-123) (isolation yield: 95%) was obtained as a white solid in the same procedure as in Reference Example 1, except that the reaction solvent was changed to 3.00 g of toluene in place of 4.00 g of 1,3-dimethyl-2-imidazolidinon and the reaction condition was changed to stirring at 90 C. for 4 hours in place of stirring at room temperature for 1 hour.

Reference Example 3

Synthesis of N-[2-fluoro-3-[benzoyl(methyl)amino]benzoyl]-3-[benzoyl(methyl)amino]-N-[4-(heptafluoroisopropan-2-yl)-2-iodo-6-(trifluoromethyl)phenyl]-2-fluorobenzamide (Compound No.: 1-124)

(8) 3.79 g of 4-(heptafluoroisopropan-2-yl)-2-iodo-6-(trifluoromethyl)aniline, 2.80 g of triethylamine, 0.06 g of N,N-dimethyl-4-aminopyridine, and 5.3 g of 2-fluoro-3-(N-methylbenzamido)benzoyl chloride were added to 7.6 g of toluene, and the mixture was stirred at 90 C. for 2 hours. The resulting reaction solution was cooled to room temperature, and the crystal precipitated upon addition of water was filtered off and washed sequentially with toluene and water to obtain 5.87 g (isolation yield: 73%) of the aimed imide compound (Compound No. 1-124) as a pale yellow solid.

(9) The .sup.1H-NMR chemical shift values of the obtained imide compound are shown below.

(10) .sup.1H-NMR (DMSO-d.sub.6, 70 C.) ppm: 8.53 (s, 1H), 7.97 (s, 1H), 7.54-7.51 (m, 4H), 7.30-7.13 (m, 12H), 3.14 (s, 6H)

(11) MS (M+H).sup.+=966

Reference Example 4

Synthesis of N-[2-fluoro-3-[4-fluorobenzoyl(methyl)amino]benzoyl]-3-[4-fluorobenzoyl(methyl)amino]-N-[2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)phenyl]-2-fluorobenzamide (Compound No.: 1-127)

(12) The aimed imide compound (Compound No. 1-127) was synthesized by the same synthetic method as in Reference Example 1, except that 2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)aniline was changed to 4-(heptafluoroisopropan-2-yl)-2-bromo-6-(trifluoromethyl)aniline, and 2-fluoro-3-(N-methylbenzamido)benzoyl chloride was changed to 2-fluoro-3-[4-fluorobenzoyl(methyl)amino]benzoyl chloride.

(13) The .sup.1H-NMR chemical shift values of the obtained imide compound are shown below.

(14) .sup.1H-NMR (DMSO-d.sub.6, 70 C.)) ppm: 8.44 (s, 1H), 7.97 (s, 1H), 7.64-7.62 (m, 2H), 7.50 (brs, 2H), 7.28-7.24 (m, 6H), 7.00-6.96 (m, 4H), 3.15 (s, 6H)

(15) MS (M+H).sup.+=954, 956

Reference Example 5

Synthesis of N-[2-fluoro-3-[4-fluorobenzoyl(methyl)amino]benzoyl]-3-[4-fluorobenzoyl(methyl)amino]-N-[4-(heptafluoroisopropan-2-yl-)-2-iodo-6-(trifluoromethyl)phenyl]-2-fluorobenzamide (Compound No.: 1-128)

(16) The aimed imide compound (Compound No. 1-128) was synthesized by the same synthetic method as in Reference Example 1, except that 2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)aniline was changed to 4-(heptafluoroisopropan-2-yl)-2-iodo-6-(trifluoromethyl)aniline, and 2-fluoro-3-(N-methylbenzamido)benzoyl chloride was changed to 2-fluoro-3-[4-fluorobenzoyl(methyl)amino]benzoyl chloride.

(17) The .sup.1H-NMR chemical shift values of the obtained imide compound are shown below.

