JP2006124375A - Method for producing 6-substituted-1-methyl-1-h-benzimidazole derivative and its production intermediate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain new production intermediates represented by formulas (IIa) and (III) for a 6-substituted-1-methyl-1-H-benzimidazole derivative represented by formula (I) being a known active ingredient of a medicine and to provide a production method suitable for mass synthesis of an N-(5-substituted-2-nitrophenyl)-N-methylamine represented by formula (II) being a production intermediate and a method for efficiently producing the 6-substituted-1-methyl-1-H-benzimidazole derivative represented by formula (I) from the production intermediate represented by formula (II). <P>SOLUTION: The method for producing the compound represented by formula (I) (R<SP>2</SP>is a phenyl group which may contain a substituent group such as a 1-6C alkyl group or the like; X is an oxygen atom, a sulfur atom or a nitrogen atom) is provided. The production intermediates for the compound represented by formula (I) are obtained. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for producing a 6-substituted-1-methyl-1-H-benzimidazole derivative and a production intermediate thereof.

The 6-substituted-1-methyl-1-H-benzimidazole derivative has an excellent insulin resistance improving action, hypoglycemic action, anti-inflammatory action, immunomodulating action, aldose reductase inhibitory action, 5-lipoxygenase inhibitory action, Those having lipid peroxide production inhibitory action, PPAR activation action, anti-osteoporosis action, leukotriene antagonism, adipogenesis promotion action, cancer cell proliferation inhibition action, calcium antagonism and the like are known. These 6-substituted-1-methyl-1-H-benzimidazole derivatives are carboxylic acid derivatives corresponding to 4-substituted-N ² -methylbenzene-1,2-diamines in which the N-methylamino group is protected. It is known that it can be synthesized by a condensation reaction with benzene, subsequent deprotection, and intramolecular dehydration (see, for example, Patent Documents 1 and 2).

4-Substituted-N ² -methylbenzene-1,2-diamines in which the N-methylamino group is protected are synthesized from, for example, N- (5-substituted-2-nitrophenyl) -N-methylamines. be able to.

  Conventionally, as a method for producing N- (5-substituted-2-nitrophenyl) -N-methylamines, a halogen atom of N- (5-halogeno-2-nitrophenyl) -N-methylamines is used as a base. A method of substitution with a nucleophile in the presence or absence is known (Non-patent Document 1). As a method for producing N- (5-halogeno-2-nitrophenyl) -N-methylamines as raw materials in this method, for example, the chlorine atom at the 2-position of 2,4-dichloronitrobenzene is substituted with methylamine. , N- (5-chloro-2-nitrophenyl) -N-methylamine is known (Patent Document 3). Since N- (5-substituted-2-nitrophenyl) -N-methylamines are raw materials for the production of 6-substituted-1-methyl-1-H-benzimidazole derivatives having high activity, As a production method, it is desired to develop a production method that is industrially more practical than the conventional production method and that is suitable for mass synthesis.

As a method for producing a 6-substituted-1-methyl-1-H-benzimidazole derivative from the obtained N- (5-substituted-2-nitrophenyl) -N-methylamines, N- ( N- (5-substituted-2-aminophenyl) -N having a methylamino group protected, obtained by protecting and then reducing the methylamino group of 5-substituted-2-nitrophenyl) -N-methylamines Although a method for producing from -methylamine is known (see Patent Document 2), there has been a development of a method for producing a 6-substituted-1-methyl-1-H-benzimidazole derivative that is shorter and more efficient. desired.
JP-A-9-295970 JP-A-11-193276 European Patent Application Publication No. 385850 Journal of Medical Chemistry [Journal of Medicinal Chemistry] (USA) Vol. 39, p 3971-31979 (1996)

  The present inventors have identified a 6-substituted-1-methyl-1-H-benzimidazole derivative (I), and N- (5-substituted-2-nitro, which is a key intermediate in the production of the derivative. As a result of intensive studies on the production method of phenyl) -N-methylamines (IIa), N- (5-substituted-2-nitrophenyl) -N-methylamines (IIa) were obtained in high yield and high purity. And then reacting 2,4-dichloronitrobenzene with methylamine in an aprotic solvent through N- (5-chloro-2-nitrophenyl) -N-methylamine in the same container. A method for producing N- (5-substituted-2-nitrophenyl) -N-methylamines (II) has been found, and further N- (5-substituted-2-nitrophenyl) -N-methylamines (II) Efficient in a short process It found a process for producing a 6-substituted-1-methyl -1-H- benzimidazole derivative (I), the present invention has been completed.

That is, the present invention
(1) The following general formula (IIa):

(In the formula, R ¹ represents a nitro group, an amino group or a t-butoxycarbonylamino group.)
A compound represented by
(2) The following general formula (III):

[Where:
R ² is a hydrogen atom,
1 to 5 selected from a C ₁ -C ₆ alkyl group optionally substituted with 1 to 5 groups selected from substituent group α, a substituent group α, a C ₁ -C ₆ alkyl group and a halomethyl group five may be substituted with a group C ₃ -C ₆ cycloalkyl,
Substituent group alpha, C ₁ -C ₆ alkyl and halomethyl 1 to 5 substituents phenyl group or substituent group may be substituted with a group selected from group alpha, C ₁ -C ₆ alkyl group and a halomethyl group A 5- or 6-membered heterocyclic group which may be substituted with 1 to 5 groups selected from the above (the heterocyclic group is 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom) including.)
Indicate

X represents an oxygen atom, a sulfur atom or a nitrogen atom (nitrogen atom, hydrogen atom, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl group, C ₆ -C ₁₀ arylcarbonyl groups, C ₁ -C _And optionally having a substituent selected from the group consisting of a ₆ alkylsulfonyl group and a C ₆ -C ₁₀ arylsulfonyl group.

Substituent group α is
C ₃ -C ₆ cycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₆ -C ₁₀ aryl group, a carboxyl group, formyl group, C ₁ -C ₆ alkylcarbonyl group, C ₆ -C ₁₀ arylcarbonyl group, C ₁ -C ₆ alkyloxycarbonyl group, C ₆ -C ₁₀ aryloxycarbonyl group, a carbamoyl group, N-C ₁ -C ₆ alkylcarbamoyl group, N, N-di-C ₁ -C ₆ alkylcarbamoyl group, a hydroxyl group, C ₁ -C ₆ alkoxy group, C ₆ -C ₁₀ aryloxy group, C ₁ -C ₆ alkylcarbonyloxy group, C ₆ -C ₁₀ arylcarbonyloxy group, an amino group, C ₁ -C ₆ alkylamino group, di C ₁ -C ₆ alkylamino group, C ₆ -C ₁₀ arylamino group, di-C ₆ -C ₁₀ arylamino group, a mercapto group, C ₁ -C ₆ alkylthio group, ₆ -C ₁₀ arylthio group, C ₁ -C ₆ alkylsulfinyl group, C ₆ -C ₁₀ arylsulfinyl group, C ₁ -C ₆ alkylsulfonyl group, C ₆ -C ₁₀ arylsulfonyl group, a sulfonic acid group, a halogen atom, A nitro group and a cyano group are shown. ]
A compound represented by
(3) In the above (2), ^{R 2} is, C ₁ -C ₆ alkyl group, or, substituted with 1 to 3 groups selected Substituent group alpha, the C ₁ -C ₆ alkyl group and a halomethyl group An optionally substituted phenyl group (the substituent group α is an amino group, a C ₁ -C ₆ alkylamino group or a halogen atom), and X is an oxygen atom,
(4) The following general formula (III):

Wherein, ^{R 2} and X represent the same meanings as ^{R 2} and X in the above (2). The following general formula (I) is characterized in that after the nitro group of the compound represented by formula (I) is reduced, dehydration condensation is performed in the molecule:

[Wherein R ² and X represent the same meaning as R ² and X in (2) above. And a method for producing a pharmacologically acceptable salt thereof,
(5) In the above (4), R ² is substituted with a C ₁ -C ₆ alkyl group, or 1 to 3 groups selected from a substituent group α, a C ₁ -C ₆ alkyl group and a halomethyl group An optionally substituted phenyl group (the substituent group α is an amino group, a C ₁ -C ₆ alkylamino group or a halogen atom), and X is an oxygen atom,
(6) The following general formula (II):

[Wherein R ² and X represent the same meaning as R ² and X in (2) above. The compound represented by the following general formula (III) is characterized in that 4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetic acid is condensed:

[Wherein R ² and X represent the same meaning as R ² and X in (2) above. ] The manufacturing method of the compound represented by these,
(7) In the above (6), R ² is substituted with 1 to 3 groups selected from a C ₁ -C ₆ alkyl group, or a substituent group α, a C ₁ -C ₆ alkyl group and a halomethyl group. A phenyl group which may be substituted (the substituent group α is an amino group, a C ₁ -C ₆ alkylamino group or a halogen atom), and X is an oxygen atom,
(8) 2,4-dichloronitrobenzene and methylamine are reacted to produce N- (5-chloro-2-nitrophenyl) -N-methylamine, and N- (5-chloro-2-nitrophenyl) In the presence of a base without isolation of -N-methylamine,
Formula ^R 2 -X-H
[Wherein R ² and X represent the same meaning as R ² and X in (2) above. ]
The following general formula (II) characterized by reacting with a compound represented by:

(Wherein R ² and X have the same meanings as described above),
(9) In the above (8), ^{R 2} is, C ₁ -C ₆ alkyl group, or, substituted with 1 to 3 groups selected Substituent group alpha, the C ₁ -C ₆ alkyl group and a halomethyl group A phenyl group which may be substituted (the substituent group α is an amino group, a C ₁ -C ₆ alkylamino group or a halogen atom), and X is an oxygen atom,
(10) N- (5-chloro-2-nitrophenyl) -N-methylamine in the presence of a base in an inert solvent is represented by the following general formula (V):

(In the formula, R ¹ represents a nitro group, an amino group or a t-butoxycarbonylamino group.)
A process for producing a compound represented by the general formula (I) according to the above (1), characterized by reacting with a compound represented by the formula:
(11) The process for producing a compound represented by the general formula (I) according to (1) above, wherein the inert solvent is degassed in (10) above,
(12) In the above (10) or (11), an antioxidant is added, and the method for producing the compound represented by the general formula (I) according to claim 1, and (13) the above ( In 12), the antioxidant is 2,6-di-t-butyl-4-methylphenol. The process for producing a compound represented by the general formula (I) according to claim 1 is provided.

  In the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. In the substituent group α, a fluorine atom or a chlorine atom is preferable.

In the present invention, the “C ₁ -C ₆ alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s -Butyl, t-butyl, pentyl, isopentyl, s-pentyl, t-pentyl, neopentyl, hexyl group. R ² is preferably a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or t-butyl group, more preferably a methyl, ethyl, propyl, isopropyl, butyl or isobutyl group. It is. The substituent for the nitrogen atom when X is a nitrogen atom is preferably a methyl, ethyl, propyl or isopropyl group, and more preferably a methyl or ethyl group.

In the present invention, the “halomethyl group” is a methyl group substituted with 1 to 3 of the “halogen atoms”, for example, a fluoromethyl, difluoromethyl, trifluoromethyl, dichloromethyl or trichloromethyl group. As a substituent of a C ₃ -C ₆ cycloalkyl group, a phenyl group, or a 5- or 6-membered heterocyclic group in the definition of R ² , preferably a fluoromethyl, difluoromethyl, trifluoromethyl or trichloromethyl group, More preferred is a trifluoromethyl group.

In the present invention, the “C ₂ -C ₆ alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms, and examples thereof include ethenyl, 1-propenyl, 3-propenyl (or allyl), 2-methylpropen-1-yl, 2-methylpropen-3-yl (or methallyl), 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-butene- 4-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methyl-1-buten-1-yl, 2-methyl-1-buten-3-yl, 2-methyl-1- Buten-4-yl, 3-methyl-2-buten-2-yl, 2-ethyl-1-buten-1-yl, 2,3-dimethyl-2-buten-1-yl, 1-penten-1- Yl, 1-penten-2-yl, 1-penten-3-yl, 1-pentene-4 1-penten-5-yl, 2-penten-1-yl, 2-penten-2-yl, 2-penten-3-yl, 2-penten-4-yl, 2-penten-5-yl, 2-methyl-1-penten-1-yl, 3-methyl-2-penten-1-yl, 3-methyl-2-penten-2-yl, 2-ethyl-1-penten-1-yl, 3- Ethyl-2-penten-1-yl, 3-ethyl-2-penten-2-yl, 1-hexen-1-yl, 1-hexen-2-yl, 2-hexen-1-yl, 2-hexene- It is a 2-yl group. In the substituent group α, a linear or branched alkenyl group having 2 to 5 carbon atoms is preferable, and an ethenyl, 2-propenyl, or 3-propenyl group is more preferable.

