JPH0625127A - Tetrahydrophthalamide derivative, method for producing the same, and herbicides containing them as active ingredients - Google Patents

Abstract

(57) [Summary] [Object] To provide a 3,4,5,6-tetrahydrophthalamide derivative having an excellent effect as an effective active ingredient of a herbicide and a method for producing the same. [Structure] By reacting tetrahydrophthalimide or tetrahydroisophthalimide having a 5-cycloalkyloxy-2,4-dihalophenyl group on the nitrogen atom with various amines, general formula (I): A tetrahydrophthalamide derivative represented by is produced.
These tetrahydrophthalamide derivatives show an excellent herbicidal effect in paddy field and upland soil treatment and foliage treatment.

Description

Detailed Description of the Invention

[0001]

[Industrial application] Chemical pesticides have become indispensable for modern agriculture in recent years. However, as a social demand for these chemical pesticides, including herbicides, drugs with low toxicity and low residue and high selectivity for crops are being used. Is desired. The present invention provides a new herbicide that should meet such social demands.

More specifically, the present invention has the general formula (I)

[0003]

[Chemical 9]

[In the formula, X ¹ represents a halogen atom, and X ² represents a hydrogen atom or a halogen atom. R ¹ represents an optionally substituted cycloalkyl group having 3 to 8 carbon atoms, R ²
Represents a hydrogen atom, a chlorine atom or a methyl group. R ³ and R ⁴ are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 9 carbon atoms, an aryl group having 6 to 10 carbon atoms, and 3 carbon atoms.
Represents an alkenyl group having 5 to 5 carbon atoms or an alkynyl group having 3 to 5 carbon atoms, or R ³ and R ⁴ may form a substituted or unsubstituted alicyclic heterocyclic ring together with the bonded nitrogen atom. ]
The present invention relates to a 3,4,5,6-tetrahydrophthalamide derivative represented by, a method for producing the same, and a herbicide containing them as an active ingredient.

[0005]

2. Description of the Related Art 3,4,5, having herbicidal activity,
Examples of the 6-tetrahydrophthalamide derivative include:
JP-A-54-154737, JP-A-55-15754
No. 6 (Japanese Patent Publication No. 63-13981), Japanese Patent Laid-Open No. 59-51
250, JP-A-60-252457, JP-A-61-161
No. 43160 or US Pat. No. 4,613,675 is known, but a compound having a cycloalkyloxy group at the 5-position of the phenyl ring on the nitrogen atom is not known.

[0006]

The development of an excellent herbicide is to protect important crops such as rice, soybean, corn, wheat or cotton and beet from weeds, and further improve the productivity of these crops for agricultural work. Labor saving, etc.
In total, it contributes to the stabilization of the food economy, and as such a herbicide, there is a strong demand for the development of a drug having the following conditions.

[0007] That is, in terms of effects, those having a wide spectrum of herbicidal activity, at the same time having high safety against crops, and also highly effective against difficult-to-control perennial weeds are desirable. From the viewpoint of labor saving, it is desired that the number of drug treatments is small and the effect can be maintained for an appropriate period.

The 3,4,5,6-tetrahydrophthalamide derivatives known from the prior art show a good herbicidal effect by themselves, but it cannot be said that they satisfy the desired conditions. In addition, the known compounds often have markedly different herbicidal activity or selectivity for crops due to slight structural differences (for example, types of substituents, positions, etc.), and the chemical structure is simply different. However, it is difficult to estimate the herbicidal activity and selectivity of a new compound in advance.

The present invention aims to provide a compound useful as an active ingredient of a herbicide which exhibits a superior herbicidal effect at a lower treatment amount, is highly safe, and is excellent in selectivity with crops. Is.

[0010]

Means for Solving the Problems From the above viewpoints, the inventors of the present invention have conducted extensive studies, and as a result, the general formula (I)

[0011]

[Chemical 10]

[Wherein X ¹ , X ² , R ¹ , R ² , R ³ and R ⁴
Represents the same meaning as described above. ], A phenyl ring 5
A 3,4,5,6-tetrahydrophthalamide derivative having a cycloalkyloxy group introduced as a substituent at the position (hereinafter referred to as the compound of the present invention) has a high herbicidal activity against weeds by a low dose treatment. In addition, the present invention has been completed by finding that the chemical damage to major crops is significantly reduced.

The compound of the present invention is a variety of weeds that are problematic in foliar treatment and soil treatment in upland fields, for example, broad-leaved weeds such as white clover, aubiyu, hibiscus, chickweed, dogwood, ragweed, novier, green foxtail, mexicograss, ochiba, It shows an excellent herbicidal effect even on low-dose treatments for grass weeds such as Aedes aegypti, and also poses a problem for major crops such as soybeans, cotton, broad-leaved crops such as beets, and grass crops such as corn and wheat. It does not show any phytotoxicity.

Further, the compound of the present invention is a variety of weeds that are problematic in paddy fields, for example, weeds such as gramineous weeds such as Tainubie and Keiubie, broad-leaved weeds such as Azena, Kasugagasa, Mizohakobe, Konagi, firefly, matsubai, tamagaya, mizugayatsuri, kurowai. It shows an excellent effect even on low-dose treatment of cyperaceae weeds and paddy weeds such as Urikawa, and the phytotoxicity to transplanted rice is very slight.

Such high selectivity of the compound of the present invention is
It is completely unexpected from the conventional 3,4,5,6-tetrahydrophthalamide derivative, and this characteristic is obviously brought about by introducing a cycloalkyloxy group at the 5-position of the phenyl ring. .

In the compound (I) of the present invention, X ¹ and X ²
Examples of the halogen atom represented by are a fluorine atom, a chlorine atom, or a bromine atom.

Examples of the cycloalkyl group represented by R ¹ include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclooctyl group and the like, which have a carbon number such as a methyl group, an ethyl group and an isopropyl group. It may be substituted with a lower alkyl group of 1 to 4 or a halogen atom such as a fluorine atom or a chlorine atom.

The alkyl group represented by R ³ and R ⁴ may have a linear or branched structure, or may have an alicyclic structure on the chain, and examples thereof include a methyl group, an ethyl group and a propyl group. , Isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, neopentyl group, isopentyl group, tert-pentyl group, 1,2-dimethylpropyl group, 1-methylbutyl group, hexyl group, Examples include isohexyl group, heptyl group, 1-ethylhexyl group, octyl group, decyl group, undecyl group, dodecyl group, cyclopropylmethyl group, cyclohexylmethyl group, 1-cyclohexenylmethyl group, 1-adamantylmethyl group, and miltanyl group. can do.

The above alkyl group is a halogen atom,
One or more lower alkoxy groups, hydroxyl groups, carboxyl groups, lower alkyloxycarbonyl groups, substituted amino groups, cyano groups and the like may be substituted, and examples of these substituted alkyl groups include a 2-chloroethyl group and a 2-bromoethyl group. , 3-fluoropropyl group, 3-bromopropyl group, 3,3,3-trifluoropropyl group, 2-hydroxyethyl group, 1-hydroxymethyl-2-methylpropyl group, 1-hydroxymethyl-2-methylbutyl group 1
-Hydroxymethyl-3-methylbutyl group, 1,1-di (hydroxymethyl) ethyl group, 1-hydroxymethyl-1-methylethyl group, 1,5-dimethyl-5-hydroxyhexyl group, 2- (2-hydroxy (Ethoxy) ethyl group, 2-methoxyethyl group, 3-methoxypropyl group, 1-methoxy-1-methylpropyl group, 3-ethoxypropyl group, 3-isopropoxypropyl group, 3-propoxypropyl group, 3-butoxypropyl group. Group, methoxycarbonylmethyl group, 1- (methoxycarbonyl) ethyl group, 1- (methoxycarbonyl) propyl group, 2-
Methoxycarbonyl-2-methylpropyl group, 1-methoxycarbonyl-3-methylbutyl group, 1-methoxycarbonyl-2,2-dimethylpropyl group, ethoxycarbonylmethyl group, 2-ethoxycarbonyl-2-methylpropyl group, 1- Carboxyethyl group, 1-carboxypropyl group, 2-carboxy-2-methylpropyl group,
1-carboxy-3-methylbutyl group, 2- (methoxycarbonyl) ethyl group, 2-carboxyethyl group, 6-
Examples thereof include a carboxyhexyl group, a 4-carboxycyclohexylmethyl group, a 3-dimethylaminopropyl group, a 1-methyl-4-diethylaminobutyl group, a 1-ethoxycarbonyl-4-piperidyl group and a cyanoethyl group.

Further, one or more of these alkyl groups may be substituted with a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a carboxyl group, a lower alkyloxycarbonyl group, a nitro group, a cyano group, etc., and an aromatic group. It may be substituted with a group or an alicyclic heterocyclic group.

Specifically, these substituted alkyl groups include benzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 4-t-butylbenzyl group, 4-methylbenzyl group, 4 -Methoxybenzyl group, 1-phenylethyl group, R-(+)-1-phenylethyl group, S-(-)-1-phenylethyl group, 1-
(4-chlorophenyl) ethyl group, 1- (4-methoxyphenyl) ethyl group, 2-phenylethyl group, 2-
(3,4-dimethoxyphenyl) ethyl group, 1-methyl-1-phenylethyl group, 1-methyl-1- (3-chlorophenyl) ethyl group, 1-methyl-1- (3-fluorophenyl) ethyl group, 1-methyl-1- (3-trifluoromethylphenyl) ethyl group, 1-methyl-1-
(4-methylphenyl) ethyl group, 1-methyl-2-
(2-hydroxyphenyl) ethyl group, 1-methyl-1
-(4-chlorophenyl) ethyl group, 1-methyl-1-
(4-Fluorophenyl) ethyl group, 1-methyl-1-
(4-Bromophenyl) ethyl group, 1-methyl-1-phenylpropyl group, 1-methyl-1- (4-chlorophenyl) propyl group, 1-methyl-1- (4-methoxyphenyl) ethyl group, 1- Methyl-1- (2,4-dichlorophenyl) ethyl group, 1- (1-naphthyl) ethyl group, 1- (2-naphthyl) ethyl group, (2-naphthyl)
Methyl group, 2-pyridylmethyl group, 2- (2-pyridyl) ethyl group, 2-picolyl group, 3-picolyl group, furfuryl group, tetrahydrofurfuryl group, 2-thiophenemethyl group, 2- (1-methyl- 2-pyrrol-2-yl) ethyl group, 2- (1-methylpyrrolidinyl) ethyl group, 2- (1-pyrrolidinyl) ethyl group, 2-morpholinoethyl group, 3-morpholinopropyl group, 2- A piperidinoethyl group etc. can be illustrated.

The cycloalkyl group represented by R ³ and R ⁴ includes a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclooctyl group, a 2-norbornyl group,
Norbornen-2-yl group, 2-bicyclo [3.2.1]
Examples thereof include an octyl group, a 3-noradamantyl group, a 1-adamantyl group and a 2-adamantyl group.
These cycloalkyl groups may be substituted with a lower alkyl group having 1 to 4 carbon atoms, a halogen atom, a hydroxyl group, an amino group or the like, and examples thereof include a 2-methylcyclohexyl group, a 2-aminocyclohexyl group and a 2-hydroxy group. Examples thereof include a cyclohexyl group and a 1- (hydroxymethyl) cyclopentyl group.

The alkenyl group or alkynyl group represented by R ³ and R ⁴ includes allyl group, methallyl group, crotyl group, prenyl group, propargyl group, 1-butyne-3.
Examples thereof include an -yl group. Further, these alkenyl group and alkynyl group may be substituted with a halogen atom such as a fluorine atom or a chlorine atom.

Examples of the aryl group represented by R ³ and R ⁴ include a phenyl group and a naphthyl group. These aryl groups may be substituted with a lower alkyl group, a halogen atom, a lower alkoxy group, a hydroxymethyl group, a trifluoromethyl group, a carboxy group, a cyano group or the like, and examples thereof include a 2-chlorophenyl group and a 2-fluorophenyl group. Group, 4-chlorophenyl group, 4-fluorophenyl group, 4-tert-butylphenyl group, 4-methylphenyl group, 4-isopropylphenyl group, 2-hydroxymethylphenyl group, 3-hydroxymethylphenyl group, 4-hydroxy Methylphenyl group, 3-chloro-4
-Cyanochlorophenyl group, 4-carboxy-3-chlorophenyl group, 5-chloro-2-trifluoromethylphenyl group, 4-chloro-2-trifluoromethylphenyl group, 2-chloro-5-trifluoromethylphenyl group, A 4-chloro-3-trifluoromethylphenyl group etc. can be illustrated.

As a group which forms a substituted or unsubstituted alicyclic heterocyclic ring with the nitrogen atom to which R ³ and R ⁴ are bonded,
Examples of the amines represented by the corresponding general formula (III) include, for example, aziridine, azetidine, piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine, 2-pyrroline, 3-pyrroline, 1,2,3,6. −
Tetrahydropyridine, pyrazolidine, pyrazoline,
Examples thereof include 1,2-piperazine, 1,3-piperazine, thiazolidine, oxazolidine, isoxazolidine, tetrahydropyridazine and hexahydropyridazine.

These alicyclic heterocyclic rings are lower alkyl groups, phenyl groups, substituted phenyl groups, benzyl groups, acetyl groups, hydroxyl groups, hydroxymethyl groups, carboxyl groups,
It may be substituted with an acetamide group, a lower alkyloxycarbonyl group or the like, and more specifically, amines (II
For example, methyl aziridine, 2,5-
Dimethylpyrrolidine, 3-hydroxypyrrolidine, proline, perhydroindole, 3-acetamidopyrrolidine, 4-carboxythiazolidine, 3,5-dimethylpiperidine, 3,3-dimethylpiperidine, isonipecotic acid, 3-hydroxypiperidine, 2, 6-dimethylpiperidine, ethyl 2-pipecolate, ethyl 3-nipecotinate, ethyl isonipecotinate, 4-benzylpiperidine, 1-phenylpiperazine, 1- (2-methylphenyl) piperazine, 1-methylpiperazine, 1-benzylpiperazine , 1- (2-methoxyphenyl) piperazine, 1- (2-chlorophenyl) piperazine, 1- (2
Examples thereof include -fluorophenyl) piperazine, 1- (4-fluorophenyl) piperazine, 1-ethoxycarbonylpiperazine and the like.

The amines (I
II) is a commercially available compound or a compound that can be easily synthesized by a known method.

Next, a method for producing the 3,4,5,6-tetrahydrophthalamide derivative which is the compound of the present invention will be described. The compound of the present invention represented by the general formula (I) has the general formula (II)

[0029]

[Chemical 11]

[In the formula, X ¹ , X ² , R ¹ and R ² have the same meanings as described above. ] 3,4,5,6-tetrahydrophthalimide derivative represented by the general formula (III)

[0031]

[Chemical 12]

[In the formula, R ³ and R ⁴ have the same meanings as described above. ] It can manufacture by making it react with the amine shown. The reaction is usually 0.5 equivalent or more, preferably 0.9 to 1.5 equivalents of the amine (II) with respect to the 3,4,5,6-tetrahydrophthalimide derivative (II).
By reacting I), the compound (I) of the present invention can be obtained in good yield.

The reaction can be carried out in a solvent, for example, a halogenated hydrocarbon solvent such as methylene chloride, chloroform, carbon tetrachloride and chlorobenzene, and a hydrocarbon such as benzene, toluene, xylene, hexane, octane and cyclohexane. System solvent, an ether solvent such as diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, a ketone solvent such as acetone and methyl ethyl ketone, an inert solvent such as acetonitrile, ethyl acetate and dimethylformamide, or a mixed solvent thereof. it can.

The reaction temperature is usually selected from the range of 0 ° C to 100 ° C. The reaction time varies depending on the reaction substrate, and the reaction is usually completed in about 5 minutes to 24 hours.

In this reaction, a catalyst may be added for the purpose of promoting the reaction. As the catalyst, a basic compound such as triethylamine, N-methylmorpholine, pyridine, N, N-dimethylaniline, potassium carbonate or sodium carbonate is usually used.

The tetrahydrophthalimide derivative represented by the general formula (II), which is a raw material for producing the compound of the present invention, can be produced according to the method described in JP-A-4-164067. That is, the general formula (V)

[0037]

[Chemical 13]

[In the formula, X ¹ , X ² and R ¹ have the same meanings as described above. ] And an aniline derivative represented by the general formula (V
I)

[0039]

[Chemical 14]

[In the formula, R ² has the same meaning as described above. ]
Can be easily produced by reacting with 3,4,5,6-tetrahydrophthalic anhydride represented by (4) in an organic solvent under heating preferably at 50 to 120 ° C (Reference Example- 1 and 2).

As the 3,4,5,6-tetrahydrophthalimide derivative represented by the general formula (II), which is a starting material for the compound of the present invention that can be produced in this manner, N- (2-fluoro- 4-chloro-5-cyclopropyloxyphenyl) -3,4,5,6-tetrahydrophthalimide, N- (2-fluoro-4-chloro-5)
-Cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide, N- {2-fluoro-4-chloro-5- (2-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydrophthalimide , N-
{2-Fluoro-4-chloro-5- (3-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydrophthalimide, N- (2-fluoro-4-chloro-
5-cyclohexyloxyphenyl) -3,4,5,6-
Tetrahydrophthalimide, N- {2-fluoro-4-
Chloro-5- (2-chlorocyclohexyl) oxyphenyl} -3,4,5,6-tetrahydrophthalimide, N
-(2-Fluoro-4-chloro-5-cyclooctyloxyphenyl) -3,4,5,6-tetrahydrophthalimide, N- (2-fluoro-4-bromo-5-cyclopropyloxyphenyl) -3, 4,5,6-tetrahydrophthalimide, N- (2-fluoro-4-bromo-5-
Cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide, N- {2-fluoro-4-bromo-5- (2-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydrophthalimide, N-
{2-Fluoro-4-bromo-5- (3-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydrophthalimide, N- (2-fluoro-4-bromo-
5-cyclohexyloxyphenyl) -3,4,5,6-
Tetrahydrophthalimide, N- (2,4-dichloro-
5-cyclopropyloxyphenyl) -3,4,5,6-
Tetrahydrophthalimide, N- (2,4-dichloro-
5-cyclopentyloxyphenyl) -3,4,5,6-
Tetrahydrophthalimide, N- {2,4-dichloro-
5- (2-methylcyclopentyl) oxyphenyl}-
3,4,5,6-tetrahydrophthalimide, N- {2,4
-Dichloro-5- (3-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydrophthalimide, N- (2,4-dichloro-5-cyclohexyloxyphenyl) -3,4,5,6- Tetrahydrophthalimide, N- (2,4-dichloro-5-cyclooctyloxyphenyl) -3,4,5,6-tetrahydrophthalimide, N- (2-Fluoro-4-chloro-5-cyclopentyloxyphenyl) -3 -Methyl-3,4,5,6-tetrahydrophthalimide, N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -4-methyl-3,4,5,6-tetrahydrophthalimide, N-
(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl) -4-chloro-3,4,5,6-tetrahydrophthalimide, N- {2-fluoro-4-chloro-5
-(3-Methylcyclopentyl) oxyphenyl} -3
-Methyl-3,4,5,6-tetrahydrophthalimide,
N- {2-fluoro-4-chloro-5- (3-methylcyclopentyl) oxyphenyl} -4-methyl-3,4,
5,6-Tetrahydrophthalimide, N- (2-fluoro-5-cyclopentyloxyphenyl) -3,4,5,
6-tetrahydrophthalimide, N- {2-fluoro-
5- (2-methylcyclopentyl) oxyphenyl}-
3,4,5,6-tetrahydrophthalimide, N- {2-
Fluoro-5- (3-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydrophthalimide,
Examples thereof include N- (2-fluoro-5-cyclohexyloxyphenyl) -4-methyl-3,4,5,6-tetrahydrophthalimide.

The compound of the present invention represented by the general formula (I) has the general formula (IV)

[0043]

[Chemical 15]

[In the formula, X ¹ , X ² , R ¹ and R ² have the same meanings as described above. ] 3,4,5,6-tetrahydroisophthalimide derivative represented by the following general formula (III)

[0045]

[Chemical 16]

[In the formula, R ³ and R ⁴ have the same meanings as described above. ] It can manufacture also by making it react with the amine shown by these. The reaction is carried out by reacting the 3,4,5,6-tetrahydroisophthalimide derivative (IV) with 0.5 equivalents or more, preferably 0.9 to 1.5 equivalents of the amines (III). The compound (I) of the present invention can be obtained efficiently.