(18) .sup.1H-NMR (DMSO-d.sub.6, 70 C.)) ppm: 8.53 (s, 1H), 7.95 (s, 1H), 7.59-7.57 (m, 2H), 7.48 (brs, 2H), 7.28-7.22 (m, 6H), 7.01-6.97 (m, 4H), 3.16 (s, 6H)

(19) MS (M+H).sup.+=1002

Reference Example 6

Synthesis of N-[2-fluoro-3-[2,6-difluorobenzoyl(methyl)amino]benzoyl]-3-[2,6-difluorobenzoyl(methyl)amino]-N-[2-bromo-4-(heptafluoroisopropan-2-yl-)-6-(trifluoromethyl)phenyl]-2-fluorobenzamide (Compound No.: 1-135)

(20) The aimed imide compound (Compound No. 1-135) was synthesized by the same synthetic method as in Reference Example 1, except that 2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)aniline was changed to 4-(heptafluoroisopropan-2-yl)-2-bromo-6-(trifluoromethyl)aniline, and 2-fluoro-3-(N-methylbenzamido)benzoyl chloride was changed to 2-fluoro-3-[2,6-difluorobenzoyl(methyl)amino]benzoyl chloride.

(21) The .sup.1H-NMR chemical shift values of the obtained imide compound are shown below.

(22) .sup.1H-NMR (DMSO-d.sub.6, 70 C.)) ppm: 8.46 (s, 1H), 8.01 (s, 1H), 7.33-7.30 (m, 4H), 7.25-7.11 (m, 5H), 6.86 (brs, 3H), 3.17 (s, 6H)

(23) MS (M+H).sup.+=990, 992

Reference Example 7

Synthesis of N-[2-fluoro-3-[4-nitrobenzoyl(methyl)amino]benzoyl]-3-[4-nitrobenzoyl(methyl)amino]-N-[2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)phenyl]-2-fluorobenzamide (Compound No.: 1-577)

(24) The aimed imide compound (Compound No. 1-577) was synthesized by the same synthetic method as in Reference Example 1, except that 2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)aniline was changed to 4-(heptafluoroisopropan-2-yl)-2-bromo-6-(trifluoromethyl)aniline, and 2-fluoro-3-(N-methylbenzamido)benzoyl chloride was changed to 2-fluoro-3-[4-nitrobenzoyl(methyl)amino]benzoyl chloride.

(25) The .sup.1H-NMR chemical shift values of the obtained imide compound are shown below.

(26) .sup.1H-NMR (DMSO-d.sub.6, 70 C.)) ppm: 8.41 (s, 1H), 8.03-8.01 (m, 4H), 7.92 (s, 1H), 7.72-7.70 (m, 6H), 7.30-7.24 (m, 2H), 3.20 (s, 6H)

(27) MS (M+Na).sup.+=1030, 1032

Reference Example 8

Synthesis of N-[2-fluoro-3-[4-nitrobenzoyl(methyl)amino]benzoyl]-3-[4-nitrobenzoyl(methyl)amino]-N-[4-(heptafluoroisopropan-2-yl)-2-iodo-6-(trifluoromethyl)phenyl]-2-fluorobenzamide (Compound No.: 1-578)

(28) The aimed imide compound (Compound No. 1-578) was synthesized by the same synthetic method as in Reference Example 1, except that 2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)aniline was changed to 4-(heptafluoroisopropan-2-yl)-2-iodo-6-(trifluoromethyl)aniline, and 2-fluoro-3-(N-methylbenzamido)benzoyl chloride was changed to 2-fluoro-3-[4-nitrobenzoyl(methyl)amino]benzoyl chloride.

(29) The .sup.1H-NMR chemical shift values of the obtained imide compound are shown below.

