JP2000007626A - N-substituted nitroaniline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having production-inhibiting activities of inflammatory cytokine, and useful as an antiinflammatory agent, a therapeutic agent for autoimmune disease against rheumatoid arthritis or the like, or the like. SOLUTION: This new compound is the one of formula I [R1 is a 1-8C alkyl, a 4-8C cycloalkyl or the like; R2 is a 1-15C alkyl, a 3-8C alkenyl or the like; R3 is a (substituted) 1-10C alkyl, phenyl or the like; X is O, S or the like], e.g. 4-cyclohexyloxy-5-geranyl-2-nitroaniline. The compound of formula I is obtained, for example, when X is S, by reacting a compound of formula II (Y1 and Y2 are each a halogen) with an alkyl chlorocarbonate in the presence of a base to provide a carbonic ester compound, nitrating the obtained carbonic ester compound to provide a compound of formula III, hydrolyzing the compound of formula III to provide a compound of formula IV, reacting the compound of formula IV with an alkylating agent in the presence of a base to provide 4-nitrophenyl ether compound, reacting the obtained 4-nitrophenyl ether compound with an alkylamine compound to provide a compound of formula V, and further reacting the compound of formula V with a mercaptan compound in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a therapeutic agent for a disease caused by these cytokines, which has an inhibitory effect on the production of cytokines such as interleukin (IL) -1, IL-5 and IL-6. -Substituted aniline derivatives useful as an agent, a therapeutic agent for autoimmune diseases against rheumatoid arthritis and the like, a therapeutic agent for bone diseases against osteoporosis and the like, and a therapeutic agent for allergic diseases, for example, N-alkyl-4-alkoxy-5-arylthionitroanilines The present invention relates to a compound and a pharmaceutically acceptable salt thereof.

[0002]

2. Description of the Related Art Conventionally, nonsteroidal anti-inflammatory drugs (NSA)
ID) has an action of inhibiting prostaglandin (PG) biosynthesis by inhibiting cyclooxygenase, and is widely used in various inflammatory and painful diseases as its main pharmacological action including antipyretic, analgesic and anti-inflammatory actions. It has been. NSA for rheumatoid arthritis
Immunomodulators (DMARDs) have been used for ID, causal purposes. Osteoporosis is classified into postmenopausal osteoporosis and senile osteoporosis, and the cause of postmenopausal osteoporosis is that postmenopausal estrogen loss excessively promotes bone resorption. As a first-line treatment for postmenopausal osteoporosis, bone resorption inhibitors such as calcitonin and estrogen have been used.

[0003] Therapeutic agents for allergic diseases include, for bronchial asthma, steroids, β2 stimulants, xanthine preparations, and antiallergic agents (formers of chemical mediators such as histamine, thromboxane A ₂ , leukotriene, release inhibitors or antagonists). In the case of allergic rhinitis, antihistamines, antiallergic agents (release inhibitors of chemical mediators such as leukotrienes), steroids, anticholinergic agents, etc. are used. In atopic dermatitis, steroids and nonsteroids are used. External anti-inflammatory agents, antiallergic agents (histamine, thromboxane A ₂ , generation of chemical mediators such as leukotriene, release inhibitors or antagonists) and the like are used.

[0004]

Conventional NSAIDs cause gastrointestinal disorders such as gastric ulcers due to their mechanism of action, and have problems in long-term continuous use. Also, DMA
RD has not yet sufficiently separated the efficacy and side effects. Furthermore,
There are problems that calcitonin used as a therapeutic agent for postmenopausal osteoporosis is limited to administration by intramuscular injection and is liable to become resistant. On the other hand, estrogen has a problem of increasing the incidence of breast cancer and endometrial cancer.
In recent years, active substances collectively called cytokines produced by immunocompetent cells have been found. IL-
1, IL-6, tumor necrosis factor, etc. are called inflammatory cytokines, and various functions as inflammatory mediators, such as activation of arachidonic acid metabolism system which is a metabolic production system of PG, migration of leukocytes, induction of acute phase proteins, etc. It has been elucidated that these inflammatory cytokine production inhibitors are expected to be used as a new-generation anti-inflammatory agent having a different mechanism of action from the past, and as a therapeutic agent for autoimmune diseases against rheumatoid arthritis and the like. Furthermore, IL-1 and IL-6 are also known as osteoclast formation promoting factors, and their production inhibitors are expected as therapeutic agents for postmenopausal osteoporosis.

However, a useful anti-inflammatory agent having an inhibitory action on IL-1 and IL-6 production, a therapeutic agent for an autoimmune disease against rheumatoid arthritis and the like, and a therapeutic agent for a bone disease against osteoporosis and the like have not been found. In allergic diseases, LAR has recently gained importance.
(Late-onset allergic reaction). The main body of LAR is eosinophilic inflammation, and cytokines such as IL-5 produced from T lymphocytes play an important role. Steroids and immunosuppressants are known to have an inhibitory effect on the production of these cytokines, but both drugs have other physiological effects, and steroids have adrenal atrophy, edema,
The occurrence of side effects such as stomach ulcer and full moon face, and the occurrence of side effects such as infectious disease, hepatic / renal disorder, and blood disorder have been problematic with immunosuppressants. Therefore, IL produced from T lymphocytes
Providing a substance that selectively inhibits the production of cytokines such as -5 can be a useful antiallergic agent with reduced side effects seen in steroids and immunosuppressants.

[0006]

Means for Solving the Problems The present inventors have proposed IL-
1. To provide a useful anti-inflammatory agent having a IL-5 or IL-6 production inhibitory effect, a therapeutic agent for an autoimmune disease against rheumatoid arthritis, a therapeutic agent for a bone disease against osteoporosis, and an antiallergic agent. As a result of intensive studies, the following N-substituted aniline derivatives, N-alkyl-4
The present inventors have found that an -alkoxy-5-arylthionitroaniline compound can achieve the object and completed the present invention. That is, the present invention provides a compound of the formula (I)

[0007]

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(Wherein R ¹ is an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 4 to 8 carbon atoms, a phenyl group which may have a substituent, or an N atom and / or An aromatic heterocyclic group having an S atom as a hetero atom,
R ² represents an alkyl group having 1 to 15 carbon atoms, a cycloalkyl group having 4 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, a nitrogen atom, an oxygen atom or a sulfur atom which is the same or different. 1-2 aromatic 5- including one ring or 6-membered ring or the formula _{(2) - (CH 2)} n -A-R 4 (2) ( wherein A is O atom, S atom, an alkoxy group, SO group or the SO ₂ group, R ⁴ is a lower alkyl group, a lower alkoxy group, an optionally substituted phenyl group, a monocyclic or bicyclic aromatic to a cycloalkyl group or N atom and / or S atoms and heteroatoms R ³ represents an alkyl group having 1 to 10 carbon atoms which may have a substituent, a phenyl group, an indolyl group, a methoxy group or a hydroxy group, Or two substituted phenyl groups, amino groups A phenyl group or an alkyl group having 1 to 2 carbon atoms, an alkoxy group having 2 to 6 carbon atoms or an alkyl group having 1 to 10 carbon atoms substituted by a carboxy group, wherein X is an O atom, S Atom, S
N-substituted nitroaniline derivative represented by O group or SO ₂ group).

The present invention relates to a derivative of the above formula (1),
R ¹ represents an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 4 to 8 carbon atoms, and R ² represents a nitrogen atom, an oxygen atom or a sulfur atom, which is the same or different.
The present invention provides an N-substituted nitroaniline derivative which represents an aromatic 5- or 6-membered ring containing 1 to 2 carbon atoms, wherein R ³ is an alkyl group having 1 to 5 carbon atoms which may have a substituent. In the present invention, in the above formula (1), R ^{3 in the} formula (1) representing an alkyl group having 1 to 5 carbon atoms which may have a substituent is a hydroxy group, a dialkylamino group, a C 2 N having at least one selected from up to 6 alkoxycarbonyl groups, phenyl groups or pyridyl groups as a substituent
-To provide substituted nitroaniline derivatives. In the present invention, in the formula (1), R ¹ represents an alkyl group having 1 to 5 carbon atoms or a cycloalkyl group having 4 to 8 carbon atoms, and R ² represents an alkyl group having 1 to 15 carbon atoms. A cycloalkyl group having 4 to 8 carbon atoms or an alkenyl group having 3 to 8 carbon atoms containing 1 or 2 carbon-carbon double bonds, and R ³ may have a substituent Provided is an N-substituted nitroaniline derivative which is an alkyl group having 1 to 10 carbon atoms. In the present invention, in the above formula (1), R ^{3 of the} formula (1) representing an alkyl group having 1 to 10 carbon atoms which may have a substituent is an alkyl group having 1 to 10 carbon atoms, A phenyl group, an indolyl group, a methoxy group or a phenyl group, an aminophenyl group or a 1- or 2-hydroxyl group having the same or different 1 or 2 hydroxyl groups, an alkoxycarbonyl group having 2 to 6 carbon atoms or a carboxyl group; And N-substituted nitroaniline derivatives having at least one selected from the group consisting of: In the present invention, further, in the formula (1), R ¹ represents a phenyl group substituted by 1 or 2 alkyl groups having 1 to 8 carbon atoms or a phenyl group, and R ² and R ³ are the same or different. Provided is an N-substituted nitroaniline derivative which is an alkyl group having 1 to 5 carbon atoms. Further, in the present invention, in the above formula (1), R ¹ is a hydrogen atom, a lower alkyl group or a phenyl group which may have a substituent, a cycloalkyl group, or a single atom having N 2 and / or S as a hetero atom. R ² represents a hydrogen atom, an alkyl group or a cycloalkyl group which may have a substituent, an alkenyl group, or a compound represented by the formula (2)-(CH ₂ ) _n- a-R ⁴ (2) (wherein, a, R ⁴ and n are as defined above) represents a group represented by, R ³ is a lower alkyl group, X is an oxygen atom N- substituted nitroaniline derivative I will provide a. The present invention includes a pharmaceutically acceptable salt of the above-mentioned N-substituted nitroaniline derivative. The present invention further provides a pharmaceutical composition containing an effective amount of the N-substituted nitroaniline derivative.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION As the alkyl group having 1 to 8 carbon atoms for R ¹ , a linear or branched methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, Isobutyl group, n-pentyl group, n-peptyl group,
Examples thereof include an n-octyl group. Examples of the cycloalkyl group having 4 to 8 carbon atoms of R ¹ and R ² include a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. R ¹ and R ⁴
Of the "optionally substituted phenyl group, or an aromatic heterocyclic group having an N atom and / or an S atom as a hetero atom" is a phenyl group, a substituted phenyl group, a cycloalkyl group, a substituted cycloalkyl group, A monocyclic or bicyclic heterocyclic group having N and / or S as a heteroatom, substituted N
And / or all monocyclic or bicyclic heterocyclic groups having S as a heteroatom. Of these, monocyclic or bicyclic heterocyclic groups having N and / or S as a heteroatom include pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, Only one nitrogen atom such as pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, etc.
5- to 6-membered monocyclic heterocyclic group containing 1 to 4 nitrogen and sulfur atoms such as a 5- to 6-membered monocyclic heterocyclic group containing up to 4 nitrogen atoms such as thiazolyl group, isothiazolyl group, thiadiazinyl group and dithiazinyl group. 5 to 6 containing only 1 to 4 sulfur atoms such as a ring group, a thienyl group, a dithiolyl group, a thiopyranyl group, a dithienyl group and a trithienyl group
Preferred are nitrogen-containing bicyclic heterocycles such as a membered monocyclic heterocyclic group, an indolyl group, an isoindolyl group, an imidazolyl group, a benzimidazolyl group, a quinolyl group, an isoquinolyl group, a phthalazinyl group, a cinnolinyl group, a quinazolyl group, and a quinoxalinyl group. Is exemplified.

Examples of the alkyl having 1 to 15 carbon atoms for R ² include an n-decanyl group and an n-dodecanyl group in addition to the alkyl groups exemplified for R ¹ . Examples of the alkenyl group having 2 to 15 carbon atoms of R ² include an ethenyl group, a 1-propenyl group, a 2-propenyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, Methyl-1-propenyl group, 1-methyl-2
-Propenyl group, 2-methyl-1-propenyl group, 2-
Methyl-2-propenyl group, 1-ethylethynyl group, 1
-Pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-1-butenyl group,
1-methyl-2-butenyl group, 1-methyl-3-butenyl group, 2-methyl-1-butenyl group, 2-methyl-2-
Butenyl group, 2-methyl-3-butenyl group, 3-methyl-1-butenyl group, 3-methyl-2-butenyl group, 3-
Methyl-3-butenyl group, 1,1-dimethyl-2-propenyl group, 1,2-dimethyl-1-propenyl group, 1,
2-dimethyl-2-propenyl group, 2-ethyl-2-propenyl group, 1-propylethynyl group, 1-isopropylethynyl group, 1,3-butadienyl group, 1-methylene-3-propenyl group, 1,3- Pentadienyl group, 1,
4-pentadienyl group, 2,4-pentadienyl group, 1
-Methylene-3-butenyl group, 1-methylene-4-butenyl group, 1-methyl-1,3-butadienyl group, 2-methyl-1,3-butadienyl group, 2-methylene-3-butenyl group, 3- Methyl-1,3-butadienyl group, 1-
Methylene-2-methyl-3-propenyl group, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-pentenyl group, 2-pentenyl group, 3 -Pentenyl group, 4-pentenyl group, 3-methyl-1-butenyl group, 2-methyl-
3-butenyl group, 1,1-dimethyl-1-propynyl group, 1,3-butadienyl group, 3-buten-1-enyl group, 1-buten-3-yl group, 1,3-pentadienyl group, 1, 4-pentadienyl group, 2,4-pentadienyl group, 3-penten-1-yl group, 1-pentene-3-
Nyl group, 4-pentene-1-nyl group, 1-pentene-4
-Nyl group, 4-pentene-2-nyl group, 2-pentene-
Examples thereof include a 4-nyl group, a geranyl group, and a farnesyl group. Among them, a geranyl group is mentioned as a preferable group. R
Alkenyl groups having ² to 3 carbon atoms of ² are also included in the above compounds.

The alkoxy group represented by A or R ³ includes
Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-
Pentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, hexyloxy group, isohexyloxy group, 1-methylpentyloxy group, 2-methylpentyloxy group, 3-methyl Pentyloxy group, 1,1-dimethylbutyloxy group,
1,2-dimethylbutyloxy group, 2,2-dimethylbutyloxy group, 1,3-dimethylbutyloxy group, 2,
3-dimethylbutyloxy group, 3,3-dimethylbutyloxy group, 1-ethylbutyloxy group, 2-ethylbutyloxy group, 1,1,2-trimethylpropyloxy group, 1,2,2-trimethylpropoxy group , 1-ethyl-1-methylpropoxy group and 1-ethyl-2-methylpropoxy group. Examples of the aromatic 5- or 6-membered ring containing one or ^two nitrogen atoms, oxygen atoms or sulfur atoms of R ² , which are the same or different, include a thiophene ring, a furan ring, an imidazole ring, an oxazole ring, a thiazole ring,
Examples thereof include a pyridine ring and a pyrimidine ring.

As the alkyl group having 1 to 10 carbon atoms for R ³ , a linear or branched methyl group, ethyl group,
Examples thereof include an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an n-pentyl group, an n-octyl group, and an n-decanyl group. Examples of the indolyl group for R ³ include a 2-indolyl group and a 3-indolyl group. Examples of the phenyl group in which one or two methoxy groups or hydroxyl groups of R ³ are the same or different and are substituted include 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2,3-dimethoxyphenyl group, ,
4-dimethoxyphenyl group, 2,5-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2,3-dihydroxyphenyl group, 2,
4-dihydroxyphenyl group, 2,5-dihydroxyphenyl group, 3,4-dihydroxyphenyl group, 2-hydroxy-3-methoxyphenyl group, 3-hydroxy-2
-Methoxyphenyl group, 4-hydroxy-2-methoxyphenyl group, 2-hydroxy-4-methoxyphenyl group,
Examples thereof include a 3-hydroxy-4-methoxyphenyl group and a 4-hydroxy-3-methoxyphenyl group.

The aminophenyl group for R ³ includes 2-aminophenyl group, 3-aminophenyl group, 4-aminophenyl group, 2,3-diaminophenyl group, 2,4-diaminophenyl group, 2,5- Diaminophenyl group, 3,4
-Diaminophenyl group and the like. Examples of the alkyl group having 1 to 10 carbon atoms substituted by one or two hydroxyl groups of R ³ include a hydroxymethyl group, a hydroxyethyl group, a 3-hydroxypropyl group, a 2-hydroxybutyl group, and a 3-hydroxybutyl group. , 4-hydroxybutyl, 3-hydroxypentyl, 4-hydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 7-hydroxyheptyl, and 10-hydroxydecanyl. The alkyl group having 1 to 5 carbon atoms substituted by the hydroxy group of R ³ is also included in the above exemplified compounds.

The alkyl group having 1 to 10 carbon atoms substituted by the alkoxycarbonyl group having 2 to 6 carbon atoms for R ³ includes methoxycarbonylmethyl, ethoxycarbonylmethyl, n-propoxycarbonylmethyl, n-butoxycarbonylmethyl group, methoxycarbonylethyl group, ethoxycarbonylethyl group, n-propoxycarbonylethyl group, n-butoxycarbonylethyl group, methoxycarbonylpropyl group, ethoxycarbonylpropyl group, n-propoxycarbonylpropyl group, n- Butoxycarbonylpropyl group, methoxycarbonylbutyl group, ethoxycarbonylbutyl group, n-propoxycarbonylbutyl group, n-butoxycarbonylbutyl group, methoxycarbonylpentyl group, methoxycarbonylhexyl group Methoxycarbonyl heptyl group,
Examples thereof include an ethoxycarbonylpentyl group, an ethoxycarbonylhexyl group, and an ethoxycarbonylheptyl group. 1 to 1 carbon atoms substituted by the carboxy group of R ³
Examples of the zero alkyl group include a carboxymethyl group, a carboxyethyl group, a 1-carboxypropyl group, a 1-carboxybutyl group, a 1-carboxypentyl group, a 1-carboxyhexyl group, and a 1-carboxyheptyl group. . Examples of the alkyl group having 1 to 5 carbon atoms substituted by the dialkylamino group of R ³ include a dialkylaminomethyl group, a dialkylaminoethyl group, a 3-dialkylaminopropyl group, a 2-dialkylaminobutyl group,
-Dialkylaminobutyl group, 4-dialkylaminobutyl group, 5-dialkylaminopentyl group and the like,
The dialkylamino group includes, for example, a dimethylamino group,
Examples thereof include a diethylamino group, a di-n-propylamino group, a diisopropylamino group, an N-methylethylamino group, an N-methylisopropylamino group, a pyrrolidino group, a piperidino group, and a morpholino group.