The reaction can be carried out in a solvent, for example, a halogenated hydrocarbon solvent such as methylene chloride, chloroform, carbon tetrachloride and chlorobenzene, and a hydrocarbon such as benzene, toluene, xylene, hexane, octane and cyclohexane. System solvent, an ether solvent such as diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane, a ketone solvent such as acetone and methyl ethyl ketone, an inert solvent such as acetonitrile, ethyl acetate and dimethylformamide, or a mixed solvent thereof. it can.

The reaction temperature is usually selected in the range of 0 ° C to 100 ° C. The reaction time varies depending on the reaction substrate, and the reaction is usually completed in about 5 minutes to 24 hours.

In this reaction, a catalyst may be added for the purpose of promoting the reaction. As the catalyst, a basic compound such as triethylamine, N-methylmorpholine, pyridine, N, N-dimethylaniline, potassium carbonate or sodium carbonate is usually used.

The tetrahydroisophthalimide derivative represented by the general formula (IV), which is a raw material for producing the compound of the present invention, can be prepared, for example, by the general formula (V).

[0051]

[Chemical 17]

[In the formula, X ¹ , X ² and R ¹ have the same meanings as described above. ] And an aniline derivative represented by the general formula (V
I)

[0053]

[Chemical 18]

[In the formula, R ² has the same meaning as described above. ]
By reacting 3,4,5,6-tetrahydrophthalic anhydride represented by the formula (II) with an organic solvent at a low temperature of preferably less than 50 ° C.

[0055]

[Chemical 19]

[In the formula, X ¹ , X ² , R ¹ and R ² have the same meanings as described above. ] To a hydroxy derivative of 3,4,5,6-tetrahydroisophthalimide, and then reacting this in the presence of a dehydrating agent (the following Reference Example- 3-1
4).

Usually, in the reaction between the aniline derivative represented by the general formula (V) and the 3,4,5,6-tetrahydrophthalic anhydride represented by the general formula (VI), the general formula (VI
I ')

[0058]

[Chemical 20]

[In the formula, X ¹ , X ² , R ¹ and R ² have the same meanings as described above. ] When the aniline derivative (V) having a cycloalkyloxy group at the 5-position of the phenyl ring is used, a general formula (VII) is obtained. Indicated by 3,
Isolated as the hydroxy derivative of 4,5,6-tetrahydroisophthalimide.

The 3,4,5,6-tetrahydrophthalimide derivative represented by the above general formula (IV), which is the starting material for the compound of the present invention which can be produced in this manner, is N- (2-fluoro). -4-chloro-5-cyclopropyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide, N- (2-fluoro-4-chloro-
5-cyclopentyloxyphenyl) -3,4,5,6-
Tetrahydroisophthalimide, N- {2-fluoro-
4-chloro-5- (2-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydroisophthalimide, N- {2-fluoro-4-chloro-5- (3-methylcyclopentyl) oxyphenyl} -3,4,5,6
-Tetrahydroisophthalimide, N- (2-fluoro-4-chloro-5-cyclohexyloxyphenyl)-
3,4,5,6-tetrahydroisophthalimide, N-
{2-Fluoro-4-chloro-5- (2-chlorocyclohexyl) oxyphenyl} -3,4,5,6-tetrahydroisophthalimide, N- (2-fluoro-4-chloro-5-cyclooctyloxyphenyl ) -3,4,5,
6-tetrahydroisophthalimide, N- (2-fluoro-4-bromo-5-cyclopropyloxyphenyl)
-3,4,5,6-tetrahydroisophthalimide, N-
(2-Fluoro-4-bromo-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide, N- {2-fluoro-4-bromo-5- (2-
Methylcyclopentyl) oxyphenyl} -3,4,5,
6-tetrahydroisophthalimide, N- {2-fluoro-4-bromo-5- (3-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydroisophthalimide, N- (2-fluoro-4- Bromo-5-cyclohexyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide, N- (2,4-dichloro-5-
Cyclopropyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide, N- (2,4-dichloro-
5-cyclopentyloxyphenyl) -3,4,5,6-
Tetrahydroisophthalimide, N- {2,4-dichloro-5- (2-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydroisophthalimide,
N- {2,4-dichloro-5- (3-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydroisophthalimide, N- (2,4-dichloro-5-cyclohexyloxyphenyl) -3 , 4,5,6-Tetrahydroisophthalimide, N- (2,4-dichloro-5-
Cyclooctyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide, N- (2-fluoro-4-)
Chloro-5-cyclopentyloxyphenyl) -3-methyl-3,4,5,6-tetrahydroisophthalimide,
N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -4-methyl-3,4,5,6-tetrahydroisophthalimide, N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) ) -4-Chloro-3,4,5,6-tetrahydroisophthalimide, N
-{2-Fluoro-4-chloro-5- (3-methylcyclopentyl) oxyphenyl} -3-methyl-3,4,
5,6-Tetrahydroisophthalimide, N- {2-fluoro-4-chloro-5- (3-methylcyclopentyl) oxyphenyl} -4-methyl-3,4,5,6-tetrahydroisophthalimide, N- ( 2-fluoro-5
-Cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide, N- {2-fluoro-5
-(2-Methylcyclopentyl) oxyphenyl}-
3,4,5,6-tetrahydroisophthalimide, N-
{2-Fluoro-5- (3-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydroisophthalimide, N- (2-fluoro-5-cyclohexyloxyphenyl) -4-methyl-3,4 Examples thereof include 5,5,6-tetrahydroisophthalimide.

The aniline derivative represented by the general formula (V), which is a raw material for producing phthalimide (II) and isophthalimide (IV), can also be produced according to the method of Reference Example described in JP-A-4-164067. Can be produced, for example, according to the method illustrated in the following reaction formula (see Reference Examples-15 to 21 below).

[0062]

[Chemical 21]

[Wherein, X ¹ , X ² and R ¹ have the same meanings as described above. Z represents a halogen atom such as bromine or iodine, or a leaving group such as a sulfonyloxy group such as a p-toluenesulfonyloxy group, a benzenesulfonyloxy group and a methanesulfonyloxy group. ]

Further, the aniline derivative represented by the general formula (V) is represented by the hydroxyaniline derivative represented by the general formula (IX) (for example, JP-B-2-26622) and the general formula R ¹ Z (VIII). The cycloalkylating agent is reacted in the presence of an interlayer transfer catalyst, for example, with heating in a two-layer system of an aqueous sodium hydroxide solution and toluene, or in the presence of a base such as potassium carbonate, a solvent such as dimethylformamide. It can also be easily produced by reacting with heating in the following (Reference Example-22 below).
~ 27).

[0065]

[Chemical formula 22]

[In the formula, X ¹ , X ² and R ¹ have the same meanings as described above. Z represents a halogen atom such as bromine or iodine, or a leaving group such as a sulfonyloxy group such as a p-toluenesulfonyloxy group and a methanesulfonyloxy group. ]

The amines represented by the general formula (III), which are the starting materials for producing the compound of the present invention, may be commercially available compounds or compounds which can be synthesized by a general synthetic chemistry method. The amine may be used in a free form, but may also be used in a salt form which does not adversely influence the reaction. Examples of the salts of amines (III) include hydrogen halides such as hydrogen chloride and hydrogen bromide, sulfuric acid,
Inorganic or organic acid salts such as acetic acid and p-toluenesulfonic acid can be used.

Hereinafter, more detailed description will be given by showing Examples and Reference Examples, but the present invention is not limited to these examples.

[0069]

【Example】

 Example-1

[0070]

[Chemical formula 23]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), propylamine (0.190 g, 3.21 mmo
l) and benzene (25 mL) as a solvent were added, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N'-propyl-3,4,5,6-.
White crystals of tetrahydrophthalamide (0.360 g, yield 30.9
%).

Melting point: 138 to 140 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.78 (3 H, t, J = 6.0 Hz), 1.
40 (2H, m), 1.70 (4H, m), 1.87 (8H, m), 2.37 (4H, m),
3.18 (2H, dt, J = 6.0 and 6.0Hz), 4.80 (1H, m), 5.85 (1
H, m), 7.11 (1H, d, J _HF = 10.5Hz), 7.97 (1H, br s), 8.
08 (1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 1200, 1390, 1485, 1500, 1620, 1
640, 2950, 3250.

Example-2

[0074]

[Chemical formula 24]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), isopropylamine (0.600 g, 10.2 mm
ol) and benzene (25 mL) as a solvent, and the mixture was stirred overnight at room temperature. After the reaction was completed, the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N'-isopropyl-3,4,5,
White crystals of 6-tetrahydrophthalamide (0.700 g, yield
60.0%) was obtained.

Melting point: 169-171 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.00 (6 H, d, J = 6.0 Hz), 1.
67 (4H, m), 1.82 (8H, m), 2.37 (4H, m), 4.05 (1H, d & se
p, J = 6.0 and 6.0Hz), 4.80 (1H, m), 5.65 (1H, d, J = 6.0
Hz), 7.10 (1H, d, J _HF = 10.5Hz), 7.95 (1H, br s), 8.14
(1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 870, 1200, 1420, 1495, 1525, 16
30, 1650, 2950, 3300.

Example-3

[0078]

[Chemical 25]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.50).
g, 4.12 mmol), butylamine (0.420 g, 5.74 mmol),
And benzene (25 mL) was added as a solvent, and the mixture was stirred at room temperature overnight. After the reaction was completed, the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N'-butyl-3,4,5,6-.
White crystals of tetrahydrophthalamide (1.11 g, yield 61.7
%).

Melting point: 142-144 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.75 (3 H, t, J = 7.0 Hz), 1.
27 (4H, m), 1.70 (4H, m), 1.90 (8H, m), 2.37 (4H, m),
3.20 (2H, m), 4.82 (1H, m), 5.83 (1H, m), 7.10 (1H, d,
J _HF = 10.5Hz), 8.00 (1H, br s), 8.12 (1H, d, J _HF = 7.5H
z) .IR (KBr disk, cm ^-1 ): 670, 860, 1195, 1250, 1410, 149
0, 1520, 1640, 2950, 3300.

Example-4

[0082]

[Chemical formula 26]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), isobutylamine (0.240 g, 3.28 mmo
l), triethylamine (0.310 g, 3.06 mmol), and benzene (25 mL) as a solvent were added, and the mixture was stirred at room temperature overnight.
After the reaction was completed, the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2
White crystals (0.936 g, yield 77.8%) of -fluoro-4-chloro-5-cyclopentyloxyphenyl) -N'-isobutyl-3,4,5,6-tetrahydrophthalamide were obtained.

Melting point: 161-163 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.77 (6 H, d, J = 6.0 Hz), 1.
5 to 2.1 (13H, m), 2.40 (4H, m), 3.07 (2H, dd, J = 6.0H
z), 4.80 (1H, m), 5.95 (1H, br t, J = 6.0Hz), 7.18 (1H,
d, J _HF = 10.5Hz), 8.10 (1H, br s), 8.20 (1H, d, J _HF =
7.5Hz) .IR (KBr disk, cm ^-1 ): 860, 1180, 1240, 1410, 1480, 15
30, 1610, 1670, 2940, 3270.

Example-5

[0086]

[Chemical 27]

An eggplant-shaped flask (50 cc) was charged with N- {2-fluoro-4-chloro-5- (3-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydrophthalimide (1.20 g, 3.18). mmol), isobutylamine (0.
360 g, 4.92 mmol), triethylamine (0.450 g, 4.44
mmol) and benzene (25 mL) as a solvent, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- {2-fluoro-4
A white crystal (0.700 g, yield 48.7%) of -chloro-5- (3-methylcyclopentyl) oxyphenyl} -N'-isobutyl-3,4,5,6-tetrahydrophthalamide was obtained.

Melting point: 144-147 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.78 (6 H, d, J = 6.0 Hz), 1.
03 and 1.10 (total 3H, each d, J = 6.0Hz), 1.30 ~ 2.30
(12H, m), 2.35 (4H, m), 3.03 (2H, dd, J = 6.0and 6.0H
z), 4.75 (1H, m), 6.03 (1H, br t, J = 6.0Hz), 7.08 (1H,
d, J _HF = 10.5Hz), 8.05 (1H, d, J _HF = 7.5Hz), 8.12 (1H,
br s) .IR (KBr disk, cm ^-1 ): 860, 1190, 1410, 1490, 1520, 16
40, 2950, 3300.

Example-6

[0090]

[Chemical 28]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00
g, 2.75 mmol), 2,2-dimethylpropylamine (0.310
g, 3.56 mmol), triethylamine (0.280 g, 2.77 mmo
l) and benzene (25 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-
Chloro-5-cyclopentyloxyphenyl) -N'-
White crystals of (2,2-dimethylpropyl) -3,4,5,6-tetrahydrophthalamide (0.660 g, yield 53.1%) were obtained.

Melting point: 173-175 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.82 (9H, s), 1.72 (4H,
m), 1.85 (8H, m), 2.37 (4H, m), 3.00 (2H, d, J = 7.5H
z), 4.73 (1H, m), 5.83 (1H, t, J = 7.5Hz), 7.07 (1H, d,
J _HF = 10.5Hz), 8.00 (1H, br s), 8.07 (1H, d, J _HF = 7.5H
z) .IR (KBr disk, cm ^-1 ): 680, 860, 1190, 1490, 1640, 295
0, 3300.

Example-7

[0094]

[Chemical 29]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), hexylamine (0.330 g, 3.26 mmo
l), triethylamine (0.310 g, 3.06 mmol), and benzene (25 mL) as a solvent were added, and the mixture was stirred at room temperature overnight.
After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-
Cyclopentyloxyphenyl) -N'-hexyl-3,
White crystals of 4,5,6-tetrahydrophthalamide (1.06
g, yield 83.3%) was obtained.

Melting point: 128-130 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.82 (3 H, t, J = 6.0 Hz), 1.
13 (8H, m), 1.70 (4H, m), 1.87 (8H, m), 2.33 (4H, m),
3.18 (2H, dt, J = 6.0 and 6.0Hz), 4.77 (1H, m), 5.88 (1
H, m), 7.10 (1H, d, J _HF = 10.5Hz), 8.00 (1H, br s), 8.
12 (1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 858, 1185, 1400, 1480, 1510, 16
40, 2900, 3270.

Example-8

[0098]

[Chemical 30]

In an eggplant-shaped flask (50 cc), N- {2-fluoro-4-chloro-5- (3-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydrophthalimide (1.26 g, 3.33) was added. mmol), hexylamine (0.41
0 g, 4.05 mmol), triethylamine (0.380 g, 3.76 mm
ol) and benzene (25 mL) as a solvent, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- {2-fluoro-4-
White crystals of chloro-5- (3-methylcyclopentyl) oxyphenyl} -N'-hexyl-3,4,5,6-tetrahydrophthalamide (1.29 g, yield 80.8%) were obtained.

Melting point: 127 to 129 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.82 (3 H, br t), 1.00 to 2.
20 (22H, m), 2.40 (4H, m), 3.22 (2H, dt, J = 6.0 and 6.0
Hz), 4.85 (1H, m), 5.90 (1H, m), 7.18 (1H, d, J _HF = 10.5
Hz), 8.07 (1H, br s), 8.18 (1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 860, 1190, 1410, 1490, 1520, 16
40, 2950, 3200.

Example-9

[0102]

[Chemical 31]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), octylamine (0.460 g, 3.56 mmo
l), triethylamine (0.310 g, 3.06 mmol), and benzene (25 mL) as a solvent were added, and the mixture was stirred at room temperature overnight.
After completion of the reaction, the reaction mixture was poured into 1N-hydrochloric acid (50 mL),
It was extracted with ethyl acetate (50 mL x 3 times). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. By recrystallizing the obtained crude product from ether, N
White crystals (0.410 g, yield 30.2%) of-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N'-octyl-3,4,5,6-tetrahydrophthalamide were obtained.

Melting point: 127-130 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.86 (3 H, t, J = 6.0 Hz), 1.
48 (12H, m), 1.68 (4H, m), 1.87 (8H, m), 2.37 (4H, m),
3.18 (2H, dt, J = 6.0 and 6.0Hz), 4.77 (1H, m), 5.90 (1
H, t, J = 6.0 Hz), 7.08 (1H, d, J _HF = 10.5Hz), 8.03 (1H,
br s), 8.09 (1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 680, 850, 970, 1020, 1180, 125
0, 1290, 1400, 1480, 1520, 1620, 2900, 3250

Example-10

[0106]

[Chemical 32]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), decylamine (0.520 g, 3.31 mmol),
Triethylamine (0.310 g, 3.06 mmol) and benzene (25 mL) as a solvent were added, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N'-decyl-3,4,5,
White crystals of 6-tetrahydrophthalamide (1.06 g, yield 7
3.8%) was obtained.

Melting point: 128 to 130 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.72 (3 H, br t, J = 6.0 Hz),
1.22 (16H, m), 1.70 (4H, m), 1.88 (8H, m), 2.37 (4H,
m), 3.17 (2H, dt, J = 6.0 and 6.0Hz), 4.75 (1H, m), 5.
83 (1H, br t, J = 6.0Hz), 7.07 (1H, d, J _HF = 10.5Hz), 7.
97 (1H, br s), 8.07 (1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 860, 1190, 1250, 1410, 1490, 15
20, 1640, 2925, 3300.

Example-11

[0110]

[Chemical 33]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), 40% dimethylamine aqueous solution (0.410
g, 3.64 mmol) and carbon tetrachloride (25 mL) were added, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and hexane was added to the obtained semi-solid to recrystallize the mixture to obtain N 2.
White crystals of-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N ', N'-dimethyl-3,4,5,6-tetrahydrophthalamide (0.410 g, yield 36.4
%).

Melting point: 136-138 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.73 (4H, m), 1.85 (8H,
m), 2.33 (4H, m), 2.91 (3H, s), 2.92 (3H, s), 4.77 (1
H, m), 7.05 (1H, d, J _HF = 10.5Hz), 7.93 (1H, d, J _HF = 7.
5Hz), 8.30 (1H, br s) .IR (KBr disk, cm ^-1 ): 870, 1190, 1280, 1395, 1500, 16
20, 2950, 3200.

Example-12

[0114]

[Chemical 34]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), cyclohexylamine (0.360 g, 3.63
mmol) and benzene (25 mL) as a solvent, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4
-Chloro-5-cyclopentyloxyphenyl) -N '
White crystals of -cyclohexyl-3,4,5,6-tetrahydrophthalamide (0.579 g, yield 45.5%) were obtained.

Melting point: 209 to 211 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.8 to 2.1 (22 H, m), 2.37 (4
H, m), 3.75 (1H, m), 4.78 (1H, m), 5.70 (1H, br d, J =
7.5Hz), 7.10 (1H, d, J _HF = 10.5Hz), 7.93 (1H, br s), 8.
13 (1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 860, 1180, 1240, 1400, 1480, 15
10, 1605, 1640, 2900, 3270.

Example-13

[0118]

[Chemical 35]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00
g, 2.75 mmol), 2-methylcyclohexylamine (0.62
0 g, 5.48 mmol) and benzene (25 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '-(2-methylcyclohexyl) -3,4,5,
White crystals of 6-tetrahydrophthalamide (0.373 g, yield
28.4%).

Melting point: 192-195 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.73 and 0.74 (tot
al 3H, each d, J = 7.0Hz), 1.10 to 2.10 (21H, m), 2.40
(4H, m), 3.43 and 4.02 (total 1H, each m), 4.77 (1H,
m), 5.59 and 5.84 (total 1H, each br d, J = 6.5 and
8.5Hz), 7.097 and 7.099 (total 1H, each d, J _HF = 10.5
Hz and 10.5Hz), 8.01 and 8.10 (total 1H, each br
s), 8.14 and 8.17 (total 1H, each d, J _HF = 7.5 and 7.
5Hz) .IR (KBr disk, cm ^-1 ): 860, 1190, 1250, 1410, 1490, 15
20, 1620, 1642, 2940, 3300.

Example-14

[0122]

[Chemical 36]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), exo-2-aminonorbornane (0.390
g, 3.51 mmol), triethylamine (0.310 g, 3.06 mmo
l) and benzene (25 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-
Chloro-5-cyclopentyloxyphenyl) -N'-
White crystals (0.474 g, yield 36.3%) of (exo-norbornyl) -3,4,5,6-tetrahydrophthalamide were obtained.