(30) .sup.1H-NMR (DMSO-d.sub.6, 70 C.) ppm: 8.49 (s, 1H), 8.03-8.02 (m, 4H), 7.92 (s, 1H), 7.70-7.67 (m, 2H), 7.49-7.48 (m, 4H), 7.25-7.24 (m, 2H), 3.21 (s, 6H)

(31) MS (M+Na).sup.+=1078

Reference Example 9

Synthesis of N-[2-fluoro-3-[benzoyl(methyl)amino]benzoyl]-3-[benzoyl(methyl)amino]-N-[2,4-bis(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)phenyl]-2-fluorobenzamide (Compound No.: 1-246)

(32) The aimed imide compound (Compound No. 1-246) was synthesized by the same synthetic method as in Reference Example 1, except that 2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)aniline was changed to 2,4-bis(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)aniline, and 2-fluoro-3-(N-methylbenzamide)benzoyl chloride was changed to 2-fluoro-3-[benzoyl(methyl)amino]benzoyl chloride.

(33) The .sup.1H-NMR chemical shift values of the obtained imide compound are shown below.

(34) .sup.1H-NMR (DMSO-d.sub.6, 70 C.)) ppm: 8.48 (s, 1H), 8.07 (s, 1H), 7.57-7.54 (m, 2H), 7.34 (brs, 2H), 7.28-7.18 (m, 14H), 3.07 (s, 6H)

(35) MS(M+H).sup.+=1008

Reference Example 10

Synthesis of N-[2-fluoro-3-[benzoyl(methyl)amino]benzoyl]-3-[benzoyl(methyl)amino]-N-[4-bromo-2-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)phenyl]-2-fluorobenzamide (Compound No.: 1-240)

(36) The aimed imide compound (Compound No. 1-240) was synthesized by the same synthetic method as in Reference Example 1, except that 2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)aniline was changed to 2-(heptafluoroisopropan-2-yl)-4-bromo-6-(trifluoromethyl)aniline, and 2-fluoro-3-(N-methylbenzamido)benzoyl chloride was changed to 2-fluoro-3-[benzoyl(methyl)amino]benzoyl chloride.

(37) The .sup.1H-NMR chemical shift values of the obtained imide compound are shown below.

(38) .sup.1H-NMR (DMSO-d.sub.6, 70 C.)) ppm: 8.52 (s, 1H), 8.09 (s, 1H), 7.51-7.48 (m, 2H), 7.28-7.26 (m, 2H), 7.21-7.19 (m, 12H), 3.08 (s, 6H)

(39) MS (M+H).sup.+=918, 920

Reference Example 11

Synthesis of N-[2-fluoro-3-[benzoyl(methyl)amino]benzoyl]-3-[benzoyl(methyl)amino]-N-[2,6-dibromo-4-(nonafluoro-sec-butyl)phenyl]-2-fluorobenzamide (Compound No.: 1-168)

(40) The aimed imide compound (Compound No. 1-168) was synthesized by the same synthetic method as in Reference Example 1, except that 2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)aniline was changed to 4-(nonafluoro-sec-butyl)-2,6-dibromoaniline, and 2-fluoro-3-(N-methylbenzamido)benzoyl chloride was changed to 2-fluoro-3-[benzoyl(methyl)amino]benzoyl chloride.

(41) The .sup.1H-NMR chemical shift values of the obtained imide compound are shown below.

(42) .sup.1H-NMR (DMSO-d.sub.6, 70 C.) ppm: 7.95 (s, 2H), 7.61-7.58 (m, 2H), 7.50 (brs, 2H), 7.29-7.26 (m, 2H), 7.22-7.16 (m, 10H), 3.21 (s, 6H)

(43) MS (M+Na).sup.+=1000, 1002

Example 1

Synthesis of 2-fluoro-3-(N-methylbenzamido)-N-(2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)phenyl)benzamide (Compound No.: 2-123)

(44) 5.0 g of N-[2-fluoro-3-[benzoyl(methyl)amino]benzoyl]-3-[benzoyl(methyl)amino]-N-[2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)phenyl]-2-fluorobenzamide (Compound No.: 1-123) obtained in Reference Example 1 and 0.07 g of N,N-dimethyl-4-aminopyridine were added to 28.3 g of toluene, and the mixture was stirred at 80 C. for 10 minutes. 10 g of a 6% aqueous sodium carbonate solution was added to the resulting reaction solution, and the mixture was stirred at 80 C. for 5 hours. Analysis of the obtained reaction solution by HPLC confirmed that the aimed aromatic amide derivative (Compound No.: 2-123) was obtained in a yield of 98.8%.