1 carbon atom substituted by the phenyl group of R ³
As the 5 to 5 alkyl groups, a phenylmethyl group, a phenylethyl group, a 3-phenylpropyl group, a 2-phenylbutyl group, a 3-phenylbutyl group, a 4-phenylbutyl group, a 3-phenylpentyl group, a 4-phenyl Examples thereof include a pentyl group and a 5-phenylpentyl group. Examples of the alkyl group having 1 to 5 carbon atoms substituted by the pyridyl group of R ³ include a 2-pyridylmethyl group, a 3-pyridylmethyl group, a 4-pyridylmethyl group, a 2-pyridylethyl group, and a 3-pyridylmethyl group.
-Pyridylethyl group, 4-pyridylethyl group, 3- (2
-Pyridyl) propyl group, 2- (2-pyridyl) propyl group, 1- (2-pyridyl) propyl group, 3- (3-pyridyl) propyl group, 3- (3-pyridyl) propyl group, 3- (4 -Pyridyl) propyl group, 4- (2-pyridyl) butyl group, 4- (3-pyridyl) butyl group, 4-
(4-pyridyl) butyl group, 3- (2-pyridyl) butyl group, 3- (3-pyridyl) butyl group, 3- (4-pyridyl) butyl group, 2- (2-pyridyl) butyl group, 2-
(3-pyridyl) butyl group, 2- (4-pyridyl) butyl group, 5- (2-pyridyl) penbutyl group, 5- (3-
A pyridyl) pentyl group, a 5- (4-pyridyl) pentyl group, a 4- (2-pyridyl) pentyl group, a 4- (3-pyridyl) pentyl group, a 4- (4-pyridyl) pentyl group,
3- (2-pyridyl) pentyl group, 3- (3-pyridyl) pentyl group, 3- (4-pyridyl) pentyl group, 2
-(2-pyridyl) pentyl group, 2- (3-pyridyl)
Examples include a pentyl group and a 2- (4-pyridyl) pentyl group.

The compound (1) of the present invention forms a salt with an acid. Further, depending on the type of the substituent, a salt with a base may be formed. The present invention also includes pharmaceutically acceptable salts of compound (1). Examples of such salts include inorganic salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid. Formic acid, propionic acid, butyric acid, butyric acid, valeric acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid Acid addition salts with organic acids such as, aspartic acid, etc .; inorganic bases such as sodium, potassium, magnesium, calcium, aluminum and the like; methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, monoethanolamine, diethanolamine, triethanolamine Ethanolamine, cyclohexylamine, lysine,
Examples thereof include salts with an organic base such as ornithine and ammonium salts. In addition, the compound of the present invention may be isolated as various solvates such as hydrates and ethanolates and polymorphic substances, and the present invention includes all of these substances.

During [0018] The present invention compounds, those particularly preferred, compounds wherein X is -O-, and the like, especially R ²
Is a hexyl group, an octyl group, or a geranyl group. Among them, preferred compounds include the compounds described in Examples, and particularly preferred examples include the following. (1) 4-cyclohexyloxy-5-geranyl-2
-Nitroaniline or a pharmaceutically acceptable salt thereof,
(2) 4- (2-fluorophenoxy) -5-geranyl-2-nitroaniline or a pharmaceutically acceptable salt thereof, (3) 4- (2,4-difluorophenoxy)-
5-geranyl-2-nitroaniline or a pharmaceutically acceptable salt thereof, (4) 4- (2- (5, 6, 7, 8-
Tetrahydronaphthyl))-5-geranyl-2-nitroaniline or a pharmaceutically acceptable salt thereof.

The compound represented by the formula (1) of the present invention can be produced by the following method. (1) The compound (Ia) of the present invention, wherein X of the compound of the formula (1) is a group represented by -S-, is, for example, a compound represented by the following reaction formula 1
Can be obtained by the method shown in FIG. [Reaction formula 1]

[0020]

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(In the reaction formula 1, R ¹ , R ² and R ³ are as defined above, R ⁵ is an alkyl group having 1 to ⁵ carbon atoms, Y ¹ and Y ² are a fluorine atom, Z represents a chlorine atom, a bromine atom or an iodine atom, and Z represents a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-
It indicates a leaving group such as a toluenesulfonyloxy group. The following is a detailed description of Reaction Scheme 1 in the order of reaction.

(A) Alkyl chlorocarbonate (III) in the presence of a base starting from 2,4-dihalophenol (II)
To give a carbonate compound (IV). Examples of the base used in this reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; sodium hydrogen carbonate; and potassium hydrogen carbonate. Alkali metal bicarbonates such as sodium hydride, alkali metal hydrides such as potassium hydride, inorganic bases such as sodium metal, potassium potassium and sodium amide or triethylamine, diisopropylethylamine, tri-n-butylamine, 1,5- Organic bases such as diazabicyclo [4.3.0] -5-nonene, 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine and N, N-dimethylaminopyridine are mentioned. This reaction can be performed in an inorganic solvent or a solvent. As the solvent used,
Methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, ethyl acetate, N, N -Dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform, carbon tetrachloride, water and the like.

(B) By nitrating the carbonate compound (IV), a 2-nitrobenzene compound (V) can be obtained. As the nitrating agent used in this reaction, acetic acid, fuming nitric acid, sodium nitrate, potassium nitrate,
Examples include iron nitrate and urea nitrate. The solvent used is preferably arbitrarily selected according to the nitrating agent, and is preferably acetic acid, acetic anhydride, trifluoroacetic acid, sulfuric acid, dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, dioxane, ethanol, or n-propanol. , Isopropanol and the like.

(C) The nitrobenzene compound (V) is hydrolyzed to give a nitrophenol compound (VI), which is then reacted with an alkylating agent (VII) in the presence of a base.
4-Nitrophenyl ether compound (VIII) can be obtained. The hydrolysis in this reaction may be an acidic or alkaline hydrolysis reaction of the ester, for example, acidic hydrolysis using hydrochloric acid, sulfuric acid, acetic acid or the like singly or in any combination, lithium hydroxide, sodium hydroxide, potassium hydroxide, Alkaline hydrolysis using lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia and the like can be mentioned. In addition, as the base used in the etherification reaction in this reaction, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, lithium carbonate, sodium carbonate, alkali metal carbonates such as potassium carbonate,
Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal hydrides such as sodium hydride and potassium hydride; inorganic bases such as metal sodium, metal potassium and sodium amide; or triethylamine, diisopropylethylamine, tri-n -Butylamine, 1,5-diazabicyclo [4.3.0]-
5-nonene, 1,8-diazabicyclo [5.4.0]-
Organic bases such as 7-undecene, pyridine, N, N-dimethylaminopyridine and the like can be mentioned. This reaction can be carried out by heating in an inorganic solvent or a solvent at a temperature ranging from room temperature to the boiling point of the reagents and solvents used. As a solvent to be used, methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, n-hexane, cyclohexane,
Benzene, toluene, xylene, chlorobenzene, pyridine, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform,
Examples include carbon tetrachloride and water. In this reaction,
Copper, copper oxide, copper halide, potassium iodide, tris [2- (2-methoxyethoxy) ethyl] amine, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, benzyltriethylammonium chloride, benzyltriethyl The reaction can also be accelerated by optionally adding a quaternary ammonium salt such as ammonium bromide or tricaptyl methyl ammonium chloride, or a crown ether such as 18-crown-6 ether.

(D) An N-alkyl-4-alkoxynitroaniline compound (X) can be obtained by reacting a 4-nitrophenyl ether compound (VIII) with an alkylamine compound (IX). This reaction is preferably performed in the presence of a base. Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, and sodium hydrogen carbonate. An alkali metal bicarbonate such as potassium bicarbonate, sodium hydride, an alkali metal hydride such as potassium hydride, metal sodium, metal potassium, an inorganic base such as sodium amide or triethylamine, diisopropylethylamine, tri-n-butylamine; 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine,
Organic bases such as N, N-dimethylaminopyridine are exemplified. This reaction can be carried out in an inorganic solvent or a solvent by heating at a temperature ranging from room temperature to the boiling point of the reagent or solvent used. As the solvent to be used, methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, n
-Hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, ethyl acetate, N,
N-dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform, carbon tetrachloride, water and the like can be mentioned. Next, the compound (I) of the present invention is reacted by reacting the N-alkyl-4-alkoxynitroaniline compound (X) with the mercaptan compound (XI) in the presence of a base.
a) can be obtained.

Examples of the base in this reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; sodium hydrogen carbonate; Alkali metal bicarbonates such as potassium,
Sodium hydride, alkali metal hydrides such as potassium hydride, metal sodium, metal potassium, inorganic bases such as sodium amide or triethylamine, diisopropylethylamine, tri-n-butylamine, 1,
5-diazabicyclo [4.3.0] -5-nonene, 1,
8-diazabicyclo [5.4.0] -7-undecene,
Organic bases such as pyridine and N, N-dimethylaminopyridine are exemplified.

This reaction can be carried out in an inorganic solvent or a solvent by heating at room temperature to the boiling point of the reagent or solvent to be used. As a solvent to be used, methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, Examples include ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform, carbon tetrachloride, water and the like. (2) Compound (Ia) in which X of compound (I) of the present invention is a group represented by -S- can also be obtained, for example, by the method shown in the following reaction formula 2. [Reaction formula 2]

[0028]

Embedded image

(In the reaction formula 2, R ¹ , R ² , R ³ , Y ¹ , Y ²
And Z are as defined above. The following shows a detailed description of the reaction formula 2 in the order of reaction. (A) A 4-nitrophenyl ether compound (XIV) can be obtained by reacting an alcohol compound (XIII) with 3,4-dihalonitrobenzene (XII) as a starting material in the presence of a base. Examples of the base used in this reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; sodium hydrogen carbonate; and potassium hydrogen carbonate. Alkali metal hydrides such as sodium hydride, potassium hydride, etc .; inorganic bases such as metal sodium, metal potassium, sodium amide; or triethylamine, diisopropylethylamine, tri-n
-Butylamine, 1,5-diazabicyclo [4.3.
0] -5-Nonene, 1,8-diazabicyclo [5.4.
0] -7-undecene, pyridine, N, N-dimethylaminopyridine and the like. The reaction is
It can be performed in an inorganic solvent or a solvent. As a solvent to be used, methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, Examples include ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform, carbon tetrachloride, water and the like. In this reaction,
Copper, copper oxide, copper halide, potassium iodide, tris [2- (2-methoxyethoxy) ethyl] amine, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, benzyltriethylammonium chloride, benzyltriethyl The reaction can also be accelerated by optionally adding a quaternary ammonium salt such as ammonium bromide or tricaptyl methyl ammonium chloride, or a crown ether such as 18-crown-6 ether.

(B) The 4-nitrophenyl ether compound can be obtained by reducing the nitro group of the 4-nitrophenyl ether compound (XIV) to an amino group. Subsequently, the 4-aminophenyl ether compound can be acetylated at the amino group without isolation and purification to obtain an acetanilide compound (XV). The reduction may be a usual reduction method of reducing a nitro group to an amino group, for example, catalytic reduction using palladium-carbon, Raney nickel, platinum or the like as a catalyst, reduction using iron or tin, sodium sulfide-ammonium chloride And reduction using sodium borohydride, lithium aluminum hydride and the like.
The solvent used in this reaction may be arbitrarily selected depending on the reduction method, and is generally methanol, ethanol,
Examples thereof include alcohols such as n-propanol, isopropanol, n-butanol and t-butanol, water, acetic acid, ethyl acetate, dioxane, tetrahydrofuran, acetonitrile and the like. Acetylation may be a conventional method for acetylating aniline, and examples of the acetylating agent include acetic acid, acetyl chloride, acetyl bromide, acetic anhydride and the like. As the solvent used for this reaction, the solvent used for the reduction reaction or ethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, N, N-dimethylformamide, dimethylsulfoxide, dichloroethane, Examples include chloroform, carbon tetrachloride, water, acetic acid, and sulfuric acid.

(C) By nitrating the acetanilide compound (XV), a 2-nitroacetanilide compound (XVI) can be obtained. Examples of the nitrating agent used in this reaction include acetic acid, fuming nitric acid, sodium nitrate, potassium nitrate, iron nitrate, and urea nitrate. The solvent used is preferably arbitrarily selected according to the nitrating agent, and is preferably acetic acid, acetic anhydride, trifluoroacetic acid, sulfuric acid, dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, dioxane, ethanol, or n-propanol. , Isopropanol and the like.

(D) The thioether compound (XVII) can be obtained by reacting the 2-nitroacetanilide compound (XVI) with the mercaptan compound (XI) in the presence of a base. The thioether compound (XVII) can give the nitroaniline compound (XVIII) by continuously hydrolyzing the acetamido group in the reaction system or by hydrolyzing after isolation. Examples of the base used in this reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; sodium hydrogen carbonate; and potassium hydrogen carbonate. Alkali metal bicarbonate, sodium hydride, etc.
Alkali metal hydrides such as potassium hydride; inorganic bases such as sodium metal, potassium metal and sodium amide; or triethylamine, diisopropylethylamine, tri-n-butylamine, 1,5-diazabicyclo [4.3.0] -5-nonene , 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine, N, N-
Organic bases such as dimethylaminopyridine are exemplified. This reaction can be performed in an inorganic solvent or a solvent. Solvents used include methanol, ethanol,
n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, ethyl acetate, N, N-dimethylformamide, Dimethyl sulfoxide, dichloroethane,
Chloroform, carbon tetrachloride, water and the like can be mentioned.

In this reaction, copper, copper oxide, copper halide, potassium iodide, tris [2- (2-methoxyethoxy) ethyl] amine, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide Quaternary ammonium salts such as benzyltriethylammonium chloride, benzyltriethylammonium bromide and tricaptylmethylammonium chloride;
The reaction can be accelerated by optionally adding a crown ether such as 8-crown-6 ether. In addition, hydrolysis is a usual method for hydrolysis of amide under basic conditions or acidic conditions.When hydrolysis is continued in the reaction system, basic conditions are preferable.As the base, for example, lithium hydroxide, Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
Examples include sodium methoxide, sodium ethoxide, potassium t-butoxide and the like. Examples of the acidic condition include a method using an acid such as hydrochloric acid, hydrobromic acid, and sulfuric acid. The solvent used in this reaction is preferably arbitrarily selected depending on the hydrolysis conditions. For example, water, methanol, ethanol, propanol, t-butanol,
Examples thereof include tetrahydrofuran, dioxane, benzene, toluene, xylene, chlorobenzene, N, N-dimethylformamide, dimethylsulfoxide, formic acid, and acetic acid.

(E) The amino group of the nitroaniline compound (XVIII) is alkylated with an alkylating agent R3-Z (XIX) in the presence of a base to give the compound (I) of the present invention.
a) can be obtained. Examples of the base used in this reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate. Alkaline metal hydrides such as sodium hydride, potassium hydride, etc .; inorganic bases such as sodium metal, potassium potassium, sodium amide or the like; or triethylamine, diisopropylethylamine, tri-n-butylamine, 1,5- Diazabicyclo [4.3.0] -5
-Nonene, 1,8-diazabicyclo [5.4.0] -7
Organic bases such as -undecene, pyridine and N, N-dimethylaminopyridine. This reaction can be carried out by heating in an inorganic solvent or a solvent at a temperature ranging from room temperature to the boiling point of the reagents and solvents used. As the solvent used, methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene,
Examples include pyridine, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform, carbon tetrachloride, water and the like. In this reaction, copper, copper oxide, copper halide, potassium iodide, tris [2- (2-methoxyethoxy) ethyl] amine,
Tetra-n-butylammonium chloride, tetra-n
The reaction can be accelerated by optionally adding quaternary ammonium salts such as -butylammonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, tricaptylmethylammonium chloride, and crown ethers such as 18-crown-6 ether. it can.

(3) In the compound of the formula (1) of the present invention, X is S
The compound represented by O or SO ₂ is, for example,
X of the present invention, which can be obtained by the method (1), can be obtained by oxidizing a compound represented by the S group. The oxidation is a normal oxidation reaction of oxidizing sulfide to sulfoxide or sulfone or a normal oxidation reaction of oxidizing sulfoxide to sulfone, such as hydrogen peroxide, t-butyl hydroperoxide, and metachloroperbenzoic acid. , Peracetic acid, sodium metaperiodate, sodium bromite, sodium hypochlorite, periodic iodobenzene and the like. Solvents used in this reaction include methanol, ethanol, n-propanol, isopropanol, dichloromethane, chloroform, carbon tetrachloride, dioxane, tetrahydrofuran, acetone, acetonitrile, ethyl acetate, ethyl ether, petroleum ether, n-hexane, cyclohexane, benzene , Toluene, xylene, chlorobenzene,
Examples include pyridine, N, N-dimethylformamide, water and the like.

Pharmaceutical compositions containing one or more of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient can be used as a carrier or excipient for commonly used pharmaceutical preparations. Tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, etc. are prepared using forms and other additives, and are orally or parenterally administered. . The dose is appropriately determined depending on the individual case in consideration of the symptoms, the age of the administration subject, sex, weight, etc., and is usually 1 to 1000 mg, preferably 50 to 200 mg per day for an adult.
Is orally administered once or several times a day in the range of 1 mg to 500 mg per adult per day.
It is administered intravenously in one to several doses, or is continuously administered intravenously in the range of 1 hour to 24 hours a day. Of course, as mentioned above, the dosage varies under various conditions,
In some cases, lower dosages may be sufficient.

As the solid composition for oral administration of the compound of the present invention, tablets, powders, granules and the like are used.
In such solid products, the one or more active substances comprise at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolodone, metasilicate. , Mixed with magnesium aluminate. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate and a disintegrant such as calcium cellulose glycolate;
Stabilizing agents such as lactose, solubilizing and / or solubilizing agents such as glutamic acid or aspartic acid may be included. The tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, if necessary. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like, and commonly used inert diluents such as purified Contains water and ethanol. The composition may contain, in addition to the inert diluent, solubilizing and / or solubilizing agents, adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, flavoring agents, and preservatives. .
Injections for parenteral administration include sterile aqueous or non-aqueous emulsions, solutions and suspensions. Diluents for aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of diluents for non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name).
Etc. Such compositions may further comprise additives such as tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), solubilizing and / or solubilizing agents. Good. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. These also produce sterile solid compositions,
Before use, it can also be used by dissolving it in sterile water or a sterile solvent for injection.