In the present invention, the “C ₂ -C ₆ alkynyl group” is a linear or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, 1-propynyl, 3-propynyl (or propargyl), 1-butyn-1-yl, 1-butyn-3-yl, 1-butyn-4-yl, 2-butyn-1-yl, 1-pentyn-1-yl, 2-pentyn-1-yl, 3- Methyl-1-pentyn-1-yl, 1-hexyn-1-yl and 2-hexyn-1-yl groups. In the substituent group α, a linear or branched alkynyl group having 2 to 5 carbon atoms is preferable, and an ethynyl, 1-propynyl or 3-propynyl group is more preferable.

In the present invention, the “C ₃ -C ₆ cycloalkyl group” is a 3- to 6-membered saturated cyclic hydrocarbon group, for example, a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

Incidentally, "C ₃ -C ₆ cycloalkyl group" in R ² may be substituted are C ₁ -C ₆ alkyl group, including such groups in R ² is preferably cyclopropyl 1-methylcyclopropyl, 2,2-dimethylcyclopropyl, cyclobutyl, 3,3-dimethylcyclobutyl, cyclopentyl or cyclohexyl group. In the substituent group α, a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group is preferable.

In the present invention, the “C ₆ -C ₁₀ aryl group” is an aromatic hydrocarbon group having 6 to 10 carbon atoms, such as a phenyl, indenyl, or naphthyl group. In the substituent group α, a phenyl group is preferable.

  In the present invention, “including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur” or “5- to 6-membered heterocyclic group” includes, for example, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-2-yl, 1H- Imidazol-4-yl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 2H-1, , 3-triazol-4-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1 2,4-thiadiazol-5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridyl, 4-pyridazyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 2-pyrazyl, 1,2 , 4-Triazin-3-yl, 1,2,4-triazin-4-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl or 1,3,5 -A triazin-2-yl group.

In R ² , 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3 -Isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridyl, 4-pyridazyl, 2-pyrimidyl, 4-pyrimidyl , 5-pyrimidyl, 2-pyrazyl or 1,3,5-triazin-2-yl group, more preferably 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-isoxazolyl, 4 -Isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isothiazole Azolyl, 4-isothiazolyl, 5-isothiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridyl, 4-pyridazyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl or 1,3,5-triazin-2-yl group.

In the present invention, the “C ₁ -C ₆ alkoxy group” is a group in which the above “C ₁ -C ₆ alkyl group” is bonded to an oxygen atom, such as methoxy, ethoxy, n-propoxy, isopropoxy, n -Butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3 1 to 6 carbon atoms such as 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy A linear or branched alkoxy group; In the substituent group α, a methoxy group is preferable.

In the present invention, the “C ₆ -C ₁₀ aryloxy group” is a group in which the “C ₆ -C ₁₀ aryl group” is bonded to an oxygen atom, such as phenoxy, α-naphthaleneoxy, β-naphthaleneoxy. It is a group. In the substituent group α, a phenoxy group is preferable.

In the present invention, the “C ₁ -C ₆ alkylcarbonyl group” is a group in which an aliphatic hydrocarbon group having 1 to 6 carbon atoms is bonded to a carbonyl group, such as acetyl, propionyl, butyryl, isobutyryl, pentanoyl. , Pivaloyl, valeryl or isovaleryl group.

The above “C ₁ -C ₆ alkylcarbonyl group” may be substituted with a halogen atom or a C ₁ -C ₆ alkoxy group, or may have an unsaturated bond with a C ₁ -C ₆ alkyl group. Good. Examples of such groups include halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl; C ₁ -C ₆ alkoxyalkylcarbonyl groups such as methoxyacetyl; (E) -2 An unsaturated alkylcarbonyl group such as methyl-2-butenoyl. In the nitrogen atom substituent and substituent group α when X is a nitrogen atom, an acetyl or propionyl group is preferred, and an acetyl group is more preferred.

In the present invention, the “C ₆ -C ₁₀ arylcarbonyl group” is a group in which the “C ₆ -C ₁₀ aryl group” is bonded to a carbonyl group, and examples thereof include benzoyl, α-naphthoyl, and β-naphthoyl. And an aromatic acyl group such as a lower alkylated arylcarbonyl group such as 2,4,6-trimethylbenzoyl and 4-toluoyl. In the nitrogen atom substituent and substituent group α in the case where X is a nitrogen atom, a benzoyl group is preferred.

In the present invention, the “C ₁ -C ₆ alkylcarbonyloxy group” is an aliphatic hydrocarbon group having 1 to 6 carbon atoms or a group in which a hydrogen atom is bonded to a carbonyloxy group, such as formyloxy, acetyl An oxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, pivaloyloxy, valeryloxy or isovaleryloxy group;

The above “C ₁ -C ₆ alkylcarbonyloxy group” may be substituted with a halogen atom or a C ₁ -C ₆ alkoxy group, or a C ₁ -C ₆ alkyl group is unsaturatedly bonded. Also good. Examples of such groups include halogenated alkylcarbonyloxy groups such as chloroacetyloxy, dichloroacetyloxy, trichloroacetyloxy, and trifluoroacetyl; C ₁ -C ₆ alkoxyalkylcarbonyloxy groups such as methoxyacetyloxy. (E) an unsaturated alkylcarbonyloxy group such as 2-methyl-2-butenoyloxy; In the substituent group α, an unsubstituted C ₁ -C ₄ alkylcarbonyloxy group is preferable, and a formyloxy or acetyloxy group is more preferable.

In the present invention, the “C ₆ -C ₁₀ arylcarbonyloxy group” is a group in which the “C ₆ -C ₁₀ aryl group” is bonded to a carbonyloxy group, such as benzoyloxy, α-naphthoyloxy or β-naphthoyloxy group.

The “C ₆ -C ₁₀ arylcarbonyloxy group” may be substituted with a C ₁ -C ₆ alkyl group. Examples of such groups include 2,4,6-trimethylbenzoyloxy, C ₁ -C ₆ alkylated arylcarbonyloxy groups such as 4-toluoyloxy. In the substituent group α, a benzoyloxy group is preferable.

In the present invention, the “C ₁ -C ₆ alkylsulfonyl group” is a group in which the “C ₁ -C ₆ alkyl group” is bonded to a sulfonyl group, such as methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, Isopropanesulfonyl, n-butanesulfonyl, isobutanesulfonyl, s-butanesulfonyl, tert-butanesulfonyl, n-pentanesulfonyl, isopentanesulfonyl, 2-methylbutanesulfonyl, neopentanesulfonyl, n-hexanesulfonyl, 4-methylpentanesulfonyl 3-methylpentanesulfonyl, 2-methylpentanesulfonyl, 3,3-dimethylbutanesulfonyl, 2,2-dimethylbutanesulfonyl, 1,1-dimethylbutanesulfonyl, 1,2-dimethylbutanesulfonyl, 1,3-dimethyl Butansul Alkenyl, a straight chain or branched chain alkanesulfonyl group having 1 to 6 carbon atoms such as 2,3-dimethylbutane sulfonyl group. In the substituent group α, a linear or branched alkanesulfonyl group having 1 to 4 carbon atoms is preferable, and a methanesulfonyl group is more preferable. The substituent for the nitrogen atom of X is preferably a methanesulfonyl group.

In the present invention, the “C ₆ -C ₁₀ arylsulfonyl group” is a group in which the “C ₆ -C ₁₀ aryl group” is bonded to a sulfonyl group, such as benzenesulfonyl, p-toluenesulfonyl, α-naphthalene. Sulfonyl, β-naphthalenesulfonyl group. In the substituent group α, a benzenesulfonyl group is preferable. The substituent for the nitrogen atom of X is preferably benzenesulfonyl or p-toluenesulfonyl group.

In the present invention, the “C ₁ -C ₆ alkoxycarbonyl group” is a group in which the “C ₁ -C ₆ alkoxy group” is bonded to a carbonyl group, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, Isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl, isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, n-hexyloxycarbonyl 4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2- Jime Butoxycarbonyl, 1,3-dimethyl-butoxycarbonyl, 2,3-dimethyl-butoxy straight or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms, such as carbonyl. In the substituent group α, a tert-butoxycarbonyl or methoxycarbonyl group is preferable, and a tert-butoxycarbonyl group is more preferable.

In the present invention, the “C ₆ -C ₁₀ aryloxycarbonyl group” is a group in which the “C ₆ -C ₁₀ aryloxy group” is bonded to a carbonyl group, such as phenoxycarbonyl, α-naphthaleneoxycarbonyl, β-naphthaleneoxycarbonyl group. In the substituent group α, a phenoxycarbonyl group is preferable.

In the present invention, the “N—C ₁ -C ₆ alkylcarbamoyl group” is a group in which the “C ₁ -C ₆ alkyl group” is bonded to the nitrogen atom of the carbamoyl group, such as N-methylcarbamoyl, N -Ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, Ns-butylcarbamoyl, Nt-butylcarbamoyl, N-pentylcarbamoyl, N-isopentylcarbamoyl, N -S-pentylcarbamoyl, Nt-pentylcarbamoyl, N-neopentylcarbamoyl, N-hexylcarbamoyl group. In the substituent group α, an N-methylcarbamoyl or N-ethylcarbamoyl group is preferable.

In the present invention, "N, N-di-C ₁ -C ₆ alkylcarbamoyl group" and the same or different on the nitrogen atom of the carbamoyl group "C ₁ -C ₆ alkyl group" is 2 or substituted group For example, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-diisopropylcarbamoyl. In the substituent group α, an N, N-dimethylcarbamoyl or N, N-diethylcarbamoyl group is preferable.

In the present invention, the “C ₁ -C ₆ alkylamino group” is a group in which the “C ₁ -C ₆ alkyl group” is bonded to an amino group, such as methylamino, ethylamino, n-propylamino, Isopropylamino, n-butylamino, isobutylamino, s-butylamino, tert-butylamino, n-pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropylamino, n-hexylamino , Isohexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethyl Butylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethyl Rubuchiruamino, 2-ethyl-butylamino group. In the substituent group α, a methylamino, ethylamino, propylamino or isopropylamino group is preferable.

In the present invention, the “di-C ₁ -C ₆ alkylamino group” is a group obtained by substituting two identical “C ₁ -C ₆ alkyl groups” with or without the same amino group. Dimethylamino, N, N-diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, N, N-di-n-butylamino, N, N-diisobutylamino, N, N-dis- Butylamino, N, N-ditert-butylamino, N, N-di-n-pentylamino, N, N-diisopentylamino, N, N-di2-methylbutylamino, N, N-dineopentyl Amino, N, N-di1-ethylpropylamino, N, N-di-n-hexylamino, N, N-diisohexylamino, N, N-di4-methylpentylamino, N, N-di-3- Methylpentylamino, N, N-di2-methylpentylamino, N, - di 1-methylpentylamino, N, N- ethylmethylamino, N, it is N- isopropyl-methyl-amino group. In the substituent group α, an N, N-dimethylamino group is preferable.

In the present invention, the “C ₆ -C ₁₀ arylamino group” is a group in which the “C ₆ -C ₁₀ aryl group” is bonded to an amino group, such as phenylamino, indenylamino, naphthylamino group. is there. In the substituent group α, a phenylamino group is preferable.

In the present invention, the term "di-C ₆ -C ₁₀ aryl group", the same or different to the amino group "C ₆ -C ₁₀ arylamino group" is two substituted groups, for example, N, N -A diphenylamino group. In the substituent group α, an N, N-diphenylamino group is preferable.

In the present invention, the “C ₁ -C ₆ alkylthio group” is a group in which the “C ₁ -C ₆ alkyl group” is bonded to a sulfur atom, for example, a methylthio, ethylthio, or t-butylthio group. In the substituent group α, a methylthio group is preferable.

In the present invention, the “C ₆ -C ₁₀ arylthio group” is a group in which the “C ₆ -C ₁₀ aryl group” is bonded to a sulfur atom. For example, phenylthio, α-naphthalenethio, β-naphthalenethio group It is. In the substituent group α, a phenylthio group is preferable.

In the present invention, the “C ₁ -C ₆ alkylsulfinyl group” is a group in which the “C ₁ -C ₆ alkyl group” is bonded to a sulfinyl group, such as a methylsulfinyl, ethylsulfinyl, t-butylsulfinyl group. It is. In the substituent group α, a methylsulfinyl group is preferable.