Example 2

Synthesis of 2-fluoro-3-(N-methylbenzamido)-N-(2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)phenyl)benzamide (Compound No.: 2-123)

(45) Compound No.: 2-123 was obtained by performing the same procedure as in Example 1, except that the procedure of adding 10 g of a 6% aqueous sodium carbonate solution to the resulting reaction solution and stirring at 80 C. for 5 hours in Example 1 was changed to a procedure of adding 10 g of a 2% aqueous sodium hydroxide solution to the resulting reaction solution and stirring at 80 C. for 5 hours.

(46) Analysis of the obtained reaction solution by HPLC confirmed that the aimed aromatic amide derivative (Compound No.: 2-123) was obtained in a yield of 99.7%.

Example 3

Synthesis of 2-fluoro-3-(4-fluoro-N-methylbenzamido)-N-(2-iodo-4-(heptafluoroisopropyl)-6-(trifluoromethyl)phenyl)benzamide (Compound No.: 2-128)

(47) 45 g of N-[2-fluoro-3-[4-fluorobenzoyl(methyl)amino]benzoyl]-3-[4-fluorobenzoyl(methyl)amino]-N-[4-(heptafluoroisopropan-2-yl)-2-iodo-6-(trifluoromethyl)phenyl]-2-fluorobenzamide (Compound No.: 1-128) obtained in Reference Example 5, 0.28 g of N,N-dimethyl-4-aminopyridine, and 74 g of a 10% aqueous potassium carbonate solution were added to 90.0 g of toluene, and the mixture was stirred at 80 C. for 8 hours. The resulting reaction solution was cooled to 50 C. and separated into an aqueous phase and an organic phase. 16.3 g of 1% hydrochloric acid and 3.2 g of sodium chloride were added to the resulting organic phase and the mixture was separated into an aqueous phase and an organic phase at 50 C. The resulting organic phase was distilled off to partially remove the solvent (toluene 37 g) under reduced pressure, and then crystallized under cooling conditions in an ice-bath. The resulting solid was washed with 11 g of toluene and dried under reduced pressure at 50 C. to obtain the aimed aromatic amide derivative (Compound No. 2-128) in an isolation yield of 94%.

Reference Example 12

Synthesis of 2-fluoro-3-(4-fluoro-N-methylbenzamido)-N-(2-iodo-4-(heptafluoroisopropyl)-6-(trifluoromethyl)phenyl)benzamide (Compound No.: 2-128)

(48) 35.0 g of 2-fluoro-3-(4-fluoro-N-methylbenzamido)benzoic acid and 0.44 g of dimethylformamide were added to 105 g of toluene, and the reaction temperature was raised to 80 C. After dropwise addition of 17.32 g of thionyl chloride thereto over a period of 30 minutes, the mixture was stirred for 1 hour. The resulting reaction solution was cooled to 50 C. and a portion of the solvent was distilled off under reduced pressure to prepare 53.98 g of a toluene solution of 2-fluoro-3-(4-fluoro-N-methylbenzamido)benzoyl chloride.