[0038]

EFFECT OF THE INVENTION The compound (1) of the present invention is IL-1
It is useful as a therapeutic agent for diseases caused by L-5 and IL-6, for example, an anti-inflammatory agent, a therapeutic agent for autoimmune diseases against rheumatoid arthritis, a therapeutic agent for bone diseases against osteoporosis, and an antiallergic agent.

Hereinafter, the present invention will be described more specifically with reference to test examples.

Test Example 1 IL-5 Production Inhibitory Activity [Test Method] The mouse Th2 clone was D10. G4.
One cell (ATCC) was prepared by fetal bovine serum 10%, penicillin 100 U / ml, streptomycin 100 μg / m
1, Sodium hepyruvate 1 mM, L-glutamine 2
The cells were suspended in RPMI-1640 medium (Gibco) supplemented with 0.05 mM mM and β-mercaptoethanol to adjust the cell number to 2 × 10 5 cells / ml. The antigen-presenting cells were obtained by suspending spleen cells of C3 / Hen mouse (8-week-old, female) in RPMI-1640 medium (Gibco),
After incubating with 30 μg / ml of mitomycin C at 37 ° C. for 30 minutes, the cells were washed three times with the above-mentioned medium solution to adjust the cell number to 1 × 10 6 cells / ml. The sample was prepared by dissolving the sample in ethanol and diluting the sample with the above-mentioned medium solution so that the final concentration of ethanol was 0.03%. D10. 100 μl each of cell suspensions of G4.1 cells and antigen-presenting cells, ConA
(Sigma) 10 μl of each of the above medium solutions of 400 μg / ml and the test compound (the compound of the present invention) was added to a V-bottom 96-well plate (manufactured by Nippon Intermed), and 5% C
The cells were cultured in an O2 incubator at 37 ° C for 48 hours. After the culture, IL-5 (pg / ml) was added to the cell supernatant by ELI.
Measurement was performed using an SA kit (ENDOGEN), and the production inhibition rate (%) was calculated (a control in which the concentration of the test compound was adjusted to 0 was used as a control). [Production inhibition rate (%) = (1-T / C) × 100: T is the amount of IL-5 produced at each concentration of the test compound, and C is the amount of IL-5 produced by the control] [Results] The test results are shown in Table 1. Shown in ~ 4

Table 1 IL-5 production inhibitory effect Test compound concentration IL-5 (Production Example No.) (μg / ml) (Production inhibition rate:%) 16 0.1 95 17 0.1 67 18 18 0.3 98 20 0.3 98 21 0.3 90 22 0.3 98 24 0.1 0.1 263 26 0.3 56

Table 2 IL-5 Production Inhibitory Activity Test Compound Concentration IL-5 (Production Example Number) (μg / ml) (Production Inhibition Rate:%) 53 1 100 54 1 65 55 1 51 56 1 92 59 1 85 60 188 61 167 62 62 161 63 171 64 187 65 187 667 66 162 67 159 59 68 1 67 71 180 80 72 1 64

Table 3 IL-5 Production Inhibiting Activity Test Compound Concentration IL-5 (Production Example No.) (μg / ml) (Production Inhibition Rate:%) 73 1 85 76 1 81

Test Example 2 Inhibition of IL-1β and IL-6 Production [Test Method and Results] Human peripheral blood mononuclear cells produce IL-1β and IL-6 by stimulating ConA.
By adding a test compound (compound of the present invention) simultaneously with ConA, IL-1β in the produced cell supernatant was
And IL-6 were measured with an ELISA kit, and the production inhibitory action or production inhibition rate (%) of the test compound was calculated (a control in which the concentration of the test compound was adjusted to 0 was used as a control). [Production inhibition rate (%) = (1-T / C) × 100: T is the amount of IL-1β or IL-6 produced at each concentration of the test compound, and C is the amount of control IL-1β or IL-6 produced] In addition, the compounds of the present invention produced by the methods of Production Examples 17, 21, 24, and 28 exhibited a 35-95% IL-1β production inhibitory action at a concentration of 0.3 μg / ml. In addition, the compounds of the present invention produced by the methods of Production Examples 16, 17, 21, 24, and 28 exhibited an IL-6 production inhibitory effect of 80 to 95% at a concentration of 0.3 µg / ml.
In addition, an inhibitory effect on IL-1β and IL-6 production was observed in all of the test compounds.

Test Example 3 IL-5 Production Inhibitory Activity (PBMC) [Test Method] Heparin-treated normal human peripheral blood was layered on lymphoprep (Daiichi Pharmaceutical) under aseptic conditions to remove red blood cells, and the cells were subjected to bovine fetus Serum 10%, penicillin 100U /
ml, RPMI containing 100 U / ml streptomycin, 10 mM Hepes buffer and 2 mM L-glutamine
Suspension in -1640 medium (Gibco) to increase cell number to 2 ×
It was adjusted to 106 cells / ml. 500 μl of the prepared cell suspension, 2.0 μg of ConA (Sigma) and 250 μl of the above-described medium solution of the test compound (the compound of the present invention) were added to a microplate (24 wells, flat bottom, manufactured by Iwaki Glass Co., Ltd.), and the mixture was placed in a 5% CO 2 incubator. Culture was performed for 48 hours. The medium solution of the sample was prepared by dissolving the sample in ethanol and then diluting with the above-mentioned medium solution so that the final concentration of ethanol became 0.05%. After the culture, the amount of IL-5 (pg / ml) in the cell supernatant was measured with an ELISA kit (Amersham), and the IC50 value (M) was determined from the production inhibition rate (%). The test compound concentration was 3
The concentration of the test compound was adjusted to 0, and the concentration of the test compound was adjusted to 0. The inhibition rate (%) = (1-T / C) × 100: T is the amount of IL-5 produced at each concentration of the test compound, and C is the amount of IL-5 produced by the control].

[0046]

Hereinafter, the present invention will be described more specifically with reference to production examples. Production Example 1 4-methoxy-N-methyl-2-nitro-5- (4-pyridylsulfinyl) aniline 1) 2-chloro-4-fluoro-5-nitroanisole 2-chloro-4-fluorophenol 19.0 g ( 0.
130 mol) and 13.1 g (0.1%) of triethylamine.
130 mol) in ethyl acetate (195 ml) at room temperature in 14.1 g (0.130 mol) of ethyl chlorocarbonate.
Was added, and the mixture was further stirred for 1 hour. Wash the reaction solution (water,
Saturated saline), dried (anhydrous magnesium sulfate) and concentrated under reduced pressure to give 2-chloro- as a colorless oil.
4-fluorophenylethyl carbonate 28.5
g (99%). Then, 28.5 g of 2-chloro-4-fluorophenyl ethyl carbonate (0.13 g
0 mol) in a 30 ml solution of concentrated sulfuric acid.
A mixture of 30 ml of concentrated sulfuric acid and 30 ml of concentrated sulfuric acid were added over 2 hours while maintaining the system temperature at 30 ° C. or lower, and the mixture was further stirred for 2 hours. The reaction solution was poured onto ice (200 g), and the precipitate was collected by filtration.
Washing (water) and drying yielded 22.7 g (95%) of 2-chloro-4-fluoro-5-nitrophenyl ethyl carbonate as pale yellow crystals. 2-chloro-4-fluoro-5-nitrophenyl without purification
A solution of 32.7 g (0.124 mol) of ethyl carbonate in 124 ml of ethyl acetate was added, and 18.6 g (0.273 mol) of a 25% aqueous ammonia solution was added at room temperature, followed by further stirring for 1 hour. 3N hydrochloric acid 100m
The organic layer was washed (saturated brine), dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. A solution of 60 ml of tetrahydrofuran containing the obtained residue was added to a suspension of 124 ml of tetrahydrofuran containing 5.0 g (0.124 mol) of 60% sodium hydride under ice cooling, and then 180 ml of dimethylformamide and 70.4 methyl iodide were added.
g (0.496 mol) was added, and the mixture was heated and stirred at 80 ° C. for 1 hour. After concentrating the reaction solution under reduced pressure to half the volume,
Then, the precipitate was collected by filtration, washed (water), and dried to give 2-chloro-4-fluoro-5-light as pale yellow crystals.
22.2 g (83%) of nitroanisole were obtained. m. p. 71 to 72 ° C (partly recrystallized with chloroform-n-hexane).

2) 5-chloro-4-methoxy-N-methyl-2-nitroaniline 2-chloro-4-fluoro-5-nitroanisole 1
After adding 34 ml (0.438 mol) of a 40% aqueous solution of methylamine at room temperature to a 150 ml solution of dimethylformamide containing 5.0 g (0.0730 mol), the mixture was further stirred for 0.75 hours. 200 ml of water was added to the reaction solution,
The precipitate was collected by filtration, washed (water), dried, and then ethyl acetate-n-
By recrystallizing from hexane, 15.2 g (96%) of 5-chloro-4-methoxy-N-methyl-2-nitroaniline as red-brown crystals was obtained. m. p. 148 to 148.5 ° C

3) 4-methoxy-N-methyl-2-nitro-5- (4-pyridylsulfenyl) aniline 6.6 g of 5-chloro-4-methoxy-N-methyl-2-nitroaniline (0.0305 mol) ) And 5.1 g (0.0457 mol) of 4-mercaptopyridine in an 80 ml solution of dimethylformamide at room temperature was added with a solution of 8 ml of water containing 3.9 g (0.0914 mol) of 95% sodium hydroxide, and then 0.5 hour After stirring, an additional 60
The mixture was heated and stirred at a temperature of 0.5 ° C for 0.5 hour. Bring the reaction to room temperature,
15 ml of 3N hydrochloric acid and then 200 ml of water were added, and the precipitate was collected by filtration, washed (water), dried and then recrystallized from ethyl acetate-n-hexane to give 4-methoxy-N-methyl-2 as reddish-brown crystals. 8.2 g (92%) of -nitro-5- (4-pyridylsulphenyl) aniline were obtained. m. p. 164.5-167 ° C

Production Example 2 N-benzyl-4-methoxy-2-nitro-5- (4-
Pyridylsulfenyl) aniline 1) 5-fluoro-4-methoxy-2-nitroacetanilide 60% sodium hydride 32.0 g (0.801 mo)
After washing l) with n-hexane, 530 ml of methanol
Was added to a methanol solution of sodium methoxide prepared by adding the above under ice-cooling, 85.0 g (0.534 mol) of 3,4-difluoronitrobenzene was added over 0.5 hours, and the mixture was further stirred at room temperature for 2 hours. Water 5
The precipitate was collected by filtration, washed (water), and dried to obtain yellow crystals. Obtained yellow crystals, iron powder 2
A mixture of a 160 ml water solution containing 37.0 g (4.24 mol) and 8.5 g (0.16 mol) of ammonium chloride was heated and stirred at 85 ° C. for 50 minutes. Reaction solution 5
After cooling to 0 ° C., 500 ml of ethyl acetate was added, and insolubles were removed by filtration through celite. Next, 53.6 g (0.53 mol) of triethylamine was added to the filtrate at room temperature, and then 54.1 g (0.53 mol) of acetic anhydride was added over 20 minutes, and the mixture was further stirred for 20 minutes. The reaction solution was washed (in the order of water and saturated saline) and dried (anhydrous magnesium sulfate) to obtain colorless crystals. In a 530 ml solution of acetic acid containing the obtained colorless crystals, 33.4 g of fuming nitric acid (0.
(53 mol) was added over 20 minutes, and the mixture was further stirred for 20 minutes. After cooling the reaction solution to 30 ° C.,
The precipitate was collected by filtration, washed (water), and dried to obtain 104 g (85%) of 5-fluoro-4-methoxy-2-nitroacetanilide as yellow crystals. m. p. 166-168 ° C

2) 4-methoxy-2-nitro-5-
(4-pyridylsulfenyl) aniline 5-fluoro-
53.5 g of 4-methoxy-2-nitroacetanilide
(0.1806 mol) in isopropanol 360
24.1 g of 4-mercaptopyridine (0.2 ml)
167 mol) and 25.9 g of sodium hydroxide (0.
100 ml of an aqueous solution containing
The mixture was heated and stirred at ℃ for 3 hours. After returning the reaction solution to room temperature, 500 ml of water was added, and the precipitate was collected by filtration, washed (water),
By drying, 4-methoxy-2-nitro-5- (4-pyridylsulfenyl) aniline 4 in orange crystals was obtained.
4.8 g (72%) were obtained. m. p. 199-201 ° C

3) N-benzyl-4-methoxy-2-
Nitro-5- (4-pyridylsulfenyl) aniline (compound of the present invention: Preparation Example 2) 0.072 g of 60% sodium hydride (0.0018 m
ol) and 0.25 g (0.0009 mol) of 4-methoxy-2-nitro-5- (4-pyridylsulfenyl) aniline in a 4 ml suspension of tetrahydrofuran containing
Was added and stirred for 1 hour. Then, 0.31 g (0.0018 mol) of benzyl bromide was added.
l) was added and the mixture was further stirred for 4 hours. After the reaction solution was extracted with ethyl acetate, the organic layer was washed (in the order of water and saturated saline), dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. -Hexane / ethyl acetate = 1: 1) and recrystallized from ethyl acetate-n-hexane to give orange-colored N-benzyl-4-methoxy-2-nitro-5- (4-pyridylsulfenyl). ) Aniline 0.0
40 g (12%) were obtained. m. p. 118.5-120 ° C

Preparations 3, 4 Pyridylsulfenyl compounds (compounds of the present invention: Preparations 3, 4) 1) N-alkyl-5-chloro-4-methoxy-2-nitroaniline compound Preparations 1-2) Production Example 1 using 3-picolylamine or ethanolamine instead of methylamine used
The following N-alkyl-5-chloro-4-methoxy-2-nitroaniline compound was obtained by amination according to the method of -2). 5-chloro-4-methoxy-N-2-nitro-N- (3
-Picolyl) aniline m. p. 142.5-143.5 ° C 5-chloro-N- (2-hydroxyethyl) -4-methoxy-2-nitroaniline m. p. 156 to 157.5 ° C

2) Pyridylsulfenyl compound (compound of the present invention: Production Examples 3 and 4) 5-chloro-4-methoxy-N used in Production Example 1-3)
5-chloro-in place of -methyl-2-nitroaniline
4-methoxy-N- (3-picolyl) -2-nitroaniline or 5-chloro-N- (2-hydroxyethyl)
Production Example 1 using -4-methoxy-2-nitroaniline
The following pyridylsulfenyl compound was obtained by thioetherification according to the method of -3). Compound of Production Example 3: 4-methoxy-2-nitro-N-
(3-picolyl) -5- (4-pyridylsulfenyl)
Aniline m. p. 142-143 ° C (recrystallized from ethyl acetate-n-hexane) Compound of Production Example 4: N- (2-hydroxyethyl) -4
-Methoxy-2-nitro-5- (4-pyridylsulphenyl) aniline m. p. 164.5 to 165.5 ° C (chloroform-n
-Recrystallized from hexane)

Production Examples 5 and 6 Pyridylsulfenyl compounds (compounds of the present invention: Production Examples 5 and 6) Instead of 4-mercaptopyridine used in Production Example 3-2), 2-mercaptothiophene or 2-mercaptothiazole was used. The following pyridylsulfenyl compound was obtained by thioetherification according to the method of Production Example 3-2). Compound of Production Example 5: 4-methoxy-2-nitro-N-
(3-picolyl) -5-thiophen-2-ylsulfenyl) aniline m. p. 137-139 ° C (recrystallized from ethyl acetate-n-hexane) Compound of Production Example 6: 4-methoxy-2-nitro-N-
(3-picolyl) -5- (2-thiazolylsulfenyl) aniline m. p. 160-160.5 ° C (recrystallized with ethyl acetate-n-hexane)

Production Example 7 4-Isopropoxy-N-methyl-2-nitro-5-
(4-pyridylsulfenyl) aniline 1) 3-fluoro-4-isopropoxyacetanilide 60% sodium hydride 8.2 g (0.204 mol)
Was washed with n-hexane and then isopropanol 320 m
of isopropoxide solution prepared by adding 1 g of 3,4-difluoronitrobenzene under ice-cooling.
(0.063 mol) was added over 20 minutes, and the mixture was further stirred at room temperature for 2 hours. 320 ml of water is added to the reaction solution, and n
-Extracted with hexane. The organic layer was washed (in the order of water and saturated saline), dried (anhydrous magnesium sulfate), and concentrated under reduced pressure to obtain a yellow oily substance. 45 m of water containing the obtained yellow oily substance, 84.0 g (1.50 mol) of iron powder and 2.4 g (0.166 mol) of ammonium chloride.
The mixture was heated and stirred at 80 ° C. for 40 minutes. After cooling the reaction solution to 50 ° C., isopropanol 150 ml
Was added, and the insoluble material was removed by filtration through Celite. Next, 17.0 g (0.166 mol) of acetic anhydride was added to the filtrate at room temperature.
After the addition over 5 minutes, the mixture was further stirred for 0.5 hour. 400 ml of water was added to the reaction solution, and the precipitate was collected by filtration, washed (water, n
-Hexane in order) and dried to give colorless crystals.
-Fluoro-4-isopropoxyacetanilide 22.
7 g (72.5%) were obtained. m. p. 110 to 111.5 ° C

2) 5-fluoro-4-isopropoxy-2-nitroacetanilide 2-fluoro-4-isopropoxyacetanilide 2
7.1 g (0.112 mol) of fuming nitric acid in a solution of acetic acid containing 2.5 g (0.107 mol) in 110 ml of acetic acid at 60 ° C.
Was added slowly, followed by stirring for 5 minutes. After the reaction solution was cooled to 30 ° C., 110 ml of water was added, and the precipitate was collected by filtration, washed (water) and dried to give 5-fluoro-4-isopropoxy-2-nitroacetanilide 2 as yellow crystals.
3.5 g (86%) were obtained. m. p. 69-70 ° C

3) 4-Isopropoxy-2-nitro-
5- (4-pyridylsulfenyl) aniline 10.0 g (0.039 mol) of 5-fluoro-4-isopropoxy-2-nitroacetanilide, 4.8 g (0.043 mol) of 4-mercaptopyridine and 5.9 g of potassium carbonate (0.043 mol) of a dimethylformamide 110 ml suspension was stirred for 1 hour under ice cooling. 110 ml of water was added to the reaction solution, and the precipitate was collected by filtration, washed (water), and dried to obtain a red-orange crystal, which was treated with 35% acetic acid.
Then, 10 ml of concentrated hydrochloric acid was added, and the mixture was heated and stirred at 100 ° C. for 40 minutes. After returning the reaction solution to room temperature,
35 g of ice and 5.0 g of sodium hydroxide (0.12 mol
120 ml of water containing 1) was added, and the precipitate was collected by filtration, washed (water), and dried to give 4-isopropoxy-2-nitro-5- (4-pyridylsulfenyl) aniline as orange crystals. 9 g (83%) were obtained. m. p. 134.5 to 136 ° C

4) 4-Isopropoxy-N-methyl-
2-nitro-5- (4-pyridylsulfenyl) aniline (compound of the present invention: Production Example 7) 0.51 g of 60% sodium hydride (0.0129 mol)
l) was washed with n-hexane and tetrahydrofuran 5
0 ml was added to form a suspension. At room temperature, 1.5 g (0.0051 mol) of 4-isopropoxy-2-nitro-5- (4-pyridylsulfenyl) aniline was added to the suspension, and the mixture was stirred for 1 hour. 0129
mol), and the mixture was further stirred for 20 hours. Water 1
Then, the precipitate was collected by filtration, washed (water) and dried, and the crude crystals obtained were recrystallized from acetone to give orange-colored 4-isopropoxy-N-methyl-2-nitro- 0.84 g (53%) of 5- (4-pyridylsulphenyl) aniline was obtained. m. p. 130-131 ° C

Production Example 8 4- (1-hexyloxy) -2-nitro-5- (4-
Pyridylsulfenyl) aniline 1) 3-Fluoro-4- (1-hexyloxy) acetanilide n instead of isopropanol used in Production Example 7-1)
-Hexanol was used for etherification according to the method of Production Example 7-1) to give 3-fluoro-4- (1
-Hexyloxy) acetanilide was obtained. m. p. 105.5-107.5 ° C (dichloromethane-
recrystallized from n-hexane).