In the present invention, the “C ₆ -C ₁₀ arylsulfinyl group” is a group in which the “C ₆ -C ₁₀ aryl group” is bonded to a sulfinyl group, such as phenylsulfinyl, α-naphthalenesulfinyl, β-naphthalene. It is a sulfinyl group. In the substituent group α, a phenylsulfinyl group is preferable.

When R ² represents a C ₁ -C ₆ alkyl group having a substituent, the number of substituents is 1 to 5, preferably 1 to 3, and more preferably 1 to 2 It is.

R ² represents a C ₁ -C ₆ alkyl group having a substituent, and when the number of substituents is 2 or more, these substituents may be the same or different from each other. R ² represents a substituent. In the case of representing a phenyl group or heterocyclic group, the number of substituents is 1 to 5, preferably 1 to 4, and more preferably 1 to 3.

When R ² represents a phenyl group or a heterocyclic group having a substituent, and the number of the substituents is 2 or more, the substituents may be the same as or different from each other.

As R ^2, preferably, C ₁ -C ₆ alkyl group, or a substituent group alpha, may be substituted with 1 to 3 groups selected from C ₁ -C ₆ alkyl group and a halomethyl group A phenyl group (the substituent group α is an amino group, a C ₁ -C ₆ alkylamino group or a halogen atom);

X is preferably an oxygen atom or a nitrogen atom (the nitrogen atom may be substituted with a hydrogen atom, a C ₁ -C ₆ alkylcarbonyl group or a C ₆ -C ₁₀ arylcarbonyl group), More preferably, it is an oxygen atom.

  The “pharmacologically acceptable salt thereof” means that the compound having the general formula (I) of the present invention has a basic group such as an amino group by reacting with an acid or a carboxyl group. In the case of having such an acidic group, it can be converted into a salt by reacting with a base, so that salt is shown.

  Salts based on basic groups are preferably inorganic such as hydrohalides such as hydrochlorides, hydrobromides, hydroiodides, nitrates, perchlorates, sulfates, phosphates, etc. Acid salts; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, arylsulfonates such as benzenesulfonate, p-toluenesulfonate, acetates, Organic acid salts such as malate, fumarate, succinate, citrate, ascorbate, tartrate, succinate, maleate; or glycine, lysine, arginine, ornithine, Amino acid salts such as glutamate and aspartate, and preferably hydrochloride.

  On the other hand, the salt based on an acidic group is preferably a metal such as an alkali metal salt such as sodium salt, potassium salt or lithium salt, an alkaline earth metal salt such as calcium salt or magnesium salt, an aluminum salt or an iron salt. Salt: inorganic salt such as ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine Salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt Organic Amine salts and the like; or glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, amino acid salts such as aspartate.

  As typical compounds of the present invention, for example, compounds listed in the following table can be mentioned, but the present invention is not limited to these compounds.

Abbreviations in the table are as follows.
Boc: t-butoxycarbonyl Bu: n-butyl cBu: cyclobutyl cHex: cyclohexyl cPen: cyclopentyl cPr: cyclopropyl Et: ethyl Hex: n-hexyl iBu: isobutyl iPr: isopropyl Me: methyl neoPen: n-pentyl Pen: n : Phenyl Pr: n-propyl sBu: sec-butyl tBu: tert-butyl

(Table 2)
――――――――――――――――――――――――
Compound X R ²
No .――――――――――――――――――――――――
1 O Me
2 O Et
3 O Pr
4 O iPr
5 O Bu
6 O iBu
7 O sBu
8 O tBu
9 O Pen
10 O neoPen
11 O Hex
12 O CF3CH _2-
13 O cPrCH _2-
14 O cBuCH _2-
15 O cPenCH _2-
16 O cHexCH _2-
17 O CH ₂ = CHCH _2-
18 O CH ₂ = CHC (Me) H-
19 O MeCH = CHCH _2-
20 O CH≡CCH _2-
21 O MeC≡CCH _2-
22 O CH≡CHC (Me) H-
23 O PhCH _2-
24 O PhC (Me) H-
25 O Ph-CH ₂ CH _2-
26 O HOCOCH _2-
27 O HCOCH _2-
28 O MeCOCH _2-
29 O PhCOCH _2-
30 O MeOCOCH _2-
31 O PhOCOCH _2-
32 O NH ₂ COCH _2-
33 O MeNHCOCH _2-
34 O Me ₂ NCOCH _2-
35 O HOCH _2-
36 O MeOCH _2-
37 O MeOCH ₂ CH _2-
38 O PhOCH _2-
39 O MeCOOCH _2-
40 O PhCOOCH _2-
41 O NH ₂ CH _2-
42 O MeNHCH _2-
43 O Me ₂ NCH _2-
44 O PhNHCH _2-
45 O Ph ₂ NCH _2-
46 O HSCH _2-
47 O MeSCH _2-
48 O MeSCH ₂ CH _2-
49 O PhSCH _2-
50 O MeSOCH _2-
51 O PhSOCH _2-
52 O MeSO ₂ CH _2-
53 O PhSO ₂ CH _2-
54 O HOSO ₂ CH _2-
55 O CH ₂ F-
56 O CHF _2-
57 O CF _3-
58 O CCl _3-
59 O NO ₂ CH _2-
60 O NO ₂ CH ₂ CH _2-
61 O NCCH _2-
62 O NCCH ₂ CH _2-
63 O cPr
64 O 1-Me-cPr
65 O 2-Me-cPr
66 O cBu
67 O 3,3-Me ₂ -cBu
68 O cPen
69 O 3,3-Me ₂ -cPen
70 O cHex
71 O 4-Me-cHex
72 O Ph
73 O 2-Me-Ph
74 O 3-Me-Ph
75 O 4-Me-Ph
76 O 3-Et-Ph
77 O 4-Et-Ph
78 O 2-Pr-Ph
79 O 4-Pr-Ph
80 O 3-Bu-Ph
81 O 4-Bu-Ph
82 O 2-Pen-Ph
83 O 4-Pen-Ph
84 O 3-Hex-Ph
85 O 4-Hex-Ph
86 O 2-iPr-Ph
87 O 4-iPr-Ph
88 O 4-iBu-Ph
89 O 4-sBu-Ph
90 O 4-neoPen-Ph
91 O 2-CH ₂ F-Ph
92 O 4-CH ₂ F-Ph
93 O 3-CHF ₂ -Ph
94 O 4-CHF ₂ -Ph
95 O 2-CF ₃ -Ph
96 O 3-CF ₃ -Ph
97 O 4-CF ₃ -Ph
98 O 2-CCl ₃ -Ph
99 O 3-CCl ₃ -Ph
100 O 4-CCl ₃ -Ph
101 O 3-CBr ₃ -Ph
102 O 2-cPr-Ph
103 O 3-cPr-Ph
104 O 4-cPr-Ph
105 O 2-cBu-Ph
106 O 4-cBu-Ph
107 O 3-cPen-Ph
108 O 4-cPen-Ph
109 O 2-cHex-Ph
110 O 4-cHex-Ph
111 O 2-CH ₂ = CH-Ph
112 O 3- (CH ₂ = CH) -Ph
113 O 3- (MeCH = CH) -Ph
114 O 4- (CH ₂ = CHCH ₂ ) -Ph
115 O 4- {CH ₂ = CHCH (Me)}-Ph
116 O 2- (CH≡C) -Ph
117 O 4- (CH≡C) -Ph
118 O 3- (MeC≡C) -Ph
119 O 2- (CH≡CCH ₂ ) -Ph
120 O 4- (MeC≡CCH ₂ ) -Ph
121 O 2-Ph-Ph
122 O 4-Ph-Ph
123 O 2-HOCO-Ph
124 O 3-HOCO-Ph
125 O 4-HOCO-Ph
126 O 2-HCO-Ph
127 O 3-HCO-Ph
128 O 4-HCO-Ph
129 O 2-MeCO-Ph
130 O 3-MeCO-Ph
131 O 4-MeCO-Ph
132 O 2-PhCO-Ph
133 O 3-PhCO-Ph
134 O 2-MeO-Ph
135 O 3-MeO-Ph
136 O 4-MeO-Ph
137 O 2-EtO-Ph
138 O 4-EtO-Ph
139 O 2-PrO-Ph
140 O 3-PrO-Ph
141 O 4-iPrO-Ph
142 O 3-BuO-Ph
143 O 4-iBuO-Ph
144 O 3-PenO-Ph
145 O 4-neoPenO-Ph
146 O 4-HexO-Ph
147 O 2-PhO-Ph
148 O 4-PhO-Ph
149 O 2-NH ₂ CO-Ph
150 O 3-NH ₂ CO-Ph
151 O 3-MeNHCO-Ph
152 O 3-Me ₂ NCO-Ph
153 O 2-HO-Ph
154 O 4-HO-Ph
155 O 2-MeOCO-Ph
156 O 4-MeOCO-Ph
157 O 4-PhOCO-Ph
158 O 3-MeCOO-Ph
159 O 4-PhCOO-Ph
160 O 2-NH ₂ -Ph
161 O 4-NH ₂ -Ph
162 O 2-MeNH-Ph
163 O 3-MeNH-Ph
164 O 4-MeNH-Ph
165 O 3-EtNH-Ph
166 O 4-PrNH-Ph
167 O 3-PrNH-Ph
168 O 2-iPrNH-Ph
169 O 3-iPrNH-Ph
170 O 4-iPrNH-Ph
171 O 2-BuNH-Ph
172 O 3-BuNH-Ph
173 O 3-sBuH-Ph
174 O 2-iBuNH-Ph
175 O 3-iBuNH-Ph
176 O 4-iBuNH-Ph
177 O 3-PenNH-Ph
178 O 3-neoPenNH-Ph
179 O 4-neoPenNH-Ph
180 O 3-HexNH-Ph
181 O 4-Me ₂ N-Ph
182 O 3-Et ₂ N-Ph
183 O 3-Me ₂ N-Ph
184 O 3-PhNH-Ph
185 O 4-Ph ₂ N-Ph
186 O 2-HS-Ph
187 O 2-MeS-Ph
188 O 2-PhS-Ph
189 O 2-MeSO-Ph
190 O 2-PhSO-Ph
191 O 2-MeSO ₂ -Ph
192 O 2-HOSO ₂ -Ph
193 O 2-F-Ph
194 O 3-F-Ph
195 O 4-F-Ph
196 O 2-Cl-Ph
197 O 3-Cl-Ph
198 O 4-Cl-Ph
199 O 4-Br-Ph
200 O 2-NO ₂ -Ph
201 O 3-NO ₂ -Ph
202 O 4-NO ₂ -Ph
203 O 2-cyano-Ph
204 O 3-cyano-Ph
205 O 4-cyano-Ph
206 O 2,4-Me ₂ -Ph
207 O 3,5-Me ₂ -Ph
208 O 3,5-Me ₂ -4-NH ₂ -Ph
209 O 3,5-Me ₂ -4-MeNH-Ph
210 O 3,5-Me ₂ -4-BocNH-Ph
211 O 3,5-Me ₂ -4-NO ₂ -Ph
212 O 3,5-Me ₂ -4-cyano-Ph
213 O 2,4-F ₂ -Ph
214 O 2,4-Cl ₂ -Ph
215 O 2,3,4,5,6-F ₅ -Ph
216 O 1H-1-Me-pyrrol-2-yll
217 O 2-furyl
218 O 2-thienyl
219 O 1H-1-Me-pyrazol-3-yl
220 O 1H-1-Me-imidazol-2-yl
221 O 3-isooxazolyl
222 O 2-oxazolyl
223 O 3-isothiazolyl
224 O 2-thiazolyl
225 O 1H-1Me-1,2,3-triazol-4-yl
226 O 1,2,4-oxadiazol-3-yl
227 O 1,2,4-thiadiazole-3-yl
228 O 2-pyridyl
229 O 3-pyridyl
230 O 4-pyridyl
231 O 3-pyridazinyl
232 O 2-pyrimidinyl
233 O 1,3,5-triazine-2-yl
234 S Me
235 S Et
236 S Pr
237 S iPr
238 S Bu
239 S iBu
240 S sBu
241 S tBu
242 S Pen
243 S neoPen
244 S Hex
245 S NH ₂ CH _2-
246 S MeNHCH _2-
247 S Me ₂ NCH _2-
248 S cPr
249 S 1-Me-cPr
250 S 2-Me-cPr
251 S cBu
252 S 3,3-Me ₂ -cBu
253 S cPen
254 S 3,3-Me ₂ -cPen
255 S cHex
256 S 4-Me-cHex
257 S Ph
258 S 4-Me-Ph
259 S 3,5-Me ₂ -Ph
260 S 4-F-Ph
261 S 3,5-F ₂ -Ph
262 S 3-NH ₂ -Ph-
263 S 4-NH ₂ -Ph-
264 S 2-MeNH-Ph
265 S 3-MeNH-Ph
266 S 4-MeNH-Ph
267 S 3-EtNH-Ph
268 S 3-PrNH-Ph
269 S 3-iPrNH-Ph
270 S 3-BuNH-Ph
271 S 3-iBuNH-Ph
272 S 2-NO ₂ -Ph
273 S 3-NO ₂ -Ph
274 S 4-NO ₂ -Ph
275 S 1H-1-Me-pyrrol-2-yl
276 S 2-furyl
277 S 2-thienyl
278 S 1H-1-Me-pyrazol-3-yl
279 S 1H-1-Me-imidazol-2-yl
280 S 3-isooxazolyl
281 S 2-oxazolyl
282 S 3-isothiazolyl
283 S 2-thiazolyl
284 S 1H-1Me-1,2,3-triazol-4-yl
285 S 1,2,4-oxadiazol-3-yl
286 S 1,2,4-thiadiazole-3-yl
287 S 2-pyridyl
288 S 3-pyridyl
289 S 4-pyridyl
290 S 3-pyridazinyl
291 S 2-pyrimidinyl
292 S 1,3,5-triazine-2-yl
――――――――――――――――――――――――
Among the compounds having the general formula (II) of the present invention, preferred compounds are exemplified compound numbers: 1 to 17, 21, 23, 28, 30, 32, 34, 36, 37, 38, 47, 49. , 52, 57, 59, 61, 68, 70, 73, 75, 77, 87, 97, 113, 118, 120, 122, 130, 133, 136, 150, 152, 136, 158, 162, 163, 165 169, 172 to 175, 177, 180, 181, 184, 191, 193, 195, 196, 198, 202, 204, 205, 207 to 211, 212, 213, 221, 223, 234 to 236, 239, 241 243, 247, 253, 257, 259, 260, 261, 263, 274, 282, 284, 287, 289, 290, 291