Melting point: 231-233 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.90-2.20 (22 H, m), 2.30
(4H, m), 3.70 (1H, m), 4.83 (1H, m), 5.75 (1H, d, J =
7.5Hz), 7.18 (1H, d, J _HF = 10.5Hz), 8.00 (1H, br s),
8.23 (1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 680, 860, 1190, 1240, 1410, 152
0, 1610, 1640, 1678, 2950, 3300.

Example-15

[0126]

[Chemical 37]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), (-)-cis-miltanylamine (0.460
g, 3.00 mmol), triethylamine (0.310 g, 3.06 mmo
l) and benzene (20 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-
Chloro-5-cyclopentyloxyphenyl) -N'-c
White crystals of is-miltanyl-3,4,5,6-tetrahydrophthalamide (0.780 g, yield 56.0%) were obtained.

Melting point: 175 to 177 ° C. Optical rotation: [α] _D = -1.03 (c = 0.962, CHCl ₃ , 20 ° C.) ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.93 (3 H, s ), 1.10 (3H,
s), 1.20 ~ 2.10 (27H, m), 2.35 (4H, m), 3.18 (2H, dd,
J = 6.0 and 1.5Hz), 4.73 (1H, m,), 5.80 (1H, m), 7.05 (1
H, d, J _HF = 10.5Hz), 7.92 (1H, br s), 8.08 (1H, d, J _HF
= 7.5Hz) .IR (KBr disk, cm ^-1 ): 860, 1180, 1240, 1400, 1520, 16
20, 2950, 3250.

Example-16

[0130]

[Chemical 38]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (0.700).
g, 1.92 mmol), pyrrolidine (0.200 g, 2.81 mmol), and benzene (25 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 1N-hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL x 3 times). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from ether / hexane to give N- (2-fluoro-4-chloro-5).
A white crystal (0.610 g, yield 72.9%) of -cyclopentyloxyphenyl) -N ', N'-tetramethylene-3,4,5,6-tetrahydrophthalamide was obtained.

Melting point: 132 to 134 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.1 to 2.1 (16 H, m), 2.38 (4
H, m), 3.38 (4H, br t, J = 7.5Hz), 4.77 (1H, m), 7.08
(1H, d, J _HF = 10.5Hz), 8.01 (1H, d, J _HF = 7.5Hz), 8.33
(1H, br s) .IR (KBr disk, cm ^-1 ): 860, 1190, 1275, 1385, 1440, 14
90, 1600, 2920, 3150.

Example-17

[0134]

[Chemical Formula 39]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (0.700).
g, 1.92 mmol), piperidine (0.210 g, 2.47 mmol), and benzene (25 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 1N-hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL x 3 times). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from ether / hexane to give N- (2-fluoro-4-chloro-5).
A white crystal (0.263 g, yield 30.5%) of -cyclopentyloxyphenyl) -N ', N'-pentamethylene-3,4,5,6-tetrahydrophthalamide was obtained.

Melting point: 113-116 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.50 (6H, m), 1.75 (4H,
m), 1.87 (8H, m), 2.33 (4H, m), 3.30 (2H, m), 3.53 (2
H, m), 4.77 (1H, m), 7.07 (1H, d, J _HF = 10.5Hz), 8.10 (1
H, d, J _HF = 7.5Hz), 8.43 (1H, br s) .IR (KBr disk, cm ^-1 ): 860, 1180, 1250, 1400, 1480, 15
20, 1615, 1650, 2900, 3250.

Example-18

[0138]

[Chemical 40]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.50).
g, 4.12 mmol), hexamethyleneimine (0.610 g, 6.15)
mmol) and benzene (25 mL) as a solvent, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4
-Chloro-5-cyclopentyloxyphenyl) -N ',
White crystals (1.55 g, yield 81.1%) of N'-hexamethylene-3,4,5,6-tetrahydrophthalamide were obtained.

Melting point: 130 to 132 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.25 to 2.10 (20 H, m), 2.33
(4H, m), 3.25 ~ 3.65 (4H, m), 4.77 (1H, m), 7.08 (1H,
d, J _HF = 10.5Hz), 8.17 (1H, d, J _HF = 7.5Hz), 8.63 (1H, b
rs) .IR (KBr disk, cm ^-1 ): 675, 860, 1190, 1240, 1405, 149
0, 1520, 1600, 1670, 2900, 3300.

Example-19

[0142]

[Chemical 41]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), morpholine (0.320 g, 3.67 mmol), and benzene (20 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N ', N'-diethyleneoxy-3,4,5,6-tetrahydrophthalamide. White crystals (0.566 g, yield 45.8%) were obtained.

Melting point: 135-137 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.75 (4H, m), 1.88 (8H,
m), 2.37 (4H, m), 3.45 (4H, m), 3.57 (4H, m), 4.82 (1
H, m), 7.17 (1H, d, J _HF = 10.5Hz), 8.18 (1H, d, J _HF = 7.
5Hz), 8.23 (1H, br s) .IR (KBr disk, cm ^-1 ): 860, 990, 1105, 1185, 1240, 141
0, 1490, 1530, 1620, 2920, 3270.

Example-20

[0146]

[Chemical 42]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), benzylamine (0.350 g, 3.27 mmo
l) and benzene (25 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N'-benzyl-3,4,5,6-tetrahydrophthalamide as white crystals ( 0.584 g, yield 45.1%) was obtained.

Melting point: 145-148 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.68 (4H, m), 1.94 (8H,
m), 2.38 (4H, m), 4.37 (1H, d, J = 6.0Hz), 4.72 (1H,
m), 6.20 (1H, br t, J = 6.0Hz), 7.07 (1H, d, J _HF = 10.0H
z), 7.13 (5H, s), 7.93 (1H, br s), 8.02 (1H, d, J = 7.5
Hz) .IR (KBr disk, cm ^-1 ): 670, 698, 730, 860, 1190, 1250,
1410, 1490, 1520, 1640, 2950, 3300.

Example-21

[0150]

[Chemical 43]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (0.500).
g, 1.37 mmol), 2-chlorobenzylamine (0.240 g,
1.69 mmol), and benzene (25 mL) as a solvent,
Stir overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This product was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl).
A white crystal (0.590 g, yield 85.4%) of -N '-(2-chlorobenzyl) -3,4,5,6-tetrahydrophthalamide was obtained.

Melting point: 181-183 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.68 (4H, m), 1.87 (8H,
m), 2.37 (4H, m), 4.42 (2H, d, J = 6.0Hz), 4.72 (1H,
m), 6.35 (1H, br t, J = 6.0Hz), 6.9 ~ 7.4 (5H, m), 7.75
(1H, br s), 8.02 (1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 750, 1420, 1500, 1540, 1623, 16
90, 3000, 3320.

Example-22

[0154]

[Chemical 44]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (0.700).
g, 1.92 mmol), 4-methylbenzylamine (0.330 g,
2.72 mmol), and benzene (25 mL) as a solvent,
Stir overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This product was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl).
White crystals of -N '-(4-methylbenzyl) -3,4,5,6-tetrahydrophthalamide (0.741 g, yield 79.7%) were obtained.

Melting point: 168 to 169 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.68 (4H, m), 1.88 (8H,
m), 2.23 (3H, s), 2.38 (4H, m), 4.33 (2H, d, J = 6.0H
z), 4.72 (1H, m), 6.25 (1H, t, J = 6.0Hz), 6.92 (2H, d,
J = 7.5Hz), 7.07 (2H, d, J = 7.5Hz), 7.13 (1H, d, J = 10.
5Hz), 8.00 (1H, brs), 8.05 (1H, d, J = 7.5Hz) .IR (KBr disk, cm ^-1 ): 870, 1200, 1420, 1500, 1530, 16
30, 1650, 2970, 3320.

Example-23

[0158]

[Chemical formula 45]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), 4-methoxybenzylamine (0.380
g, 2.77 mmol), triethylamine (0.310 g, 3.06 mmo
l) and benzene (20 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was recrystallized from ether / hexane to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '. White crystals (0.520 g, yield 37.8%) of-(4-methoxybenzyl) -3,4,5,6-tetrahydrophthalamide were obtained.

Melting point: 161-162 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.67 (4H, m), 1.83 (8H,
m), 2.33 (4H, m), 3.67 (3H, s), 4.28 (2H, d, J = 6.0H
z), 4.67 (1H, m), 6.07 (1H, m), 6.53 (2H, d, J = 9.0H
z), 6.95 (2H, d, J = 9.0Hz), 7.02 (1H, d, J _HF = 10.5Hz),
7.83 (1H, br s), 7.92 (1H, d, J = 7.5Hz) .IR (KBr disk, cm ^-1 ): 610, 820, 860, 1040, 1180, 125
0, 1410, 1510, 1620, 2950, 3275.

Example-24

[0162]

[Chemical formula 46]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.50).
g, 4.12 mmol), R-(+)-1-phenylethylamine (0.
650 g, 5.36 mmol) and benzene (25 mL) as a solvent were added, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-
Fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '-(1-phenylethyl) -3,4,5,6-
White crystals of tetrahydrophthalamide (1.20 g, yield 60.0
%).

Melting point: 176 to 178 ° C. Optical rotation: [α] _D = + 30.30 (c = 0.970, CHCl ₃ , 20 ° C.) ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.35 (3 H, d , J = 7.5Hz), 1.
67 (4H, m), 1.87 (8H, m), 2.35 (4H, m), 4.72 (1H, m),
5.03 (1H, dq, J = 7.5 and 7.5Hz), 6.07 (1H, d, J = 7.5H
z), 7.07 (1H, d, J _HF = 10.5Hz), 7.10 (5H, s), 7.83 (1H,
br s), 8.07 (1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 700, 860, 1190, 1250, 1405, 151
0, 1640, 2950, 3300.

Example-25

[0166]

[Chemical 47]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.10).
g, 2.75 mmol), S-(-)-1-phenylethylamine (0.
400 g, 3.30 mmol), triethylamine (0.310 g, 3.06
mmol) and benzene (25 mL) as a solvent, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4
-Chloro-5-cyclopentyloxyphenyl) -N '
A white crystal (0.945 g, yield 70.9%) of-(1-phenylethyl) -3,4,5,6-tetrahydrophthalamide was obtained.

Melting point: 173-175 ° C. Optical rotation: [α] _D = −27.36 (c = 0.994, CHCl ₃ , 20 ° C.) ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.33 (3 H, d , J = 7.5Hz), 1.
70 (4H, m), 1.83 (8H, m), 2.33 (4H, m), 4.70 (1H, m),
5.02 (1H, dq, J = 7.5Hz and 7.5Hz), 6.10 (1H, d, J = 7.5H
z), 7.02 (1H, d, J _HF = 10.5Hz), 7.10 (5H, s), 7.83 (1H,
br s), 8.03 (1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 690, 878, 1182, 1400, 1480, 151
0, 1620, 1640, 2950, 3250.

Example-26

[0170]

[Chemical 48]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00
g, 2.75 mmol), (±) -1-phenylethylamine (0.43
3 g, 3.57 mmol), triethylamine (0.310 g, 3.06 mm
ol) and benzene (25 mL) as a solvent, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-
Chloro-5-cyclopentyloxyphenyl) -N'-
White crystals of (1-phenylethyl) -3,4,5,6-tetrahydrophthalamide (1.069 g, yield 80.0%) were obtained.

Melting point: 169 to 171 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.35 (3 H, d, J = 7.5 Hz), 1.
70 (4H, m), 1.90 (8H, m), 2.37 (4H, m), 4.78 (1H, m),
5.07 (1H, dq, J = 7.5 and 7.5Hz), 6.15 (1H, d, J = 7.5H
z), 7.12 (1H, d, J _HF = 10.5Hz), 7.20 (5H, s), 7.93 (1H,
br s), 8.12 (1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 700, 870, 1200, 1258, 1410, 149
0, 1520, 1622, 1640, 2950, 3300.

Example-27

[0174]

[Chemical 49]

An eggplant-shaped flask (50 cc) was charged with N- {2-fluoro-4-chloro-5- (3-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydrophthalimide (1.00 g, 2.65). mmol), R-(+)-1-phenylethylamine (0.530 g, 4.37 mmol), triethylamine (0.340 g, 0.470 mmol), and benzene (25
(mL), and stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration.
This was washed with hexane and dried to give N-
White crystals of {2-fluoro-4-chloro-5- (3-methylcyclopentyl) oxyphenyl} -N '-(1-phenylethyl) -3,4,5,6-tetrahydrophthalamide (1.297 g, yield Rate 98.1%).

Melting point: 176-179 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.02 and 1.10 (total 3 H,
each d, J = 6.0 and 6.0Hz), 1.37 (3H, d, J = 7.5Hz), 1.
68 (4H, m), 1.80 ~ 2.30 (7H, m), 2.38 (4H, m), 4.78 (1H,
m), 5.10 (1H, dq, J = 7.5 and 7.5Hz), 6.17 (1H, d, J =
7.5Hz), 7.13 (1H, d, J _HF = 10.5Hz), 7.31 (5H, s), 8.00
(1H, br s), 8.13 (1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 700, 1190, 1410, 1482, 1520, 16
20, 1640, 2950, 3300.

Example-28

[0178]

[Chemical 50]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclohexyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00
g, 2.65 mmol), R-(+)-1-phenylethylamine (0.
65 g, 5.36 mmol), triethylamine (0.268 g, 2.65 m
mol) and benzene (25 mL) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-chloro-
White crystals of 5-cyclohexyloxyphenyl) -N '-(1-phenylethyl) -3,4,5,6-tetrahydrophthalamide (1.09 g, yield 82.3%) were obtained. $ Melting point: 156-159 ° C Optical rotation: [α] _D = +34.69 (c = 0.980, CHCl ₃ , 20 ° C) ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.37 (3H, d, J = 7.5Hz), 1.
25 ~ 2.20 (14H, m), 2.38 (4H, m), 4.25 (1H, m), 5.09 (1
H, dq, J = 7.5 and 7.5Hz), 6.12 (1H, d, J = 7.5Hz), 7.0
4 (1H, d, J _HF = 10.5Hz), 7.20 (5H, s), 7.92 (1H, br s),
8.12 (1H, d, J _{H F} = 7.5Hz) .IR (KBr disk, cm ^-1 ): 700, 1180, 1405, 1480, 1518, 16
20, 1640, 2950, 3290.

Example-29

[0181]

[Chemical 51]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), R-(+)-1- (1-naphthyl) ethylamine (0.570 g, 3.33 mmol), triethylamine (0.310
g, 3.06 mmol) and benzene (25 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '-{1- (1-naphthyl) ethyl} -3,4,
White crystals of 5,6-tetrahydrophthalamide (0.950 g,
Yield 64.7%) was obtained.

Melting point: 198-201 ° C. Optical rotation: [α] _D = -32.67 (c = 1.010, CHCl ₃ , 20 ° C.) ¹ H-NMR (CDCl ₃ / DMSO-d ₆ , TMS, ppm): δ 1. 48 (3H, d, J = 7.
5Hz), 1.67 (4H, m), 1.83 (8H, m), 2.33 (4H, m), 4.63
(1H, m), 5.77 (1H, dq, J = 7.5 and 7.5Hz), 7.01 (1H,
d, J _HF = 10.5Hz), 7.20 ~ 8.20 (8H, m), 9.10 (1H, br s) .IR (KBr disk, cm ^-1 ): 678, 770, 860, 1185, 1250, 141
0, 1485, 1520, 1620, 1640, 2910, 3270.

Example-30

[0185]

[Chemical 52]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), S-(-)-1- (1-naphthyl) ethylamine (0.570 g, 3.33 mmol), triethylamine (0.310
g, 3.06 mmol) and benzene (25 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '-{1- (1-naphthyl) ethyl} -3,4,
White crystals of 5,6-tetrahydrophthalamide (0.410 g,
Yield 27.9%) was obtained.

Melting point: 196 to 199 ° C. Optical rotation: [α] _D = + 31.56 (c = 1.039, CHCl ₃ , 20 ° C.) ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.47 (3 H, d , J = 7.5Hz), 1.
67 (4H, m), 1.80 (8H, m), 2.30 (4H, m), 4.65 (1H, m),
5.77 (1H, dq, J = 7.5 and 7.5Hz), 7.00 (1H, d, J _HF = 10.5
Hz), 7.15 ~ 8.20 (8H, m), 9.08 (1H, br s) .IR (KBr disk, cm ^-1 ): 770, 860, 1190, 1410, 1480, 152
0, 1620, 1640, 2920, 3260.

Example-31

[0189]

[Chemical 53]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00
g, 2.75 mmol), 2- (3,4-dimethoxyphenyl) ethylamine (0.600 g, 3.31 mmol), triethylamine
(0.310 g, 3.06 mmol), and benzene (20 m
L) was added and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N-
White crystals of (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '-{2- (3,4-dimethoxyphenyl) ethyl} -3,4,5,6-tetrahydrophthalamide (1.16 g , Yield 77.5%) was obtained.

Melting point: 159 to 161 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.70 (4H, m), 1.88 (8H,
m), 2.38 (4H, m), 2.62 (2H, t, J = 7.5Hz), 3.48 (2H, d
t, J = 6.0 and 7.5Hz), 3.87 (6H, s), 4.80 (1H, m), 5.9
2 (1H, br t, J = 6.0Hz), 6.70 (2H, m), 6.75 (1H, dt, J =
9.0Hz), 7.17 (1H, d, J _HF = 10.5Hz), 8.10 (1H, br s), 8.
18 (1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 1122, 1200, 1260, 1415, 1490, 1
520, 1620, 2950, 3195.

Example-32

[0193]

[Chemical 54]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (0.800).
g, 2.20 mmol), 2-aminomethylnaphthalene (0.380
g, 2.42 mmol), triethylamine (0.240 g, 2.37 mmo
l) and benzene (25 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-
Chloro-5-cyclopentyloxyphenyl) -N'-
White crystals (0.200 g, yield 17.5%) of (2-naphthylmethyl) -3,4,5,6-tetrahydrophthalamide were obtained.

Melting point: 174 to 175 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.77 (12 H, m), 2.37 (4 H,
m), 4.48 (2H, d, J = 7.0Hz), 6.27 (1H, m), 6.86 (1H, d,
J _HF = 10.5Hz), 7.2 ~ 8.1 (9H, m) .IR (KBr disk, cm ^-1 ): 858, 1182, 1405, 1480, 1520, 16
20, 1640, 2925, 3250.

Example-33

[0197]

[Chemical 55]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (2.00
g, 5.50 mmol), 2- (aminomethyl) pyridine (0.710
g, 6.57 mmol), triethylamine (0.610 g, 6.03 mmo
l) and benzene (40 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-
Chloro-5-cyclopentyloxyphenyl) -N'-
White crystals (1.410 g, yield 54.2%) of (2-pyridyl) methyl-3,4,5,6-tetrahydrophthalamide were obtained.

Melting point: 144 to 148 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.40 to 2.0 (12 H, m), 2.42
(4H, m), 4.52 (2H, d, J = 6.0Hz), 4.69 (1H, m), 7.03 (1
H, d, J _HF = 10.5Hz), 7.30 (2H, m), 7.50 (1H, m), 7.97
(1H, br s), 7.98 (1H, d, J _HF = 7.5Hz), 8.43 (1H, d, J =
4.5Hz) .IR (KBr disk, cm ^-1 ): 750, 850, 1190, 1240, 1400, 148
0, 1520, 1640, 2925, 3300.

Example-34

[0201]

[Chemical 56]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), furfurylamine (0.320 g, 3.29 mmo
l) and acetonitrile (25 mL) as a solvent were added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This product was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl).
Light brown crystals of -N'-furfuryl-3,4,5,6-tetrahydrophthalamide (0.860 g, yield 68.0%) were obtained.

Melting point: 152-153 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.68 (4H, m), 1.85 (8H,
m), 2.36 (4H, m), 4.27 (2H, d, J = 6.0Hz), 4.63 (1H,
m), 5.98 (2H, br s), 6.15 (1H, m), 6.92 (1H, br s),
6.95 (1H, d, J _HF = 10.5Hz), 7.78 (1H, br s), 7.97 (1H,
d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 1190, 1260, 1410, 1520, 1640, 2
950, 3290.

Example-35

[0205]

[Chemical 57]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), propargylamine (0.180 g, 3.27 mm
ol) and benzene (25 mL) as a solvent, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was recrystallized from chloroform / hexane to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '. -Propargil-
White crystals of 3,4,5,6-tetrahydrophthalamide (0.36
6 g, yield 31.8%) was obtained.