(49) After 23.7 g of 2-iodo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)aniline and 0.32 g of N,N-dimethyl-4-aminopyridine were added to 47.4 g of toluene, the toluene solution of 2-fluoro-3-(4-fluoro-N-methylbenzamido)benzoyl chloride prepared above was added thereto at 20 C. and the mixture was stirred. The temperature of the resulting reaction solution was raised to 80 C. and then 16.0 g of triethylamine was dropwise added thereto over a period of 30 minutes. The mixture was stirred at 95 C. for 3 hours. The resulting reaction solution was cooled to 40 C., and 79.86 g of water was added thereto and the mixture was stirred at 30 C. for 30 minutes. The resulting reaction solution was cooled to 0 C. and stirred for 1 hour. The precipitated solid was filtered off, washed successively with 20.0 g of toluene and 39.9 g of water and dried under reduced pressure at 50 C. to obtain 48.4 g of N-[2-fluoro-3-[4-fluorobenzoyl(methyl)amino]benzoyl]-3-[4-fluorobenzoyl(methyl)amino]-N-[4-(heptafluoroisopropan-2-yl)-2-iodo-6-(trifluoromethyl)phenyl]-2-fluorobenzamide (Compound No.: 1-128).

Example 4

(50) 45 g of N-[2-fluoro-3-[4-fluorobenzoyl(methyl)amino]benzoyl]-3-[4-fluorobenzoyl(methyl)amino]-N-[4-(heptafluoroisopropan-2-yl)-2-iodo-6-(trifluoromethyl)phenyl]-2-fluorobenzamide (Compound No.: 1-128) obtained in Reference Example 12, 0.28 g of N,N-dimethyl-4-aminopyridine, and 74 g of a 10% aqueous potassium carbonate solution were added to 90.0 g of toluene, and the mixture was stirred at 80 C. for 8 hours. The resulting reaction solution was cooled to 50 C. and separated into an aqueous phase and an organic phase. 16.3 g of 1% hydrochloric acid and 3.2 g of sodium chloride were added to the resulting organic phase to separate into an aqueous phase and an organic phase at 50 C. The resulting organic phase was distilled off under reduced pressure to remove a portion (toluene 37 g) of the solvent, and then crystallized under the conditions in an ice-bath. The resulting solid was washed with 11 g of toluene and dried under reduced pressure at 50 C. to obtain 30.2 g of the aimed aromatic amide derivative (Compound No.: 2-128) in a total yield of 86%.

Example 5

Synthesis of 2-fluoro-3-(N-methylbenzamido)-N-(2-bromo-4-(heptafluoroisopropyl)-6-(trifluoromethyl)phenyl)benzamide (Compound No.: 2-123)

(51) 40.0 g of 2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)aniline, 1.17 g of N,N-dimethyl-4-aminopyridine, and 29.0 g of triethylamine were added to 40.0 g of toluene, and the temperature was raised to 95 C. After dropwise addition of a 33.5% toluene solution of 2-fluoro-3-(N-methylbenzamido)benzoyl chloride over a period of 30 minutes to the resulting reaction solution, the mixture was stirred at 95 C. for 4 hours. 100 g of a 10% aqueous sodium carbonate solution was added to the resulting reaction solution, and the mixture was stirred at 85 C. for 3 hours. The resulting reaction solution was separated into an aqueous phase and an organic phase at 85 C. while the reaction solution was hot, and 40 g of a 10% aqueous sodium carbonate solution was added to the resulting organic phase. The mixture was stirred at 80 C. for 1 hour and the resulting reaction solution was again separated into an aqueous phase and an organic phase at 80 C. while the reaction solution was hot, and 40 g of water was added to the resulting organic phase, followed by separation into an aqueous phase and an organic phase at 80 C. After cooling the resulting organic phase to room temperature, the solution was stirred in an ice bath for 4 hours. The precipitated solid was filtered off and dried under reduced pressure at 60 C. to obtain 58.12 g of the aimed aromatic amide derivative (Compound No.: 2-123) in a yield of 93% as determined by HPLC.