It is.
More preferably, exemplified compound numbers: 1, 2, 4, 30, 34, 37, 47, 68, 75, 136, 163, 165, 167, 169, 175, 184, 195, 202, 205, 207, 208 , 209, 210, 211, 213, 257, 260, 282, 291


It is.

More preferably,
Exemplary Compound No. 1: (2- {4-[(2,4-Dioxo-1,3-thiazolidin-5-yl) methyl] phenoxy} -N- (5-methoxy-2-nitrophenyl) -N-methyl Acetamide),
Illustrative compound number 169: (2- {4- [2,4-dioxo-1,3-thiazolidin-5-yl] methyl} phenoxy} -N- [5- (3-isopropylaminophenoxy) -2-nitrophenyl ] -N-methylacetamide),
Exemplary compound number 208: (N- [5- (4-amino-3,5-dimethylphenoxy) -2-nitrophenyl] -2- {4- [2,4-dioxo-1,3-thiazolidine-5 Yl] methyl} phenoxy} -N-methylacetamide),
Exemplary Compound No. 210: (4- {3-[({4-[(2,4-Dioxo-1,3-thiazolidin-5-yl) methoxy] phenoxy} acetyl) (methyl) amino] -4-nitrophenoxy } -2,6-dimethylphenylcarbamate t-butyl),
Illustrative compound number 211: (N- [5- (3,5-dimethyl-4-nitrophenoxy) -2-nitrophenyl] -2- {4- [2,4-dioxo-1,3-thiazolidine-5 Yl] methyl} phenoxy} -N-methylacetamide).
It is.

  The present invention provides novel production intermediates (IIa) and (III) of 6-substituted-1-methyl-1-H-benzimidazole derivatives (I), which are known pharmaceutically active ingredients. Furthermore, a production intermediate, a production method for obtaining N- (5-substituted-2-nitrophenyl) -N-methylamines (II) in high yield and high purity, and the production intermediate (II) A production method suitable for mass synthesis is provided. By using the production method of the present invention, the production intermediate (II) can be easily produced from the raw material compound in one-pot with a high yield, and even when the production intermediate is synthesized in large quantities with a high yield and a high purity. Thus, it can be produced by a simple operation using an inexpensive reagent.

  The 6-substituted-1-methyl-1-H-benzimidazole derivative (I) is also N- (5-substituted-2-aminophenyl) -N-, which requires a conventional methylamino group protection reaction. From N- (5-substituted-2-nitrophenyl) -N-methylamines (II) that can be produced by the method of the present invention without passing through methylamine, it is efficient in a short step without carrying out a protective reaction. Well, it can be manufactured.

  The method for producing Compound (I), Compound (II), Compound (IIa) and Compound (III) of the present invention will be described in detail below.

  Compound (II) can be produced, for example, by the following method.

In addition, compound (IIa) which is a novel production intermediate is compound (II) wherein 1 to 5 groups in which R ² is selected from substituent group α, C ₁ -C ₆ alkyl group and halomethyl group And more specifically, a compound in which R ² is substituted with 4-substituted-3,4-dimethylphenyl-4-yl, and a compound (II) It is a compound included in Compound (IIa) is produced according to the following production method of compound (II). More specifically, in the second step described later, N- (5-chloro-2-nitrophenyl) -N-methyl is used. An amine can be produced by reacting with a compound represented by the following general formula (V), which is a hydroxyaryl, and this reaction will be described later in particular as Step 2a.

In the above formula and the following description, R ¹ , R ² and X are as defined above.

  In the method of the present invention, after the first step of producing N- (5-chloro-2-nitrophenyl) -N-methylamine by reacting compound 2,4-dichloronitrobenzene and methylamine, N- ( Without isolating 5-chloro-2-nitrophenyl) -N-methylamine, the compound (II) is reacted with water, alcohols, phenols, hydrogen sulfide, mercaptans, ammonia, amines, or amides. ) Is manufactured. In addition, when it is desired to isolate N- (5-chloro-2-nitrophenyl) -N-methylaniline produced in the first step, for example, it can be isolated according to the method described in Patent Document 3. it can.

Hereinafter, the first step and the second step will be described in detail.
(First step)
The first step is a step of producing N- (5-chloro-2-nitrophenyl) -N-methylamine by reacting compound 2,4-dichloronitrobenzene with methylamine in an inert solvent under normal pressure. is there.

  As an inert solvent used in this step, the compounds 2,4-dichloronitrobenzene, methylamine, and N- (5-chloro-2-nitrophenyl) -N-methylamine, which are raw materials, are dissolved to some extent and reacted. There is no particular limitation as long as it does not inhibit. Examples of such a solvent include ethers such as diethyl ether, diisobutyl ether, dibutyl ether, t-butyl methyl ether, cyclopropyl methyl ether, dimethyl cellosolve, tetrahydrofuran, or dioxane; dimethylformamide, dimethylacetamide, N, N -Amides such as dimethylimidazolidinone or hexamethylphosphoric triamide; Sulfoxides such as dimethyl sulfoxide or sulfolane; or a mixed solvent thereof, preferably ethers, amides, or sulfoxides. More preferably, it is tetrahydrofuran, dimethylformamide, dimethylacetamide, or dimethylsulfoxide.

  The methylamine used in this step is added as a gas or as a solution. When added as a solution, the solvent is not particularly limited as long as it dissolves methylamine. Such solvents include alcohols such as water, methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, t-butyl alcohol or methyl cellosolve; pentane, hexane, heptane, octane, isooctane, petroleum ether, cyclohexane, Hydrocarbons such as methylcyclohexane, ethylcyclohexane, benzene, toluene, xylene, or mesitylene; ethers such as diethyl ether, diisobutyl ether, dibutyl ether, t-butyl methyl ether, cyclopropyl methyl ether, dimethyl cellosolve, tetrahydrofuran, or dioxane Dimethylformamide, dimethylacetamide, N, N-dimethylimidazolidinone, or hexamethylphosphoric triamide Or sulfoxides such as dimethyl sulfoxide or sulfolane, preferably water, alcohols, ethers, amides, or sulfoxides, and more preferably water, methanol, ethanol, tetrahydrofuran, Dimethylformamide, dimethylacetamide, or dimethylsulfoxide.

  In this step, when a methylamine solution is used, its concentration is not particularly limited, but is usually 1% to a saturated solution, preferably 10% to a saturated solution, and more preferably 20% to a saturated solution. It is a solution.

  The amount of methylamine used in this step is not particularly limited as long as it is 1 equivalent or more with respect to the compound (I) to be used, but is preferably 1 to 10 equivalents, more preferably 3 To 6 equivalents.

  The reaction temperature in this step is not particularly limited, but is usually 0 ° C. to reflux temperature, preferably room temperature to 120 ° C., and more preferably 40 ° C. to 90 ° C.

  The normal pressure in this step indicates atmospheric pressure, but may be lower or higher than the atmospheric pressure depending on the structure of the reaction vessel or the like. The pressure is not limited, but is usually 0.5 to 10 atmospheres, preferably 0.9 to 2 atmospheres.

  The reaction time in this step is not particularly limited, but is usually 15 minutes to 24 hours, preferably 15 minutes to 6 hours, and more preferably 30 minutes to 3 hours.

After completion of the reaction in this step, the second step is continued without post-treatment.

(Second step)
The second step is carried out following the first step without isolating the N- (5-chloro-2-nitrophenyl) -N-methylaniline produced in the first step.

  In the second step, without isolating N- (5-chloro-2-nitrophenyl) -N-methylaniline, in the presence of a base, water, alcohols, hydroxyaryls, hydrogen sulfide, mercaptans, ammonia , Reacting with amines or amides to produce compound (II).

  In this step, the inert solvent used in the first step is used as it is.

  The base used in this step may be reacted directly with water, alcohols, hydroxyaryls, hydrogen sulfide, mercaptans, ammonia, amines, or amides, which have been reacted in advance.

  The amount of the base used in this step is usually 1 to 2 equivalents with respect to water, alcohols, hydroxyaryls, hydrogen sulfide, mercaptans, ammonia, amines or amides used, preferably 1 to 1.6 equivalents, more preferably 1.2 equivalents.

The alcohol used in this step is not particularly limited as long as it may be a linear or branched C ₁ -C ₆ alkyl alcohol which may have a substituent. For example, methanol, ethanol, propanol, isopropyl alcohol , Butanol, isobutyl alcohol, s-butyl alcohol, t-butyl alcohol, pentanol, isopentyl alcohol, s-pentyl alcohol, t-pentyl alcohol, neopentyl alcohol, hexanol, allyl alcohol, propargyl alcohol, benzyl alcohol, pyridine- 4-ylmethanol, 2-methoxyethanol, 2-methylthioethanol, 2,2,2-trifluoroethanol, 2-cyanoethanol, etc., preferably methanol, ethanol, propanol, isopropyl alcohol Le, butanol, isobutyl alcohol, s- butyl alcohol, t- butyl alcohol, allyl alcohol, propargyl alcohol or benzyl alcohol.

  Although there is no limitation in particular in hydroxyaryl used at this process, For example, phenol, 2-methylphenol, 4-methylphenol, 4-ethylphenol, 4-propylphenol, 3-isopropylphenol, 4-phenylphenol, 4-carboxyphenol, 4-formylphenol, 4-acetylphenol, 4-benzoylphenol, 4-methoxyphenol, 2-ethoxyphenol, 4-propoxyphenol, 3-isopropoxyphenol, 4-phenoxyphenol, 4-aminophenol 2- (N-methylamino) phenol, 3- (N, N-dimethylamino) phenol, 3- (N-isopropylamino) phenol, 4-amino-3,5-dimethylphenol, 3-morpholinophenol, 4 -(N-phenyl Mino) phenol, 4- (N, N-diphenylamino) phenol, 4- (N-methylcarbamoyl) phenol, 4- (N, N-dimethylcarbamoyl) phenol, 4- (methylthio) phenol, 2- (phenylthio) Phenol, 3- (methylsulfinyl) phenol, 4- (phenylsulfinyl) phenol, 4- (methylsulfonyl) phenol, 3- (phenylsulfonyl) phenol, 3-hydroxybenzenesulfonic acid, 2-fluorophenol, 3-fluorophenol 4-fluorophenol, 3,5-difluorophenol, 2-chlorophenol, 4-chlorophenol, 2,4-dichlorophenol, 4-bromophenol, 3-nitrophenol, 3,5-dimethyl-4-nitro Phenol, 2-cyanophenol, 3-cyanophenol, 4 Cyanophenol, 2-hydroxypyridine (tautomer of 2-pyridone), 3-hydroxypyridine, 4-hydroxypyridine, preferably phenol, 4-methylphenol, 3-isopropylphenol, 3,5-dimethyl Phenol, 4-methoxyphenol, 3-isopropoxyphenol, 4-aminophenol, 2- (N-methylamino) phenol, 3- (N, N-dimethylamino) phenol, 3- (N-isopropylamino) phenol, 4-amino-3,5-dimethylphenol, 3-morpholinophenol, 4- (methylthio) phenol, 2-fluorophenol, 3-fluorophenol, 4-fluorophenol, 3,5-difluorophenol, 2-chlorophenol 4-chlorophenol, 2,4-dichlorophenol, 4 Bromophenol, 3-nitrophenol, 3,5-dimethyl-4-nitrophenol, 3-cyanophenol, 4-cyanophenol.