Melting point: 153-156 ° C. ¹ H-NMR (CDCl ₃ / DMSO-d ₆ , TMS, ppm): δ 1.70 (4 H, m), 1.8
5 (8H, m), 2.00 (1H, t, J = 3.0Hz), 2.38 (4H, m), 3.97
(2H, dd, J = 3.0 and 5.0Hz), 4.78 (1H, m), 7.11 (1H,
d, J _HF = 10.5Hz), 7.38 (1H, m), 8.10 (1H, d, J _HF = 7.5H
z), 8.53 (1H, br s) .IR (KBr disk, cm ^-1 ): 630, 660, 865, 1190, 1250, 129
0, 1410, 1490, 1520, 1642, 2950, 3300.

Example-36

[0209]

[Chemical 58]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00
g, 2.75 mmol) and tetrahydrofuran (20 m
L) was added, 25% ammonia water was excessively injected, and the mixture was further stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were filtered off, washed with hexane and dried to give N- (2-fluoro-4-chloro-5).
-Cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalamide white crystals (0.400 g, yield 38.2
%).

Melting point: 200 to 201 ° C. ¹ H-NMR (CDCl ₃ + DMSO-d ₆ , TMS, ppm): δ1.65 to 1.82 (12
H, m), 2.34 (4H, m), 2.54 (2H, br s), 4.69 (1H, m),
7.00 (1H, d, J _HF = 10.5Hz), 7.95 (1H, d, J _HF = 7.5Hz),
8.60 (1H, br s) .IR (KBr disk, cm ^-1 ): 870, 960, 1160, 1190, 1240, 126
0, 1280, 1390, 1520, 1610, 1640, 2950, 3300, 3450.

Example-37

[0213]

[Chemical 59]

In a round-bottomed flask (100 cc), methylamine hydrochloride (1.70 g, 24.8 mmol) and potassium carbonate (1.70 g, 12.3 g) were added.
mmol) and acetonitrile (5 mL) as a solvent, and the mixture was stirred at room temperature. After confirming the generation of carbon dioxide gas, N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (5.88
g, 16.2 mmol) was added and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N'-methyl-3,4,5,6.
-White crystals of tetrahydrophthalamide (4.79 g, 74.
9%).

Melting point: 179 to 180 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.68 (4H, m), 1.87 (8H,
m), 2.35 (4H, m), 2.71 (3H, d, J = 5.4Hz), 4.77 (1H,
m), 5.89 (1H, br s), 7.08 (1H, d, J _HF = 10.5Hz), 7.97
(1H, br s), 7.98 (1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 868, 1174, 1196, 1244, 1418, 14
90, 1532, 1550, 1616, 1650, 1684, 2950, 3310.

Example-38

[0217]

[Chemical 60]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (0.500).
g, 1.37 mmol) and benzene (30 mL) as a solvent were added, and ethylamine (0.900 g, 20.0 mmol) was blown thereinto, followed by stirring at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were filtered off, washed with hexane and dried to give N- (2-fluoro-4-chloro-
5-cyclopentyloxyphenyl) -N'-ethyl-
White crystals of 3,4,5,6-tetrahydrophthalamide (0.39
0 g, yield 69.4%) was obtained.

Melting point: 187-189 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.00 (3 H, t, J = 7.5 Hz), 1.
67 (4H, m), 1.85 (8H, m), 2.33 (4H, m), 3.20 (2H, dq, J
= 3.0 and 6.0Hz), 4.72 (1H, m), 5.82 (1H, brt, J = 3.0H
z), 7.01 (1H, d, J _HF = 9.0Hz), 7.89 (1H, br s), 8.02 (1
H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 860, 1190, 1250, 1410, 1480, 15
20, 1600, 1620, 1640, 1670, 2925, 3300.

Example-39

[0221]

[Chemical formula 61]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (0.900).
g, 2.47 mmol), (S)-(+)-sec-butylamine (0.235
g, 3.21 mmol), N-methylmorpholine (0.270 g, 2.67
mmol) and benzene (25 mL) as a solvent, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4
-Chloro-5-cyclopentyloxyphenyl) -N '
White crystals of-(sec-butyl) -3,4,5,6-tetrahydrophthalamide (0.300 g, yield 27.8%) were obtained.

Melting point: 174 to 175 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.77 and 0.91 (t
otal 3H, each t, J = 7.4 and 7.3Hz), 1.00 and 1.17 (t
otal 3H, each d, J = 6.6 and 6.6Hz), 1.35 and 1.52 (t
otal 2H, each qui, J = 7.3 and 7.3Hz), 1.62 (2H, m),
1.71 (4H, m), 1.88 (6H, m), 2.39 (4H, m), 4.78 and
4.83 (total 1H, each m), 5.60 and 6.02 (total 1H, ea
ch d, J _HF = 10.2 and 10.2Hz), 7.99 (total 1H, br s),
8.15 and8.24 (total 1H, each d, J _HF = 7.2 and 7.1Hz),
9.09 (1H, br s) .IR (KBr disk, cm ^-1 ): 680, 860, 1190, 1250, 1410, 149
0, 1520, 1600, 1620, 1640, 1670, 2950, 2975, 3275.

Example-40

[0225]

[Chemical formula 62]

An eggplant-shaped flask (25 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (0.500).
g, 1.37 mmol) and 2-methoxyethylamine (0.118 g,
1.57 mmol), and benzene (15 mL) as a solvent,
It was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained crystals were isolated by filtration. After washing with hexane and thoroughly drying, N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-
White crystals (0.232 g, yield 38.6%) of N '-(2-methoxyethyl) -3,4,5,6-tetrahydrophthalamide were obtained.

Melting point: 151-151.5 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.64 (4 H, m), 1.71
(2H, m), 1.85 (2H, m), 1.89 (4H, m), 2.38 (2H, m), 2.
41 (2H, m), 3.20 (3H, s), 3.31 (2H, t, J = 5.2Hz), 3.40
(2H, dt, J = 5.2 and 5.2Hz), 4.80 (1H, m), 6.15 (1H,
t, J = 5.2Hz), 7.11 (1H, d, J _HF = 10.2Hz), 7.96 (1H, br
s), 8.13 (1H, d, J _HF = 7.2Hz) .IR (KBr disk, cm ^-1 ): 860, 1125, 1196, 1250, 1412, 14
88, 1518, 1604, 1630, 1644, 1670, 2950, 3280.

Example-41

[0229]

[Chemical formula 63]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (0.900).
g, 2.47 mmol), (±) -trans-1,2-diaminocyclohexane (0.282 g, 2.47 mmol), triethylamine
(0.250 g, 2.47 mmol), and benzene (20 m
L) was added and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was recrystallized from hexane to give N- (2-fluoro-4-chloro-5).
A white crystal (0.340 g, yield 28.8%) of -cyclopentyloxyphenyl) -N '-(2-aminocyclohexyl) -3,4,5,6-tetrahydrophthalamide was obtained.

Melting point: 143-146 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.02 (1 H, m), 1.23
(4H, m), 1.55 (4H, m), 1.62 (6H, m), 1.72 (6H, m), 2.
35 (6H, m), 3.25 and 3.47 (total 1H, each dt, J = 4.3
and 11.1Hz, J = 4.1 and 15.0Hz), 4.78 (1H, m), 5.84 (1
H, d, J = 8.51Hz), 7.11 (1H, d, J _HF = 10.2Hz), 8.02 (1H,
br s), 8.07 and 8.12 (total 1H, eachd, J _HF = 7.5 and
7.2Hz) .IR (KBr disk, cm ^-1 ): 680, 870, 1190, 1250, 1290, 133
0, 1360, 1400, 1410,1450, 1500, 1550, 1620, 1650,
2900, 2950, 3250, 3300.

Example-42

[0233]

[Chemical 64]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00
g, 2.75 mmol), (−)-R, R-1,2-diaminocyclohexane (0.314 g, 2.75 mmol), triethylamine
(0.306 g, 3.06 mmol) and benzene (30 m
L) was added and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were separated by filtration, washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '. -(2
-Aminocyclohexyl) -3,4,5,6-tetrahydrophthalamide was obtained as white crystals (0.110 g, yield 8.4%).

Melting point: 143-145 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.12-1.42 (8 H, m), 1.72
(4H, m), 1.85 (8H, m), 2.38 (6H, m), 3.47 (1H, d, J =
9.0Hz), 4.79 (1H, m), 5.87 (1H, br d, J = 9.0Hz), 7.13
(1H, d, J _HF = 10.5Hz), 8.12 (1H, br s), 8.15 (1H, d, J
_HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 600, 860, 1190, 1250, 1360, 141
0, 1480, 1510, 1550, 1620, 1640, 1670, 2850, 2950,
3300, 3350.

Example-43

[0237]

[Chemical 65]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), ethyl 4-amino-1-piperidinecarboxylate (0.620 g, 3.60 mmol), triethylamine (0.310 g, 3.06 mmol), and benzene (2
(5 mL) was added, and the mixture was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was recrystallized from ether to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '-(. 1-
Ethoxycarbonyl-4-piperidyl) -3,4,5,6
-White crystals of tetrahydrophthalamide (0.732 g, yield 5
0.9%) was obtained.

Melting point: 194-196 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.23 (3 H, t, J = 7.1)
Hz), 1.63 (2H, m), 1.17 ~ 1.77 (7H, m), 1.81 ~ 1.96 (7
H, m), 2.38 (4H, br d, J = 6.9Hz), 2.85 and 2.96 (tota
l 2H, each dt, J = 2.7 and 12.1Hz, J = 3.1 and 11.1H
z), 3.86 ~ 3.96 (3H, m), 4.09 and 4.12 (2H, each q,
J = 7.1 and 7.1Hz), 4.78 (1H, m), 5.76 (1H, d, J = 5.8H
z), 7.12 (1H, d, J _HF = 10.2Hz), 7.78 and 7.84 (1H, eac
h br s), 8.11 and 8.21 (1H, each d, J _HF = 7.2 and 7.1
Hz). IR (KBr disk, cm ^-1 ): 1140, 1180, 1220, 1240, 1310, 1
400, 1430, 1480, 1510, 1620, 1630, 1690, 2900, 325
0.

Example-44

[0241]

[Chemical formula 66]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), β-phenylethylamine (0.333 g,
2.75 mmol) and benzene (8 mL) / hexane (1
(2 mL) was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction,
The solvent was distilled off under reduced pressure, and the precipitated crystals were filtered off, washed with hexane and dried to give N- (2-fluoro-
4-chloro-5-cyclopentyloxyphenyl)-
White crystals (0.840 g, yield 62.9%) of N '-(2-phenylethyl) -3,4,5,6-tetrahydrophthalamide were obtained.

Melting point: 165 to 166 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.65 (4H, m), 1.85 (8H,
m), 2.31 (4H, m), 2.64 (2H, t, J = 6.0Hz), 3.43 (2H, q,
J = 6.0Hz), 4.65 (1H, m), 5.74 (1H, br t, J = 6.0Hz),
6.96 ~ 7.16 (6H, m), 7.95 (1H, br s), 8.02 (1H, d, J _HF
= 7.5Hz) .IR (KBr disk, cm ^-1 ): 690, 860, 1190, 1250, 1410, 148
0, 1520, 1540, 1600, 1620, 1640, 2950, 3275.

Example-45

[0245]

[Chemical formula 67]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), thiazolidine (0.245 g, 2.75 mmo
l), triethylamine (4 drops) and benzene as solvent
(15 mL) / hexane (10 mL) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crude product was recrystallized from ether / hexane,
White crystal of N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -2-thiazolinocarbonyl-1-cyclohexene-1-carboxylic acid amide (0.365
g, yield 29.3%) was obtained.

Melting point: 135 to 136 ° C. 400 Mz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.69 (2 H, m), 1.75
(4H, m), 1.89 (6H, m), 2.35 and 2.45 (total 2H, each
s), 2.96 (2H, m), 3.68 (1H, t, J = 6.2Hz), 3.81 (1H, t,
J = 6.5Hz), 4.40 (1H, s), 4.55 (1H, s), 4.79 (1H, m),
7.10 and 7.15 (1H, each d, J _HF = 10.3 and 9.7Hz), 8.
00 (1H, d, J _HF = 7.2Hz), 8.03 (1H, br s) .IR (KBr disk, cm ^-1 ): 875, 1170, 1195, 1240, 1410, 14
90, 1530, 1620, 1640, 1675, 2950, 3350.

Example-46

[0249]

[Chemical 68]

An eggplant-shaped flask (100 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.50).
g, 4.12 mmol), 3,3-dimethylpiperidine (0.513 g,
4.53 mmol), triethylamine (0.542 g, 5.36 mmol),
And, benzene (50 mL) / hexane (10 mL) was added as a solvent, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was recrystallized from ether / hexane to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '. , N'-
White crystals of (2,2-dimethylpentamethylene) -3,4,5,6-tetrahydrophthalamide (1.30 g, yield 66.3%)
Got

Melting point: 115-117 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.825 (6 H, d, J = 6.
0Hz), 1.75 ~ 1.85 (16H, m), 2.28 (4H, m), 2.94 (1H,
s), 3.27 (2H, m), 3.50 (1H, m), 4.75 (1H, m), 7.09 an
d 7.11 (total 1H, each d, J _HF = 10.2 and 10.1Hz), 8.0
7 and 8.16 (total1H, each d, J _HF = 7.2 and 7.2Hz), 8.
59 and 8.63 (total 1H, each br s) .IR (KBr disk, cm ^-1 ): 860, 1190, 1240, 1280, 1410, 14
40, 1490, 1520, 1610, 1670, 2850, 2925.

Example-47

[0253]

[Chemical 69]

In an eggplant-shaped flask (50 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), 3,5-dimethylpiperidine (0.311
g, 2.75 mmol) and benzene (25 mL) as a solvent were added, and the mixture was stirred at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was recrystallized from hexane to give N- (2-fluoro-4-chloro-5-
Cyclopentyloxyphenyl) -N ', N'-(3,5-
White crystals of dimethylpentamethylene) -3,4,5,6-tetrahydrophthalamide (0.806 g, yield 61.5%) were obtained.

Melting point: 134-136 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.71 (1 H, qui, J = 1
2.3Hz), 0.85 (6H, d, J = 6.5Hz), 1.47 (1H, br s), 1.62
~ 1.65 (2H, m), 1.74 (4H, m), 1.85 and 1.89 (total 7
H, each m), 2.01 (1H, t, J = 12.4 and 12.1Hz), 2.48 (1
H, t, J = 12.5 and 12.2), 2.10 ~ 2.70 (5H, m), 3.57 (1
H, dt, J = 13.0 and 2.1Hz), 4.53 (1H, dt, J = 12.9 and
2.0Hz), 4.79 (1H, m), 7.10 (1H, d, J _HF = 10.1Hz), 8.07
(1H, d, J _{H F} = 7.2Hz), 8.43 (1H, br s) .IR (KBr disk, cm ^-1 ): 670, 700, 845, 1160, 1190, 123
5, 1250, 1400, 1430,1480, 1510, 1600, 1660, 2925,
3025, 3300.

Example-48

[0257]

[Chemical 70]

In an eggplant-shaped flask (50 cc), N- {2-fluoro-4-chloro-5- (3-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydrophthalimide (1.00 g, 2.65) was added. mmol), morpholine (0.231 g,
2.65 mmol), triethylamine (0.268 g, 2.65 mmo
l) and benzene (30 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were separated by filtration, washed with hexane and dried to give N- {2-fluoro-4-chloro-5- (3-methylcyclopentyl) oxy. Phenyl} -N ', N'-diethyleneoxy-3,4,5,6-tetrahydrophthalamide white crystals (1.03 g, yield 83.8%) were obtained.

Melting point: 200 to 202 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.03 and 1.09 (tot
al 3H, each d, J = 6.6and 6.6Hz), 1.17and 1.43 (total
1H, each m), 1.66 and 1.74 (total 4H, each s), 1.7
8 ~ 1.87 (1H, m), 1.91 ~ 2.12 (total 3H, each m), 2.1
7 ~ 2.30 (total6H, each m), 3.39 (2H, br s), 3.51 (2H,
br s), 3.57 (4H, br s), 4.70 and 4.80 (total 1H, ea
ch m), 7.116 and 7.120 (total 1H, each d, J _HF = 10.2
and 10.2Hz), 8.08 and 8.09 (1H, each d, J _HF = 7.2 and
7.2Hz), 8.17 (1H, br s) .IR (KBr disk, cm ^-1 ): 860, 1105, 1190, 1240, 1410, 14
60, 1490, 1530, 1620, 2850, 2950.

Example-49

[0261]

[Chemical 71]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol) and N-methylpiperazine (0.330 g, 3.29
mmol), triethylamine (0.100 g, 0.988 mmol) and benzene (10 mL) as a solvent, and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained crystals were isolated by filtration. After washing with hexane and thoroughly drying, N- (2-fluoro-4-chloro-5-
Cyclopentyloxyphenyl) -N ', N'-(N "-methyldiethyleneimino) -3,4,5,6-tetrahydrophthalamide white crystals (0.907 g, yield 71.1%) were obtained.

Melting point: 115-116 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.62 (2 H, m), 1.74
(4H, m), 1.85 (2H, m), 1.89 (4H, m), 2.18 (3H, s), 2.
30 (8H, m), 3.40 (2H, m), 3.59 (2H, m), 4.79 (1H, m),
7.11 (1H, d, J _HF = 10.1Hz), 8.14 (1H, d, J _HF = 7.2Hz),
8.30 (1H, br s) .IR (KBr disk, cm ^-1 ): 830, 1000, 1022, 1141, 1170, 11
98, 1240, 1256, 1274, 1292, 1384, 1434, 1442, 146
0, 1484, 1500, 1518, 1602, 1650, 1682, 2810, 2890,
2950, 3260.

Example-50

[0265]

[Chemical 72]

An eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide (1.00).
g, 2.75 mmol), 2,6-dimethylpiperazine (cis / tran
s, 0.377 g, 3.30 mmol), triethylamine (0.330 g,
3.26 mmol) and benzene (20 mL) / hexane (20 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After the reaction,
The solvent was distilled off under reduced pressure, and the precipitated crystals were filtered off, washed with hexane and dried to give N- (2-fluoro-
4-chloro-5-cyclopentyloxyphenyl)-
N ', N'-{bis (2-methylethylene) imino} -3,
White crystals of 4,5,6-tetrahydrophthalamide (0.640
g, yield 48.7%) was obtained.

Melting point: 115-116 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.03 (6 H, br d, J =
1.7Hz), 1.56 ~ 1.69 (3H, m), 1.74 (4H, br s), 1.89 (6
H, m), 2.18 (2H, t, J = 11.7Hz), 2.39 ~ 2.59 (4H, br
s), 2.62 (2H, t, J = 11.1Hz), 3.49 (1H, d, J = 11.0Hz),
4.44 and 4.46 (total 1H, d, J _HF = 11.7Hz), 4.79 (1H,
m), 7.10 (1H, d, J _HF = 10.1Hz), 8.09 (1H, d, J _HF = 6.8H
z), 8.35 (1H, br s) .IR (KBr disk, cm ^-1 ): 700, 810, 860, 890, 1040, 1080,
1170, 1190, 1240, 1320, 1360, 1410, 1440, 1520, 1
610, 1670, 2850, 2950, 3350.

Example-51

[0269]

[Chemical formula 73]

In a round-bottomed flask (25 cc), methylamine hydrochloride (0.200 g, 2.96 mmol) and potassium carbonate (0.400 g, 2.
89 mmol) and acetonitrile (5 mL) as a solvent were stirred at room temperature. After confirming the generation of carbon dioxide, N- (2-
Fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide
(0.650 g, 1.79 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 1N-hydrochloric acid (20 mL) and extracted with ethyl acetate (40 mL x 3 times). The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. The precipitated crystals were isolated by filtration, washed with hexane and dried sufficiently to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl).
White crystals (0.380 g, yield 53.8%) of -N'-methyl-3,4,5,6-tetrahydrophthalamide were obtained. Melting point and spectral data are as shown in Example-37.

Example-52

[0272]

[Chemical 74]

In an eggplant-shaped flask (50 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol) and isopropylamine (0.190 g, 3.21
mmol), triethylamine (0.280 g, 2.77 mmol) and benzene (20 mL) as a solvent, and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained crystals were isolated by filtration. After washing with hexane and thoroughly drying, N- (2-fluoro-4-chloro-5-
Cyclopentyloxyphenyl) -N'-isopropyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.
892 g, yield 76.7%) were obtained. The melting point and the spectral data are as shown in Example-2.