2) 5-Fluoro-4- (1-hexyloxy) -2-nitroacetanilide In place of 3-fluoro-4-isopropoxyacetanilide used in Production Example 7-2), 3-fluoro-4- ( Using 1-hexyloxy) acetanilide and nitrating it according to the method of Production Example 7-2), 5-fluoro-4-
(1-Hexyloxy) -2-nitroacetanilide was obtained. m. p. 88.5-89 ° C (recrystallized with dichloromethane-n-hexane)

3) 4- (1-hexyloxy) -2-
Nitro-5- (4-pyridylsulfenyl) aniline Instead of 5-fluoro-4-isopropoxy-2-nitroacetanilide used in Production Example 7-3), 5-fluoro-4- (1-hexyloxy)- 4- (1-hexyloxy) was obtained by thioetherification using 2-nitroacetanilide according to the method of Production Example 7-3).
-2-Nitro-5- (4-pyridylsulphenyl) aniline was obtained. m. p. 144.5 to 145.5 ° C (recrystallized with isopropyl alcohol-n-hexane)

4) 4- (1-hexyloxy) -N-
Methyl-2-nitro-5- (4-pyridylsulfenyl) aniline (compound of the present invention: Production Example 8) 4-Isopropoxy-2-nitro-5- (4-pyridyl) used in Production Example 7-4) 4- (1-hexyloxy) -2-nitro- instead of sulfenyl) acetanilide
N-alkylation was performed using 5- (4-pyridylsulfenyl) aniline according to the method of Production Example 7-4) to give 4- (1-hexyloxy) -N-methyl-2.
-Nitro-5- (4-pyridylsulphenyl) aniline was obtained. m. p. 100.5 to 101.5 ° C (ethyl acetate-n-
Recrystallized with hexane)

Production Examples 9 and 10 N-alkyl-4- (1-hexyloxy) -2-nitro-5- (4-pyridylsulfenyl) aniline compound Instead of methyl iodide used in Production Example 8-4) Is subjected to N-alkylation using ethyl iodide or 2-morpholinoethyl chloride according to the method of Production Example 8-4) to give the following N-alkyl-4- (1-hexyloxy) -2- Nitro-5- (4-pyridylsulfenyl)
An aniline compound was obtained. Compound of Production Example 9: N-ethyl-4- (1-hexyloxy) -2-nitro-5- (4-pyridylsulfenyl) aniline NMR (200 MHz, CDCl3) [delta]: 0.88 (3
H, q, J = 7 Hz), 1.09 to 1.48 (9H,
m), 1.52 to 1.75 (2H, m), 3.12 to
3.27 (2H, m), 3.92 (2H, t, J = 6H)
z), 6.77 (1H, s), 7.20 (2H, br)
d, J = 6 Hz), 7.64 (1H, s), 7.86
(1H, brs), 7.85 (2H, brd, J = 6H)
z) Compound of Production Example 10: 4- (1-hexyloxy) -N
-(2-morpholinoethyl) -2-nitro-5- (4-
Pyridylsulfenyl) aniline NMR (200 MHz, CDCl3) δ: 0.83 (3
H, brs), 1.05-1.20 (6H, m), 1.
61 (2H, brs), 2.23 (4H, brs),
2.32 (2H, t, J = 6 Hz), 3.20 (2H, t, J = 6 Hz)
q, J = 6 Hz), 3.75 (4H, brs), 3.9
6 (2H, t, J = 7 Hz), 6.80 (1H, s),
7.19 (2H, brs), 7.66 (1H, s),
8.42 (1H, brs), 8.49 (2H, brs)

Production Example 11 4-Cyclohexyloxy-N-methyl-2-nitro-
5- (4-pyridylsulfenyl) aniline 1) 4-cyclohexyloxy-3-fluoronitrobenzene 60% sodium hydride 37.7 g (0.943 mo
l) in a suspension of 1600 ml of tetrahydrofuran at room temperature at 94.4 g of cyclohexanol (0.943 mol).
l) was added and stirred for 1 hour. Then, 100 g (0.629 mol) of 3,4-difluoronitrobenzene was added to 1.
After the addition over 5 hours, the mixture was further stirred for 2.5 hours. After the reaction solution was extracted with n-hexane, the organic layer was washed (in the order of water and saturated saline), dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. : N-hexane / ethyl acetate = 50: 1) to give 4
125.8 g (84%) of -cyclohexyloxy-3-fluoronitrobenzene were obtained. m. p. 44-45 ° C

2) 4-Cyclohexyloxy-3-fluoroacetanilide 78.9 g (0.330 mol) of 4-cyclohexyloxy-3-fluoronitrobenzene, 82.9 g of iron powder
(1.484 mol) and 5.3 g of ammonium chloride
(0.099 mol) of a mixture of 140 ml of an aqueous solution was heated and stirred at 85 ° C. for 3.5 hours. After the temperature of the reaction solution was returned to room temperature, 200 ml of ethyl acetate was added, and insolubles were removed by filtration through celite. The filtrate is dried (anhydrous magnesium sulfate),
The residue obtained by concentration under reduced pressure was dissolved in 330 ml of isopropanol, and 40.4 g of acetic anhydride was added under ice cooling.
(0.396 mol), and then added at room temperature for 0.5 hour.
Stirred for hours. 500 ml of water was added to the reaction solution, and the precipitate was collected by filtration, and the crude crystals obtained were recrystallized from ethyl acetate-n-hexane to give 61.8 g of colorless crystals of 4-cyclohexyloxy-3-fluoroacetanilide. (7
4.5%). m. p. 123.5-124.5 ° C

3) 4-Cyclohexyloxy-5-fluoro-2-nitroacetanilide Acetic acid containing 54.5 g (0.217 mol) of 4-cyclohexyloxy-3-fluoroacetanilide 220 m
14.3 g of fuming nitric acid (0.227 m
ol) over 15 minutes, followed by stirring for another 5 minutes. After the temperature of the reaction solution was returned to room temperature, 300 ml of water was added, and the crude crystals obtained by filtering the precipitate were recrystallized from ethyl acetate-n-hexane to give 4-cyclohexyloxy-yellow crystals. 58.7 g (92%) of 5-fluoro-2-nitroacetanilide were obtained. m. p. 120-121.5 ° C

4) 4-Cyclohexyloxy-2-nitro-5- (4-pyridylsulfenyl) aniline 53.5 g (0.181 mol) of 4-cyclohexyloxy-5-fluoro-2-nitroacetamylamide, 4-
24.1 g (0.217 mol) of mercapropyridine and 73 ml of a 20% aqueous sodium hydroxide solution (0.43 g)
(3 mol) in 360 ml of isopropyl alcohol was heated and stirred at 60 ° C. for 1 hour. After the reaction solution was returned to room temperature, 500 ml of water was added, and the precipitate was collected by filtration, washed (water), and dried to give orange-colored 4-cyclohexyloxy-2-nitro-5- (4-pyridylsulfenyl). ) 44.8 g (72%) of aniline were obtained. m. p. 87-89 ° C

5) 4-Cyclohexyloxy-N-methyl-2-nitro-5- (4-pyridylsulfenyl)
Aniline (compound of the present invention: Production Example 11) 4-cyclohexyloxy-2-nitro is used instead of 4-isopropoxy-2-nitro-5- (4-pyridylsulfenyl) aniline used in Production Example 7-4) −5- (4
Production Example 7 using (-pyridylsulfenyl) aniline
By N-methylation according to the method of 4), 4
-Cyclohexyloxy-N-methyl-2-nitro-5
-(4-Pyridylsulfenyl) aniline was obtained. m. p. 116 to 117.5 ° C (recrystallized with ethyl acetate-n-hexane)

Production Examples 12 to 15 N-alkyl-4-cyclohexyloxy-2-nitro-5- (4-pyridylsulfenyl) aniline compound (compound of the present invention: Production Examples 12 to 15) Production Example 11-5) By using ethyl iodide, benzyl bromide, (2-bromoethyl) benzene or methyl bromoacetate in place of methyl iodide used in the above, N-alkylation was carried out according to the method of Production Example 11-5). The following N-alkyl-4-cyclohexyloxy-2-nitro-5- (4-pyridylsulfenyl) aniline compound was obtained. Compound of Production Example 12: 4-cyclohexyloxy-N-
Ethyl-2-nitro-5- (4-pyridylsulfenyl) aniline NMR (200 MHz, CDCl3) [delta]: 1.01-1.0
2.08 (10H, m), 1.28 (3H, t, J = 6
Hz), 3.01-3.26 (2H, m), 4.25
(1H, m), 6.00 (1H, s), 7.18-7.
26 (2H, m), 7.70 (1H, s), 7.83
(1H, brs), 8.52 (2H, m) Compound of Production Example 13: N-benzyl-4-cyclohexyloxy-2-nitro-5- (4-pyridylsulfenyl) aniline NMR (200 MHz, CDCl3) [delta] : 1.19-
1.98 (10H, m), 4.28 (1H, m), 4.
34 (2H, d, J = 7 Hz), 6.43 (1H,
s), 7.08 to 7.42 (7H, m), 7.70 (1
H, s), 8.32-8.50 (3H, m) Compound of Preparation 14: 4-cyclohexyloxy-N-
Phenethyl-2-nitro-5- (4-pyridylsulfenyl) aniline NMR (200 MHz, CDCl3) [delta]: 1.18-
1.90 (10H, m), 2.91 (2H, t, J = 7
Hz), 3.38 (2H, q, J = 7 Hz), 4.24
(1H, m), 6.73 (1H, s), 7.06-7.
40 (7H, m), 7.68 (1H, s), 7.98
(1H, brt), 8.47 to 8.58 (2H, m) Compound of Production Example 15: 4-cyclohexyloxy-N-
Methoxycarbonylmethyl-2-nitro-5- (4-pyridylsulphenyl) aniline m. p. 99-101 ° C (recrystallized with chloroform-n-hexane)

Production Example 16 4-methoxy-N-methyl-2-nitro-5- (4-pyridylsulfinyl) aniline 4-methoxy-N-methyl-2- obtained by the method of Production Example 1
Chloroform 2 containing 2.0 g (0.0069 mol) of nitro-5- (4-pyridylsulfenyl) aniline
1.8 g of m-chloroperbenzoic acid in 0 ml solution under ice-cooling
(0.0104 mol) was added slowly, and the mixture was stirred for 1.5 hours. Wash the reaction solution (saturated sodium bicarbonate,
The residue obtained by concentrating under reduced pressure under reduced pressure is dried by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 2: 1). Chloroform-n
By recrystallization from hexane, 4-methoxy-
1.5 g (72%) of N-methyl-2-nitro-5- (4-pyridylsulfinyl) aniline were obtained. m. p. 205-206 ° C

Production Examples 17 to 28 Sulfoxide compounds (compounds of the present invention: Production Examples 17 to 2)
8) The compounds of the present invention obtained by the methods of Production Examples 2 to 4 and 7 to 15 were oxidized according to the method of Production Example 16 to obtain the sulfoxide compounds of the present invention shown in the table.

[0073]

[Table 5]

Production Example 29 4-Methoxy-N-methyl-5-methylthio-2-nitroaniline 1) 5-fluoro-4-methoxy-2-nitroacetanilide 60% sodium hydride 32.0 g (0.801 mol)
After washing l) with n-hexane, 530 ml of methanol
The methoxide solution prepared by adding
85.0 g of 3,4-difluoronitrobenzene (0.5
34 mol) over 0.5 hours, and further added at room temperature for 2 hours.
Stirred for hours. 500 ml of water was added to the reaction solution, and the precipitate was collected by filtration, washed (water), and dried to obtain yellow crystals. The obtained yellow crystals, 237.0 g of iron powder (4.24 m
ol) and 8.5 g of ammonium chloride (0.16 mol
l) containing a mixture of 160 ml of water at 85 ° C.
The mixture was heated and stirred for minutes. After the reaction solution was cooled to 50 ° C., 500 ml of ethyl acetate was added, and insolubles were removed by filtration through celite.
Next, 53.6 g of triethylamine was added to the filtrate at room temperature.
(0.53 mol), and then 54.1 g of acetic anhydride was added.
(0.53 mol) was added over 20 minutes, and the mixture was further stirred for 20 minutes. The reaction solution was washed (in the order of water and saturated saline) and dried (anhydrous magnesium sulfate) to obtain colorless crystals. 33.4 g (0.53 mol) of fuming nitric acid was added to a solution of 530 ml of acetic acid containing the obtained colorless crystals at 60 ° C.
After the addition over 0 minutes, the mixture was further stirred for 20 minutes. After the reaction solution was cooled to 30 ° C., 750 ml of water was added, and the precipitate was collected by filtration, washed (water), and dried to give 104 g (85%) of 5-fluoro-4-methoxy-2-nitroacetanilide as yellow crystals. ) Got. m. p. 166-168 ° C

2) 4-methoxy-5-methylthio-2
-Nitroaniline A 15% aqueous solution of methyl mercaptan in a 50 ml solution of isopropanol containing 3.0 g (0.013 mol) of 5-fluoro-4-methoxy-2-nitroacetanilide 7.
5 ml (0.016 mol) and 3.2 ml of a 20% aqueous sodium hydroxide solution were added, and the mixture was heated with stirring at 60 ° C. for 2 hours. After returning the reaction solution to room temperature, the precipitate was collected by filtration, washed (water), and dried to give 2.9 g of 4-methoxy-5-methylthio-2-nitroaniline (98%) as orange crystals.
%). m. p. 174-176 ° C

3) 4-methoxy-N-methyl-5-methylthio-2-nitroaniline (compound of the present invention: Production Example 29) 0.47 g of 60% sodium hydride (0.0117 mol)
l) was washed with n-hexane and tetrahydrofuran 5
0 ml was added to form a suspension. 4-methoxy- at room temperature
1.0 g of 5-methylthio-2-nitroaniline (0.0
After stirring for 1 hour, methyl iodide was added.
79 g (0.0056 mol) was added, and the mixture was further stirred for 4 hours. 25 ml of water was added to the reaction solution, and the precipitate was collected by filtration, washed (water), and dried.
N-methyl-5-methylthio-2-nitroaniline 0.
92 g (86%) were obtained. m. p. 164.5-167 ° C

Production Examples 30 to 34 Thioether Compounds (Compounds of the Invention: Production Examples 30 to 3
4) 1-propanethiol, 1-hexanethiol, 1-hexane instead of methyl mercaptan used in Production Example 29-2)
Using nonanthiol, 1-dodecanethiol or geranylmercaptan, sulfenylation according to the method of Production Example 29-2), and then N-methylation according to the method of Production Example 29-3) The following thioether compound was obtained. Compound of Production Example 30: 4-methoxy-N-methyl-2-
Nitro-5- (1-propylthio) aniline m. p. 126 to 127 ° C (recrystallized from isopropanol) Compound of Production Example 31: 5- (1-hexylthio) -4-
Methoxy-N-methyl-2-nitroaniline m. p. 101 to 101.5 ° C (recrystallized from isopropanol) Compound of Production Example 32: 4-methoxy-N-methyl-2-
Nitro-5- (1-nonanylthio) aniline m. p. 116.5 to 117.5 ° C (recrystallized from isopropanol) Compound of Production Example 33: 5- (1-dodecanylthio) -4
-Methoxy-N-methyl-2-nitroaniline m. p. 104.5 to 105.5 ° C (recrystallized from isopropanol) Compound of Production Example 34: 5-geranylthio-4-methoxy-N-methyl-2-nitroaniline m. p. 67-68.5 ° C (recrystallized with n-hexane)

Production Example 35 4-methoxy-5-methylthio-2-nitro-N- (2
-Picolyl) aniline 1) 2-chloro-4-fluoro-
19.0 g of 5-nitroanisole 2-chloro-4-fluorophenol (0.
130 mol) and 13.1 g (0.1%) of triethylamine.
130 mol) in ethyl acetate (195 ml) at room temperature in 14.1 g (0.130 mol) of ethyl chlorocarbonate.
Was added, and the mixture was further stirred for 1 hour. Wash the reaction solution (water,
Saturated saline), dried (anhydrous magnesium sulfate) and concentrated under reduced pressure to give 2-chloro- as a colorless oil.
4-fluorophenylethyl carbonate 28.5
g (99%). Then, 28.5 g of 2-chloro-4-fluorophenyl ethyl carbonate (0.13 g
0 mol) in a 30 ml solution of concentrated sulfuric acid.
A mixture of 30 ml of concentrated sulfuric acid and 30 ml of concentrated sulfuric acid were added over 2 hours while maintaining the system temperature at 30 ° C. or lower, and the mixture was further stirred for 2 hours. The reaction solution was poured onto ice (200 g), and the precipitate was collected by filtration.
Washing (water) and drying yielded 22.7 g (95%) of 2-chloro-4-fluoro-5-nitrophenyl ethyl carbonate as pale yellow crystals. 2-chloro-4-fluoro-5-nitrophenyl without purification
A solution of 32.7 g (0.124 mol) of ethyl carbonate in 124 ml of ethyl acetate was added, and 18.6 g (0.273 mol) of a 25% aqueous ammonia solution was added at room temperature, followed by further stirring for 1 hour. 3N hydrochloric acid 100m
The organic layer was washed (saturated brine), dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. A solution of 60 ml of tetrahydrofuran containing the obtained residue was added to a suspension of 124 ml of tetrahydrofuran containing 5.0 g (0.124 mol) of 60% sodium hydride under ice cooling, and then 180 ml of dimethylformamide and 70.4 methyl iodide were added.
g (0.496 mol) was added, and the mixture was heated and stirred at 80 ° C. for 1 hour. After concentrating the reaction solution under reduced pressure to half the volume,
Then, the precipitate was collected by filtration, washed (water), and dried to give 2-chloro-4-fluoro-5-light as pale yellow crystals.
22.2 g (83%) of nitroanisole were obtained. m. p. 71 to 72 ° C (partly recrystallized with chloroform-n-hexane)

2) 5-chloro-4-methoxy-2-nitro-N- (2-picolyl) aniline 2-chloro-4-fluoro-5-nitroanisole,
2.0 g (0.0097 mol) triethylamine
A dimethylformamide 10 ml solution containing 2 g (0.0016 mol) and 1.3 g (0.0117 mol) of 2-picolylamine was stirred at room temperature for 17 hours. 20 ml of water was added to the reaction solution, and the precipitate was collected by filtration, washed (water) and dried, and the obtained crude crystals were recrystallized from ethyl acetate-n-hexane to give 5-chloro-4- red-brown crystals. 2.5 g (87%) of methoxy-2-nitro-N- (2-picolyl) aniline were obtained. m. p. 145 to 146 ° C

3) 4-methoxy-5-methylthio-2
-Nitro-N- (2-picolyl) aniline (compound of the present invention: Production Example 35) According to the method of Production Example 29-3), 5-chloro-4-methoxy-2-nitro-N- (2- By thioetherifying (picolyl) aniline, the compound of the present invention was converted to 4-
Methoxy-5-methylthio-2-nitro-N- (2-picolyl) aniline was obtained. m. p. 133.5 to 135 ° C (recrystallized from ethyl acetate-n-hexane)

Production Examples 36 to 46 Thioether compounds (compounds of the present invention: Production Examples 36 to 4)
6) 1) Amino compound Instead of 2-picolylamine used in Production Example 35-2), 3-picolylamine, 4-picolylamine, (2-pyridyl) ethylamine, 3-indolylethylamine,
3,4-dimethoxybenzylamine, 3,4-dihydroxyphenethylamine, 4-aminobenzylamine, ethanolamine, 3-hydroxypropylamine, 6-
Hydroxypropylamine or 1,3-dihydroxy-
The amino compound shown in Table 6 was obtained by amination using 2-propylamine according to the method of Production Example 35-2).