  The mercaptans used in this step are not particularly limited. For example, methyl mercaptan, ethyl mercaptan, propyl mercaptan, isopropyl mercaptan, butyl mercaptan, isobutyl mercaptan, s-butyl mercaptan, t-butyl mercaptan, pentyl mercaptan, isopentyl. Mercaptan, s-pentyl mercaptan, t-pentyl mercaptan, neopentyl mercaptan, hexyl mercaptan, allyl mercaptan, propargyl mercaptan, benzyl mercaptan, pyridin-4-ylmethyl mercaptan, 2-methoxyethyl mercaptan, phenyl mercaptan, 2-methylphenyl mercaptan 4-methylphenyl mercaptan, 4-ethylphenyl mercaptan, 4-propylphenyl mercapa Butane, 3-isopropylphenyl mercaptan, 4-phenyl mercaptan, 4-carboxyphenyl mercaptan, 4-acetylphenyl mercaptan, 4-methoxyphenyl mercaptan, 2-ethoxyphenyl mercaptan, 4-propoxyphenyl mercaptan, 3-isopropoxyphenyl mercaptan, 4-phenoxyphenyl mercaptan, 4-aminophenyl mercaptan, 2- (N-methylamino) phenyl mercaptan, 3- (N, N-dimethylamino) phenyl mercaptan, 3- (N-isopropylamino) phenyl mercaptan, 4-amino -3,5-dimethylphenyl mercaptan, 3-morpholinophenyl mercaptan, 4- (N-phenylamino) phenyl mercaptan, 4- (methylthio) phenyl mercaptan, 2- ( Phenylthio) phenyl mercaptan, 3- (methylsulfinyl) phenyl mercaptan, 4- (methylsulfonyl) phenyl mercaptan, 3- (phenylsulfonyl) phenyl mercaptan, 2-fluorophenonyl mercaptan, 3-fluorophenyl mercaptan, 4-fluorophenyl mercaptan 3,5-difluorophenyl mercaptan, 2-chlorophenyl mercaptan, 4-chlorophenyl mercaptan, 2,4-dichlorophenyl mercaptan, 3-nitrophenyl mercaptan, 3,5-dimethyl-4-nitrophenyl mercaptan, 2-cyanophenyl mercaptan 3-cyanophenyl mercaptan, 4-cyanophenyl mercaptan, 2-pyridyl mercaptan (2-thiopyridone tautomer), 3-pyridyl mercaptan, 4- Pyridyl mercaptan, preferably methyl mercaptan, ethyl mercaptan, propyl mercaptan, isopropyl mercaptan, butyl mercaptan, isobutyl mercaptan, t-butyl mercaptan, neopentyl mercaptan, allyl mercaptan, benzyl mercaptan, pyridin-4-ylmethyl mercaptan, Phenyl mercaptan, 4-methylphenyl mercaptan, 4-ethylphenyl mercaptan, 4-propylphenyl mercaptan, 3-isopropylphenyl mercaptan, 4-phenyl mercaptan, 4-carboxyphenyl mercaptan, 4-methoxyphenyl mercaptan, 3-isopropoxyphenyl mercaptan 4-phenoxyphenyl mercaptan, 4-aminophenyl mercaptan, 2- ( -Methylamino) phenyl mercaptan, 3- (N, N-dimethylamino) phenyl mercaptan, 3- (N-isopropylamino) phenyl mercaptan, 4-amino-3,5-dimethylphenyl mercaptan, 3-morpholinophenyl mercaptan, 4 -(N-phenylamino) phenyl mercaptan, 4- (methylthio) phenyl mercaptan, 2- (phenylthio) phenyl mercaptan, 3- (methylsulfinyl) phenyl mercaptan, 4- (methylsulfonyl) phenol, 3- (phenylsulfonyl) phenol 2-fluorophenonyl mercaptan, 3-fluorophenyl mercaptan, 4-fluorophenyl mercaptan, 3,5-difluorophenyl mercaptan, 2-chlorophenyl mercaptan, 4-chlorophenyl mercaptan, 2,4-dichloro Rophenyl mercaptan, 3-nitrophenyl mercaptan, 3,5-dimethyl-4-nitrophenyl mercaptan, 2-cyanophenyl mercaptan, 3-cyanophenyl mercaptan, 4-cyanophenyl mercaptan, 2-pyridyl mercaptan (2-thiopyridone Mutant), 3-pyridyl mercaptan, 4-pyridyl mercaptan.

  The amines used in this step are not particularly limited. For example, methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, s-butylamine, t-butylamine, pentylamine, isopentylamine, s-pentyl Amine, t-pentylamine, neopentylamine, hexylamine, allylamine, propargylamine, benzylamine, pyridin-4-ylmethylamine, 2-methoxyethylamine, phenylamine, 2-methylphenylamine, 4-methylphenylamine, 4-ethylphenylamine, 4-propylphenylamine, 3-isopropylphenylamine, 4-phenylamine, 4-carboxyphenylamine, 4-methoxyphenylamine, 2-ethoxyphenylamine, 4 -Propoxyphenylamine, 3-isopropoxyphenylmeramine, 4-phenoxyphenylamine, 2- (N-methylamino) phenylamine, 3- (N, N-dimethylamino) phenylamine, 3- (N-isopropylamino) ) Phenylamine, 4-amino-3,5-dimethylphenylamine, 3-morpholinophenylamine, 4- (N-phenylamino) phenylmeramine, 4- (methylthio) phenylmeramine, 2- (phenylthio) phenylamine 3- (methylsulfinyl) phenylamine, 4- (methylsulfonyl) phenylamine, 3- (phenylsulfonyl) phenylamine, 2-fluorophenonylamine, 3-fluorophenylamine, 4-fluorophenylamine, 3,5 -Difluorophenylamine, 2-chlorophenylamine, 4-chloro Phenylamine, 2,4-dichlorophenylamine, 3-nitrophenylamine, 3,5-dimethyl-4-nitrophenylamine, 2-cyanophenylamine, 3-cyanophenyl mercaptan, 4-cyanophenylamine, 2-pyridylamine, 3-pyridylamine, 4-pyridylamine, N, N-dimethylamine, N, N-diisopropylamine, pyrrolidine, morpholine, N-methyl-N-phenylamine, preferably methylamine, ethylamine, propylamine , Isopropylamine, butylamine, isobutylamine, t-butylamine, neopentylamine, hexylamine, allylamine, benzylamine, pyridin-4-ylmethylamine, phenylamine, 2-methylphenylamine, 4-methylphenylamine, 4- D Tylphenylamine, 3-isopropylphenylamine, 4-phenylamine, 4-methoxyphenylamine, 2-ethoxyphenylamine, 3-isopropoxyphenylamine, 4-phenoxyphenylamine, 2- (N-methylamino) phenylamine 3- (N, N-dimethylamino) phenylamine, 3- (N-isopropylamino) phenylamine, 4-amino-3,5-dimethylphenylamine, 3-morpholinophenylamine, 4- (N-phenylamino) ) Phenylmeramine, 4- (methylthio) phenylmeramine, 2- (phenylthio) phenylamine, 3- (methylsulfinyl) phenylamine, 4- (methylsulfonyl) phenylamine, 2-fluorophenonylamine, 3-fluoro Phenylamine, 4-fluorophenylamine, 3,5-diph Lolophenylamine, 2-chlorophenylamine, 4-chlorophenylamine, 2,4-dichlorophenylamine, 3-nitrophenylamine, 3,5-dimethyl-4-nitrophenylamine, 2-cyanophenylamine, 3-cyanophenyl mercaptan 4-cyanophenylamine, 3-pyridylamine, 4-pyridylamine, N, N-dimethylamine, N, N-diisopropylamine, pyrrolidine, morpholine, N-methyl-N-phenylamine.

  The amides used in this step are not particularly limited. For example, acetamide, benzamide, methanesulfonylamide, benzenesulfonylamide, N-methylacetamide, N-isopropylacetamide, N-phenylacetamide, N- There are methylbenzamide, N-methylmethanesulfonylamide, N-butylmethanesulfonylamide, N-methylbenzenesulfonylamide, and preferably acetamide, benzamide, methanesulfonylamide, N-methylacetamide, N-isopropylacetamide N-methylmethanesulfonylamide.

  The reaction temperature in this step is not particularly limited, but is usually 0 ° C. to reflux temperature, preferably room temperature to 180 ° C., more preferably 40 ° C. to 150 ° C.

  The reaction time in this step is not particularly limited, but is usually 15 minutes to 24 hours, preferably 15 minutes to 6 hours, and more preferably 30 minutes to 3 hours.

  After the completion of the reaction in this step or after the post-treatment, it is made acidic, neutral or basic according to the physical properties of the product compound (II), followed by isolation operations such as extraction and filtration. . After isolation, the product may be used as it is, or may be used after purification by a usual purification method such as distillation, recrystallization, sublimation, distribution, or chromatography, if necessary.

In particular, oxidizing impurities may be by-produced in the second step, and the yield of the target compound (I) may be reduced or the purity may be reduced. In such a case, degassing the inert solvent, adding an antioxidant, or degassing the inert solvent and adding an antioxidant further suppresses by-product impurities, and the target compound ( I) can be obtained with high yield and high purity by a simple operation. The antioxidant is not particularly limited as long as the antioxidant effect is recognized, but 2,4-di-t-butyl-4-methylphenol is preferable.

(Step 2a)
Step 2a is a step of producing compound (IIa), which is a novel production intermediate of the present invention, and the isolated N- (5-chloro-2-nitrophenyl) -N-methylaniline or Compound (V) which is one of hydroxyaryls in the presence of a base without isolating N- (5-chloro-2-nitrophenyl) -N-methylaniline produced in one step:

(In the formula, R ¹ has the same meaning as described above.)
In particular, the step of producing the compound (IIa) is described by taking it out and can be carried out according to the method described in the second step.

The base used in this step may be reacted directly with the compound (V) previously reacted as a salt. The amount of the base used in this step is generally 1 to 2 equivalents, preferably 1 to 1.6 equivalents, and more preferably, relative to compound (V), as in the second step. Is 1.2 equivalents.

  The reaction temperature in this step is not particularly limited, but is usually 0 ° C. to reflux temperature, preferably room temperature to 180 ° C., more preferably 40 ° C. to 150 ° C.

  The reaction time in this step is not particularly limited, but is usually 15 minutes to 24 hours, preferably 15 minutes to 6 hours, and more preferably 30 minutes to 3 hours.

  After completion of the reaction in this step or after the post-treatment, the product is made acidic, neutral, or basic according to the physical properties of the product compound (IIa), and then subjected to isolation operations such as extraction and filtration. . After isolation, the product may be used as it is, or may be used after purification by a usual purification method such as distillation, recrystallization, sublimation, distribution, or chromatography, if necessary.

  In the step 2a, as in the case of the second step, oxidizing impurities may be by-produced, and the yield of the target compound (I) may be reduced or the purity may be reduced. In such a case, as described in the second step, if the inert solvent is degassed or an antioxidant is added, or if the inert solvent is degassed and an antioxidant is further added, the impurities are added. The target compound (I) can be obtained in high yield and high purity by a simple operation. The antioxidant is not particularly limited as long as the antioxidant effect is recognized, but 2,4-di-t-butyl-4-methylphenol is preferable.

Next, the method for producing the compound (I) of the present invention and the production intermediate compound (III) will be described in detail below.

In the above formula and the following description, R ² and X are as defined above.
(Third step)
The third step is a step for producing the compound (III) of the present invention by condensing the compound (II) and 4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetic acid.

This step is performed by an acid halide method, an active esterification method, or a mixed acid anhydride method described in detail below.
(Acid halide method)
In the acid halide method, 4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetic acid is reacted with a halogenating agent such as thionyl chloride or oxalyl chloride in an inert solvent, and the halogenated 4- [ (2,4-Dioxothiazolidin-5-yl) methyl] phenoxyacetyl is prepared by amidation with compound (II) or a salt thereof in an inert solvent in the presence or absence of a base. Done.

  The halogenating agent used in the halogenation reaction is not particularly limited as long as it can convert a carboxylic acid into an acid halide. Examples of such a halogenating agent include thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride and the like, and preferably thionyl chloride, oxalyl chloride, phosphorus pentachloride. Particularly preferred is thionyl chloride.