Example-53

[0275]

[Chemical 75]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol) and benzylamine (0.300 g, 2.80 mmo
l) and benzene (20 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained crystals were isolated by filtration. White crystals of N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N'-benzyl-3,4,5,6-tetrahydrophthalamide by washing with hexane and drying thoroughly.
(0.947 g, yield 73.1%) was obtained. Melting point and spectral data are as shown in Example-20.

Example-54

[0278]

[Chemical 76]

In an eggplant-shaped flask (50 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), 2- (3,4-dimethoxyphenyl) ethylamine (0.740 g, 4.08 mmol) and benzene (20 mL) as a solvent were added, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained crystals were isolated by filtration. After washing with hexane and thoroughly drying, N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '-{2- (3,4-dimethoxyphenyl) ethyl} -3,4, White crystals of 5,6-tetrahydrophthalamide (1.35 g, yield 90.1%) were obtained. Melting point and spectral data are as shown in Example-31.

Example-55

[0281]

[Chemical 77]

In an eggplant-shaped flask (25 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol) and morpholine (0.240 g, 2.75 mmol),
And benzene (10 mL) was added as a solvent, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 1N-hydrochloric acid (20 mL) and extracted with ethyl acetate (30 mL × 3 times). The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, the solvent was evaporated under reduced pressure, and the obtained crystals were isolated by filtration. This was washed with hexane and dried thoroughly to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N ', N'-diethyleneoxy-3,4,5,6-tetrahydro. White crystals of phthalamide (1.
17 g, yield 93.9%) was obtained. Melting point and spectral data are as shown in Example-19.

Example-56

[0284]

[Chemical 78]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), N-ethyl-N-propylamine
(0.300 g, 3.44 mmol) and benzene (10 m
L) was added and stirred overnight at room temperature. After completion of the reaction, the reaction mixture was poured into 2N-hydrochloric acid (20 mL), and ethyl acetate (30 mL x 3
Times). The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. Then, the obtained oily substance is subjected to column chromatography (active alumina, developing solvent: ethyl acetate / hexane = 1/8).
By performing purification, an oily product of N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N'-ethyl-N'-propyl-3,4,5,6-tetrahydrophthalamide (0.698 g, yield 56.3%) was obtained.

400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.79
and 0.84 (total 3H, each t, J = 7.4and 7.4Hz), 0.97 a
nd 1.09 (total 3H, each t, J = 7.1 and 7.1Hz), 1.44 a
nd1.51 (total 2H, each tq, J = 7.4 and 7.4Hz), 1.62 (2
H, m), 1.74 (4H, m), 1.88 (6H, m), 2.34 (4H, br s) 3.
16 (1H, t, J = 7.4Hz), 3.28 (1H, q, J = 7.1Hz), 3.29 (1H,
t, J = 7.4Hz), 3.38 (1H, br s), 4.78 (1H, m), 7.101 a
nd 7.098 (total 1H, each d, J _HF = 10.1 and 10.1Hz), 8.
111 and 8.114 (total 1H, each d, J _HF = 7.2 and 7.2H
z), 8.53 and 8.55 (total 1H, each br s) .IR (neat, cm ^-1 ): 750, 862, 978, 1176, 1190, 1244, 12
80, 1410, 1432, 1490, 1524, 1610, 1644, 1680, 288
0, 2950, 2980, 3340.

Example-57

[0288]

[Chemical 79]

An eggplant-shaped flask (25 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (0.
500 g, 1.37 mmol), 2-methoxyethylamine (0.110
g, 1.46 mmol) and benzene (8 mL) as a solvent were added, and the mixture was stirred at room temperature for 5 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-
Fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '-(2-methoxyethyl) -3,4,5,6-
White crystals of tetrahydrophthalamide (0.501 g, yield 83.3
%). Melting point and spectral data are shown in Example-40.
As shown in.

Example-58

[0291]

[Chemical 80]

In a eggplant-shaped flask (25 cc), add 2 parts of hydrobromic acid.
-Aminoethyl bromide (0.280 g, 1.37 mmol) and potassium carbonate (0.110 g, 0.796 mmol) were added, and the mixture was stirred in an acetonitrile solvent at room temperature until no gas was generated. Then, N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (0.500 g, 1.37 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into 1N-hydrochloric acid (20 mL) and extracted with ethyl acetate (30 mL × 3 times). The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. The precipitated crystals were isolated by filtration, washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '-(2-bromoethyl)-.
White crystals of 3,4,5,6-tetrahydrophthalamide (0.64
4 g, yield 96.4%) was obtained.

Melting point: 140-142 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.63 (6 H, m), 1.
73 (4H, m), 1.89 (2H, m), 2.39 (2H, m), 2.42 (2H, m),
3.35 (2H, t, J = 5.8Hz), 3.65 (2H, dt, J = 5.8 and 5.8H
z), 4.80 (1H, m), 6.25 (1H, t, 5.8Hz), 7.11 (1H, d, J
_HF = 10.2Hz), 7.85 (1H, br s), 8.13 (1H, d, J _HF = 7.2H
z) .IR (KBr disk, cm ^-1 ): 860, 1196, 1245, 1280, 1300, 13
60, 1390, 1410, 1430, 1442, 1490, 1504, 1538, 162
8, 1642, 1670, 2940, 3250, 3320.

Example-59

[0295]

[Chemical 81]

An eggplant-shaped flask (25 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (0.
500 g, 1.37 mmol) and ethanolamine (0.085 g, 1.39 m)
mol) and benzene (10 mL) as a solvent, and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the obtained crystals were isolated by filtration. After washing with hexane and drying sufficiently, N- (2-fluoro-
4-chloro-5-cyclopentyloxyphenyl)-
White crystals (0.511 g, yield 87.8%) of N '-(2-hydroxyethyl) -3,4,5,6-tetrahydrophthalamide were obtained.

Melting point: 150 to 152 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.38 to 2.07 (12 H, m), 2.39
(4H, m), 2.73 (1H, m), 3.39 (2H, td, J = 5.4 and 5.4H
z), 3.63 (2H, t, J = 5.4Hz), 4.82 (1H, m), 6.45 (1H, br
t, J = 5.4Hz), 7.18 (1H, d, J _HF = 10.5Hz), 8.08 (1H, d,
J _HF = 7.5Hz), 8.09 (1H, br s) .IR (KBr disk, cm ^-1 ): 864, 1034, 1198, 1256, 1298, 13
28, 1362, 1392, 1415, 1490, 1502, 1608, 1644, 289
0, 2950, 3280.

Example-60

[0299]

[Chemical formula 82]

An eggplant-shaped flask (25 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (0.
500 g, 1.37 mmol), 2-ethylaminoethanol (0.150
g, 1.68 mmol) and benzene (8 mL) as a solvent were added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and diethyl ether was added to the obtained oily substance for crystallization. The crystals were isolated by filtration, washed with hexane and thoroughly dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-.
N'-ethyl-N '-(2-hydroxyethyl) -3,4,
White crystals of 5,6-tetrahydrophthalamide (0.241 g,
Yield 38.8%) was obtained.

Melting point: 132-133 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.05 and 1.13 (tot
al 3H, each t, J = 7.2 and 7.2Hz), 1.61 (4H, m), 1.72
~ 2.04 (8H, m), 2.36 (4H, br s), 2.44 (1H, brs), 3.37
and 3.46 (total 2H, each q, J = 7.2 and 7.2Hz), 3.41
(1H, t, J = 5.4Hz), 3.52 (1H, br s), 3.70 and 3.77 (to
tal 2H, each d, J _HF = 5.4 and 5.4Hz), 4.77 (1H, m), 7.
10 and 7.12 (total 1H, each d, J _HF = 10.2 and 10.2H
z), 8.07 (1H, d, J _HF = 7.4Hz), 8.10 and 8.19 (total 1
H, each br s) .IR (KBr disk, cm ^-1 ): 860, 1050, 1178, 1190, 1258, 13
60, 1412, 1430, 1452, 1492, 1540, 1596, 1640, 167
0, 2890, 2950, 3230, 3240.

Example-61

[0303]

[Chemical 83]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), bis (2-chloroethyl) amine
(1.26 g, 8.89 mmol), and benzene (15 mL) as a solvent.
And stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 1N-hydrochloric acid (20 mL) and ethyl acetate (30 mL x 3 times).
It was extracted with. After drying the organic layer over anhydrous magnesium sulfate,
The desiccant was removed and the solvent was distilled off under reduced pressure. Then
The obtained oily substance was purified by column chromatography (activated alumina, developing solvent: ethyl acetate / hexane = 1/8) to give N- (2-fluoro-4-chloro-
White crystals (0.514 g, yield 36.9%) of 5-cyclopentyloxyphenyl) -N ', N'-bis (2-chloroethyl) -3,4,5,6-tetrahydrophthalamide were obtained.

Melting point: 120 to 122 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.62 (2 H, m), 1.71
~ 1.97 (10H, m), 2.39 (2H, m), 2.43 (2H, m), 3.59 (2H,
t, J = 6.4Hz), 3.65 to 3.77 (6H, m), 4.78 (1H, m), 7.11
(1H, d, J _HF = 10.3Hz), 8.07 (1H, br s), 8.12 (1H, d, J
_HF = 7.2Hz) .IR (KBr disk, cm ^-1 ): 738, 872, 884, 1038, 1178, 119
0, 1200, 1212, 1242, 1301, 1420, 1442, 1462, 1495,
1524, 1628, 1692, 2980, 3500.

Example-62

[0307]

[Chemical 84]

In an eggplant-shaped flask (50 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (0.
490 g, 1.35 mmol), L-valine methyl ester (0.230
g, 1.75 mmol) and benzene (30 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was recrystallized from hexane to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '-(. 1-methoxycarbonyl-2-methylpropyl) -3,4,5,6-tetrahydrophthalamide white crystals (0.535 g, yield 80.0
%).

Melting point: 146-148 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.776 and 0.842 (t
otal 3H, each d, J = 3.0Hz), 1.70 (4H, m), 1.83 (8H,
m), 2.38 (4H, m), 3.60 (3H, s), 4.46 (1H, dd, J = 12.0 a
nd 3.0Hz), 4.31 (1H, m), 6.24 (1H, br d, J = 9.0Hz),
7.01 (1H, d, J _HF = 10.5Hz), 7.82 (1H, br s), 8.10 (1H,
d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 860, 1185, 1245, 1320, 1360, 14
10, 1430, 1490, 1530, 1620, 1650, 1750, 2950, 327
Five.

Example-63

[0311]

[Chemical 85]

Sodium hydride (in oil 60%, 0.210 g, 5.25 mmol) was placed in a two-necked eggplant type flask (50 cc),
The oil was removed by washing with hexane under an argon atmosphere. After cooling to 0 ° C, N-methylbenzylamine (0.410
g, 3.38 mmol) in THF (4 mL) slowly,
The temperature was raised to room temperature, and the mixture was stirred for 20 minutes. Next, -70 ° C
Cooled to N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.02 g, 2.80 mmol) in THF.
The solution (10 mL) was gradually added dropwise, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was mixed with 1N hydrochloric acid (30
(mL) and extracted with ethyl acetate (30 mL x 3 times). After drying the organic layer over anhydrous magnesium sulfate, the desiccant was removed and the solvent was distilled off. Then, the obtained oily substance is purified by column chromatography (activated alumina, developing solvent: ethyl acetate / hexane = 1/4) to give N- (2
-Fluoro-4-chloro-5-cyclopentyloxyphenyl) -N'-benzyl-N'-methyl-3,4,5,6
-Tetrahydrophthalamide oil (0.420 g, yield 30.9
%).

400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.58
~ 1.76 (6H, m), 1.80 ~ 1.99 (6H, m), 2.36 (2H, m), 2.44
(2H, m), 2.85 and 2.87 (total 3H, each s), 4.48 and
4.58 (total 2H, each br s), 4.77 and 4.81 (total 1
H, each br m), 7.05 to 7.17 (5H, m), 7.28 and 7.30
(total 1H, each m), 8.08 and 8.12 (total 1H, each
d, J _HF = 7.2Hz and 7.2Hz), 8.42 and 8.44 (total 1H, e
ach br s). IR (neat, cm ^-1 ): 700, 738, 862, 976, 1039, 1178, 119
2, 1244, 1280, 1410,1434, 1450, 1490, 1520, 1612,
1642, 1680, 1740, 2890, 2960, 3350.

Example-64

[0315]

[Chemical 86]

In an eggplant-shaped flask (50 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), cumylamine (0.370 g, 2.74 mmo
l), triethylamine (0.310 g, 3.06 mmol) and benzene (10 mL) as a solvent, and stirred at room temperature overnight.
Heated at ° C for 5 hours. After completion of the reaction, the reaction mixture cooled to room temperature was poured into 1N-hydrochloric acid (50 mL), and ethyl acetate (50 m
(L × 3 times). The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. The precipitated crude product was recrystallized from ether / hexane to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N'-cumyl-3,4,5,6.
-White crystals of tetrahydrophthalamide (0.220 g, yield 1
6.1%).

Melting point: 206-207 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.58 (6 H, s), 1.70
(4H, m), 1.92 (8H, m), 2.38 (4H, m), 4.80 (1H, m), 6.
09 (1H, br s), 7.10 (1H, d, J _HF = 10.2Hz), 7.13 to 7.19
(3H, m), 7.27 ~ 7.29 (2H, m), 8.03 (1H, br s), 8.25 (1
H, d, J _HF = 7.2) .IR (KBr disk, cm ^-1 ): 695, 758, 860, 1168, 1185, 124
0, 1305, 1360, 1405, 1440, 1485, 1520, 1545, 1608,
1635, 2940, 2980, 3270, 3320.

Example-65

[0319]

[Chemical 87]

In an eggplant-shaped flask (50 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), 4-methylcumylamine (0.620 g,
4.15 mmol), N-methylmorpholine (0.310 g, 3.06 mmo
l) and benzene (15 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was mixed with 1N hydrochloric acid (50 m
L) and extracted with chloroform (40 mL x 3 times). The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. By recrystallizing the precipitated crude product from ethyl acetate / acetone, N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '-(4-methylcumyl) -3,4,5, White crystals of 6-tetrahydrophthalamide (0.487 g, yield 34.5%)
Got

Melting point: 192-194 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.57 (6 H, s), 1.63
(2H, m), 1.70 (4H, m), 1.89 (2H, m), 1.92 (4H, m), 2.
24 (3H, m), 2.37 (2H, m), 2.39 (2H, m), 4.81 (1H, m),
6.04 (1H, br s), 6.94 (2H, d, J = 8.0Hz), 7.09 (1H, d,
J _HF = 10.2Hz), 7.16 (2H, d, J = 8.0Hz), 8.04 (1H, br s),
8.25 (1H, d, J = 7.2Hz) .IR (KBr disk, cm ^-1 ): 815, 865, 1172, 1188, 1241, 130
8, 1360, 1410, 1488, 1524, 1544, 1610, 1641, 2940,
2980, 3280.

Example-66
(N-FUTA-4)

[0323]

[Chemical 88]

In an eggplant-shaped flask (50 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), 4-fluorocumylamine (0.600
g, 3.92 mmol), N-methylmorpholine (0.330 g, 3.26
mmol) and benzene (10 mL) as a solvent, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was recrystallized from ethyl acetate / acetone to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N. A white crystal (0.417 g, yield 29.3%) of '-(4-fluorocumyl) -3,4,5,6-tetrahydrophthalamide was obtained.

Melting point: 213-215 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.60 (6H, s), 1.70 (6H,
m), 1.95 (6H, m), 2.38 (4H, m), 4.83 (1H, m), 6.12 (1
H, br s), 6.86 (2H, t, J _HF = 9.0Hz), 7.2 ~ 7.4 (2H, m),
7.16 (1H, d, J _HF = 10.5Hz), 8.02 (1H, br s), 8.35 (1H,
d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 838, 864, 1164, 1172, 1196, 123
0, 1244, 1310, 1362, 1408, 1444, 1484, 1510, 1540,
1608, 1624, 1640, 1678, 2940, 3260, 3310.

Example-67

[0327]

[Chemical 89]

In an eggplant-shaped flask (50 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), 3-fluorocumylamine (0.430
g, 2.81 mmol), triethylamine (0.290 g, 2.87 mmo
l) and benzene (10 mL) as a solvent were added, the mixture was stirred at room temperature overnight, and heated at 50 ° C. for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration.
This was washed with hexane and dried to give N-
(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '-(3-fluorocumyl) -3,4,
White crystals of 5,6-tetrahydrophthalamide (0.167 g,
Yield 11.7%) was obtained.

Melting point: 231-234 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.56 (6 H, m), 1.65
(2H, m), 1.71 (4H, m), 1.87 (2H, m), 1.90 (4H, m),
2.37 (2H, m), 2.39 (2H, m), 4.81 (1H, m), 6.12 (1H, br
s), 6.83 (1H, dddd, J _HF = 8.05Hz, J = 7.9, 2.4 and 1.0
Hz), 6.95 (1H, ddd, J _HF = 10.6, J = 2.4 and 2.1Hz), 7.0
4 (1H, ddd, J _HF = 6.9 and 1.0 and 2.1Hz), 7.08 (1H, d
d, J = 7.9 and 6.9Hz), 7.11 (1H, d, J _HF = 10.2Hz), 7.96
(1H, br s), 8.24 (1H, d, J _HF = 7.2Hz) .IR (KBr disk, cm ^-1 ): 699, 782, 868, 1190, 1266, 124
2, 1310, 1412, 1494,1530, 1546, 1612, 1645, 2950,
3290.

Example-68

[0331]

[Chemical 90]

In an eggplant-shaped flask (50 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (0.
900 g, 2.74 mmol), 4-chlorocumylamine (0.600 g,
3.54 mmol), N-methylmorpholine (0.300 g, 2.97 mmo
l) and benzene (15 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-
Chloro-5-cyclopentyloxyphenyl) -N'-
White crystals (0.404 g, yield 30.7%) of (4-chlorocumyl) -3,4,5,6-tetrahydrophthalamide were obtained.

Melting point: 218 to 219 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.55 (6 H, s), 1.65
(2H, m), 1.71 (4H, m), 1.88 (2H, m), 1.91 (4H, m), 2.
35 (2H, m), 2.39 (2H, m), 4.81 (1H, m), 6.11 (1H, br
s), 7.06 (2H, d, J = 8.6Hz), 7.12 (1H, d, J _HF = 10.2Hz),
7.19 (2H, d, J = 8.6Hz), 7.97 (1H, br s), 8.24 (1H, d,
J _HF = 7.2Hz) .IR (KBr disk, cm ^-1 ): 830, 864, 1176, 1196, 1242, 131
5, 1404, 1484, 1518,1540, 1608, 1620, 1642, 1678,
2940, 2980, 3260, 3320.

Example-69

[0335]

[Chemical Formula 91]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), 3-chlorocumylamine (0.630 g,
3.71 mmol), N-methylmorpholine (0.670 g, 6.62 mmo
l) and benzene (10 mL) as a solvent were added, and the mixture was stirred at room temperature overnight and heated at 50 ° C. for 7 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration.
This was washed with hexane and dried to give N-
(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '-(3-chlorocumyl) -3,4,5,
White crystals of 6-tetrahydrophthalamide (0.859 g, yield
58.6%).

Melting point: 222-226 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.55 (6H, s), 1.70 (6H,
m), 1.88 (6H, m), 2.38 (4H, m), 4.82 (1H, m), 6.18 (1
H, br s), 7.16 (1H, d, J _HF = 10.5Hz), 7.18 (3H, m), 7.
34 (1H, s), 8.03 (1H, br s), 8.32 (1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 698, 781, 1172, 1190, 1242, 130
5, 1360, 1408, 1490,1525, 1538, 1610, 1642, 2950,
2980, 3280.

Example-70

[0339]

[Chemical Formula 92]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), 4-bromocumylamine (0.770 g,
3.60 mmol), N-methylmorpholine (0.310 g, 3.06 mmo
l) and benzene (15 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N'-.
White crystals (0.515 g, yield 32.4%) of (4-bromocumyl) -3,4,5,6-tetrahydrophthalamide were obtained.

Melting point: 214-216 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.54 (6H, s), 1.69 (6H,
m), 1.90 (6H, m), 2.36 (4H, m), 4.83 (1H, m), 6.14 (1
H, br s), 7.16 (1H, d, J _HF = 10.5Hz), 7.28 (2H, d, J =
6.0Hz), 7.37 (2H, d, J = 6.0Hz), 8.03 (1H, br s), 8.33
(1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 821, 865, 1176, 1195, 1242, 131
5, 1408, 1490, 1518,1540, 1610, 1621, 1642, 1678,
2940, 2980, 3260, 3320.