[0082]

[Table 6]

2) Thioether compounds (compounds of the present invention: Production Examples 36 to 46) The amine compounds shown in Table 7 were thioetherified according to the method of Production Example 35-3) to give the compounds of the present invention shown in Table 7. A thioether compound was obtained.

[0084]

[Table 7]

Production Example 47 N- (2-ethoxycarbonylethyl) -4-methoxy-5-methylthio-2-nitroaniline 1) 2,4-difluoro-5-nitroanisole 2 used in Production Example 35-1) By using 2,4-difluorophenol instead of -chloro-4-fluorophenol and producing according to the method of Production Example 35-1), 2,4-difluoro-5-nitroanisole was obtained. m. p. 94-96 ° C (recrystallized with ethyl acetate-n-hexane)

2) N- (2-ethoxycarbonylethyl) -5-fluoro-4-methoxy-2-nitroaniline 2-chloro-4-fluoro- used in Production Example 35-2)
2,4-difluoro- in place of 5-nitroanisole
By amination using 5-nitroanisole according to the method of Production Example 35-2), N- (2-ethoxycarbonylethyl) -5-fluoro-4-methoxy-
2-Nitroaniline was obtained. m. p. 77-79 ° C

3) N- (2-ethoxycarbonylethyl) -4-methoxy-5-methylthio-2-nitroaniline (compound of the present invention: Production Example 47) -(2-ethoxycarbonylethyl) -5-fluoro-4-methoxy-2
Thioetherification of -nitroaniline to give N- (2-ethoxycarbonylethyl) of the compound of the present invention.
4-Methoxy-5-methylthio-2-nitroaniline was obtained. m. p. 96-97.5 ° C (recrystallized with ethyl acetate)

Production Example 48 N- (2-carboxyethyl) -4-methoxy-5-methylthio-2-nitroaniline (compound of the present invention: Production Example 48) Compound of the present invention obtained by the method of Production Example 47 N- (2
-Ethoxycarbonylethyl) -4-methoxy-5-methylthio-2-nitroaniline 0.55 g (0.001
5 ml of a 1 N aqueous sodium hydroxide solution was added to a 7.5 ml solution of 2: 1 tetrahydrofuran-ethanol containing 75 mol) at room temperature, followed by stirring for 0.5 hour. After adding 2 ml of 3N hydrochloric acid to the reaction solution and extracting with ethyl acetate, the organic layer was washed (in order of water and saturated saline), dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The obtained residue is chloroform-
By recrystallizing with n-hexane, N- (2-carboxyethyl) -4 which is a compound of the present invention in the form of orange crystals is obtained.
-Methoxy-5-methylthio-2-nitroaniline
48 g (96%) were obtained. m. p. 161-12.5 ° C

Production Examples 49 to 51 Thioether Compounds (Compounds of the Invention: Production Examples 49 to 5
1) 1) 4-Alkoxy-5-fluoro-2-nitroacetanilide compound Using ethanol, n-propanol or isopropanol instead of methanol used in Production Example 29-1), and following the method of Production Example 29-1) To give the following 4-alkoxy-5-fluoro-2
-A nitroacetanilide compound was obtained. 4-ethoxy-5-fluoro-2-nitroacetanilide m. p. 121.5-122.5 ° C 5-fluoro-2-nitro-4-propoxyacetanilide m. p. 111-113 ° C 5-fluoro-4-isopropoxy-2-nitroacetanilide m. p. 69-70 ° C

2) Thioether compound 4-ethoxy-5-method according to the method of Production Example 29-2)
Fluoro-2-nitroacetanilide, 5-fluoro-
2-nitro-4-propoxyacetanilide or 5-
The following thioether compound was obtained by thioetherifying fluoro-4-isopropoxy-2-nitroacetanilide. 4-ethoxy-5-methylthio-2-nitroaniline m. p. 155-156.5 ° C 5-Methylthio-2-nitro-4-propoxyaniline m. p. 150-151.5 ° C 4-isopropoxy-5-methylthio-2-nitroaniline m. p. 134.5 to 136 ° C

3) 4-Alkoxy-N-methyl-5
Methylthio-2-nitroaniline compound (compound of the present invention: Production Examples 49, 50, and 51) 4-ethoxy-5 according to the method of Production Example 29-3)
Methylthio-2-nitroaniline, 5-methylthio-2
-Nitro-4-propoxyaniline or 4-isopropoxy-5-methylthio-2-nitroaniline is N-methylated to give the following compound of the present invention:
-Alkoxy-N-methyl-5-methylthio-2-nitroaniline compound was obtained. Compound of Production Example 49: 4-ethoxy-N-methyl-5-
Methylthio-2-nitroaniline m. p. 170 to 171.5 ° C (recrystallized from acetone) Compound of Production Example 50: N-methyl-5-methylthio-2
-Nitro-4-propoxyaniline m. p. 116-118 ° C (recrystallized from acetone) Compound of Production Example 51: 4-isopropoxy-N-methyl-5-methylthio-2-nitroaniline m. p. 113.5-116 ° C (recrystallized with acetone)

Production Example 52 N-benzyl-4-cyclohexyloxy-5-cyclohexylthio-2-nitroaniline (compound of the present invention:
Production Example 52) 1) 4-7.7 g of 4-cyclohexyloxy-3-fluoronitrobenzene 60% sodium hydride (0.943 mo)
l) in a suspension of 1600 ml of tetrahydrofuran at room temperature at 94.4 g of cyclohexanol (0.943 mol).
l) was added and stirred for 1 hour. Then, 100 g (0.629 mol) of 3,4-difluoronitrobenzene was added to 1.
After the addition over 5 hours, the mixture was further stirred for 2.5 hours. After the reaction solution was extracted with n-hexane, the organic layer was washed (in the order of water and saturated saline), dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. : N-hexane / ethyl acetate = 50: 1) to give 4
125.8 g (84%) of -cyclohexyloxy-3-fluoronitrobenzene were obtained. m. p. 44-45 ° C

2) 4-Cyclohexyloxy-3-fluoroacetanilide 78.9 g (0.330 mol) of 4-cyclohexyloxy-3-fluoronitrobenzene, 82.9 g of iron powder
(1.484 mol) and 5.3 g of ammonium chloride
(0.099 mol) of a mixture of 140 ml of an aqueous solution was heated and stirred at 85 ° C. for 3.5 hours. After the temperature of the reaction solution was returned to room temperature, 200 ml of ethyl acetate was added, and insolubles were removed by filtration through celite. The filtrate is dried (anhydrous magnesium sulfate),
The residue obtained by concentration under reduced pressure was dissolved in 330 ml of isopropanol, and 40.4 g of acetic anhydride was added under ice cooling.
(0.396 mol), and then added at room temperature for 0.5 hour.
Stirred for hours. 500 ml of water was added to the reaction solution, and the precipitate was collected by filtration, and the crude crystals obtained were recrystallized from ethyl acetate-n-hexane to give 61.8 g of 4-cyclohexyloxy-3-fluoroacetanilide as colorless crystals ( 7
4.5%). m. p. 123.5-124.5 ° C

3) 4-Cyclohexyloxy-5-fluoro-2-nitroacetanilide Acetic acid containing 54.5 g (0.217 mol) of 4-cyclohexyloxy-3-fluoroacetanilide 220 m
14.3 g of fuming nitric acid (0.227 m
ol) over 15 minutes, followed by stirring for another 5 minutes. After the reaction solution was returned to room temperature, 300 ml of water was added, and the precipitate was collected by filtration. The crude crystals obtained were recrystallized from ethyl acetate-n-hexane to give yellow crystals.
58.7 g (92%) of -cyclohexyloxy-5-fluoro-2-nitroacetanilide were obtained. m. p. 120-121.5 ° C

4) 4-Cyclohexyloxy-5-cyclohexylthio-2-nitroaniline Using cyclohexanethiol in place of methylmercaptan used in Production Example 29-2), according to the method of Production Example 1-2) By thioetherification, 4-cyclohexyloxy-5-cyclohexylthio-2-nitroaniline was obtained. m. p. 118-119 ° C (recrystallized from petroleum ether-n-hexane)

5) N-benzyl-4-cyclohexyloxy-5-cyclohexylthio-2-nitroaniline (compound of the present invention: Preparation Example 52) Instead of methyl iodide used in Preparation Example 29-3), bromide is used. Using benzyl and N- according to the method of Production Example 1-3)
By benzylation, the compound of the present invention, N-
Benzyl-4-cyclohexyloxy-5-cyclohexylthio-2-nitroaniline was obtained. m. p. 118.5-120 ° C (recrystallized with ethyl acetate-n-hexane)

Production Example 53 4-methoxy-N-methyl-5-methylthio-2-nitroaniline 4-methoxy-N-methyl-5 obtained by the method of Production Example 29
-Methylthio-2-nitroaniline 0.26 g (0.0
0.21 g (0.0014 mol) of m-chloroperbenzoic acid in a 20 ml solution of chloroform containing 0.11 mol) under ice-cooling.
After l) was gradually added, the mixture was stirred for 2 hours. The reaction solution is washed (saturated sodium hydrogen carbonate, water, and saturated saline in this order), dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. The residue obtained is recrystallized with acetone to give orange crystals of the present invention. 0.20 g of 4-methoxy-N-methyl-5-methylthio-2-nitroaniline which is a compound of
(74%). m. p. 181 to 181.5 ° C

Production Examples 54 to 72 Sulfoxide compounds (compounds of the present invention: Production Examples 54 to 7)
2) Production Examples 30 to 33, 35, 36, 38 to 46, and 48 to
The compound of the present invention obtained by the method of No. 51 was oxidized according to the method of Production Example 54 to obtain a sulfoxide compound of the present invention shown in Table 4.

[0099]

[Table 8]

Production Example 73 4- (2-isopropylphenoxy) -5-methylthio-2-nitroaniline 1) 3-Fluoro-4- (2-isopropylphenoxy) nitrobenzene phenol was hydroxylated with 25.0 g (0.183 mol). Water 370 containing 7.3 g (0.183 mol) of sodium
18. ml solution and 3,4-difluoronitrobenzene
5 g (0.122 mol) was added in order, and the mixture was heated under reflux for 2.5 hours. The reaction solution was returned to room temperature and extracted with toluene.
The organic layer was washed (5% aqueous sodium hydroxide solution, water, and saturated saline in this order), dried (anhydrous magnesium sulfate), concentrated under reduced pressure, and 3-fluoro-4- (2-isopropylphenoxy) nitrobenzene as a brown oily substance was obtained. 30.3g (90
%). NMR (200 MHz, CDCl3) δ: 1.26 (6H, d, J = 6 Hz), 2.95 (1H,
m), 6.94 (1H, t, J = 10Hz), 7.00 (2H, m), 7.28 (2H, m), 7.95 (1
H, m), 8.08 (1H, dd, J = 2,10Hz)

2) 3-Fluoro-4- (2-isopropylphenoxy) acetanilide 30.0 g (0.109 mol) of 3-fluoro-4- (2-isopropylphenoxy) nitrobenzene, iron powder 3
A mixture of 33 ml of an aqueous solution containing 6.5 g (0.654 mol) and 1.8 g (0.033 mol) of ammonium chloride was heated and stirred at 85 ° C. for 0.5 hour. After the temperature of the reaction solution was returned to room temperature, 110 ml of isopropanol was added, and insolubles were removed by filtration through celite. Acetic anhydride 1 was added to the filtrate at room temperature.
After gradually adding 2.2 g (0.120 mol), the mixture was further stirred for 10 minutes. 400 ml of water was added to the reaction solution, and the precipitate was collected by filtration, washed (in the order of water and n-hexane), and 3-fluoro-4- (2-isopropylphenoxy) as colorless crystals.
27.5 g (88%) of acetanilide were obtained. m. p124.5. ~ 126 ° C

3) 5-Fluoro-4- (2-isopropylphenoxy) -2-nitroacetanilide 60% was added to a 90 ml solution of acetic acid containing 26.5 g (0.092 mol) of 3-fluoro-4- (2-isopropylphenoxy) acetanilide. Nitric acid 6.1 with heating and stirring at ℃
g (0.097 mol) was gradually added, and the mixture was further stirred for 0.5 hour. The reaction solution was returned to room temperature, 270 ml of water was added,
Extracted with ethyl acetate. The organic layer is washed (a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline), dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. Ethyl acetate-n-
By recrystallizing from hexane, 26.5 g (87%) of 5-fluoro-4- (2-isopropylphenoxy) -2-nitroacetanilide as yellow crystals was obtained. m. p. 79-80 ° C

4) 4- (2-isopropylphenoxy)
-5-Methylthio-2-nitroaniline A 20% aqueous sodium hydroxide solution 4.0 ml (0 ml) was added to a 30 ml suspension of isopropyl alcohol containing 3.0 g (0.00902 mol) of 5-fluoro-2-nitro-4-phenoxyacetanilide. 0.0199 mol) and 15%
6.8 ml of an aqueous solution of sodium methyl mercaptan (0.
[00992 mol), and the mixture was heated and stirred at 60 ° C for 2 hours. The reaction solution was returned to room temperature, water was added, and the precipitate was collected by filtration.
The obtained crystal was recrystallized from chloroform-n-hexane to give orange-colored 4- (2-isopropylphenoxy) -5-methylthio-2-nitroaniline 1.5.
g (51%) were obtained. m. p. 131 ~ 132.5 ° C

5) 4- (2-isopropylphenoxy) -N-methyl-5-methylthio-2-nitroaniline (compound of the present invention) 0.16 g of 60% sodium hydride (0.0039 mol)
l) was washed with n-hexane and tetrahydrofuran 20
To the resulting suspension was added 0.50 g (0.0016 mol) of 4- (2-isopropylphenoxy) -5-fluoro-2-nitroacetanilide at room temperature. After stirring for 1 hour, 0.37 g of methyl iodide was added. (0.0019 mol)
Was added and the mixture was further stirred for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed (saturated brine), dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-n-hexane. By doing
This gave 0.37 g (71%) of 4- (2-isopropylphenoxy) -N-methyl-5-methylthio-2-nitroaniline, a compound of the present invention, as orange crystals. m. p. 147.5-148.5 ° C

Production Example 74 4- (2,4-Di-t-amylphenoxy) -N-methyl-5-methylthio-2-nitroaniline 1) 4- (2,4-di-t-amylphenoxy)- 3
-Fluoronitrobenzene 60% sodium hydride 4.3 g (0.107 mol)
To a suspension of 160 ml of tetrahydrofuran containing
Di-t-amylphenol 25.0 g (0.071 mol)
l), and the mixture was stirred for 30 minutes, and 11.3 g (0.107 mol) of 3,4-difluoronitrobenzene was added.
Stirred for hours. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with toluene. The organic layer was washed (5% aqueous sodium hydroxide solution, water, and saturated saline) and dried (anhydrous magnesium sulfate). The organic layer was concentrated under reduced pressure, and silica gel column chromatography (eluent: n-hexane / acetic acid) By purifying with ethyl = 30: 1), 4-yellow oil was obtained.
21.7 g (82%) of (2,4-di-t-amylphenoxy) -3-fluoronitrobenzene were obtained. NMR (200 MHz, CDCl3) δ: 0.68 (6H, dd, J = 8, 15 Hz), 1.30 (6H,
s), 1.33 (6H, s), 1.55-1.80 (4H, m), 6.79 (1H, d, J = 8Hz), 6.
91 (1H, dd, J = 8,10Hz), 7.17 (1H, dd, J = 2,8Hz), 7.35 (1H, d, J
= 2Hz), 7.97 (1H, m), 8.09 (1H, dd, J = 2,10Hz).