  The amount of the halogenating agent used in the halogenation reaction is not particularly limited as long as it is 1 equivalent or more with respect to 4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetic acid to be used. Is 1 to 2 equivalents, more preferably 1 to 1.2 equivalents.

  The inert solvent used is not particularly limited as long as it does not inhibit the reaction. Examples of such solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin, or petroleum ether; aromatic hydrocarbons such as benzene, toluene, and xylene; acetonitrile, propionitrile, and benzonitrile. Nitriles such as; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; formamide, Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; sulfolane, and mixtures thereof; Rogenated hydrocarbons, nitriles, ethers or amides, and mixtures thereof, more preferably acetonitrile, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, or mixtures thereof, particularly preferably dichloromethane. Or acetonitrile.

  The halogenation reaction may proceed more rapidly by adding a catalyst.

  When a catalyst is added, an amine, an amine derivative or a nitrogen-containing heterocyclic compound is usually used as the catalyst.

  When an amine is used, a tertiary amine is usually used. Examples of such an amine include trialkylamines such as trimethylamine, triethylamine, diisopropylethylamine or tributylamine; N, N-dimethylaniline, N, N-diethyl. And dialkylarylamines such as aniline; or diarylalkylamines such as diphenylmethylamine.

  Examples of amine derivatives include N, N-dialkylamides such as dimethylformamide and dimethylacetamide.

  Examples of nitrogen-containing heterocyclic compounds include pyridine, N, N-dimethyl-4-aminopyridine, imidazole, and triazole.

  Preferred is trimethylamine, triethylamine, diisopropylethylamine, tributylamine, N, N-dimethylaniline, dimethylformamide, dimethylacetamide, pyridine, or N, N-dimethyl-4-aminopyridine, more preferably triethylamine, Dimethylformamide, pyridine or N, N-dimethyl-4-aminopyridine is particularly preferred, and dimethylformamide is particularly preferred.

  The amount of the catalyst to be used is not particularly limited, but is usually 0.01 to 20 equivalents, preferably 0.1 to 10 equivalents, more preferably 0.1 to the halogenating agent to be used. 3 to 5 equivalents.

  The reaction temperature in this step varies depending on the raw material compounds, reagents and the like, but is usually −20 ° C. to 150 ° C., preferably −10 ° C. to 100 ° C., more preferably −10 to 40 ° C. .

  The reaction time of the halogenation reaction varies depending on the raw material compounds, reagents, reaction temperature, etc., but is usually 30 minutes to 80 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 6 hours.

  After completion of the halogenation reaction, the halogenated 4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetyl or a salt thereof may be isolated and then subjected to an amidation reaction or isolated. The amidation may be carried out without any isolation, and preferably the amidation reaction should be carried out without isolation.

  The amidation reaction is a step for producing compound (III), and reacts 4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetyl with compound (II) in an inert solvent. To achieve this.

  If a base is used in this step, the reaction may proceed rapidly. When a base is used in this step, examples of the base used include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. Salts; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; lithium methoxide, sodium methoxide Alkali metal alkoxides such as sodium ethoxide, potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline N, N-diethylani 1,5-diazabicyclo [4.3.0] nano-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0]- Organic amines such as 7-undecene (DBU), preferably organic amines, more preferably triethylamine, tributylamine or pyridine, and particularly preferably triethylamine.

  The amidation reaction is usually performed in an inert solvent. The inert solvent is not particularly limited as long as it does not inhibit the reaction. Such inert solvents include, for example, aliphatic hydrocarbons such as hexane, heptane, ligroin, or petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; acetonitrile, propionitrile, benzo Nitriles such as nitriles; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; Amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; and mixtures thereof Preferably halogenated hydrocarbons, nitriles, ethers or amides, and mixtures thereof, and more preferably acetonitrile, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide or mixtures thereof. Particularly preferred is dichloromethane or acetonitrile.

  The reaction temperature of the amidation reaction varies depending on the raw material compounds, reagents and the like, but is usually −20 ° C. to 150 ° C., and preferably −20 ° C. to 100 ° C.

  The reaction time of the amidation reaction varies depending on the raw material compounds, reagents, reaction temperature, etc., but is usually 30 minutes to 80 hours. It is preferably 1 to 48 hours.

(Active esterification method)
In the active esterification method, 4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetic acid and an active esterifying agent are reacted in an inert solvent in the presence or absence of a base, It is carried out by producing an ester and reacting with compound (II) to produce compound (III).

  The active esterifying agent used in the active esterification method is, for example, an N-hydroxy compound such as N-hydroxysuccinimide, 1-hydroxybenztriazole, or N-hydroxy-5-norbornene-2,3-dicarboxylimide. Disulfide compounds such as dipyridyl disulfide; carbodiimides such as dicyclohexylcarbodiimide; or condensing agents such as carbonyldiimidazole and triphenylphosphine.

  The inert solvent used in the active esterification method is not particularly limited as long as it does not inhibit the reaction. Examples of such solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin, or petroleum ether; aromatic hydrocarbons such as benzene, toluene, and xylene; acetonitrile, propionitrile, and benzonitrile. Nitriles such as; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; formamide, Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; sulfolane, and mixtures thereof, preferably halogenated Hydrocarbons, nitriles, ethers or amides, and mixtures thereof, more preferably acetonitrile, dichloromethane, chloroform, tetrahydrofuran, dioxane, dimethylformamide or mixtures thereof, particularly preferably. , Tetrahydrofuran, dioxane, or acetonitrile.

  When a base is used in the active esterification method, the same base as that used in the acid halide method described above can be used.

  The reaction temperature of the active esterification method varies depending on the raw material compounds, reagents and the like, but is usually −70 ° C. to 150 ° C., and preferably −20 ° C. to 100 ° C.

  The reaction time of the active esterification method varies depending on the raw material compounds, reagents, reaction temperature and the like, but is usually 10 minutes to 80 hours, preferably 30 minutes to 12 hours.

(Mixed acid anhydride method)
In the mixed acid anhydride method, 4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetic acid is reacted with a mixed acid anhydride agent in an inert solvent in the presence or absence of a base. This is carried out by producing mixed acid anhydrides and reacting with compound (II) to produce compound (III).

  Examples of the mixed acid anhydride agent used in the mixed acid anhydride method include halogenated alkanoyls such as acetyl chloride or pivaloyl chloride; chlorocarbonates such as methyl chlorocarbonate, ethyl chlorocarbonate, or phenyl chlorocarbonate; Cyanophosphoric acids such as diethyl cyanophosphonate and diphenyl cyanophosphonate are used.

  The inert solvent used in the mixed acid anhydride method is not particularly limited as long as it does not inhibit the reaction. Examples of such solvents include aliphatic hydrocarbons such as hexane, heptane, ligroin, or petroleum ether; aromatic hydrocarbons such as benzene, toluene, and xylene; acetonitrile, propionitrile, and benzonitrile. Nitriles such as; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; formamide, Amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide; sulfolane, and mixtures thereof, preferably halogenated Hydrocarbons, nitriles, ethers or amides, and mixtures thereof, more preferably acetonitrile, dichloromethane, chloroform, tetrahydrofuran, dioxane, dimethylformamide or mixtures thereof, particularly preferably. , Tetrahydrofuran, dioxane, or acetonitrile.

  When a base is used in the mixed acid anhydride method, the same base as that used in the acid halide method described above can be used.

  The reaction temperature of the mixed acid anhydride method varies depending on the raw material compounds, reagents and the like, but is usually −70 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.

  The reaction time of the mixed acid anhydride method varies depending on the raw material compounds, reagents, reaction temperature and the like, but is usually 10 minutes to 80 hours, preferably 30 minutes to 12 hours.

  After completion of the reaction of acid halogenation, active esterification method, and mixed acid anhydride method, compound (III) is subjected to normal post-treatment, neutralization treatment as necessary, extraction, natural crystallization, etc. Is separated from the reaction mixture. The obtained compound (III) may be used in the next step as it is, or may be used after purification by a usual purification method such as recrystallization, reprecipitation, chromatography or the like, if necessary.

(4th process)
The fourth step is a step of producing Compound (I) or a pharmacologically acceptable salt thereof by reducing the nitro group of Compound (III) in a solvent and further allowing dehydration condensation in the molecule. It proceeds via compound (IV) as an intermediate.

  The reduction of the nitro group in this step can be performed by a method generally known as a method of reducing the nitro group, but is usually performed by catalytic hydrogenation.

  The catalyst used in this step is not particularly limited as long as it is usually used for catalytic hydrogenation. As such a catalyst, for example, a palladium-carbon catalyst, a platinum-carbon catalyst, Raney nickel, a Wilkinson complex and the like are used, and preferably a palladium-carbon catalyst or a platinum-carbon catalyst.

  The hydrogen pressure in this step is not particularly limited as long as it is 1 atm or higher, but is usually 1 to 20 atm, and preferably 1 to 10 atm.

  The solvent used in this step is not particularly limited as long as it dissolves compound (III) to some extent and does not inhibit the reaction. Examples of such a solvent include aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether, cyclohexane, and methylcyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene; Acids; Carboxylic acid esters such as ethyl acetate and butyl acetate; Nitriles such as acetonitrile, propionitrile and benzonitrile; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; Amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; and mixtures thereof, preferably alcohols, carboxylic acids, carboxylic acid esters. Tellurium, nitriles, ethers or amides, and mixtures thereof, more preferably methanol, carboxylic acid esters, acetonitrile, tetrahydrofuran, dimethylacetamide or mixtures thereof, particularly preferably methanol. Or a mixed solvent of methanol and dimethylacetamide.

  The reaction may be promoted by adding an acid in this step. In order to obtain a pharmacologically acceptable salt of compound (I) as it is, an acid may be added.

  When an acid is added in this step, the acid to be added is not particularly limited. For example, organic acids such as hydroxyacetic acid, oxalic acid and citric acid; or hydrohalic acids such as hydrochloric acid and bromic acid are used. Preferably, it is hydrochloric acid.

  In the case of adding an acid in this step, the amount of the acid to be added is not particularly limited, but is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to compound (IV).

  The reaction temperature in this step is not particularly limited, but is usually 0 ° C to 150 ° C, preferably room temperature to 100 ° C.

  After completion of the reaction in this step, after the post-treatment, the product is made acidic, neutral, or basic according to the physical properties of the product, and then an isolation operation is performed. After isolation, the product may be purified as it is or, if necessary, by a conventional purification method such as recrystallization or chromatography.

  Examples of the present invention will be described below in more detail, but the scope of the present invention is not limited thereto.

(Example 1)
N- [5- (4-Amino-3,5-dimethylphenoxy) -2-nitrophenyl] -N-methylamine (Step 2a)
To a solution of 4.0 g of N- (5-chloro-2-nitrophenyl) -N-methylamine in N, N-dimethylacetamide (56 mL) was added 2.9 g of 4-amino-3,5-dimethylphenol under ice cooling. And 2.9 g of potassium t-butoxide were added and stirred at 75-80 ° C. for 1 hour. After adding 74 mL of water, it was gradually cooled to room temperature. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 4.9 g of the target compound as yellow crystals (yield 80%).
Magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm: 2.20 (s, 6H), 2.90 (d, J = 4.9 Hz, 3H), 3.57 (s, 2H), 6.16-6 .21 (m, 2H), 6.71 (s, 2H), 8.11 (d, J = 9.3 Hz, 1H), 8.20 (brs, 1H).

(Example 2)
N- [5- (4-Amino-3,5-dimethylphenoxy) -2-nitrophenyl] -N-methylamine (Step 2a)
To a solution of 8.00 g of N- (5-chloro-2-nitrophenyl) -N-methylamine in N, N-dimethylacetamide (112 mL), 0.24 g of 2,6-di-tert-butyl-4-methylphenol. Was added. 4-amino-3,5-dimethylphenol 6.47g and potassium t-butoxide 5.29g were added here, and it stirred at 60 degreeC for 30 minutes. After adding 4 mL of water, 120 mL of water was added dropwise over 2 hours, and then gradually cooled to room temperature. The precipitated crystals were separated by filtration, washed with 80 mL of water, and dried under reduced pressure to obtain 11.45 g of the target compound as yellow crystals (yield 93%).

  The obtained target product showed a nuclear magnetic resonance spectrum similar to that shown in Example 1.