Example-71

[0343]

[Chemical formula 93]

In an eggplant-shaped flask (50 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), 3-trifluoromethylcumylamine (0.730 g, 3.59 mmol), N-methylmorpholine (0.320
g, 3.16 mmol) and benzene (15 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained crude product was recrystallized from chloroform / acetone to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '. −
White crystals of (3-trifluoromethylcumyl) -3,4,5,6-tetrahydrophthalamide (0.360 g, yield 23.1%)
Got

Melting point: 231-235 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.58 (6 H, s), 1.63
(2H, m), 1.72 (4H, m), 1.87 (2H, m), 1.90 (4H, m), 2.
36 (2H, m), 2.40 (2H, m), 4.81 (1H, m), 6.17 (1H, br
s), 7.11 (1H, d, J _HF = 10.2Hz), 7.22 (1H, dd, J = 7.7 an
d 7.7Hz), 7.41 (1H, d, J = 7.7Hz), 7.72 (1H, d, J = 7.7H
z), 7.55 (1H, s), 8.17 (1H, br s), 8.23 (1H, d, J _HF =
7.2Hz) .IR (KBr disk, cm ^-1 ): 702, 810, 870, 1078, 1130, 117
5, 1198, 1248, 1318,1339, 1410, 1490, 1524, 1548,
1610, 1622, 1644, 1680, 2960, 3270, 3320.

Example-72

[0347]

[Chemical 94]

In an eggplant-shaped flask (50 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), 1-phenyl-1-methylpropylamine (0.540 g, 3.62 mmol), N-methylmorpholine
(0.310 g, 3.06 mmol) and benzene as solvent (15 mL)
And stirred at room temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2
-Fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '-(1-phenyl) -1-methylpropyl-3,4,5,6-tetrahydrophthalamide white crystals
(0.403 g, yield 28.6%) was obtained.

Melting point: 195 to 198 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.67 (3 H, t, J = 7.4)
Hz), 1.59 (3H, s), 1.6 ~ 2.0 (14H, m), 2.39 (4H, m),
4.79 (1H, m), 6.07 (1H, br s), 7.10 (1H, d, J H F = 10.2H
z), 7.1 ~ 7.2 (5H, m), 8.07 (1H, br s), 8.25 (1H, d, J
_HF = 7.2Hz) .IR (KBr disk, cm ^-1 ): 700, 761, 862, 1170, 1184, 124
1, 1310, 1360, 1402,1444, 1480, 1518, 1538, 1610,
1621, 1644, 1678, 2880, 2940, 2980, 3260, 3310.

Example-73

[0351]

[Chemical 95]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), 1- (4-chlorophenyl) -1-
Methylpropylamine (0.760 g, 4.14 mmol), N-methylmorpholine (0.310 g, 3.06 mmol), and benzene (15 mL) as a solvent were added, and the mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was poured into 2N-hydrochloric acid (30 mL) and extracted with ethyl acetate (30 mL x 3 times). The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. By recrystallizing the obtained crude product from ethyl acetate / acetone, N- (2-fluoro-4-chloro-
5-cyclopentyloxyphenyl) -N '-{1-
(4-chlorophenyl) -1-methylpropyl} -3,
White crystals of 4,5,6-tetrahydrophthalamide (0.298
g, yield 19.8%) was obtained.

Melting point: 200-201 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.68 (3 H, t, J = 7.4)
Hz), 1.56 (3H, s), 1.6 ~ 1.9 (14H, m), 2.40 (4H, m),
4.80 (1H, m), 6.08 (1H, br s), 7.04 (1H, d, J = 8.6Hz),
7.11 (1H, d, J _HF = 10.3Hz), 7.14 (1H, d, J = 8, 6Hz),
8.00 (1H, br s), 8.25 (1H, d, J _HF = 7.2Hz) .IR (KBr disk, cm ^-1 ): 830, 868, 1174, 1192, 1244, 131
8, 1408, 1490, 1518,1608, 1620, 1642, 1678, 2950,
2980, 3270.

Example-74

[0355]

[Chemical 96]

A eggplant-shaped flask (25 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (0.
500g, 1.37 mmol), diallylamine (0.216 g, 2.22 mmo
l) and benzene (10 mL) as a solvent were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was mixed with 1N-hydrochloric acid (10
(mL) and extracted with ethyl acetate (20 mL x 3 times). The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. Next, the obtained oily substance was purified by column chromatography (activated alumina, developing solvent: ethyl acetate / hexane = 1/1).
The solvent was distilled off under reduced pressure, and the precipitated crystals were filtered off to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N ', N'-diallyl-3,4,5,
White crystals of 6-tetrahydrophthalamide (0.165 g, yield
26.1%).

Melting point: 74 to 76 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.58 to 1.98 (12 H,
m), 2.34 (2H, m), 2.43 (2H, m), 3.86 (2H, br d, J = 5.2
Hz), 3.98 (2H, br s), 4.79 (1H, m), 4.98 (1H, dd, J = 1
0.2 and 1.3Hz), 5.06 (1H, dd, J = 17.2 and 1.3Hz), 5.
12 (1H, dd, J = 17.1 and 1.3Hz), 5.18 (1H, dd, J = 10.3
and 1.3Hz), 5.57 (1H, ddt, J = 10.2 and 17.2 and 6.0H
z), 5.65 (1H, ddt, J = 10.3 and 17.1 and 5.7Hz), 7.10
(1H, d, J _HF = 10.2Hz), 8.11 (1H, d, J _HF = 7.2Hz), 8.37
(1H, br s) .IR (KBr disk, cm ^-1 ): 862, 930, 978, 1175, 1185, 124
3, 1408, 1488, 1528,1610, 1625, 1642, 1672, 2870,
2950, 2980, 3350.

Example-75

[0359]

[Chemical 97]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), 4-fluoroaniline (0.310 g, 2.
79 mmol) and benzene (10 mL) as a solvent were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This product was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl).
White crystals of -N '-(4-fluorophenyl) -3,4,5,6-tetrahydrophthalamide (0.950 g, yield 72.7%)
Got

Melting point: 209 to 210 ° C. 400 MHz ¹ H-NMR (CDCl ₃ + DMSO-d ₆ , TMS, ppm): δ1.59 (2 H,
m), 1.76 (4H, m), 1.79 (6H, m), 2.45 (4H, m), 4.62 (1
H, m), 6.94 (2H, dd, J = 8.8 and J _HF = 8.8Hz), 7.07 (1H,
d, J _HF = 10.1Hz), 7.54 (2H, dd, J = 8.8 and J _HF = 4.9H
z), 7.79 (1H, d, J _HF = 7.1Hz), 8.88 (1H, br s), 9.56 (1
H, br s) .IR (KBr disk, cm ^-1 ): 694, 830, 861, 1195, 1212, 122
8, 1240, 1260, 1284,1316, 1360, 1390, 1408, 1500,
1510, 1530, 1612, 1642, 2950, 3260.

Example-76

[0363]

[Chemical 98]

In an eggplant-shaped flask (50 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), 4-chloroaniline (0.350 g, 2.74
mmol) and benzene (10 mL) as a solvent, the mixture was stirred at room temperature overnight, and heated at 50 to 70 ° C. for 7 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. This was washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '-(4-chlorophenyl) -3,4,5,6-tetrahydrophthalamide. Of white crystals (0.576 g, yield 42.8%) were obtained.

Melting point: 221-222 ° C. ¹ H-NMR (CDCl ₃ + DMSO-d ₆ , TMS, ppm): δ1.50-2.00 (12 H,
m), 2.45 (4H, m), 4.58 (1H, m), 7.03 (1H, d, J _HF = 10.5
Hz), 7.18 (2H, d, J = 9.0Hz), 7.52 (2H, d, J = 9.0Hz),
7.77 (1H, d, J _HF = 7.5Hz), 8.61 (1H, br s), 9.23 (1H, b
rs) .IR (KBr disk, cm ^-1 ): 825, 862, 1190, 1255, 1290, 131
5, 1360, 1400, 1495, 1518, 1526, 1536, 1598, 1610,
1645, 2950, 3250.

Example-77

[0367]

[Chemical 99]

A eggplant-shaped flask (50 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), 4-methylaniline (0.350 g, 3.27
mmol), triethylamine (0.290 g, 2.87 mmol) and benzene (15 mL) as a solvent, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 1N-hydrochloric acid (50 mL) and extracted with chloroform (40 mL × 3 times). The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. The precipitated crystals were isolated by filtration, washed with hexane and dried to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl).
A white crystal (0.396 g, yield 30.6%) of -N '-(4-methylphenyl) -3,4,5,6-tetrahydrophthalamide was obtained.

Melting point: 214-215 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.66 (2 H, m), 1.74
(4H, m), 1.79 (6H, m), 2.28 (3H, s), 2.46 (4H, m), 4.
65 (1H, m), 7.05 (2H, d, J = 8.1Hz), 7.06 (1H, d, J _HF = 1
0.2Hz), 7.32 (2H, d, J = 8.1Hz), 7.67 (1H, br s), 7.82
(1H, d, J _HF = 7.0Hz), 7.89 (1H, br s) .IR (KBr disk, cm ^-1 ): 820, 861, 1190, 1250, 1258, 132
2, 1408, 1490, 1518, 1530, 1602, 1644, 2940, 3280.

Example-78

[0371]

[Chemical 100]

In an eggplant-shaped flask (50 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.
00 g, 2.75 mmol), 4-tert-butylaniline (0.410
g, 2.75 mmol) and benzene (10 mL) as a solvent were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into 1N-hydrochloric acid (50 mL) and chloroform (40 mL x 3 times).
It was extracted with. The organic layer is dried over anhydrous magnesium sulfate,
After removing the desiccant, the solvent was distilled off under reduced pressure. The precipitated crystals were isolated by filtration and washed with hexane to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N '-(4-tert-butylphenyl) -3. White crystals of (4,5,6-tetrahydrophthalamide) (0.533 g, yield 37.8%) were obtained.

Melting point: 192-197 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.26 (9 H, s), 1.5
~ 1.8 (12H, m), 2.45 (4H, m), 4.65 (1H, m), 7.06 (1H,
d, J _HF = 10.1Hz), 7.27 (2H, d, J = 8.5Hz), 7.36 (2H, d,
J = 8.5Hz), 7.71 (1H, br s), 7.89 (1H, d, J _HF = 7.0Hz),
7.93 (1H, br s) .IR (KBr disk, cm ^-1 ): 835, 862, 1190, 1250, 1264, 132
2, 1362, 1410, 1490,1518, 1604, 1645, 2960, 3290.

Example-79

[0375]

[Chemical 101]

A eggplant-shaped flask (25 cc) was charged with N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (0.
500 g, 1.37 mmol), 1- (4-fluorophenyl) piperazine (0.250 g, 1.39 mmol), and benzene as solvent.
(10 mL) was added, and the mixture was stirred at room temperature for 45 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained oily substance was crystallized from hexane to give N- (2-fluoro-4-).
Chloro-5-cyclopentyloxyphenyl) -N ', N'
A white crystal (0.651 g, yield 87.3%) of-{N "-(4-fluorophenyl) diethyleneimino} -3,4,5,6-tetrahydrophthalamide was obtained.

Melting point: 116-118 ° C. 400 MHz ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.52 (2 H, m), 1.68
(4H, m), 1.76 (6H, m), 2.37 (4H, m), 2.67 ~ 3.14 (4H,
m), 3.40 ~ 4.14 (4H, m), 4.59 (1H, m), 6.73 (1H, ddd,
J _HF = 6.8Hz and J = 6.8 and 2.3Hz), 6.76 (1H, ddd, J _HF =
6.8Hz and J = 6.8 and 2.3Hz), 6.93 (1H, ddd, J _HF = 12.9
Hz and J = 6.8 and 2.3Hz), 6.94 (1H, ddd, J _HF = 12.9Hz
and J = 6.8 and 2.3Hz), 7.12 (1H, d, J _HF = 10.2Hz), 8.0
4 (1H, d, J _HF = 7.2Hz), 8.23 (1H, br s) .IR (KBr disk, cm ^-1 ): 830, 1000, 1175, 1190, 1218, 12
38, 1252, 1285, 1405, 1438, 1490, 1510, 1528, 161
8, 1678, 2840, 2870, 2950, 3330.

Example-80

[0379]

[Chemical 102]

In an eggplant-shaped flask (25 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (0.
490 g, 1.35 mmol) and N-methylpiperazine (0.222 g, 2.
22 mmol) and benzene (8 mL) as a solvent were added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained oily substance was crystallized from hexane to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -N ', N'. White crystals (-0.530 g, yield 84.6%) of-(N "-methyldiethyleneimino) -3,4,5,6-tetrahydrophthalamide were obtained. The melting point and the spectral data are as shown in Example-49. Is.

Reference Example-1

[0382]

[Chemical 103]

2-Fluoro-4-chloro-5-cyclopentyloxyaniline (0.50 g, 2.18 mmol) and 3,4,5,
6-Tetrahydrophthalic anhydride (0.398 g, 2.61 mmol)
A solution of and acetic acid (3.0 mL) was stirred under reflux for 3 hours. Water (20 mL) was added to the obtained reaction solution, and ethyl acetate (20 mL x 3
Times). After drying the organic layer, the solvent was distilled off under reduced pressure, and the resulting pale yellow oily substance was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 8 /
1) and N- (2-fluoro-4-chloro-5-
Cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalimide colorless transparent oil (0.513 g, 1.4
1 mmol, yield 65%) was obtained. Add ethanol (1.0
(mL) and recrystallized to obtain a white solid.

Melting point: 69.0 to 75.2 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.30 to 2.10 (12 H, m), 2.40
(4H, m), 4.68 (1H, m), 6.75 (1H, d, J _HF = 7.0Hz), 7.20
(1H, d, J _HF = 9.0Hz) .IR (KBr disk, cm ^-1 ): 1200, 1385, 1430, 1505, 1725.

Reference Example-2

[0386]

[Chemical 104]

In a eggplant-shaped flask (50 cc), 2-fluoro-5-cyclopentyloxyaniline (330 mg, 1.69 mm
ol), 3,4,5,6-tetrahydrophthalic anhydride (258 m
g, 1.70 mmol) and acetic acid (10 mL) as a solvent were added, and the mixture was heated under reflux for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (20 mL × 3 times). The organic layers were combined, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent was distilled off under reduced pressure. The obtained dark red oil (345 mg) was separated and purified by silica gel chromatography (developing solvent: hexane / ethyl acetate = 4/1) to obtain the desired N- (2-fluoro-5-cyclopentyloxyphenyl) -3. , 4,5
A pale yellow oil of 6-tetrahydrophthalimide (171 mg,
0.575 mmol, yield 34%) was obtained.

¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.39 to 2.04 (1
2H, m), 2.15 (4H, m), 4.73 (1H, m), 6.42 ~ 6.83 (3H,
m).

Reference Example-3

[0390]

[Chemical 105]

In a eggplant-shaped flask (100 cc), 2-fluoro-4-chloro-5-cyclopentyloxyaniline (12.
3 g, 53.6 mmol), 3,4,5,6-tetrahydrophthalic anhydride (8.15 g, 53.6 mmol) and acetic acid as a solvent (20 mL)
And hexane (20 mL) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the precipitated crystals were isolated by filtration. This product was washed with hexane and dried thoroughly to obtain N
White crystals of-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide hydroxy derivative (16.1 g, yield 78.8%)
Got

Melting point: 98.0 to 99.0 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.61 (2H, m), 1.81 (4H,
m), 1.86 (6H, m), 2.42 (4H, m), 3.60 (2H, br s), 4.75
(1H, m), 6.36 (1H, d, J _HF = 8.2Hz), 6.98 (1H, d, J _HF = 1
0.4Hz) .IR (KBr disk, cm ^-1 ): 3250, 2950, 1700, 1670, 1630, 1
610, 1510, 1420, 1390, 1285, 1260, 1190, 870, 720. Elemental analysis value (calculated value; C ₁₉ H ₂₁ ClFNO ₄ ,%): C; 59.78 (59.7
6), H; 5.64 (5.55), N; 3.62 (3.67).

Reference Example-4

[0394]

[Chemical formula 106]

In an eggplant-shaped flask (50 cc), 2-fluoro-4-chloro-5-cyclopentyloxyaniline (3.4
7 g, 15.1 mmol), 3,4,5,6-tetrahydrophthalic anhydride (2.30 g, 15.1 mmol) and acetone (30
(mL) and charged at 45 ° C. for 2 hours and 30 minutes. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (30 mL), and the precipitated crystals were isolated by filtration and dried sufficiently. Further, this was washed with hexane to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6.
-White crystals of a tetrahydroisophthalimide hydroxy derivative (4.88 g, yield 84.6%) were obtained. The spectrum data and the like are as shown in Reference Example-3.

Reference Example-5

[0397]

[Chemical formula 107]

A eggplant-shaped flask (50 cc) was charged with 2-fluoro-4-chloro-5-cyclopentyloxyaniline (2.5
6 g, 11.2 mmol), 3,4,5,6-tetrahydrophthalic anhydride (1.72 g, 11.3 mmol) and benzene (10
(mL) and was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (20 mL), and ethyl acetate (20 mL x 3
Times). The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. When the NMR spectrum of the obtained crude product was measured, it was N- (2-fluoro-4-chloro-5-
In addition to the cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide hydroxy derivative, N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3, represented by the general formula (VII ′), 4,5
It was possible to confirm the absorption attributable to 6-tetrahydrophthalamic acid. Spectral data is shown below,
The feature is that two protons on the phenyl ring are greatly shifted in a low magnetic field as compared with the isoimide hydroxy form. ¹ H-NMR (CDCl ₃ + DMSO-d ₆ , TMS, ppm): δ1.83 (12 H, m), 2.
21 ~ 2.67 (4H, m), 4.75 (1H, m), 7.10 (1H, d, J _HF = 10.5
Hz), 8.02 (1H, d, J _HF = 7.5Hz). Then, the obtained crude product was recrystallized from ethyl acetate / hexane to give N- (2-fluoro-4-chloro-5-cyclopentyloxy). Phenyl) -3,4,5,6
-White crystals of a tetrahydroisophthalimide hydroxy derivative (3.54 g, yield 83.1%) were obtained. No phthalamic acid was found in this product. The spectrum data and the like are as shown in Reference Example-3.

Reference Example-6

[0400]

[Chemical 108]

A eggplant-shaped flask (100 cc) was charged with 2-fluoro-4-chloro-5-cyclopentyloxyaniline (3.5
0 g, 15.2 mmol) was added, and acetic acid (15 mL) was added and dissolved. Next, 3,4,5,6-tetrahydrophthalic anhydride (2.50 g, 16.4 mmol) was added under ice-cooling, and the mixture was left at 15
Stir for minutes. After the reaction was completed, the reaction mixture was mixed with 2N hydrochloric acid (20
(mL) and extracted with ethyl acetate (30 mL x 3 times). The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. The obtained crude product (a small amount of N- (2-fluoro-4-chloro-5-
The formation of cyclopentyloxyphenyl) -3,4,5,6-tetrahydrophthalamic acid was confirmed by NMR. Is recrystallized from ethyl acetate / hexane to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide hydroxy compound as white crystals (4.08 g). , Yield 7
0.1%) was obtained. The spectrum data and the like are as shown in Reference Example-3.

Reference Example-7

[0403]

[Chemical 109]

In an eggplant-shaped flask (100 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide hydroxy compound (5.00 g, 13.1 mmol) was added. And benzene (20 mL) as a solvent were added and dissolved. To this solution, N, N'-dicyclohexylcarbodiimide (2.70 g, 13.1 mmol) was added under ice cooling, then the temperature was gradually raised to room temperature, and the mixture was stirred for 24 hours as it was. After completion of the reaction, the precipitated N, N'-dicyclohexylurea was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. This product was separated and purified using a silica gel column (ethyl acetate / hexane = 1/7) to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,
6-Tetrahydroisophthalimide (3.09 g, yield 64.8
%) Pale yellow crystals were obtained.

Melting point: 98.0-99.0 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.64 (2H, m), 1.84 (2H,
m), 1.90 (8H, m), 2.42 (2H, m), 2.59 (2H, m), 4.80 (1
H, m), 6.86 (1H, d, J _HF = 7.2Hz), 7.15 (1H, d, J _{H F} = 9.6
Hz) .IR (KBr disk, cm ^-1 ): 2950, 2890, 1810, 1780, 1680, 1
660, 1495, 1390, 1265, 1190, 1020, 970, 900, 860,
850. Elemental analysis value (calculated value; C ₁₉ H ₁₉ ClFNO ₃ ,%): C; 62.84 (62.7
3), H; 5.28 (5.26), N; 3.84 (3.85) .MS (m / e, relative intensity): 366 (M ⁺ +3, 0.47), 365 (M
⁺ +2, 2.80), 364 (M ⁺ +1, 1.80), 363 (M ⁺ , 7.95), 295 (10
0), 216 (3.15), 108 (14.38), 79 (32.18), 69 (10.71), 4
1 (49.27).