2) 4- (2,4-Di-t-amylphenoxy) -3-fluoroacetanilide 21.3 g (0.0057 mol) of 4- (2,4-di-t-amylphenoxy) -3-fluoronitrobenzene ), Iron powder 19.9g
(0.3422 mol) and 0.9 g of ammonium chloride
(0.0171 mol) of a mixture of 17 ml of an aqueous solution was heated and stirred at 85 ° C. for 20 minutes. After the temperature of the reaction solution was returned to room temperature, 90 ml of isopropanol was added, and insolubles were removed by filtration through celite. 6.4 g of acetic anhydride (0.0627 m
ol) was slowly added, followed by stirring at room temperature for 10 minutes. 200 ml of water was added to the reaction solution, isopropanol was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 4: 1 to 1: 2) to give 4- (2) as a yellow oil. , 4-di-t-
Amylphenoxy) -3-fluoroacetanilide 2
0.9 g (95%) was obtained. NMR (200 MHz, CDCl3) δ: 0.68 (6H, dt, J = 1, 6 Hz), 1.26 (6H,
s), 1.39 (6H, s), 1.60 (2H, q, J = 1,6Hz), 1.85 (2H, q, J = 6Hz),
2.17 (3H, s), 6.60 (1H, d, J = 10Hz), 6.88 (1H, dd, J = 10,10H
z), 7.03 (1H, dd, J = 2,10Hz), 7.08 (1H, m), 7.26 (1H, d, J = 2H
z), 7.55 (1H, dd, J = 2, 12Hz), 7.60 (1H, broad).

3) 4- (2,4-Di-t-amylphenoxy) -5-fluoro-2-nitroacetanilide Using 4- (2,4-di-t-amylphenoxy) -3-fluoroacetanilide, Nitration was carried out according to the method of Production Example 73-3) to give 4- (yellow oil).
(2,4-Di-t-amylphenoxy) -5-fluoro-2-nitroacetanilide was obtained [purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 15: 1)]. NMR (200 MHz, CDCl3) δ: 0.68 (3H, t, J = 6 Hz), 0.69 (3H, t, J = 6
Hz), 1.29 (6H, s), 1.35 (6H, s), 1.63 (2H, q, J = 6Hz), 1.80 (2
H, q, J = 6Hz), 2.30 (3H, s), 6.67 (1H, d, J = 8Hz), 7.10 (1H, dd,
J = 2,8Hz), 7.32 (1H, d, J = 2Hz), 7.80 (1H, m, J = 8Hz), 8.75 (1
H, d, J = 12Hz), 10.38 (1H, broad).

4) 4- (2,4-Di-t-amylphenoxy) -5-methylthio-2-nitroaniline 4- (2,4-di-t-amylphenoxy) -5-fluoro-2-nitro Production Example 73- Using acetanilide
By thioetherification according to the method of 4),
Orange crystalline 4- (2,4-di-t-amylphenoxy)
-5-Methylthio-2-nitroaniline was obtained. m. p. 146 to 147.5 ° C (recrystallization solvent: diethyl ether-n-hexane).

5) 4- (2,4-Di-t-amylphenoxy) -N-methyl-5-methylthio-2-nitroaniline (compound of the present invention) 4- (2,4-di-t-amyl) Production Example 73-5) using phenoxy) -5-methylthio-2-nitroaniline
N-methylation according to the method of 4- (2,4-di-t-amylphenoxy) -N-methyl-5-methylthio-2-nitroaniline which is a compound of the present invention in the form of orange crystals I got m. p. 129.5 to 130 ° C (recrystallized from ethyl acetate-n-hexane).

Production Example 75 4- (2-isopropylphenoxy) -N-methyl-5
-Methylsulfinyl-2-nitroaniline (compound of the present invention) 4- (2) which is the compound of the present invention obtained by the method of Production Example 73
-Isopropylphenoxy) -N-methyl-5-methylthio-2-nitroaniline 0.15 g (0.0004 m
ol) and 0.08 g (0.0005 mol) of m-chloroperbenzoic acid was added to a solution of 10 ml of chloroform containing ice and stirred for 2 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed (a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline in this order), dried (anhydrous magnesium sulfate), and concentrated under reduced pressure. Ethyl-n-
By recrystallization from hexane, 0.08 g (54%) of 4- (2-isopropylphenoxy) -N-methyl-5-methylsulfinyl-2-nitroaniline was obtained. m. p. 193-194 ° C

Production Example 76 N-methyl-5-methylsulfinyl-2-nitro-4
-(2-Phenylphenoxy) aniline 1) 3-Fluoro-4- (2-phenylphenoxy) nitrobenzene Production Example 73 using 2-phenylphenol instead of 2-isopropylphenol used in Production Example 73-1).
-1) by etherification according to the method
-Fluoro-4- (2-phenylphenoxy) nitrobenzene was obtained. m. p. 73.5-75 ° C

2) 3-Fluoro-4- (2-phenylphenoxy) acetanilide 3-fluoro-4- (2-phenylphenyloxy) nitrobenzene was reduced with the nitro group according to the method of Preparation Example 73-2). By acetylation, 3-fluoro-4- (2-phenylphenoxy) acetanilide was obtained. m. p. 174 to 175 ° C (recrystallized with ethyl acetate-n-hexane)

3) 5-Fluoro-2-nitro-4-
(2-Phenylphenoxy) acetanilide 3-fluoro-4- (2-phenylphenoxy) acetanilide was nitrated according to the method of Production Example 73-3) to give 5-fluoro-2-nitro-4- ( 2
-Phenylphenoxy) acetanilide was obtained. m. p. 89 to 90.5 ° C (recrystallized with ethyl acetate-n-hexane)

4) 5-Methylthio-2-nitro-4-
(2-phenylphenoxy) aniline 3-fluoro-2
-Nitro-4- (2-phenylphenoxy) acetanilide was thioetherified according to the method of Production Example 73-4) to give 5-methylthio-2-nitro-4-.
(2-Phenylphenoxy) aniline was obtained. m. p. 184.5-185.5 ° C (recrystallized with isopropanol)

5) 5-Methylsulfinyl-2-nitro-4- (2-phenylphenoxy) aniline 3-methylthio-2-nitro-4- (2-phenylphenoxy) aniline was prepared according to the method of Production Example 3. By oxidation, 5-methylsulfinyl-2-nitro-4
-(2-Phenylphenoxy) aniline was obtained. m. p. 195.5-196.5 ° C (recrystallized with acetone)

6) N-methyl-5-methylsulfinyl-2-nitro-4- (2-phenylphenoxy) aniline (compound of the present invention) 3-methylsulfinyl-2-nitro-4- (2-phenylphenoxy) The compound of the present invention, N-methyl-5-methylsulfinyl-2-nitro-4- (2-phenylphenoxy) aniline, is obtained by N-methylating aniline according to the method of Production Example 73-5). I got m. p. 133-134 ° C (recrystallized with ethyl acetate-n-hexane)

Reference Example 1 4-cyclohexyloxy-5
-Fluoro-2-nitroacetanilide (M-20) a) 4-Cyclohexyloxy-3-fluoronitrobenzene 94 g of cyclohexanol was added to a 1.3 L suspension of tetrahydrofuran containing 37 g of 60% sodium hydride,
Stirred at room temperature for 1 hour. Then, 100 g of 3,4-difluoronitrobenzene was added over 3 hours under ice cooling, and the mixture was stirred at the same temperature for 3.5 hours and at room temperature for 12 hours. 3N hydrochloric acid was added to the reaction solution, and extracted with n-hexane. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate,
The extract was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 50: 1) to obtain 79 g (52%) of 4-cyclohexyloxy-3-fluoronitrobenzene as yellow crystals. . Melting point: 44-45 ° C

B) 4-Cyclohexyloxy-3-fluoronitroanilide A mixture of 100 g of an aqueous solution containing 79 g of 4-cyclohexyloxy-3-fluoronitrobenzene, 83 g of iron powder and 5.3 g of ammonium chloride was heated at 85 ° C. for 3.5 hours. Stirred. After returning the reaction solution to room temperature, ethyl acetate 20 was added.
The insoluble matter to which 0 ml was added was filtered off through celite. The filtrate was dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The obtained residue is dissolved in 330 ml of isopropyl alcohol,
Under ice cooling, 40 g of acetic anhydride was added, and the mixture was stirred at room temperature for 30 minutes. 500 ml of water was added to the reaction solution, and the precipitate was collected by filtration.
The obtained crystals were recrystallized from ethyl acetate-n-hexane to give colorless crystals of 4-cyclohexyloxy-3.
-62 g (75%) of fluoroacetanilide were obtained. Melting point: 123.5-124.5 ° C

C) 4-Cyclohexyloxy-5-fluoro-2-nitroanilide In a 220 ml solution of acetic acid containing 54.5 g of 4-cyclohexyloxy-3-fluoroacetanilide was added 14 g of nitric acid under heating and stirring at 60 ° C. for 15 minutes. The mixture was stirred for 5 minutes. The reaction solution was returned to room temperature, 300 ml of water was added, and the precipitate was collected by filtration. The obtained crude crystals were recrystallized from ethyl acetate-n-hexane to give 59 g (92%) of colorless crystals of 4-cyclohexyloxy-5-fluoro-2-nitroacetanilide. Melting point: 120-121.5 ° C

Reference Example 2 5-Fluoro-2-nitro-4
-(2-phenylphenyloxy) acetanilide a) 3-Fluoro-4- (2-phenylphenyloxy) nitrobenzene Substituted with cyclohexanol used in Reference Example 1-a), 2-phenylphenol was used. By etherification according to the method of a), 3-fluoro-
4- (2-Phenylphenyloxy) nitrobenzene was obtained. Melting point: 73.5-75 ° C

B) 3-Fluoro-4- (2-phenylphenyloxy) acetanilide A 3-fluoro-4- (2-phenylphenyloxy) nitrobenzene is reduced to a nitro group according to the method of Reference Example 1-b). The resulting crude crystals were recrystallized from ethyl acetate-n-hexane to give 3-fluoro-4- (2-phenylphenyloxy) acetanilide. Melting point: 174-175 ° C

C) 5-Fluoro-2-nitro-4-
(2-Phenylphenyloxy) acetanilide 3-Fluoro-4- (2-phenylphenyloxy) acetanilide was nitrated according to the method of Reference Example 1-c), and the obtained crude crystals were subjected to ethyl acetate-n-hexane. By recrystallizing with 5-fluoro-2-nitro-4-
(2-Phenylphenyloxy) acetanilide was obtained. Melting point: 89-90.5 ° C

Reference Example 3 4- (2-isopropylphenyloxy) -5-fluoro-2-nitroacetanilide a) 4- (2-isopropylphenyloxy) -3-
4- (2-isopropylphenyloxy) was obtained by etherifying fluoronitrobenzene using 2-isopropylphenol in place of cyclohexanol used in Reference Example 1-a) according to the method of Reference Example 1-a).
-3-Fluoronitrobenzene was obtained. Nuclear magnetic resonance spectrum (CDCl3, TMS internal standard) δ: 1.21 (6H, d, J = 6 Hz), 3.15 (1H, m), 6.83 (1H, dd, J = 10, 10H)
z), 6.90 ~ 7.00 (1H, m), 7.18 ~ 7.30 (2H, m), 7.40 (1H, m), 7.
94 (1H, m), 8.10 (1H, dd, J = 2,10Hz)

B) 4- (2-isopropylphenyloxy) -3-fluoroacetanilide 4- (2-isopropylphenyloxy) -3-fluoronitrobenzene is reduced with a nitro group according to the method of Reference Example 1-b). The resulting crude crystals were recrystallized from toluene-n-hexane to give 4- (2-isopropylphenyloxy) -3-fluoroacetanilide. Melting point: 84.5-86 ° C

C) 4- (2-Isopropylphenyloxy) -5-fluoro-2-nitroacetanilide 4- (2-isopropylphenyloxy) -3-fluoroacetanilide was prepared according to the method of Reference Example 1-c). By nitration, 4- (2-isopropylphenyloxy) -5-fluoro-2-nitroacetanilide was obtained. Nuclear magnetic resonance spectrum (CDCl3, TMS internal standard) δ: 1.25 (6H, d, J = 6 Hz), 2.30 (3H, s), 3.26 (1H, m), 6.81 (1H,
m), 7.19 (2H, m), 7.38 (1H, m), 7.74 (1H, d, J = 6Hz), 8.77 (1H,
(d, J = 12Hz)

Reference Example 4 5-Fluoro-2-nitro-4
-(5,6,7,8-Tetrahydronaphthalene-2-
Yloxy) acetanilide a) 3-Fluoro-4- (5,6,7,8-tetrahydronaphthalen-2-yloxy) nitrobenzene Instead of cyclohexanol used in Reference Example 1-a), 2-hydroxy-5,6, 3-fluoro-4- (5,6,7,
8-Tetrahydronaphthalen-2-yloxy) nitrobenzene was obtained. Melting point: 71-72 ° C

B) 3-Fluoro-4- (5,6,7,8
-Tetrahydronaphthalen-2-yloxy) acetanilide 3-fluoro-4- (5,6,7,8-tetrahydronaphthalen-2-yloxy) nitrobenzene Reference Example 1
The nitro group is reduced and acetylated according to the method of -b), and the obtained crude crystals are recrystallized from ethyl acetate-n-hexane to give 3-fluoro-4- (5,6,7,
8-Tetrahydronaphthalen-2-yloxy) acetanilide was obtained. Melting point: 164-166C

C) 5-Fluoro-2-nitro-4-
(5,6,7,8-Tetrahydronaphthalen-2-yloxy) acetanilide Reference Example 1 is based on 3-fluoro-4- (5,6,7,8-tetrahydronaphthalen-2-yloxy) acetanilide.
-Nitrogenation according to the method of -c), and the resulting crude crystals were recrystallized from diethyl ether-n-hexane to give 5-fluoro-2-nitro-4- (5,6,7,8
-Tetrahydronaphthalen-2-yloxy) anilide was obtained. Melting point: 105-107 ° C

Reference Example 5 4- (2,4-difluorophenyloxy) -5-fluoro-2-nitroacetanilide a) 4- (2,4-difluorophenyloxy) -3-
4- (2,4-fluoronitrobenzene) was converted to 4- (2,4- Difluorophenyloxy) -3-fluoronitrobenzene was obtained. Melting point: 40.5-41.5 ° C

B) 4- (2,4-Difluorophenyloxy) -3-fluoroacetanilide 4- (2,4-difluorophenyloxy) -3-fluoronitrobenzene was prepared according to the method of Reference Example 1-b). The nitro group was reduced and acetylated, and the resulting crude crystals were recrystallized from dichloromethane-n-hexane to give 4
-(2,4-Difluorophenyloxy) -3-fluoroacetanilide was obtained. Melting point: 117-118 ° C

C) 4- (2,4-Difluorophenyloxy) -5-fluoro-2-nitroacetanilide Using 4- (2,4-difluorophenyloxy) -3-fluoroacetanilide as in Reference Example 1-c) The resulting crude crystals were recrystallized from dichloromethane-n-hexane to give 4- (2,4-difluorophenyloxy) -5-fluoro-2-nitroacetanilide. Melting point: 130.5-132 ° C

Reference Example 6 5-Fluoro-2-nitro-4
-(5,6,7,8-Tetrahydronaphthalen-1-yloxy) acetanilide a) 3-Fluoro-4- (5,6,7,8-tetrahydronaphthalen-1-yloxy) nitrobenzene Reference Example 1-a) Instead of the cyclohexanol used in
By using 1-hydroxy-5,6,7,8-tetrahydronaphthalene and performing etherification according to the method of Reference Example 1-a), 3-fluoro-4- (5,6,7,
8-Tetrahydronaphthalen-1-yloxy) nitrobenzene was obtained. Melting point: 59.5-60.5 ° C

B) 3-Fluoro-4- (5,6,7,
8-Tetrahydronaphthalen-1-yloxy) acetanilide Reference Example 1 using 3-fluoro-4- (5,6,7,8-tetrahydronaphthalen-1-yloxy) nitrobenzene
The nitro group is reduced and acetylated according to the method of -b), and the obtained crude crystals are recrystallized from dichloromethane-n-hexane to give 3-fluoro-4- (5,6,
7,8-Tetrahydronaphthalen-1-yloxy) acetanilide was obtained. Melting point: 131-132 ° C

C) 5-Fluoro-2-nitro-4-
(5,6,7,8-Tetrahydronaphthalen-1-yloxy) acetanilide Reference Example 1 is based on 3-fluoro-4- (5,6,7,8-tetrahydronaphthalen-1-yloxy) acetanilide.
-Nitrogenation according to the method of -c), and the resulting crude crystals were recrystallized from dichloromethane-n-hexane to give 5-fluoro-2-nitro-4- (5,6,7,8
-Tetrahydronaphthalen-1-yloxy) anilide was obtained. Melting point: 123.5-124.5 ° C

Reference Example 7 4- (2-Fluorophenyloxy) -5-fluoro-2-nitroacetanilide a) 4- (2-Fluorophenyloxy) -3-fluoronitrobenzene Cyclo used in Reference Example 1-a) 4- (2-fluorophenyloxy) -3-fluoronitrobenzene was obtained by etherification using 2-fluorophenol in place of hexanol according to the method of Reference Example 1-a). Nuclear magnetic resonance spectrum (CDCl3, TMS internal standard) δ: 6.87 (1H, m), 7.10-7.40 (4H, m), 7.97 (1H, m), 8.08 (1H, d
(d, J = 2,10Hz)

B) 4- (2-Fluorophenyloxy) -3-fluoroacetanilide The nitro group of 4- (2-fluorophenyloxy) -3-fluoronitrobenzene was reduced according to the method of Reference Example 1-b). The crude crystals obtained were recrystallized from dichloromethane-n-hexane to give 4- (2
-Fluorophenyloxy) -3-fluoroacetanilide was obtained. Melting point: 110.5-112 ° C

C) 4- (2-Fluorophenyloxy) -5-fluoro-2-nitroacetanilide 4- (2-fluorophenyloxy) -3-fluoroacetanilide was prepared according to the method of Reference Example 1-c). Nitration was performed, and the obtained crude crystals were recrystallized from ethyl acetate-n-hexane to obtain 4- (2-fluorophenyloxy) -5-fluoro-2-nitroacetanilide. Melting point: 146-147 ° C

Reference Example 8 4- (2-benzoylphenoxy) -5-fluoro-2-nitroacetanilide a) 4- (2-benzoylphenoxy) -3-fluoronitrobenzene 130 ml of tetrahydrofuran containing 5.0 g of 60% sodium hydride Add 2-benzoylphenol 25 to the suspension.
After stirring for 20 minutes, 13.4 g of 3,4-difluoronitrobenzene was added, and the mixture was concentrated under reduced pressure. 1.3 g of tris [2- (2-methoxyethoxy) ethyl] amine was added to the obtained residue, and the mixture was heated and stirred at 110 ° C. for 1.5 hours. The reaction solution was returned to room temperature, 35 ml of 3N hydrochloric acid was added, and the mixture was extracted with toluene. The organic layer was washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (developing solvent: n-hexane).
26 g (93%) of 4- (2-benzoylphenoxy) -3-fluoronitrobenzene as a yellow oil were obtained. Nuclear magnetic resonance spectrum (CDCl3, TMS internal standard) δ: 6.92 (1H, dd, J = 8,10Hz), 7.12 (1H, dd, J = 1,8Hz), 7.35-
7.50 (3H, m), 7.51-7.67 (3H, m), 7.72-7.82 (2H, m), 7.88
~ 8.00 (2H, m)