(Example 3)
N- [5- (3,5-Dimethyl-4-nitrophenoxy) -2-nitrophenyl] -N-methylamine (Step 2a)
To a solution of 0.86 g N- (5-chloro-2-nitrophenyl) -N-methylamine and 0.76 g 3,5-dimethyl-4-nitrophenol in N, N-dimethylacetamide (12 mL) at room temperature 0.554 g of t-butoxide was added, and the mixture was stirred at the same temperature for 20 minutes, at 100 ° C. for 10 minutes, at 125 ° C. for 45 minutes, and at 140 ° C. for 1 hour. After the reaction mixture was cooled to 0 ° C., 3N hydrochloric acid was added to adjust the pH to about 3. The precipitated crystals were separated by filtration and washed with 3N hydrochloric acid and then with water. The obtained crystals were air-dried for 3 days to obtain 1.16 g of the target compound (yield 80%).
Magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm: 2.32 (s, 6H), 2.97 (d, J = 5.1 Hz, 3H), 6.23 (dd, J = 9.5 Hz, J = 2.4 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 6.82 (s, 2H), 8.20 (d, J = 9.5 Hz, 1H).

(Example 4)
N- (5-methoxy-2-nitrophenyl) -N-methylamine (first and second steps)
To a solution of 3.0 g of 2,4-dichloronitrobenzene in N, N-dimethylacetamide (30 mL) was added 4.9 g of a 40% aqueous methylamine solution at room temperature, and the mixture was stirred at 75 to 80 ° C. for 2 hours. Then, 7.6 g of 28% sodium methoxide solution (methanol solution) was added and stirred at the same temperature for 1.5 hours, and 1.6 g of methanol solution of sodium methoxide (28%) was further added. In addition, the mixture was stirred at the same temperature for 1 hour. After adding 60 mL of water, it was gradually cooled to room temperature. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 2.2 g of the target compound as yellow crystals (yield 77%).
Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm: 3.01 (d, J = 4.9 Hz, 3H), 3.89 (s, 3H), 6.13 (d, J = 2.4 Hz, 1H), 6.25 (dd, J = 9.5 Hz, J = 2.7 Hz, 1H), 8.16 (d, J = 9.5 Hz, 1H), 8.29 (brs, 1H) .

(Example 5)
N- [5- (4-Amino-3,5-dimethylphenoxy) -2-nitrophenyl] -N-methylamine (first and second steps)
To a solution of 3.0 g of 2,4-dichloronitrobenzene in N, N-dimethylacetamide (30 mL) was added 4.9 g of a 40% aqueous methylamine solution at room temperature, and the mixture was stirred at 75-80 ° C. for 1.5 hours. 4-Amino-3,5-dimethylphenol (2.2 g), potassium t-butoxide (3.5 g), and N, N-dimethylacetamide (15 mL) were added, and the mixture was stirred at the same temperature for 3 hours. After adding 60 mL of water, it was gradually cooled to room temperature. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 3.0 g of the target compound as yellow crystals (yield 67%).

  The nuclear magnetic resonance spectrum was consistent with that obtained in Example 1.

(Example 6)
N- [5- (4-t-butoxycarbonylamino-3,5-dimethylphenoxy) -2-nitrophenyl] -N-methylamine N- [5- (4-amino-3] obtained in Example 5 , 5-dimethylphenoxy) -2-nitrophenyl] -N-methylamine in a solution of 40.00 g of toluene (400 ml) at room temperature was added 21.13 g of triethylamine and 33.42 g of di-t-butyldicarbonate. Reflux for hours. To this, 12.15 g of di-t-butyl dicarbonate and 7.04 g of triethylamine were added, and the mixture was further refluxed for 2 hours. After cooling to room temperature, the organic layer is washed 3 times with 100 ml of 10% hydrochloric acid, then twice with 60 ml of 20% hydrochloric acid, then twice with 100 ml of 5% aqueous sodium bicarbonate, and finally with 100 ml of water. Washed. The obtained organic layer was stored refrigerated for a whole day and night, ethylcyclohexane (120 ml) was added thereto, and the mixture was stirred at 0 ° C. for 1 hour. The precipitated crystals were separated by filtration and washed with 0 ° C. toluene-ethylcyclohexane (1: 4, 100 ml). The obtained crystals were dried at 40 ° C. under reduced pressure to obtain 48.79 g of the target compound (yield 91%).
Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm: 1.53 (brs, 9H), 2.27 (s, 6H), 2.93 (d, J = 4.9 Hz, 3H), 5.84 ( brs, 1H), 6.20 (dd, J = 2.4 Hz, J = 9.5 Hz, 1H), 6.31 (brs, 1H), 6.80 (s, 2H), 8.14 (d , J = 9.5 Hz, 1H), 8.19 (brd, 1H).

(Example 7)
N- [5- (3,5-Dimethyl-4-nitrophenoxy) -2-nitrophenyl] -2- {4- [2,4-dioxo-1,3-thiazolidin-5-yl] methyl} phenoxy} -N-methylacetamide (third step) (Exemplary Compound No. 211)
To a suspension of 1.07 g of 4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetic acid in acetonitrile (10 ml) at 0 ° C. was added 0.46 g of thionyl chloride and 0.2 ml of dimethylformamide. The mixture was stirred at the same temperature for 20 minutes, 10 ° C. for 20 minutes, 30 ° C. for 20 minutes, and further at 40 ° C. for 30 minutes. To this was added 1.01 g of N- [5- (3,5-dimethyl-4-nitrophenoxy) -2-nitrophenyl] -N-methylamine and 0.04 g of N, N-dimethylaminopyridine, and the mixture was added at 53 ° C. Stir for 2 hours. The reaction mixture was cooled to 0 ° C., 3N-hydrochloric acid (30 ml) was added, and the mixture was extracted with ethyl acetate (80 ml). The organic layer was washed with 16 ml of saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and then concentrated to dryness to obtain 2.09 g of the desired product as an orange amorphous (yield 99%).
Nuclear magnetic resonance spectrum (Because it is mainly a mixture of two types of rotationally hindered isomers, it is described in a range where distinctive and assignable peaks can be distinguished.) (400 MHz, CDCl ₃ ) δ ppm: 2.33 ( _{s, 6H, Ar-CH 3} ), 3.26 and 3.27 (s, 3H, NCH 3), 8.09 (brm, 1H, CONHCO).

(Example 8)
2- {4-[(2,4-Dioxo-1,3-thiazolidin-5-yl) methyl] phenoxy} -N- (5-methoxy-2-nitrophenyl) -N-methylacetamide (third step) (Exemplary compound number 1)
To a suspension of 8.00 g of 4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetic acid in acetonitrile (64 ml), 3.38 g of thionyl chloride and 3.2 ml of dimethylformamide were added at room temperature. The mixture was stirred at 30 ° C. for 30 minutes and at 40 ° C. for 30 minutes. N- (5-methoxy-2-nitrophenyl) -N-methylamine (3.84 g) and N, N-dimethylaminopyridine (0.32 g) were added thereto, and acetonitrile (16 ml) was further added, followed by stirring at the same temperature for 1 hour. did. The reaction mixture was cooled to 0 ° C., water (32 ml) was added, and the mixture was extracted with ethyl acetate (80 ml). The organic layer was washed twice with 16 ml of saturated aqueous sodium bicarbonate and concentrated to dryness to obtain 9.67 g of the desired product as an orange amorphous (yield 100%).
Nuclear magnetic resonance spectrum (Because it is a mixture of two types of rotationally hindered isomers, the isomers having a large abundance ratio are described in a range that can be distinguished.) (400 MHz, DMSO-d ₆ ) δ ppm: 2.9-3 .1 (m, 2H), 3.2 (s, 3H), 3.91 (s, 3H), 4.36 (d, J = 14.9 Hz, 1H), 4.54 (d, J = 14.9 Hz, 1H), 4.6-4.9 (m, 1H), 4.99 (brs, 1H), 6.76 (d, J = 8.8 Hz, 2H), 7.0- 7.2 (m, 4H), 7.35 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 9.3 Hz, 1H).

Example 9
4- {3-[({4-[(2,4-Dioxo-1,3-thiazolidin-5-yl) methoxy] phenoxy} acetyl) (methyl) amino] -4-nitrophenoxy} -2,6- T-Butyl dimethylphenylcarbamate (third step) (Exemplary Compound No. 210)
To a suspension of 15.00 g of 4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetic acid in acetonitrile (150 ml) at room temperature was added 6.92 g of thionyl chloride and 12.0 ml of dimethylformamide at room temperature. And stirred for 1.5 hours. A solution of N- [5- (4-t-butoxycarbonylamino-3,5-dimethylphenoxy) -2-nitrophenyl] -N-methylamine (20.00 g) in dimethylformamide (60 ml) -acetonitrile (75 ml) was added thereto. In addition, more acetonitrile (35 ml) was added. To this, 2.61 g of N, N-dimethylaminopyridine was added and stirred for 5 hours. Ethyl acetate (300 ml) was poured into the reaction mixture. The organic layer was washed with 100 ml of 20% brine, 100 ml of 5% aqueous sodium bicarbonate, then 100 ml of water, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane = 1: 10 to 2: 1) to obtain 24.44 g of the desired product as yellow crystals (yield 70%).
Nuclear magnetic resonance spectrum (Because it is mainly a mixture of two types of rotationally hindered isomers, it should be described within the range in which distinctive and assignable peaks can be distinguished.) (400 MHz, CDCl ₃ ) δ ppm: 1.52 ( _{brs, 9H, C (CH 3} ) 3), 2.271 and 2.275 (s, 6H, Ar-CH 3), 3.25 (s, 3H, NCH 3), 5.97 (brm, 1H, CONH-Ar), 9.00 (brm, 1H, CONHCO).

(Example 10)
5- [4- (6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione hydrochloride (fourth step)
2- {4-[(2,4-Dioxo-1,3-thiazolidin-5-yl) methyl] phenoxy} -N- (5-methoxy-2-nitrophenyl) -N-methylacetamide 444.7 mg methanol To a solution of (20 ml) -dimethylacetamide (5 ml) was added 0.344 ml of concentrated hydrochloric acid and 244 mg of 10% water-containing palladium on carbon catalyst. The inside of the container was replaced with hydrogen (5 kg / cm ² ) and stirred at 50 ° C. for 3.5 hours. After cooling to room temperature, the reaction mixture was filtered to obtain a pale yellow filtrate. When the filtrate was concentrated to about 5 g, crystals were precipitated. The obtained crystals were filtered off and washed with methanol to obtain 210 mg of the desired product as white crystals (yield 48%).
Nuclear magnetic resonance spectrum (500 MHz, DMSO-d ₆ ) δ: 3.11 (dd, J = 8.9 Hz, J = 14.2 Hz, 1H), 3.34 (dd, J = 4.5 Hz, J = 14.2 Hz, 1H), 3.88 (s, 3H), 3.96 (s, 3H), 4.90 (dd, J = 4.5 Hz, J = 8.9 Hz, 1H) , 5.60 (s, 2H), 7.12 (brm, J = 8.7 Hz, 1H), 7.12 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 12.03 (s, 1H).

(Example 11)
5- (4-{[6- (4-amino-3,5-dimethylphenoxy) -1-methyl-1-H-benzimidazol-2-yl] methoxy} benzyl) -1,3-thiazolidine-2, 4-dione dihydrochloride (4th step)
4- {3-[({4-[(2,4-Dioxo-1,3-thiazolidin-5-yl) methoxy] phenoxy} acetyl) (methyl) amino] -4-nitrophenoxy} -2,6- To a solution of 1.00 g of t-butyl dimethylphenylcarbamate in methanol (10 ml) was added 100 mg of 7.5% palladium carbon and 0.74 g of 38% hydrochloric acid, and the inside of the reaction vessel was replaced with nitrogen and then replaced with hydrogen ( 4 kg / cm ² ). The reaction mixture was stirred at 52 ° C. for 5 hours, cooled to room temperature, and insolubles were filtered off. The insoluble material was washed with methanol (30 ml), and the filtrate and washings were combined and concentrated. Methanol (18 ml) was added to the resulting residue. To this were added 0.62 g of 38% hydrochloric acid and methanol (2 ml), and the mixture was refluxed for 4 hours. After cooling to room temperature, the precipitated crystals were filtered and washed with methanol (5 ml) to obtain 230 mg of the intended product as slightly yellow crystals (yield 26%).
Nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD) δ ppm: 2.40 (s, 6H), 3.19 (dd, J = 8.5 Hz, J = 13.9 Hz, 1H), 3.39 (dd , J = 3.9 Hz, J = 13.9 Hz, 1H), 4.03 (s, 3H), 4.74 (dd, J = 3.9 Hz, J = 8.5 Hz, 1H), 5.71 (s, 2H), 6.91 (s, 2H), 7.15 (d, J = 8.8 Hz, 2H), 7.30 (dd, J = 8.8 Hz, 2H), 7.34 (dd, J = 2.2 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H).