Reference Example-8

[0407]

[Chemical 110]

In an eggplant-shaped flask (100 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide hydroxy compound (5.80 g, 15.2 mmol) was added. And chloroform (30 mL) as a solvent were added and dissolved. In this solution, N, N '
-Dicyclohexylcarbodiimide (3.20 g, 15.5 mmo
l) was added under ice-cooling, then gradually warmed to room temperature and stirred for 24 hours as it was. After completion of the reaction, N, N'precipitated
-Dicyclohexylurea is removed by Celite filtration,
The filtrate was concentrated under reduced pressure to obtain a crude product. This product was separated and purified using a silica gel column (ethyl acetate / hexane = 1/6) to give N- (2-fluoro-4-).
Chloro-5-cyclopentyloxyphenyl) -3,4,
5,6-Tetrahydroisophthalimide (3.59 g, yield 6
(4.9%) pale yellow crystals were obtained. The spectral data and the like are shown in Reference Example-7.

Reference Example-9

[0410]

[Chemical 111]

In an eggplant-shaped flask (100 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide hydroxy compound (8.00 g, 20.9 mmol) was added. , N, N′-dicyclohexylcarbodiimide (4.32 g, 20.9 mmol) and toluene (80 mL) as a solvent were added, and the mixture was stirred at room temperature for 24 hours.
After completion of the reaction, the precipitated N, N'-dicyclohexylurea was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. This product was separated and purified using a silica gel column (ethyl acetate / hexane = 1/7) to give N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-. Light yellow crystals of tetrahydroisophthalimide (2.57 g, yield 33.7%) were obtained. The spectral data and the like are shown in Reference Example-7.

Reference Example-10

[0413]

[Chemical 112]

In an eggplant-shaped flask (100 cc), N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide hydroxy compound (3.00 g, 7.86 mmol) was added. And benzene (20 mL) as a solvent were added and dissolved. To this solution, N, N'-diisopropylcarbodiimide (1.30 g, 10.3 mmol) was added under ice-cooling, then the temperature was gradually raised to room temperature, and 2
Stir for 4 hours. After completion of the reaction, the precipitated N, N′-diisopropylurea was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. This product was separated and purified using a silica gel column (ethyl acetate / hexane = 1/5) to give N- (2-fluoro-4-chloro-5).
A pale yellow crystal of -cyclopentyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide (1.08 g, yield 37.8%) was obtained. The spectral data and the like are shown in Reference Example-7.

Reference Example-11

[0416]

[Chemical 113]

A eggplant-shaped flask (100 cc) was charged with 2-fluoro-4-chloro-5- (3-methylcyclopentyl) oxyaniline (2.80 g, 11.5 mmol), 3,4,5,6-tetrahydrophthalic anhydride. The product (1.74 g, 11.4 mmol) and acetone (50 mL) as a solvent were added, and the mixture was stirred at 45 ° C. for 7 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL x 3 times). The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. By recrystallizing the obtained crude product from ether / hexane, N- {2-fluoro-
A white crystal (2.90 g, yield 63.8%) of 4-chloro-5- (3-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydroisophthalimide hydroxy derivative was obtained.

Melting point: 83.0 to 85.0 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.02 and 1.09 (total 3H,
each d, J = 6.7 and 6.7Hz), 1.1 ~ 1.5 (2H, m), 1.81 (6
H, m), 1.9 to 2.12 (2H, m), 2.27 (1H, m), 2.43 (4H, m),
3.75 (2H, br s), 4.64 and 4.68 (total 1H, each m),
6.340 and 6.343 (total 1H, each d, J _HF = 8.2 and 8.2
Hz), 6.993 and 6.997 (total 1H, eachd, J _HF = 10.4 an
d 10.4Hz) .IR (KBr disk, cm ^-1 ): 3200, 2925, 2850, 1690, 1630, 1
600, 1530, 1480, 1400, 1280, 1250, 1180, 860. Elemental analysis value (calculated value; C ₂₀ H ₂₃ ClFNO ₄ ,%): C; 60.63 (60.6
8), H; 5.99 (5.86), N; 3.59 (3.54).

Reference Example-12

[0420]

[Chemical 114]

A eggplant-shaped flask (100 cc) was charged with N- {2-fluoro-4-chloro-5- (3-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydroisophthalimide hydroxy compound (3.00). g, 7.58 mmol) and chloroform (30 mL) as a solvent were added and dissolved. To this solution, N, N'-dicyclohexylcarbodiimide
(1.56 g, 7.56 mmol) was added under ice-cooling, then the temperature was gradually raised to room temperature, and the mixture was stirred for 24 hours as it was. After completion of the reaction, the precipitated N, N'-dicyclohexylurea was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. This product was separated and purified using a silica gel column (ethyl acetate / hexane = 1/8) to give N-
Yellow crystals of {2-fluoro-4-chloro-5- (3-methylcyclopentyl) oxyphenyl} -3,4,5,6-tetrahydroisophthalimide (0.21 g, yield 7.3%) were obtained.

Melting point: 100.0 to 101.0 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.03 and 1.10 (total 3H,
each d, J = 4.2 and 6.7Hz), 1.15 ~ 1.50 (2H, m), 1.83
(4H, m), 1.97 (2H, m), 4.70 and 4.75 (total 1H, m),
6.83 and 6.85 (total 1H, each d, J _HF = 7.14 and 7.15H
z), 7.14 and 7.17 (total 1H, each d, J _HF = 9.63 and
9.63Hz) .IR (KBr disk, cm ^-1 ): 2950, 1790, 1680, 1500, 1395, 1
270, 1180, 1020, 910, 880, 850. Elemental analysis value (calculated value; C ₂₀ H ₂₁ ClFNO ₃ ,%): C; 63.56 (63.5
7), H; 5.78 (5.61), N; 3.82 (3.71) .MS (m / e, relative intensity): 380 (M ⁺ +3, 0.25), 379 (M
⁺ +2, 2.05), 378 (M ⁺ +1, 1.40), 377 (M +, 6.06), 295 (10
0), 224 (3.83), 143 (3.80), 108 (11.66), 107 (10.0), 9
9 (6.29), 79 (26.92), 56 (26.64), 55 (36.29), 41 (37.1
0).

Reference Example-13

[0424]

[Chemical 115]

A eggplant-shaped flask (50 cc) was charged with 2-fluoro-4-chloro-5-cyclohexyloxyaniline (1.6
4 g, 6.73 mmol), 3,4,5,6-tetrahydrophthalic anhydride (1.02 g, 6.70 mmol) and acetone (25
(mL) and charged at 45 ° C. for 7 hours. After the reaction was completed, the reaction mixture was poured into 1N hydrochloric acid (50 mL), and ethyl acetate (30 mL) was added.
(× 3 times). The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed, and the solvent was evaporated under reduced pressure. By recrystallizing the obtained crude product from ether / hexane, N- (2-fluoro-4-chloro-5-cyclohexyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide hydroxy compound is off-white. Crystal (1.89
g, yield 70.9%) was obtained.

Melting point: 81.0 to 83.0 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.33 (3H, m), 1.58 (3H,
m), 1.81 (6H, m), 1.93 (2H, m), 2.43 (4H, m), 3.70 (2
H, br s), 4.11 (1H, m), 6.41 (1H, d, J _HF = 8.3Hz), 7.0
0 (1H, d, J _HF = 10.4Hz) .IR (KBr disk, cm ^-1 ): 3200, 2920, 1690, 1630, 1540, 1
490, 1410, 1280, 1260, 1190, 950. Elemental analysis value (calculated value; C ₂₀ H ₂₃ ClFNO ₄ ): C; 60.45 (60.68),
H; 5.88 (5.86), N; 3.46 (3.54).

Reference Example-14

[0428]

[Chemical formula 116]

In an eggplant-shaped flask (100 cc), N- (2-fluoro-4-chloro-5-cyclohexyloxyphenyl) -3,4,5,6-tetrahydroisophthalimide hydroxy compound (3.50 g, 8.84 mmol) was added. And chloroform (60 mL) as a solvent were added and dissolved. In this solution, N, N '
-Dicyclohexylcarbodiimide (1.82 g, 8.82 mmo
l) was added under ice-cooling, then gradually warmed to room temperature and stirred for 24 hours as it was. After completion of the reaction, N, N'precipitated
-Dicyclohexylurea is removed by Celite filtration,
The filtrate was concentrated under reduced pressure to obtain a crude product. This product was separated and purified using a silica gel column (ethyl acetate / hexane = 1/10) to give N- (2-fluoro-4).
-Chloro-5-cyclohexyloxyphenyl) -3,
Light yellow crystals of 4,5,6-tetrahydroisophthalimide (2.19 g, yield 65.6%) were obtained.

Melting point: 78.0 to 80.0 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.35 (2H, m), 1.53 (1H,
m), 1.61 (3H, m), 1.83 (6H, m), 1.94 (2H, m), 2.42 (2
H, m), 2.57 (2H, m), 4.19 (1H, m), 6.87 (1H, d, J _HF = 7.
2Hz), 7.15 (1H, d, J _HF = 9.7Hz) .IR (KBr disk, cm ^-1 ): 2900, 1770, 1665, 1490, 1270, 1
190, 1050, 1015, 890, 840. Elemental analysis value (calculated value; C ₂₀ H ₂₁ ClFNO ₃ ,%): C; 63.76 (63.5
7), H; 5.70 (5.61), N; 3.91 (3.71) .MS (m / e, relative intensity): 380 (M ⁺ +3, 0.26), 379 (M
⁺ +2, 2.20), 378 (M ⁺ +1, 1.53), 377 (M ⁺ , 6.44), 297 (3
3.59), 296 (16.72), 295 (100), 108 (11.74), 79 (27.2
1), 54 (11.89), 34 (36.06).

Reference Example-15

[0432]

[Chemical 117]

A 20 L three-necked flask equipped with a stirrer and a dropping funnel was charged with 2-chloro-4-fluorophenol.
(4.4 Kg, 30 mol), triethylbenzylammonium chloride (17.1 g) and methylene chloride (7 L) were added, and the mixture was cooled in an ice bath. Then, 5N-sodium hydroxide aqueous solution (6 L)
Was slowly added and stirred vigorously. Next, trichloromethyl chloroformate (885 mL, 7.35 mol) was slowly added dropwise at room temperature over about 6 hours, and the reaction solution was stirred overnight after the addition.
After the reaction was completed, the organic layer was separated, and the aqueous layer was further methylene chloride.
It was extracted with (1000 mL × 2 times). The organic layers were combined, washed with 1N-aqueous sodium hydroxide solution (4 L) and water (5 L), and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off from the organic layer under reduced pressure to give a white solid of bis (2-chloro-4-fluorophenyl) carbonate (4.9
Kg, 15.4 mol, yield 100%) was obtained.

Melting point: 91.0 to 92.0 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 6.87 to 7.4 (6 H, m). IR (KBr disk, cm ⁻¹ ): 1180, 1250, 1290, 1500 , 1605, 1
780.

Reference Example-16

[0436]

[Chemical 118]

Bis (2-chloro-4-fluorophenyl) carbonate (801 g, 2.5 mol) was placed in a 5 L three-necked flask equipped with a dropping funnel and a stirrer, and sulfuric acid (98
%, 2000 mL) was added and stirred thoroughly. Then, with vigorous stirring, nitric acid (60%, 400 mL) and sulfuric acid (98%, 400 mL).
The mixed acid prepared above was slowly added dropwise over 7 hours so that the reaction temperature did not rise above the dropping funnel. After completion of the dropwise addition, the mixture was vigorously stirred for 1 hour and then added to cold water (5000 mL), and precipitated bis (2-chloro-4-fluoro-5-).
Nitrophenyl) carbonate white solid (1026 g, 2.5
mol, yield 100%) was obtained. This product can be purely isolated as white needle crystals by recrystallization from toluene or ethyl acetate.

Melting point: 165.0 to 165.5 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ7.58 (2 H, d, J _HF = 9.9 Hz),
8.25 (2H, d, J _HF = 8.3Hz) .IR (KBr disk, cm ^-1 ): 1180, 1240, 1355, 1495, 1540, 1
605, 1797.

Reference Example-17

[0440]

[Chemical formula 119]

In a 10 L three-necked flask equipped with a stirrer, bis (2-chloro-4-fluoro-5-nitrophenyl) carbonate (1.2 Kg, 2.9 mol), toluene (7 L) as a solvent and 5% Pd / catalyst as a catalyst. Add C (200 g),
Hydrogen gas was introduced with vigorous stirring. Although heat was generated as the reaction proceeded, the reaction temperature was maintained at 60 to 70 ° C. by introducing hydrogen at such a rate that hydrogen gas did not come out of the system. After completion of the reaction, the reaction mixture was heated (60 to 70 ° C.) and the catalyst was filtered off. The organic layer of the filtrate was separated and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was distilled off under reduced pressure to give bis (2-chloro-4-fluoro-5).
-Aminophenyl) carbonate (1.01Kg, 2.89 mol,
A white solid with a yield of 99.6% was obtained.

Melting point: 136.0-137.0 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 3.83 (4 H, br s), 6.71 (2 H,
d, J _HF = 8.5Hz), 7.08 (2H, d, J _HF = 10.5Hz) .IR (KBr disk, cm ^-1 ): 1155, 1190, 1235, 1260, 1510, 1
640, 1780, 3500.

Reference Example-18

[0444]

[Chemical 120]

In a 10 L three-necked flask equipped with a stirrer and a dropping funnel, bis (2-chloro-4-fluoro-5) was added.
-Aminophenyl) carbonate (1.75 Kg, 5.0 mol) and potassium carbonate (1.04 Kg, 7.5 mol) and toluene (6 L) as a solvent were added. Methyl chloroformate (770 m
L, 9.9 mol) was added dropwise, and the mixture was stirred at 60 to 70 ° C (bath temperature) for 5 hours. After completion of the reaction, the reaction mixture was filtered, washed with toluene, 1N-hydrochloric acid and water, and then sufficiently dried to give a white solid of bis (2-chloro-4-fluoro-5-methoxycarbonylaminophenyl) carbonate.
(2.10 Kg, 4.51 mol, yield 90.2%) was obtained.

Melting point: 212.0 to 214.0 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 3.80 (6H, s), 6.87 (2H, br
s), 7.19 (2H, d, J _HF = 10.2Hz), 8.22 (2H, d, J _HF = 8.3H
z) .IR (KBr disk, cm ^-1 ): 1217, 1240, 1420, 1490, 1553, 1
630, 1740, 1790.

Reference Example-19

[0448]

[Chemical 121]

A three-necked flask (5 L) was charged with bis (2-chloro-
4-fluoro-5-methoxycarbonylaminophenyl) carbonate (1.28 Kg, 2.76 mol), potassium carbonate
(286 g, 2.05 mol) and methanol (2.5 L) as a solvent were added, and the mixture was heated with stirring at 50 ° C. for 1.5 hours. After the reaction was completed, the reaction mixture cooled to room temperature was treated with 1N-hydrochloric acid (10 L) / ice (5 K
g) into the mixture with stirring. The precipitated white solid was filtered and sufficiently dried to give N- (2-fluoro-4-
Methyl chloro-5-hydroxyphenyl) carbamate
(1.20 Kg, 5.46 mol, yield 99.0%) was obtained.

Melting point: 140.0-141.0 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 3.79 (3 H, s), 5.53 (1 H,
s), 6.75 (1H, br s), 7.05 (1H, d, J _HF = 10.5Hz), 7.82
(1H, d, J _HF = 7.5Hz) .IR (KBr disk, cm ^-1 ): 1250, 1430, 1560, 1630, 1717.

Reference Example-20

[0452]

[Chemical formula 122]

In a 10 L three-necked flask equipped with a stirrer and a Dimroth, methyl N- (2-fluoro-4-chloro-5-hydroxyphenyl) carbamate (1.64 Kg, 7.47) was added.
mol), cyclopentyl-p-toluenesulfonate (1.
80 Kg, 7.48 mol), potassium carbonate (1.03 Kg, 7.46 mo)
l) and potassium iodide (12.3 g, 1.0 mol%) were added, acetone (7.5 L) was added as a solvent, and the mixture was heated under reflux for 4 hours. After completion of the reaction, the reaction solution was taken out and 0.5N-hydrochloric acid (20 L) was added with vigorous stirring. Precipitated methyl N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) carbamate white solid (2.0 Kg, 6.95 mol, yield 9
(3.1%) was isolated by filtration and dried thoroughly.

Melting point: 120.0 to 123.0 ° C. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.40 to 2.10 (8 H, m), 3.77
(3H, s), 4.77 (1H, m), 6.82 (1H, br s), 7.07 (1H, d, J
_{. HF = 10.5Hz), 7.83 (} 1H, d, J HF = 7.5Hz) IR (KBr disk, cm -1): 1190, 1255, 1415, 1500, 1535, 1
714.

Reference Example-21

[0456]

[Chemical 123]

Methyl N- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) carbamate (2.2
To an ethanol (3 L) solution of 5 Kg, 7.85 mol) was added 4N-potassium hydroxide aqueous solution (4.75 L), and the mixture was heated under reflux for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water (5 L) was added, and the mixture was extracted with toluene (5 L × 2 times). The organic layer was washed with water and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to give an oily substance of 2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.75
Kg, 7.62 mol, yield 98.3%) was obtained.

Boiling point: 143 to 145 ° C./1.5 mmHg. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.40 to 2.00 (8 H, m), 3.72
(2H, br s), 4.67 (1H, m), 6.39 (1H, d, J _HF = 9.0Hz), 7.
04 (1H, d, J _HF = 11.0Hz) .IR (neat, cm ^-1 ): 1185, 1245, 1420, 1510, 1630, 3400,
3500.

Reference Example-22

[0460]

[Chemical formula 124]

A 2-necked eggplant-shaped flask (25 cc) was charged with 2-chloro-4-fluoro-5-aminophenol (1.02 g,
6.28 mmol), potassium carbonate (1.72 g, 12.4 mmol), potassium iodide (4.0 mg, 0.024 mmol) and N as a solvent,
N-Dimethylformamide (5 mL) was added, and the mixture was stirred at 80 ° C for 1 hr. Then cyclopentyl bromide (1.00 g,
6.71 mmol) was added, and the mixture was further stirred at 80 ° C. for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with toluene (20 mL × 3 times). The organic layers were combined, washed with water (10 mL) and saturated saline (10 mL), and dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent was distilled off under reduced pressure to give 2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.43 g, 6.23
mmol, yield 99.0%) was obtained.

Boiling point: 143-145 ° C./1.5 mmHg ¹ H-NMR (CDCl ₃ , TMS): δ 1.40-2.00 (8H, m), 3.72 (2H,
s), 4.67 (1H, m), 6.39 (1H, d, J _HF = 9.0Hz), 7.04 (1H,
d, J _HF = 11.0Hz) .IR (neat, cm ^-1 ): 3500, 3400, 1630, 1510, 1420, 1245,
1185.

Reference Example-23

[0464]

[Chemical 125]

In a 500 cc three-necked flask equipped with a stirrer, 2-chloro-4-fluoro-5-aminophenol (10.0 g, 61.9 mmol), cyclopentyl methanesulfonate (10.3 g, 62.9 mmol) and tetrabutylammonium were added. Bromide (0.51 g, 1.58 mmol) in toluene (50 m
L) A solution was prepared. Then, 48% aqueous sodium hydroxide solution (30 mL) was slowly added, and the mixture was heated with stirring at 80 ° C. for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature and washed with water (150
mL) was added and extracted with toluene (50 mL x 2 times). The organic layers were combined, washed with water (100 mL x 2 times), and the solvent was evaporated under reduced pressure to give 2-fluoro-4-chloro-5-
Cyclopentyloxyaniline (13.5 g, 59.0 mmol, yield 95.2%, HPLC purity 98.6%) was obtained.