B) 4- (2-benzoylphenoxy)
-3-Fluoroacetanilide Using 21 g of 4- (2-benzoylphenoxy) -3-fluoronitrobenzene, reduction and acetylation were carried out according to the method of Reference Example 1-b), and the obtained crude crystals were ethyl acetate-n- By recrystallizing with hexane, colorless crystals 4
26 g (93%) of-(2-benzoylphenoxy) -3-fluoroacetanilide were obtained. Melting point: 111-112.5 ° C

C) 4- (2-benzoylphenoxy)
Nitration according to the method of Reference Example 1-c) using 19 g of -5-fluoro-2-nitroacetanilide 4- (2-benzoylphenoxy) -3-fluoroacetanilide, and the obtained crude crystals were separated into isopropanol-
By recrystallizing from n-hexane, 12 g (53%) of 4- (2-benzoylphenoxy) -5-fluoro-2-nitroacetanilide was obtained. Melting point: 100-101.5 ° C

Reference Example 9 4- (2,4-di-t-amylphenoxy) -5-fluoro-2-nitroacetanilide a) 4- (2,4-di-t-amylphenoxy) -3
-Fluoronitrobenzene 25.0 g (71 mmol) of 2,4-di-t-amylphenol was added to a suspension of 160 ml of tetrahydrofuran containing 4.3 g (107 mmol) of 60% sodium hydride, and stirred for 30 minutes.
11.4 g of 3,4-difluoronitrobenzene (107
mmol) and stirred for 3 hours. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with toluene. The organic layer was washed with a 5% aqueous sodium hydroxide solution, water and saturated saline, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = Purification by 30: 1) yielded 22 g (82%) of 4- (2,4-di-t-amylphenoxy) -3-fluoronitrobenzene as a yellow oil. Nuclear magnetic resonance spectrum (CDCl3, TMS internal standard) δ: 0.68 (6H, dd, J = 8, 15 Hz), 1.30 (6H, s), 1.33 (6H, s), 1.55
~ 1.80 (4H, m), 6.79 (1H, d, J = 8Hz), 6.91 (1H, dd, J = 8,10H
z), 7.17 (1H, dd, J = 2,8Hz), 7.35 (1H, d, J = 2Hz), 7.97 (1H,
m), 8.09 (1H, dd, J = 2,10Hz)

B) 4- (2,4-di-t-amylphenoxy) -3-fluoroacetanilide 21 g (5.7 mmol) of 4- (2,4-di-t-amylphenoxy) -3-fluoronitrobenzene Iron powder 2
0 g (342 mmol) and 0.9 g of ammonium chloride
A mixture of 17 ml of an aqueous solution containing
The mixture was heated with stirring at 20 ° C for 20 minutes. After the temperature of the reaction solution was returned to room temperature, 90 ml of isopropanol was added, and insolubles were removed by filtration through celite. After gradually adding 6.4 g (63 mmol) of acetic anhydride to the filtrate, the mixture was stirred at room temperature for 10 minutes. Water 20
0 ml was added, isopropanol was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 4: 1 to 1: 2) to give 4- (2,4-diethyl) as a yellow oil. -T-Amylphenoxy) -3-fluoroacetanilide 21 g (95%) was obtained. Nuclear magnetic resonance spectrum (CDCl3, TMS internal standard) δ: 0.68 (6H, dt, J = 1, 6 Hz), 1.26 (6H, s), 1.39 (6H, s), 1.60
(2H, q, J = 1,6Hz), 1.85 (2H, q, J = 6Hz), 2.17 (3H, s), 6.60 (1
H, d, J = 10Hz), 6.88 (1H, t, J = 10Hz), 7.03 (1H, dd, J = 2,10H
z), 7.08 (1H, m), 7.26 (1H, d, J = 2Hz), 7.55 (1H, dd, J = 2,12H
z), 7.60 (1H, br)

C) 4- (2,4-Di-t-amylphenoxy) -5-fluoro-2-nitroacetanilide Using 4- (2,4-di-t-amylphenoxy) -3-fluoroacetanilide, By nitration according to the method of Reference Example 1-c), yellow oily 4- (2,2) was obtained.
4-di-t-amylphenoxy) -5-fluoro-2-
Nitroacetanilide was obtained [silica gel column chromatography (developing solvent: n-hexane / ethyl acetate =
15: 1). Nuclear magnetic resonance spectrum (CDCl3, TMS internal standard) δ: 0.68 (3H, t, J = 6 Hz), 0.69 (3H, t, J = 6 Hz), 1.29 (6H, s), 1.
35 (6H, s), 1.63 (2H, q, J = 6Hz), 1.80 (2H, q, J = 6Hz), 2.30 (3
H, s), 6.67 (1H, d, J = 8Hz), 7.10 (1H, dd, J = 2,8Hz), 7.32 (1H,
d, J = 2Hz), 7.80 (1H, m, J = 8Hz), 8.75 (1H, d, J = 12Hz), 10.38
(1H, br)

Reference Example 10 5-Fluoro-4- (1-hexyloxy) -2-nitroacetanilide a) 3-Fluoro-4- (1-hexyloxy) acetanilide 5.3% (0.13 mol) of 60% sodium hydride ) Was washed with n-hexane, and tetrahydrofuran 130
ml and then 13.5 g of n-hexanol to the n-hexanoxide solution prepared under ice-cooling.
17.6 g of 4-difluoronitrobenzene (0.11 m
ol) over 30 minutes and further stirred at room temperature overnight. Water was added to the reaction solution, and extracted with n-hexane. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a yellow oily substance. A mixture of the obtained yellow oily substance, 18 g of water containing 25 g of iron powder and 1 g of ammonium chloride was heated and stirred at 85 ° C. for 15 minutes. After cooling the reaction solution to 50 ° C,
30 ml of isopropanol was added, and insolubles were removed by filtration through Celite. Then, 6.9 g of acetic anhydride was added to the filtrate at room temperature.
After adding over a period of minutes, the mixture was further stirred for 0.5 hour. 100 ml of water was added to the reaction solution, and the precipitate was collected by filtration, water and then n-
After washing with hexane and drying, 3 colorless crystals are obtained.
14 g (86%) of -fluoro-4- (1-hexasiloxy) acetanilide were obtained. Melting point: 105.5-107.5 ° C

B) 5-Fluoro-4- (1-hexyloxy) -2-nitroacetanilide Instead of 3-fluoro-4-cyclohexyloxyacetanilide used in Reference Example 1-c), 3-fluoro-4- ( Nitration was performed using 1-hexyloxy) acetanilide according to the method of Reference Example 1-c), and the obtained crude crystals were recrystallized from dichloromethane-n-hexane to give 5-fluoro-4- (1 15 g (93%) of -hexyloxy) -2-nitroacetanilide were obtained. Melting point: 88.5-89C

Reference Example 11 5-Fluoro-4-methoxy-2-nitroacetanilide 5-fluoro-4-methoxy-2-nitroacetanilide 60% sodium hydride 32 g (0.8 mol) was added to n-
After washing with hexane, 85 g (0.5 mol) of 3,4-difluoronitrobenzene was added to a methoxide solution prepared by adding 530 ml of methanol under ice cooling.
It was added over 5 hours, and further stirred at room temperature for 2 hours. 500 ml of water was added to the reaction solution, and the precipitate was collected by filtration, washed with water,
Drying yielded yellow crystals. A mixture of the obtained yellow crystals, 237 g (4.2 mol) of iron powder and 8.5 g (0.16 mol) of ammonium chloride in 160 ml of water was heated and stirred at 85 ° C. for 50 minutes. After the reaction solution was cooled to 50 ° C., 500 ml of ethyl acetate was added, and insolubles were removed by filtration through celite. Next, 53.6 g (0.53 mol) of triethylamine was added to the filtrate at room temperature, and then 54 g (0.53 mol) of acetic anhydride was added over 20 minutes, and the mixture was further stirred for 20 minutes. The reaction solution was washed with water and saturated saline, and dried over anhydrous magnesium sulfate to obtain colorless crystals. 33.4 g of fuming nitric acid was added to a 530 ml solution of acetic acid containing the obtained colorless crystals at 60 ° C.
(0.53 mol) over 20 minutes and then 2 more minutes.
Stirred for 0 minutes. After cooling the reaction solution to 30 ° C.,
50 ml was added, and the precipitate was collected by filtration, washed with water, and dried to give 5-fluoro-4-methoxy- yellow crystals.
104 g (85%) of 2-nitroacetanilide were obtained. Melting point: 166-168 ° C

Reference Example 12 4-methoxy-N-methyl-
2-Nitro-5- (4-pyridylthio) aniline a) 2-chloro-4-fluoro-5-nitroanisole 19 g of 2-chloro-4-fluorophenol (0.13
mol) and 13 g of triethylamine (0.13 mol
After adding 14 g (0.13 mol) of ethyl chlorocarbonate to a 195 ml solution of ethyl acetate containing l) at room temperature, the mixture was further stirred for 1 hour. The reaction solution was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 29 g (99%) of 2-chloro-4-fluorophenylethyl carbonate as a colorless oily substance. Was. Then, 30 ml of 70% nitric acid and 30 ml of concentrated sulfuric acid were added to a 30 ml solution of concentrated sulfuric acid containing 29 g (0.13 mol) of 2-chloro-4-fluorophenylethyl carbonate.
The mixture was added over 2 hours while maintaining the temperature inside the system at 30 ° C. or lower, followed by stirring for 2 hours. The reaction solution was placed on ice (2
00g), and the precipitate was collected by filtration, washed with water, and dried to give 2-chloro-4-fluoro-5-nitrophenylethyl carbonate 33 as pale yellow crystals.
g (95%). 2-chloro-4 without purification
-Fluoro-5-nitrophenyl ethyl carbonate (32.7 g, 0.12 mol) in ethyl acetate (124 ml)
After the solution was prepared, 19 g of a 25% aqueous ammonia solution was added at room temperature.
(0.27 mol), and the mixture was further stirred for 1 hour. 100 ml of 3N hydrochloric acid was added to the reaction solution, and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of 60 ml of tetrahydrofuran containing the obtained residue was added to a suspension of 124 ml of tetrahydrofuran containing 5 g (0.12 mol) of 60% sodium hydride under ice-cooling, and then 180 ml of dimethylformamide and 70.4 g of methyl iodide (0 And the mixture was heated and stirred at 80 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure to half the volume, 500 ml of water was added, and the precipitate was collected by filtration and washed with water.
Drying yielded 22 g (83%) of 2-chloro-4-fluoro-5-nitroanisole as pale yellow crystals. Melting point:. 71 to 72 ° C (partly recrystallized with chloroform-n-hexane)

B) 5-chloro-4-methoxy-N-methyl-2-nitroaniline 2-chloro-4-fluoro-5-nitroanisole 15
g (0.07 mol) containing dimethylformamide 15
0mM solution at room temperature with 40% methylamine aqueous solution 34m
After adding 1 (0.44 mol), the mixture was further stirred for 1 hour. 200 ml of water was added to the reaction solution, and the precipitate was collected by filtration, washed with water, dried, and recrystallized from ethyl acetate-n-hexane to give 5-chloro-4-methoxy-N-methyl as red-brown crystals. -2-Nitroaniline 15 g (96
%). Melting point:. 148 to 148.5 ° C

C) 4-methoxy-N-methyl-2-nitro-5- (4-pyridylthio) aniline 6.6 g (31 mmol) of 5-chloro-4-methoxy-N-methyl-2-nitroaniline and 4- An 80 ml solution of dimethylformamide containing 5.1 g (46 mmol) of mercaptopyridine was added at room temperature with a solution of 8 ml of water containing 3.9 g (91 mmol) of 95% sodium hydroxide, and the mixture was stirred for 0.5 hour. For 0.5 hour. The reaction solution is returned to room temperature and 3N hydrochloric acid 15m
Then, 200 ml of water was added, and the precipitate was collected by filtration, washed with water, dried and recrystallized from ethyl acetate-n-hexane to give 4-methoxy-N-methyl-red-brown crystals.
2-nitro-5- (4-pyridylthio) aniline 8.2
g (92%). Melting point:. 164.5-167 ° C

Production Example 77 4-Cyclohexyloxy-
5.0 g of 5-fluoro-2-nitroacetanilide
(16.9 mmol) and sodium hydride 0.8 g (20.3 mmo)
l) was suspended in 7 ml of geraniol,
The mixture was refluxed under heating for an hour. After cooling, dilute with ethyl acetate,
The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (elution solvent: n-hexane: ethyl acetate = 10: 1), and recrystallized from ethyl acetate-n-hexane to give 4-cyclohexyloxy-5-geranyloxy. 2.1 g (32%) of -2-nitroaniline were obtained. Melting point: 111.0-112.0 Mass spectrometry value (m / z): 388 (M +)

Production Example 78 4-Cyclohexyloxy-
1 g of 5-fluoro-2-nitroacetanilide (3.4 mmo
l), 0.4 g (4.1 mmol) of phenol and 0.3 g (4.1 mmol) of potassium hydroxide were suspended in 20 ml of methyl alcohol, and refluxed under heating at 100 ° C. for 2 hours. The crude product formed by adding water was collected by filtration, dissolved in 1 ml of a 20% aqueous sodium hydroxide solution and 10 ml of ethanol, and dissolved at 60 ° C. in 1 ml.
Heated for 0 minutes. The reaction mixture was cooled to room temperature, and the resulting crude product was collected by filtration, purified by recrystallization from isopropanol-n-hexane, and 1.1 g of 4-cyclohexyloxy-5-phenoxy-2-nitroaniline (49%). ) Got. Melting point: 113-115 ° C Mass spec (m / z): 328 (M +)

Production Example 79 4- (2-Fluorophenoxy) -5-geranyloxy-2-nitroanilide
5 g (1.2 mmol), sodium hydride 0.1 g
(3.1 mmol) was suspended in 5 ml of tetrahydrofuran and stirred at room temperature for 2 hours. 0.1 ml of methyl iodide was added, and the mixture was further stirred for 2 hours. The precipitate formed by adding water was collected by filtration, and recrystallized from ethyl acetate and n-hexane to give 4-
(2-Fluorophenoxy) -5-geranyloxy-1
0.4 g (77%) of -methyl-2-nitroanilide were obtained. Melting point: 134-135 ° C Mass spec (m / z): 414 (M +)

Production Example 80 4-Cyclohexyloxy-
1.0 g of 5-fluoro-2-nitroacetanilide
(3.4 mmol), sodium hydride 0.2 g (4.1 m
mol), 0.5 g of cinnamyl alcohol and 3 ml of dimethylformamide, and recrystallized from ethyl acetate-n-hexane to give 4-cyclohexyloxy-5- (3-phenyl-2). -Propenyloxy) -2-nitroanilide 0.05 g (4%)
I got Melting point: 139-140 ° C Mass spec (m / z): 368 (M +)

Production Example 81 4-Cyclohexyloxy-
1.0 g of 5-fluoro-2-nitroacetanilide
(3.4 mmol), sodium hydride 0.2 g (4.1 m
mol), 3-pentyn-1-ol (3 ml) and recrystallization from ethyl acetate-n-hexane to give 4-cyclohexyloxy-5- (2
-Pentynyloxy) -2-nitroanilide 0.2 g
(18%). Melting point: 137.5-138 ° C Mass spec (m / z): 318 (M +)

Production Example 82 4-Cyclohexyloxy-
1.0 g of 5-fluoro-2-nitroacetanilide
(3.4 mmol), sodium hydride 0.2 g (4.1 m
mol) and trans-2-dodecenol (3 ml), and recrystallized from ethyl acetate-n-hexane to give 5-(-2-dodecenyloxy)-.
4-cyclohexyloxy-2-nitroanilide 0.
2 g (11%) were obtained. Melting point: 84.5-85 ° C Mass spec (m / z): 418 (M +)

Production Example 83 4-Cyclohexyloxy-
1.0 g of 5-fluoro-2-nitroacetanilide
(3.4 mmol), sodium hydride 0.2 g (4.1 m
mol) and isoamyl alcohol (15 ml), and recrystallized from ethyl acetate-n-hexane using the same method as in Production Example 77 to give 5-isoamyloxy-4-cyclohexyloxy-2-nitroanilide (0.4 g, 37%). )
I got Melting point: 111.5-112.5 ° C Mass spec (m / z): 322 (M +)

Production Example 84 4-Cyclohexyloxy-
2 g of 5-fluoro-2-nitroacetanilide (6.8 m
mol), 0.3 g (8.1 mmol) of sodium hydride and 3 ml of nerol, and recrystallized from ethyl acetate-n-hexane to obtain 4-cyclohexyloxy-5-enyloxy-2. -Nitroanilide
6 g (63%) were obtained. Melting point: 79-81.5 ° C Mass spec (m / z): 388 (M +)

Production Example 85 4-Cyclohexyloxy-
2 g of 5-fluoro-2-nitroacetanilide (6.8 m
mol), sodium hydride 0.3 g (8.1 mmol), 2-
Using 5 ml of ethylthioethanol and recrystallization from ethyl acetate-n-hexane using the same method as in Production Example 77, 4-cyclohexyloxy-2-nitro-5- (2-
1.1 g (46%) of ethylthioethoxy) anilide were obtained. Melting point: 91-92 ° C Mass spec (m / z): 340 (M +)

Production Example 86 4-Cyclohexyloxy-
0.5 g (1.5 mmol) of 2-nitro-5- (2-ethylthioethoxy) anilide and sodium m-perbenzoate
0.4 g (2.2 mmol) was dissolved in 15 ml of chloroform and stirred for 2 hours under ice cooling. The chloroform layer was washed with water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, recrystallized from ethyl acetate, and recrystallized from ethyl acetate to give 4-cyclohexyloxy-2-nitro-5- (2-ethylsulfinylethoxy) anilide. 0.1 g (26%) was obtained. Melting point: 139.5-140.5 ° C Mass spec (m / z): 356 (M +)