Example 6

Synthesis of N-(2,4-bis(heptafluoroisopropyl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-methylbenzamido)benzamide (Compound No.: 2-246)

(52) Using N-[2-fluoro-3-[benzoyl(methyl)amino]benzoyl]-3-[benzoyl(methyl)amino]-N-[2,4-bis(heptafluoroisopropyl)-6-(trifluoromethyl)phenyl]-2-fluorobenzamide (Compound No.: 1-246) obtained in Reference Example 9, the aimed aromatic amide derivative (Compound No.: 2-246) was obtained by the method described in Example 2.

(53) The .sup.1H-NMR chemical shift values of the obtained aromatic amide derivative are shown below.

(54) .sup.1H-NMR (DMSO-d.sub.6, 70 C.) : 10.45 (1H, s), 8.33 (1H, s), 7.99 (1H, s), 7.60 (1H, t, J=7.6 Hz), 7.48-7.47 (1H, m), 7.31-7.23 (6H, m), 3.34 (3H, s)

Example 7

Synthesis of N-(4-bromo-2-(heptafluoroisopropyl)-6-(trifluoromethyl)phenyl)-2-fluoro-3-(N-methylbenzamido)benzamide (Compound No.: 2-240)

(55) Using N-[2-fluoro-3-[benzoyl(methyl)amino]benzoyl]-3-[benzoyl(methyl)amino]-N-[4-bromo-2-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)phenyl]-2-fluorobenzamide (Compound No.: 1-240) obtained in Reference Example 10, the aimed aromatic amide derivative (Compound No.: 2-240) was obtained by the method described in Example 2.

(56) The .sup.1H-NMR chemical shift values of the obtained aromatic amide derivative are shown below.

(57) .sup.1H-NMR (DMSO-d.sub.6, 70 C.) : 10.12 (1H, s), 8.36 (1H, d, J=2.1 Hz), 8.00 (1H, s), 7.55 (1H, t, J=7.6 Hz), 7.44 (1H, t, J=6.4 Hz), 7.32-7.23 (3H, m), 3.34 (3H, s)

Example 8

Synthesis of 2-fluoro-3-(N-methylbenzamido)-N-(2-bromo-4-(heptafluoroisopropyl)-6-(trifluoromethyl)phenyl)benzamide (Compound No.: 2-123)

(58) 529.5 g of 2-fluoro-3-(N-methylbenzamido)benzoic acid and 27.5 g of dimethylformamide were added to 772 g of toluene, and the temperature was raised to 40 C. Then, a mixed solution of 237.0 g of thionyl chloride and 237.0 g of toluene were added thereto over a period of 2 hours, followed by further addition of 50 g of toluene. After stirring for 4 hours, the mixture was depressurized and cooled to 25 C. to prepare 1678.5 g of a toluene solution of 2-fluoro-3-(N-methylbenzamido)benzoyl chloride.

(59) 327.0 g of 2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)aniline, 9.5 g of N,N-dimethyl-4-aminopyridine, and 233.5 g of triethylamine were added to 163.5 g of toluene, and 1641.5 g of a toluene solution of 2-fluoro-3-(N-methylbenzamido)benzoyl chloride prepared above was added thereto at 95 C. After further addition of 163.5 g of toluene, the mixture was stirred for 5 hours to perform the imidation reaction. Thereafter, the reaction solution was cooled to 85 C. and 817.5 g of a 10% aqueous sodium carbonate solution was added. The mixture was stirred for 4 hours to carry out the hydrolysis. Then, the reaction solution was separated into an organic phase A and an aqueous phase A at 85 C. while the reaction solution was hot. 328.0 g of a 10% aqueous sodium carbonate was added to the resulting organic phase A and the mixture was stirred at 80 C. for 1 hour, followed by separation into an organic phase B and an aqueous phase B. 330 g of water was added to the resulting organic phase B and the mixture was stirred at 80 C. for 30 minutes, after which time a liquid separation was performed to obtain an organic phase C.