Claims (13)

The following general formula (IIa):

(In the formula, R ¹ represents a nitro group, an amino group or a t-butoxycarbonylamino group.)
A compound represented by The following general formula (III):

[Where:
R ² is a hydrogen atom,
1 to 5 selected from a C ₁ -C ₆ alkyl group optionally substituted with 1 to 5 groups selected from substituent group α, a substituent group α, a C ₁ -C ₆ alkyl group and a halomethyl group five may be substituted with a group C ₃ -C ₆ cycloalkyl,
Substituent group alpha, C ₁ -C ₆ alkyl and halomethyl 1 to 5 substituents phenyl group or substituent group may be substituted with a group selected from group alpha, C ₁ -C ₆ alkyl group and a halomethyl group A 5- or 6-membered heterocyclic group which may be substituted with 1 to 5 groups selected from (the heterocyclic group is 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom) including.)
Indicate

X represents an oxygen atom, a sulfur atom or a nitrogen atom (nitrogen atom, hydrogen atom, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl group, C ₆ -C ₁₀ arylcarbonyl groups, C ₁ -C _And optionally having a substituent selected from the group consisting of a ₆ alkylsulfonyl group and a C ₆ -C ₁₀ arylsulfonyl group.

Substituent group α is
C ₃ -C ₆ cycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₆ -C ₁₀ aryl group, a carboxyl group, formyl group, C ₁ -C ₆ alkylcarbonyl group, C ₆ -C ₁₀ arylcarbonyl group, C ₁ -C ₆ alkyloxycarbonyl group, C ₆ -C ₁₀ aryloxycarbonyl group, a carbamoyl group, N-C ₁ -C ₆ alkylcarbamoyl group, N, N-di-C ₁ -C ₆ alkylcarbamoyl group, a hydroxyl group, C ₁ -C ₆ alkoxy group, C ₆ -C ₁₀ aryloxy group, C ₁ -C ₆ alkylcarbonyloxy group, C ₆ -C ₁₀ arylcarbonyloxy group, an amino group, C ₁ -C ₆ alkylamino group, di C ₁ -C ₆ alkylamino group, C ₆ -C ₁₀ arylamino group, di-C ₆ -C ₁₀ arylamino group, a mercapto group, C ₁ -C ₆ alkylthio group, ₆ -C ₁₀ arylthio group, C ₁ -C ₆ alkylsulfinyl group, C ₆ -C ₁₀ arylsulfinyl group, C ₁ -C ₆ alkylsulfonyl group, C ₆ -C ₁₀ arylsulfonyl group, a sulfonic acid group, a halogen atom, A nitro group and a cyano group are shown. ]
A compound represented by In Claim 2, R ² may be substituted with a C ₁ -C ₆ alkyl group, or 1 to 3 groups selected from a substituent group α, a C ₁ -C ₆ alkyl group and a halomethyl group. A compound which is a good phenyl group (the substituent group α is an amino group, a C ₁ -C ₆ alkylamino group or a halogen atom), and X is an oxygen atom. The following general formula (III):

[Where:
R ² is a hydrogen atom,
1 to 5 selected from a C ₁ -C ₆ alkyl group optionally substituted with 1 to 5 groups selected from substituent group α, a substituent group α, a C ₁ -C ₆ alkyl group and a halomethyl group five may be substituted with a group C ₃ -C ₆ cycloalkyl,
Substituent group alpha, C ₁ -C ₆ alkyl and halomethyl 1 to 5 substituents phenyl group or substituent group may be substituted with a group selected from group alpha, C ₁ -C ₆ alkyl group and a halomethyl group A 5- or 6-membered heterocyclic group which may be substituted with 1 to 5 groups selected from (the heterocyclic group is 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom) including.)
Indicate

X represents an oxygen atom, a sulfur atom or a nitrogen atom (nitrogen atom, hydrogen atom, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl group, C ₆ -C ₁₀ arylcarbonyl groups, C ₁ -C _And optionally having a substituent selected from the group consisting of a ₆ alkylsulfonyl group and a C ₆ -C ₁₀ arylsulfonyl group.

Substituent group α is
C ₃ -C ₆ cycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₆ -C ₁₀ aryl group, a carboxyl group, formyl group, C ₁ -C ₆ alkylcarbonyl group, C ₆ -C ₁₀ arylcarbonyl group, C ₁ -C ₆ alkyloxycarbonyl group, C ₆ -C ₁₀ aryloxycarbonyl group, a carbamoyl group, N-C ₁ -C ₆ alkylcarbamoyl group, N, N-di-C ₁ -C ₆ alkylcarbamoyl group, a hydroxyl group, C ₁ -C ₆ alkoxy group, C ₆ -C ₁₀ aryloxy group, C ₁ -C ₆ alkylcarbonyloxy group, C ₆ -C ₁₀ arylcarbonyloxy group, an amino group, C ₁ -C ₆ alkylamino group, di C ₁ -C ₆ alkylamino group, C ₆ -C ₁₀ arylamino group, di-C ₆ -C ₁₀ arylamino group, a mercapto group, C ₁ -C ₆ alkylthio group, ₆ -C ₁₀ arylthio group, C ₁ -C ₆ alkylsulfinyl group, C ₆ -C ₁₀ arylsulfinyl group, C ₁ -C ₆ alkylsulfonyl group, C ₆ -C ₁₀ arylsulfonyl group, a sulfonic acid group, a halogen atom, A nitro group and a cyano group are shown. ]
After reducing the nitro group of the compound represented by the following general dehydration condensation in the molecule, the following general formula (I):

(Wherein R ² and X are as defined above) and a method for producing a pharmacologically acceptable salt thereof. In claim 4, R ² may be substituted with a C ₁ -C ₆ alkyl group, or 1 to 3 groups selected from a substituent group α, a C ₁ -C ₆ alkyl group and a halomethyl group. A compound which is a good phenyl group (the substituent group α is an amino group, a C ₁ -C ₆ alkylamino group or a halogen atom), and X is an oxygen atom. The following general formula (II):

[Where:
R ² is a hydrogen atom,
1 to 5 selected from a C ₁ -C ₆ alkyl group optionally substituted with 1 to 5 groups selected from substituent group α, a substituent group α, a C ₁ -C ₆ alkyl group and a halomethyl group five may be substituted with a group C ₃ -C ₆ cycloalkyl,
Substituent group alpha, C ₁ -C ₆ alkyl and halomethyl 1 to 5 substituents phenyl group or substituent group may be substituted with a group selected from group alpha, C ₁ -C ₆ alkyl group and a halomethyl group A 5- or 6-membered heterocyclic group which may be substituted with 1 to 5 groups selected from the above (the heterocyclic group is 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom) including.)
Indicate

X represents an oxygen atom, a sulfur atom or a nitrogen atom (nitrogen atom, hydrogen atom, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl group, C ₆ -C ₁₀ arylcarbonyl groups, C ₁ -C _And optionally having a substituent selected from the group consisting of a ₆ alkylsulfonyl group and a C ₆ -C ₁₀ arylsulfonyl group.

Substituent group α is
C ₃ -C ₆ cycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₆ -C ₁₀ aryl group, a carboxyl group, formyl group, C ₁ -C ₆ alkylcarbonyl group, C ₆ -C ₁₀ arylcarbonyl group, C ₁ -C ₆ alkyloxycarbonyl group, C ₆ -C ₁₀ aryloxycarbonyl group, a carbamoyl group, N-C ₁ -C ₆ alkylcarbamoyl group, N, N-di-C ₁ -C ₆ alkylcarbamoyl group, a hydroxyl group, C ₁ -C ₆ alkoxy group, C ₆ -C ₁₀ aryloxy group, C ₁ -C ₆ alkylcarbonyloxy group, C ₆ -C ₁₀ arylcarbonyloxy group, an amino group, C ₁ -C ₆ alkylamino group, di C ₁ -C ₆ alkylamino group, C ₆ -C ₁₀ arylamino group, di-C ₆ -C ₁₀ arylamino group, a mercapto group, C ₁ -C ₆ alkylthio group, ₆ -C ₁₀ arylthio group, C ₁ -C ₆ alkylsulfinyl group, C ₆ -C ₁₀ arylsulfinyl group, C ₁ -C ₆ alkylsulfonyl group, C ₆ -C ₁₀ arylsulfonyl group, a sulfonic acid group, a halogen atom, A nitro group and a cyano group are shown. ]
A compound represented by the following general formula (III), characterized in that 4-[(2,4-dioxothiazolidin-5-yl) methyl] phenoxyacetic acid is condensed:

(Wherein R ² and X are as defined above). According to claim 6, R ² is, C ₁ -C ₆ alkyl group, or a substituent group alpha, be substituted with 1 to 3 groups selected from C ₁ -C ₆ alkyl group and a halomethyl group A production method in which a good phenyl group (the substituent group α is an amino group, a C ₁ -C ₆ alkylamino group or a halogen atom), and X is an oxygen atom. 2,4-Dichloronitrobenzene and methylamine are reacted to produce N- (5-chloro-2-nitrophenyl) -N-methylamine, and N- (5-chloro-2-nitrophenyl) -N- In the presence of a base without isolating methylamine,
Formula ^R 2 -X-H
[Where:
R ² is a hydrogen atom,
1 to 5 selected from a C ₁ -C ₆ alkyl group optionally substituted with 1 to 5 groups selected from substituent group α, a substituent group α, a C ₁ -C ₆ alkyl group and a halomethyl group five may be substituted with a group C ₃ -C ₆ cycloalkyl,
Substituent group alpha, C ₁ -C ₆ alkyl and halomethyl 1 to 5 substituents phenyl group or substituent group may be substituted with a group selected from group alpha, C ₁ -C ₆ alkyl group and a halomethyl group A 5- or 6-membered heterocyclic group which may be substituted with 1 to 5 groups selected from (the heterocyclic group is 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom) including.)
Indicate

X represents an oxygen atom, a sulfur atom or a nitrogen atom (nitrogen atom, hydrogen atom, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl group, C ₆ -C ₁₀ arylcarbonyl groups, C ₁ -C _And optionally having a substituent selected from the group consisting of a ₆ alkylsulfonyl group and a C ₆ -C ₁₀ arylsulfonyl group.

Substituent group α is
C ₃ -C ₆ cycloalkyl group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₆ -C ₁₀ aryl group, a carboxyl group, formyl group, C ₁ -C ₆ alkylcarbonyl group, C ₆ -C ₁₀ arylcarbonyl group, C ₁ -C ₆ alkyloxycarbonyl group, C ₆ -C ₁₀ aryloxycarbonyl group, a carbamoyl group, N-C ₁ -C ₆ alkylcarbamoyl group, N, N-di-C ₁ -C ₆ alkylcarbamoyl group, a hydroxyl group, C ₁ -C ₆ alkoxy group, C ₆ -C ₁₀ aryloxy group, C ₁ -C ₆ alkylcarbonyloxy group, C ₆ -C ₁₀ arylcarbonyloxy group, an amino group, C ₁ -C ₆ alkylamino group, di C ₁ -C ₆ alkylamino group, C ₆ -C ₁₀ arylamino group, di-C ₆ -C ₁₀ arylamino group, a mercapto group, C ₁ -C ₆ alkylthio group, ₆ -C ₁₀ arylthio group, C ₁ -C ₆ alkylsulfinyl group, C ₆ -C ₁₀ arylsulfinyl group, C ₁ -C ₆ alkylsulfonyl group, C ₆ -C ₁₀ arylsulfonyl group, a sulfonic acid group, a halogen atom, A nitro group and a cyano group are shown. ]
A compound represented by the following general formula (II):

(Wherein R ² and X are as defined above). According to claim 8, R ² is, C ₁ -C ₆ alkyl group, or a substituent group alpha, be substituted with 1 to 3 groups selected from C ₁ -C ₆ alkyl group and a halomethyl group A production method in which a good phenyl group (the substituent group α is an amino group, a C ₁ -C ₆ alkylamino group or a halogen atom), and X is an oxygen atom. N- (5-chloro-2-nitrophenyl) -N-methylamine in the presence of a base in an inert solvent is represented by the following general formula (V):

(In the formula, R ¹ represents a nitro group, an amino group or a t-butoxycarbonylamino group.)
A method for producing a compound represented by the general formula (I) according to claim 1, wherein the compound is reacted with the compound represented by the formula:   The method for producing a compound represented by the general formula (I) according to claim 1, wherein the inert solvent is degassed.   The method for producing a compound represented by formula (I) according to claim 1, wherein an antioxidant is added.   The method for producing a compound represented by the general formula (I) according to claim 1, wherein the antioxidant is 2,6-di-t-butyl-4-methylphenol.