Production Example 87 4-Cyclohexyloxy-
2 g of 5-fluoro-2-nitroacetanilide (6.8 m
mol), sodium hydride 0.3 g (8.1 mmol), 2-
Using 2-ml of (2-pyridylthio) ethanol and recrystallization from ethyl acetate using the same method as in Production Example 77, 4-cyclohexyloxy-2-nitro-5- (2-
1.3 g of (2-pyridylthio) ethoxy) anilide
(49%). Melting point: 101-102 ° C Mass spec (m / z): 389 (M +)

Production Example 88 4-Cyclohexyloxy-
0.6 g (1.4 mmol) of 2-nitro-5- (2- (2-pyridylthio) ethoxy) anilide and 0.3 g (1.6 mmol) of sodium m-perbenzoate in 10 ml of chloroform
And stirred under ice cooling for 1 hour. The chloroform layer was washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, recrystallized from ethyl acetate-n-hexane, and recrystallized from 4-cyclohexyloxy-2-nitro-5- (2
-(2-pyridylsulfinyl) ethoxy) anilide
0.4 g (75%) was obtained. Melting point: 130.5-132 ° C Mass spectrometry value (m / z): 405 (M +)

Production Example 89 4-Cyclohexyloxy-
2 g of 5-fluoro-2-nitroacetanilide (6.8 m
mol), 0.3 g (8.1 mmol) of sodium hydride and 5 ml of ethoxyethanol, and recrystallized from ethyl acetate-n-hexane to give 4-
1.3 g (61%) of cyclohexyloxy-2-nitro-5- (2-ethoxyethoxy) anilide were obtained. Melting point: 67-69 ° C Mass spec (m / z): 324 (M +)

Production Example 90 4-Cyclohexyloxy-
2 g of 5-fluoro-2-nitroacetanilide (6.8 m
mol), 0.3 g (8.1 mmol) of sodium hydride and 5 ml of carbitol and recrystallized from ethyl acetate-n-hexane to give 4-cyclohexyloxy-2-nitro- 5- (2- (2-ethoxy) ethoxyethoxy) anilide 2.0 g (53%)
I got Melting point: ° C Mass spec (m / z): 368 (M +)

Production Example 91 4-cyclohexyloxy-
2.0 g of 5-fluoro-2-nitroacetanilide
(6.8 mmol), sodium hydride 0.8 g (20.3
mmol), 2.4 ml of 2-pyrrolidinoethanol
1.9 g (82%) of 4-cyclohexyloxy-5- (2-pyrrolidinoethoxy) -2-nitroanilide was obtained in the same manner as in Production Example 77 using 30 ml of dimethylformamide and 2 ml of dimethylformamide. Was. Melting point: 84-86 ° C Mass spec (m / z): 349 (M +)

Production Example 92 4-Cyclohexyloxy-
2.0 g of 5-fluoro-2-nitroacetanilide
(6.8 mmol), sodium hydride 0.8 g (20.3
mmol), 2.6 ml of 2-Molinofolinoethanol
(20.3 mmol) and 30 ml of dimethylformamide, using the same method as in Production Example 77, to give 4-cyclohexyloxy-5- (2-morinophorinoethoxy) -2-.
2.0 g (80%) of the nitroanilide were obtained. Melting point: 131-132 ° C Mass spec (m / z): 365 (M +)

Production Example 93 0.2 g of sodium hydride
(4.0 mmol) and 5 ml of cyclohexanol were stirred at room temperature for 1 hour, and then 1.0 g of 4-cyclohexyloxy-5-fluoro-2-nitroacetanilide (3.4 m
mol), benzhydrol 1.0 g (4.0 mmol)
And 5 ml of cyclohexanol, and the mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 10: 1) to obtain a residue.
-Cyclohexyloxy-5- (bis (4-methoxyphenyl) methoxy) -2-nitroaniline 0.5 g
(34%). Mass spectrometry (m / z): 388 (M +) Nuclear magnetic resonance spectrum (CDCl3, TMS internal standard) δ: 1.24-2.04 (10H, m), 3.59 (6H, s), 4.10 (1H, sp, J = 4Hz),
5.52 (1H, d, J = 7Hz), 6.39 (0.5H, s), 6.47 (0.5H, s), 6.86
(4H, dt, J = 4,8Hz), 7.21 (4H, dt, J = 4,8Hz), 7.62 (1H, d, J = 8H
z), 8.52 (1H, d.like)

Production Example 94 4-Cyclohexyloxy-
1.0 g of 5-fluoro-2-nitroacetanilide
(3.4 mmol), potassium hydroxide 0.5 g (8.0 mm
ol), 0.4 ml of 3-fluorophenol (mmo
l), Production Example 7 using 10 ml of dimethyl sulfoxide
Using a method similar to that of 8-cyclohexyloxy-
1.0 g (82%) of 5- (3-fluorophenoxy) -2-nitroanilide was obtained. Melting point: 79.0-80.0 ° C Mass spec (m / z): 346 (M +)

Production Example 95 4-cyclohexyloxy-5-fluoro-2-nitroacetanilide 1.0 g
(3.4 mmol), potassium hydroxide 0.5 g (8.0 mm
ol), 0.4 g of 4-hydroxypyridine (4.1 mm
ol) and 4-cyclohexyloxy-5- (4-pyridyloxy) -2-nitroanilide using the same method as in Production Example 78 using 10 ml of dimethyl sulfoxide.
0.8 g (67%) was obtained. Melting point: 285 ° C (decomposition) Mass spec (m / z): 329 (M +)

Production Example 96 1.0 g of 4-methoxy-5-fluoro-4-methoxy-2-nitroacetanilide
(4.4 mmol), 0.2 g of sodium hydride (4.1 m
mol) and 50 ml of isopropanol, and recrystallized from ethyl acetate-n-hexane to give 5-isopropyloxy-4-methoxy-2.
0.2 g (23%) of nitroanilide were obtained. Melting point: 176.5-177.5 ° C Mass spec (m / z): 226 (M +)

Production Example 97 5-Fluoro-2-nitro-
4- (2-phenylphenoxy) acetanilide 1.
0 g (2.7 mmol), sodium hydride 0.1 g
(3.3 mmol) and 5 g of geranyl alcohol, recrystallized from ethyl acetate using the same method as in Production Example 77, and 0.4 g of 5-geranyloxy-2-nitro-4- (2-phenylphenoxy) anilide was obtained. (34%). Melting point: 102-103 ° C Mass spec (m / z): 458 (M +)

Production Example 98 4- (2-isopropylphenoxy) -5-fluoro-2-nitroacetanilide
1.0 g (3.4 mmol), sodium hydride 0.2
g (4.1 mmol) and geraniol (3 ml) and recrystallized from ethyl acetate-n-hexane to give 4- (2-isopropylphenoxy)-
0.3 g of 5-geranyloxy-2-nitroanilide
(22%). Melting point: 88.5-89.5 ° C Mass spec (m / z): 424 (M +)

Production Example 99 4- (5, 6, 7, 8-tetrahydronaphth-2-yloxy) -5-fluoro-2
2.0 g (5.8 mmol) of nitroacetanilide,
Using a method similar to that of Production Example 77 using 0.3 g (7.0 mmol) of sodium hydride and 5 ml of geraniol, recrystallization from ethyl acetate-n-hexane gave 4-
((5,6,7,8-tetrahydronaphth-2-yloxy) -5-geranyloxy-2-nitroanilide
0.7 g (25%) was obtained. Melting point: 80.0-82.0 ° C Mass spec (m / z): 436 (M +)

Production Example 100 4- (2,4-Difluorophenoxy) -5-fluoro-2-nitroacetanilide 1.0 g (3.1 mmol), sodium hydride
Using the same method as in Production Example 77 using 0.2 g (3.7 mmol) and 3 ml of geraniol, recrystallization from ethyl acetate-n-hexane gave 4- (2,4-difluorophenoxy) -5-geranyloxy-. 2-nitroanilide
0.1 g (10%) was obtained. Melting point: 94.5-95.5 ° C Mass spec (m / z): 418 (M +)

Production Example 101 4- (5, 6, 7, 8-tetrahydronaphth-1-yloxy) -5-fluoro-
2.0 g of 2-nitroacetanilide (5.8 mmol
l), 0.3 g (7.0 mmol) of sodium hydride,
Using 5 ml of geraniol and the same method as in Production Example 77, recrystallization from ethyl acetate-n-hexane gave 4-
((5,6,7,8-tetrahydronaphth-1-yloxy) -5-geranyloxy-2-nitroanilide
0.4 g (17%) was obtained. Melting point: 114-115 ° C Mass spec (m / z): 436 (M +)

Production Example 102 4- (2-Fluorophenoxy) -5-fluoro-2-nitroacetanilide
2.0 g (6.5 mmol), sodium hydride 0.3
g (7.8 mmol) and 5 ml of geraniol, and recrystallized from ethyl acetate-n-hexane to give 4- (2-fluorophenoxy) -5-
Geranyloxy-2-nitroanilide 0.9 g (35
%). Melting point: 76-77 ° C Mass spec (m / z): 400 (M +)

Production Example 103 4- (2-Benzoylphenoxy) -5-fluoro-2-nitroacetanilide
2.0 g (5.1 mmol), sodium hydride 0.2
g (6.1 mmol) and geraniol (5 ml) and recrystallized from ethyl acetate-n-hexane to give 4- (2-benzoylphenoxy) -5.
-Geranyloxy-2-nitroanilide 1.8 g (7
2%). Melting point: ° C Mass spectrometry (m / z): 486 (M +) Nuclear magnetic resonance spectrum (CDCl3, TMS internal standard) δ: 1.58 (3H, s), 1.60 (3H, s), 1.64 (3H, s) , 2.03 (4H, s), 4.4
6 (2H, d, J = 6Hz), 5.03 (1H, br), 5.24 (1H, t, J = 6Hz), 6.12 (1
H, s), 6.16 (2H, s), 6.78 (1H, d, J = 9Hz), 7.14 (1H, t, J = 9H
z), 7.33 -7.68 (8H, m), 7.69 (1H, s), 7.88 (2H, m)

Production Example 104 4- (2,4-Diisoamylphenoxy) -5-fluoro-2-nitroanilide
2.0 g (4.6 mmol), sodium hydride 0.2
g (3.7 mmol) and 5 ml of geraniol and recrystallizing from ethyl acetate-n-hexane to give 4- (2,4-diisoamylphenoxy) -5-geranyloxy-2 -Nitroanilide 0.
3 g (13%) were obtained. Melting point: 69-71 ° C Mass spec (m / z): 522 (M +)

Production Example 105 4-Normalhexyloxy-5-fluoro-2-nitroacetanilide 2.0
g (6.7 mmol), sodium hydride 0.3 g (8.0
mmol) and geraniol (5 ml).
Recrystallization from ethyl acetate-n-hexane using the same method as described above yielded 0.6 g (21%) of 4-normalhexyloxy-5-geranyloxy-2-nitroanilide. Melting point: 77-79 ° C Mass spec (m / z): 390 (M +)

Production Example 106 1.5 g of N-methyl, 5-fluoro-4-methoxy-2-nitroanilide (7.5 m
mol), sodium hydride 0.4 g (9.0 mmol)
l), using 10 ml of geraniol and N-methyl, 5-geranyloxy-4-
1.9 g (75%) of methoxy-2-nitroanilide were obtained. Mass spectrometry value (m / z): 334 (M +) Nuclear magnetic resonance spectrum (CDCl 3, TMS internal standard) δ: 1.60 (3H, s), 1.66 (3H, s), 1.78 (3H, s), 2.10 ( 4H, s.lik
e), 3.02 (3H, d, J = 6Hz), 3.38 (3H, s), 4,73 (2H, d, J = 7Hz), 5.
07 (1H, m), 5.48 (1H, t, J = 6Hz), 6.15 (1H, s), 7.60 (1H, s), 8.
44 (1H, d, J = 6Hz)

Production Example 107 4-Cyclohexyloxy-5- (4-pyridyloxy) -2-nitroanilide
0.3 g (0.9 mmol), sodium hydride 0.1 g
(2.3 mmol), methyl iodide 0.1 ml (1.1 mm
ol) and recrystallized from acetone using the same method as in Production Example 79, to give 0.2 g (73%) of N-methyl, 4-cyclohexyloxy-5- (4-pyridyloxy) -2-nitroanilide. I got Melting point: 289 ° C (decomposition) Mass spec (m / z): 343 (M +)

Production Example 108 N-methyl, 4-methoxy-2-nitro-5- (4-pyridylthio) anilide
1.0 g (3.4 mmol), sodium hydride 0.3 g
(6.9 mmol) and 3.4 ml of geranyl bromide
(17 mmol) was suspended in 20 ml of tetrahydrofuran and stirred at room temperature for 5 days. The precipitate formed by adding water is removed and silica gel column chromatography (elution solvent;
Purified with n-hexane: ethyl acetate = 10: 1) and recrystallized from n-hexane-petroleum ether to give 4-cyclohexyloxy-5-geranyloxy-2-nitroaniline.
1 g (32%) was obtained. Using the same method as in Production Example 77, 0.2 g (13%) of N-methyl, 5-geranylthio-4-methoxy-2-nitroanilide was obtained. Nuclear magnetic resonance spectrum (CDCl3, TMS internal standard) δ: 1.58 (3H, s), 1.66 (3H, s), 1.77 (3H, s), 2.08 (4H, s.lik
e), 3.02 (3H, d, J = 6Hz), 3.62 (2H, d, J = 7Hz), 3.86 (3H, s), 5.
07 (1H, m), 5.34 (1H, t, J = 7Hz), 6.48 (1H, s), 7.52 (1H, s), 8.
22 (1H, d.like, J = 6Hz).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/40 ABG A61K 31/40 ABG 31/44 ABC 31/44 ABC C07C 317/36 C07C 317/36 323 / 37 323/37 C07D 209/14 C07D 209/14 213/38 213/38 213/71 213/71 (72) Inventor Toshio Nakamura 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. F-term (reference) 4C055 AA01 BA01 BA02 BA06 BA27 BB04 BB10 CA01 CA02 CA06 CA27 CB04 CB10 DA01 DA06 DA27 DA47 DB04 DB10 DB15 4C086 AA02 AA03 BC13 BC17 BC73 NA14 ZA97 ZB08 ZB11 ZB13 ZB15 4C204 BB01 A02 FB01 A02 NA14 ZA97 ZB08 ZB11 ZB13 ZB15 ZB22 ZC02 4H006 AA01 AA03 AB20 AB22 AB27 BJ20 BJ50 BM30 BM72 BN10 BN30 BP30 BR60 BU26 BU46 BV25 TA05 TB42

Claims (9)

[Claims] (1) Formula (1) (Wherein, R ¹ represents an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 4 to 8 carbon atoms, a phenyl group which may have a substituent, or an N atom and / or an S atom. R ² represents an alkyl group having 1 to 15 carbon atoms, a cycloalkyl group having 4 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms,
Nitrogen atom, an aromatic 5-membered ring containing one or two identical or different oxygen atom or a sulfur atom or a 6-membered ring or the formula _{(2) - (CH 2)} n -A-R 4 (2) ( wherein A Represents an O atom, an S atom, an alkoxy group, an SO group or an SO ₂ group, and R ⁴ represents a lower alkyl group, a lower alkoxy group, a phenyl group optionally having a substituent, a cycloalkyl group or an N atom and / or S R ³ represents a monocyclic or bicyclic aromatic heterocyclic group having an atom as a hetero atom), and R ³ is an alkyl group having 1 to 10 carbon atoms which may have a substituent, a phenyl group, A phenyl group, an aminophenyl group or one or two hydroxyl groups, a C2-C6 alkoxycarbonyl group or a carboxy group-substituted carbon atom substituted with one or two indolyl groups, methoxy groups or hydroxyl groups, which are the same or different; Shows the child number 1-10 alkyl group, X is, O atom, S atom, N- substituted nitroaniline derivative represented by SO represents a group or a SO ₂ group). 2. The formula (1) according to claim 1, wherein R ¹
Is an alkyl group having 1 to 8 carbon atoms or 4 carbon atoms
Represents 2 to 8 cycloalkyl groups, R ² represents an aromatic 5- or 6-membered ring containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms, which are the same or different, and R ³ has a substituent. The N-substituted nitroaniline derivative according to claim 1, which is an alkyl group having 1 to 5 carbon atoms which may be substituted. ^3. The alkyl group represented by R ^{3 in} the formula (1) is a substituent selected from a hydroxy group, a dialkylamino group, an alkoxycarbonyl group having 2 to 6 carbon atoms, a phenyl group and a pyridyl group. The N-substituted nitroaniline derivative according to claim 2, which has the following formula: 4. The method according to claim 1, wherein R ¹
Represents an alkyl group having 1 to 5 carbon atoms or a cycloalkyl group having 4 to 8 carbon atoms, and R ² represents an alkyl group having 1 to 15 carbon atoms and cycloalkyl having 4 to 8 carbon atoms. A alkenyl group having 3 to 8 carbon atoms containing 1 or 2 carbon-carbon double bonds, and R ³ is an alkyl group having 1 to 10 carbon atoms which may have a substituent. The N-substituted nitroaniline derivative according to claim 1. 5. An alkyl group of R ^{3 in} the formula (1) wherein the alkyl group having 1 to 10 carbon atoms, the phenyl group, the indolyl group, the methoxy group or the hydroxyl group is the same or different and is substituted by 1 or 2 phenyl groups. 5. The N- according to claim 4, which has at least one selected from the group consisting of a group, an aminophenyl group, one or two hydroxyl groups, an alkoxycarbonyl group having 2 to 6 carbon atoms and a carboxyl group.
Substituted nitroaniline derivatives. 6. The formula (1) according to claim 1, wherein R ¹
Represents a phenyl group substituted by one or two alkyl groups having 1 to 8 carbon atoms or a phenyl group, and R ² and R ³
The N-substituted nitroaniline derivative according to claim 1, wherein each represents the same or different alkyl group having 1 to 5 carbon atoms. 7. The formula (1) according to claim 1, wherein R ¹
Represents a hydrogen atom, a lower alkyl group, a phenyl group which may have a substituent, a cycloalkyl group, or a monocyclic or bicyclic aromatic heterocyclic group having N and / or S as a hetero atom. , R ² are a hydrogen atom, an alkyl group or a cycloalkyl group which may have a substituent, an alkenyl group, or a group represented by the formula (2)-(CH ₂ ) _n -A-R ⁴ (where A represents , R ⁴ and n have the same meanings as in formula (2) according to claim 1), R ³ represents a lower alkyl group, and X is an oxygen atom. . 8. The method according to claim 1, which is a pharmaceutically acceptable salt.
8. The N-substituted nitroaniline derivative according to any one of claims to 7. 9. A pharmaceutical composition comprising an effective amount of the N-substituted nitroaniline derivative according to claim 1.