(60) The reaction solution of the resulting organic phase C was cooled to 0 C. over a period of 12 hours and the precipitated solid was filtered off. The solid was washed with 327.5 g of toluene and dried under reduced pressure at 50 C. to obtain 389.0 g of 2-fluoro-3-(N-methylbenzamido)-N-(2-bromo-4-(heptafluoroisopropyl)-6-(trifluoromethyl)phenyl)benzamide (Compound No.: 2-123) with a purity of 99.3 wt % in a yield of 75.9%.

(61) 1707.5 g of a mixed solution of the aqueous phase A and the aqueous phase B obtained above (16.8% aqueous 2-fluoro-3-(N-methylbenzamido)benzoic acid sodium salt solution) was added to 766.5 g of 10% hydrochloric acid at 70 C. over a period of 1 hour, and the mixture was stirred for 1 hour. Thereafter, the mixture was cooled to 30 C. and stirred for 1 hour. The precipitated solid (2-fluoro-3-(N-methylbenzamido)benzoic acid) was filtered off. The resulting solid was washed with 860 g of water and dried under reduced pressure at 60 C. to recover 293.5 g of 2-fluoro-3-(N-methylbenzamido)benzoic acid with a purity of 95.6 wt % in a yield of 98.0%.

(62) 200 g of 2-fluoro-3-(N-methylbenzamido)benzoic acid recovered above and 10.2 g of dimethylformamide were added to 300 g of toluene and the temperature was raised to 40 C. Then, a mixed solution of 101.9 g of thionyl chloride and 100 g of toluene was added thereto under reduced pressure and the mixture was stirred for 3 hours. After depressurization, the reaction solution was cooled to 20 C. to prepare 608.2 g of a toluene solution of a recovered 2-fluoro-3-(N-methylbenzamido)benzoyl chloride.

(63) 40.0 g of 2-bromo-4-(heptafluoroisopropan-2-yl)-6-(trifluoromethyl)aniline, 1.15 g of N,N-dimethyl-4-aminopyridine, and 28.6 g of triethylamine were added to 20.0 g of toluene, and 196.1 g of a toluene solution of the recovered 2-fluoro-3-(N-methylbenzamido)benzoyl chloride prepared above was added thereto at 85 C. After further addition of 20.0 g of toluene, the mixture was stirred for 4 hours to perform an imidation reaction.

(64) Subsequently, 99.8 g of a 10% aqueous sodium carbonate solution was added thereto, and the mixture was stirred for 3 hours to perform a hydrolysis reaction. Then, the reaction solution was separated into an organic phase A and an aqueous phase A at 80 C. while the reaction solution was hot. 39.9 g of a 10% aqueous sodium carbonate solution was further added to the resulting organic phase A, the mixture was stirred for 1 hour to carry out the hydrolysis reaction. Then, the reaction solution was separated into an organic phase B and an aqueous phase B. 40 g of water was added to the resulting organic phase B and the mixture was stirred at 80 C. for 30 minutes, followed by liquid separation to obtain the organic phase C. The resulting organic phase C was cooled to 0 C. over a period of 12 hours, thereby to precipitate a solid. The precipitated solid was filtered off, washed with 40.0 g of toluene, and dried under reduced pressure at 60 C. to obtain 55.8 g of 2-fluoro-3-(N-methylbenzamido)-N-(2-bromo-4-(heptafluoroisopropyl)-6-(trifluoromethyl)phenyl)benzamide (Compound No.: 2-123) with a purity of 99.0 wt % in a yield of 89.7%.

(65) As described above, the aimed aromatic amide derivative can be obtained in a high yield according to the method of producing an aromatic amide derivative of the present invention.

(66) The disclosure of Japanese Patent Application No. 2015-247774, filed Dec. 18, 2015 is incorporated by reference herein in its entirety.

(67) All publications, patent applications, and technical standards mentioned in this specification are herein incorporated by reference to the same extent as if such individual publication, patent application, or technical standard was specifically and individually indicated to be incorporated by reference.

(68) Each and every compatible combination of the embodiments described in this application is explicitly disclosed herein, as if each and every combination was individually and explicitly recited.