Reference Example-24

[0467]

[Chemical formula 126]

In a 2000 cc three-necked flask equipped with a stirrer, 2-chloro-4-fluoro-5-aminophenol (75.0 g, 0.464 mol), cyclopentyl bromide.
(76.3 g, 0.512 mol), tetrabutylammonium bromide (3.03 g, 9.41 mmol), and potassium iodide (776 mg,
A solution of 4.67 mmol) in toluene (500 mL) was prepared. Then, 40% aqueous sodium hydroxide solution (500 mL) was slowly added, and the mixture was heated with stirring at 80 ° C (hot water bath: 85 to 90 ° C) for 7 hours. After the reaction was completed, the reaction solution was cooled to room temperature and water (500 mL)
Was added and extracted with toluene (400 mL x 2 times). The organic layers were combined, washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. After removing the desiccant,
By distilling off the solvent under reduced pressure, 2-fluoro-4
-Chloro-5-cyclopentyloxyaniline (87.2 g,
0.380 mol, yield 81.8%) was obtained.

Reference Example-25

[0470]

[Chemical 127]

In a 50 cc eggplant-shaped flask equipped with a stirrer, 2-chloro-4-fluoro-5-aminophenol (1.02 g, 6.29 mmol), cyclopentyl p-toluenesulfonate (1.56 g, 6.50 mmol), tetrabutyl was added. A solution of ammonium bromide (242 mg, 0.75 mmol) and potassium iodide (262 mg, 1.57 mmol) in toluene (20 mL) was prepared. Then, 40% sodium hydroxide aqueous solution (20 m
L) was slowly added, and the mixture was heated with stirring at 100 ° C. for 2 hours.
After completion of the reaction, the reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3 times). The organic layers were combined, washed with water (10 mL) and saturated saline (10 mL), and dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent was distilled off under reduced pressure to give 2-fluoro-4-chloro-5-cyclopentyloxyaniline (1.44 g, 6.27).
mmol, yield 99.6%) was obtained.

Reference Example-26

[0473]

[Chemical 128]

Eggplant-shaped flask (50 cc) was charged with 2-chloro-
4-Fluoro-5-aminophenol (1.62 g, 10.0 mm
ol), cyclopentyl methanesulfonate (1.70 g, 10.4
mmol) and tetrabutylammonium bromide (327 mg,
A toluene (10 mL) solution of 1.01 mmol) and potassium iodide (333 mg, 2.00 mmol) was prepared. Then, 48% aqueous sodium hydroxide solution (7.5 mL) was slowly added, and the temperature was adjusted to 80 ° C.
The mixture was heated and stirred for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with toluene (20 mL × 2 times). The organic layers were combined, water (10 mL) and saturated brine (10 mL).
(mL) and washed. Concentrated hydrochloric acid (1.2 m
L) was added, and the mixture was sufficiently stirred, and 2-fluoro-4-chloro-5 was added.
-Cyclopentyloxyaniline hydrochloride was precipitated.
The white solid was isolated by filtration, washed with ethyl acetate and then with toluene, and dried (yield 2.33 g, 8.74 mmol, yield 87.4%).

Melting point: 145.0 to 147.0 ° C. ¹ H-NMR (CDCl ₃ + DMSO-d ₆ , TMS, ppm): δ 1.40 to 2.10 (8 H,
m), 4.74 (1H, m), 7.20 (1H, d, J _HF = 9.0Hz), 7.57 (1H,
d, J _HF = 6.0Hz), 10.40 (3H, br s) .IR (KBr disk, cm ^-1 ): 2850, 2610, 1500, 1200, 875.

This hydrochloride was added to an aqueous sodium hydroxide solution and extracted with toluene, whereby free 2-fluoro-4-chloro-5-cyclopentyloxyaniline could be obtained.

Reference Example-27

[0478]

[Chemical formula 129]

In a 200 cc eggplant-shaped flask equipped with a stirrer, 2-chloro-4-fluoro-5-aminophenol (3.00 g, 18.6 mmol), 3-methylcyclopentyl was added.
p-toluenesulfonate (4.60 g, 18.6 mmol), tetrabutylammonium bromide (300 mg, 0.93 mmol),
And potassium iodide (300 mg, 1.81 mmol) in toluene (3
0 mL) solution was prepared. Then, 48% aqueous sodium hydroxide solution (30 mL) was slowly added, and the mixture was heated with stirring at 100 ° C. for 48 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3 times). The organic layers were combined, water (10 mL) and saturated brine (10 mL).
After washing with, it was dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent is distilled off under reduced pressure.
Fluoro-4-chloro-5- (3-methylcyclopentyl) oxyaniline (1.94 g, 7.96 mmol, yield 42.9%)
Was obtained as a brown oil.

¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.02 and 1.1
0 (total 3H, each d, J = 6.0Hz), 1.22-2.58 (7H, m),
3.75 (2H, br s), 4.65 (1H, m), 6.33 (1H, d, J _HF = 8.0H
z), 6.98 (1H, d, J _HF = 10.0Hz).

Reference Example-28

[0482]

[Chemical 130]

In a 100 cc eggplant-shaped flask equipped with a stirrer, 2-chloro-4-fluoro-5-aminophenol (1.03 g, 6.40 mmol), cyclohexyl p-toluenesulfonate (1.69 g, 6.66 mmol), tetrabutyl was added. A solution of ammonium bromide (124 mg, 0.38 mmol) and potassium iodide (100 mg, 0.60 mmol) in toluene (15 mL) was prepared. Then, a 40% aqueous sodium hydroxide solution (15
(mL) was slowly added, and the mixture was heated with stirring at 100 ° C for 48 hours. After completion of the reaction, the reaction solution was cooled to room temperature and water (10 mL)
Was added, and the mixture was extracted with ethyl acetate (20 mL x 3 times). The organic layers were combined, washed with water (10 mL) and saturated saline (10 mL), and dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent was distilled off under reduced pressure to obtain a crude product (1.06 g). By separating and purifying this by silica gel column chromatography (ethyl acetate / hexane = 1/9), 2-fluoro-4-chloro-5-cyclohexyloxyaniline (0.75 g, 3.08 mmol, yield 48.1%) was obtained. Obtained as a colorless oil.

¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.15 to 2.06 (1
0H, m), 3.46 (1H, br s), 3.95 ~ 4.25 (1H, m), 6.39 (1
H, d, J _HF = 9.0Hz), 6.97 (1H, d, J _HF = 11.5Hz). IR (neat, cm ^-1 ): 3500, 3400, 2940, 2860, 1630, 1505,
1240, 1190.

Reference Example-29

[0486]

[Chemical 131]

Eggplant-shaped flask (50 cc) was charged with 3-amino-
4-Fluorophenol (1.00 g, 7.87 mmol), cyclopentyl methanesulfonate (1.29 g, 7.87 mmol) and tetrabutylammonium bromide (127 mg, 0.394 mmo
A solution of l) in toluene (20 mL) was prepared. Then 48%
Slowly add aqueous sodium hydroxide solution (10 mL), and add 8
The mixture was heated and stirred at 0 ° C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (20 mL) was added, and toluene (20 mL x 3 times) was added.
It was extracted with. The organic layers were combined and washed with water (20 mL x 2). The solvent was distilled off from the obtained toluene solution under reduced pressure to give 2-fluoro-5-cyclopentyloxyaniline (660 mg, 3.38 mmol, yield 43%).

¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.40 to 2.10 (8
H, m), 3.85 (2H, br s), 4.72 (1H, m), 6.24 ~ 6.55 (3H,
m), 6.73 (1H, dd, J = 5.6 and 9.2Hz).

Reference Example-30

[0490]

[Chemical 132]

A eggplant-shaped flask (50 cc) was charged with 3-amino-
4-fluorophenol (1.00 g, 7.87 mmol), cyclopentyl p-toluenesulfonate (1.92 g, 7.99 mmo)
l), tetrabutylammonium bromide (127 mg, 0.394
mmol) and potassium iodide (64 mg, 0.39 mmol) in toluene (10 mL) were prepared. Then, 48% aqueous sodium hydroxide solution (10 mL) was slowly added, and the mixture was heated with stirring at 80 ° C. for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with toluene (20 mL × 2 times). The organic layers were combined, water (20 mL) and saturated brine (20 mL).
Washed with. The solvent was distilled off from the obtained toluene solution under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (developing solvent: hexane / ethyl acetate = 9 /
By separating and purifying in 1), the desired 2-fluoro-
5-Cyclopentyloxyaniline (1.24 g, 6.33 mmo
l, yield 80.5%) was obtained.

Tables 1 to 4 show examples of the compounds of the present invention which can be produced according to the methods of the above-exemplified examples and reference examples.

[0493]

[Chemical 133]

[0494]

Table 1 Table 1 Tetrahydrophthalamide derivative represented by the general formula (I) ────────────────────────── No. X ¹ X ² R ¹ R ² R ³ R ⁴ ────────────────────────── 1 F Cl cyclopentyl H propyl H 2 F Cl cyclopentyl H isopropyl H 3 F Cl cyclopentyl H butyl H 4 F Cl cyclopentyl H isobutyl H 5 F Cl 3-methyl- H isobutyl H cyclopentyl 6 F Cl cyclopentyl H neopentyl H 7 F Cl cyclopentyl H hexyl H 8 F Cl 3-methyl- H hexyl H cyclopentyl 9 F Cl cyclopentyl H octyl H 10 F Cl cyclopentyl H decyl H 11 F Cl cyclopentyl H methyl methyl 12 F Cl cyclopentyl H cyclohexyl H 13 F Cl cyclopentyl H 2-methylcyclohexyl H 14 F Cl cyclopentyl H exo-norbornyl H 15 F Cl cyclopentyl H (-) - cis-myrtanyl H 16 F Cl cyclopentyl H - (CH 2) 4 - 17 F Cl cyclopentyl H - (CH 2) 5 - 18 F Cl cyclopentyl H - (CH 2) 6 - 19 F Cl cyclopentyl H - _{CH 2 CH 2 OCH 2 CH 2} - 20 F Cl cyclopentyl H benzyl H ──── ─────────────────────

[0495]

Table 2 Table 2 Tetrahydrophthalamide derivative represented by the general formula (I) ────────────────────────── No. X ¹ X ² R ¹ R ² R ³ R ⁴ ────────────────────────── 21 F Cl cyclopentyl H 2-chlorobenzyl H 22 F Cl cyclopentyl H 4 -Methylbenzyl H 23 F Cl cyclopentyl H 4-methoxybenzyl H 24 F Cl cyclopentyl H R-(+)-1-phenylethyl H 25 F Cl cyclopentyl H S-(-)-1-phenylethyl H 26 F Cl cyclopentyl H (±) -1-phenylethyl H 27 F Cl 3-methyl- H R-(+)-1-phenylethyl H cyclopentyl 28 F Cl cyclohexyl H S-(+)-1-phenylethyl H 29 F Cl cyclopentyl H R-(+)- 1- (1-naphtyl) ethyl H 30 F Cl cyclopentyl H S-(-)-1- (1-naphtyl) ethyl H 31 F Cl cyclopentyl H 2- (3,4-dimethoxy- H phenyl) ethylhomoveratryl 32 F Cl cyclopentyl H 2-naphthylmethyl H 33 F Cl cyclopentyl H 2-pyridylmethyl H 34 F Cl cyclopentyl H furfuryl H 35 F Cl cyclopentyl H propargyl H 36 F Cl cyclopentyl HHH 37 F Cl cyclopentyl H methyl H 3 8 F Cl cyclopentyl H ethyl H 39 F Cl cyclopentyl H sec-butyl H 40 F Cl cyclopentyl H 2-methoxyethyl H ────────────────────────── ─

[0496]

Table 3 Table 3 Tetrahydrophthalamide derivative represented by the general formula (I) ────────────────────────── No. X ¹ X ² R ¹ R ² R ³ R ⁴ ────────────────────────── 41 F Cl cyclopentyl H 2-aminocyclohexyl H 42 F Cl cyclopentyl H 2 -aminocyclohexyl H 43 F Cl cyclopentyl H 1 -ethoxycarbonyl- H 4-piperidyl 44 F Cl cyclopentyl H 2-phenylethyl H 45 F Cl cyclopentyl H -CH 2 SCH 2 CH 2 - 46 F Cl cyclopentyl H -CH 2 C (Me 2 _{) CH 2 CH 2 CH 2 -} 47 F Cl cyclopentyl H -CH 2 CH (Me) CH 2 CH (Me) CH 2 - 48 F Cl 3-methyl- H -CH 2 CH 2 OCH 2 CH 2 - cyclopentyl 49 F _{Cl cyclopentyl H -CH 2 CH 2 N} (Me) CH 2 CH 2 - 50 F Cl cyclopentyl H -CH 2 CH (Me) NHCH (Me) CH 2 - 51 F Cl cyclopentyl H ethyl propyl 52 F Cl cyclopentyl H 2- bromoethyl H 53 F Cl cyclopentyl H 2-hydroxyethyl H 54 F Cl cyclopentyl H 2-hydroxyethyl ethyl 55 F Cl cyclopentyl H 2-chloroethyl 2-chloro-ethyl 56 F Cl cyclopentyl H 1-methoxyc arbonyl- H 2-methylpropyl 57 F Cl cyclopentyl H benzyl methyl 58 F Cl cyclopentyl H cumyl H ───────────────────────────

[0497]

Table 4 Table 4 Tetrahydrophthalamide derivative represented by general formula (I) ────────────────────────── No. X ¹ X ² R ¹ R ² R ³ R ⁴ ────────────────────────── 59 F Cl cyclopentyl H 4-methylcumyl H 60 F Cl cyclopentyl H 4 -fluorocumyl H 61 F Cl cyclopentyl H 3-fluorocumyl H 62 F Cl cyclopentyl H 4-chlorocumyl H 63 F Cl cyclopentyl H 3-chlorocumyl H 64 F Cl cyclopentyl H 4-bromocumyl H 65 F Cl cyclopentyl H 3-trifluoromethylcumyl H 66 F Cl cyclopentyl H 1-phenyl-1-methylpropyl H 67 F Cl cyclopentyl H 1- (4-chlorophenyl) -1- H methylpropyl 68 F Cl cyclopentyl H allyl allyl 69 F Cl cyclopentyl H 4-fluorophenyl H 70 F Cl cyclopentyl H 4 -chlorophenyl H 71 F Cl cyclopentyl H 4-methylphenyl H 72 F Cl cyclopentyl H 4-tert-butylphenyl H 73 F Cl cyclopentyl H 4- (4-fluorophenyl)-H ────────────── ─────────────

The compound of the present invention thus obtained has excellent performance as a herbicide as described above.

When the compound of the present invention is used as a herbicide, it can be used as it is, but generally, one or several kinds of auxiliary agents can be mixed and used as a herbicide. Usually, as an auxiliary agent, various carriers, extenders, solvents,
It is preferable that a surfactant, a stabilizer and the like are mixed and formulated into a form such as a wettable powder, an emulsion, a powder, a granule and a flowable agent by a conventional method before use.

Examples of the solvent which is one of the auxiliary agents in the herbicides containing the compound of the present invention as an active ingredient include, for example, water, alcohols, ketones, ethers, aliphatic and aromatic hydrocarbons and halogenated hydrocarbons. Suitable compounds are acid amides, esters, nitriles, etc., and one or a mixture of two or more of them is used.

Examples of the extender include clays such as kaolin and bentonite, talc and talc such as pyrophyllite, diatomaceous earth,
Mineral powders such as oxides of white carbon and soybean powders, plant powders such as CMC, etc. are used. Further, a surfactant may be used as a spreading agent, a dispersant, an emulsifier, and a penetrant. Examples of the surfactant include nonionic surfactants, cationic surfactants and amphoteric surfactants. These surfactants are utilized as one kind or a mixture of two or more kinds depending on the application.

Preferable uses of the herbicide containing the compound of the present invention as an active ingredient include soil treatment, water surface treatment, foliage treatment and the like, and a particularly excellent effect by application of the control weeds from before germination to at the time of larvae. Can be mentioned.

Further, a herbicide containing the compound of the present invention as an active ingredient is another active ingredient which does not inhibit the herbicidal activity of the present active ingredient, such as other herbicides, insecticides, fungicides, plant growth regulators. It is also possible to mix and use agents and the like.

Next, the present invention will be described in more detail with reference to formulation examples of a herbicide containing the compound of the present invention as an active ingredient, and test examples for examining the herbicidal effect of the present herbicide. The parts are parts by weight.

Formulation Example-1 (Emulsion) As an emulsion, 20 parts of the compound of the present invention, 35 parts of xylene, 40 parts of cyclohexanone, and sorbole 900A (manufactured by Toho Chemical).
An emulsion was obtained by uniformly mixing 5 parts. Other compounds of the present invention were processed in the same manner as above to obtain an emulsion.

Formulation Example-2 (Wettable powder) As the wettable powder, a mixture of 50 parts of the compound of the present invention, 25 parts of diatomaceous earth, 22 parts of clay and 3 parts of Lunox R100C (manufactured by Toho Kagaku Co., Ltd.) is uniformly mixed and pulverized. I got a Japanese medicine.

Formulation Example-3 (Granule) As a granule, a mixture of 5 parts of the compound of the present invention, 35 parts of bentonite, 55 parts of talc, and 5 parts of sodium ligninsulfonate is uniformly mixed and pulverized, and then water is added and kneaded. Then, after granulating with an extrusion granulator, it was dried and sized to obtain granules. The compound of the present invention was treated in the same manner as above to obtain granules.

Using the preparations prepared according to the methods exemplified above, the herbicidal effects of the compounds of the present invention were investigated according to the methods shown in the following test examples. The herbicidal effect on the test plant and the phytotoxicity on the test product were determined according to the criteria (Table 5) shown below.

[0509]

[Table 5]

As a control compound, a commercially available compound (A) was used for the effect of pre-soil treatment in paddy soil, and a commercially available compound (B) was used for the effect of upland soil treatment and the effect of foliar treatment. Using the formulation method and the treatment method, the herbicidal activity and phytotoxicity to crops were investigated by the same criteria, and the results are shown in the table.

[0511]

[Chemical 134]

[0512]

[Chemical 135]

Test Example-1 (Effect on paddy field weeds) Pads of 1 / 1,000 are are filled with paddy field soil, and seeds of Taenubie, Pleurotus cornucopia, Leek, Firefly, Matsubai, and other annual broad-leaved weeds and 2. Rice seedlings (variety: Koshihikari) at the 5-leaf stage were sown or transplanted and kept in a flooded state. One day later, the wettable powder or emulsion of the compound of the present invention prepared according to Formulation Example was diluted and subjected to dropwise treatment so that a predetermined dose per ares was obtained. On the 15th day after the treatment, the herbicidal effect on the test plant and the phytotoxicity against rice were investigated according to the criteria of 1 to 5 and the results shown in Tables 6 to 18 were obtained.

[0514]

[Table 6]

[0515]

[Table 7]

[0516]

[Table 8]

[0517]

[Table 9]

[0518]

[Table 10]

[0519]

[Table 11]

[0520]

[Table 12]

[0521]

[Table 13]

[0522]

[Table 14]

[0523]

[Table 15]

[0524]

[Table 16]

[0525]

[Table 17]

[0526]

[Table 18]

Test Example-2 (Effect of Treatment of Upland Soil) A bat having an area of 10 × 10 cm ² and a depth of 5 cm was filled with upland soil, and seeds of barnyardgrass, crabgrass, pearl millet, white pearl oyster, and corn were sown. The top was covered with 0.5 cm of soil. On the next day, the wettable powder or emulsion of the compound of the present invention prepared according to Formulation Example was diluted and evenly dispersed on the soil cover so that a predetermined dose per ares was obtained. On the 15th day after the treatment, the herbicidal effect on the test weeds and the phytotoxicity on the corn were examined in the same manner as in Test Example 1. The results are shown in Tables 19 to 24.

[0528]

[Table 19]

[0529]

[Table 20]

[0530]

[Table 21]

[0531]

[Table 22]

[0532]

[Table 23]

[0533]

[Table 24]

Test Example 3 (Effect of foliar treatment) A field soil was packed in a vat having an area of 10 × 10 cm ² and a depth of 5 cm.
And corn seeds were sowed, and the foliar part of the plant grown after 15 days was diluted with the wettable powder or emulsion of the compound of the present invention prepared according to the formulation example, and the concentration was adjusted to a predetermined concentration. It was spray treated. After processing 1
On day 0, the herbicidal effect on the test weeds and the phytotoxicity against corn were examined in the same manner as in Test Example-1. The results are shown in Tables 25 to 34.

[0535]

[Table 25]

[0536]

[Table 26]

[0537]

[Table 27]

[0538]

[Table 28]

[0539]

[Table 29]

[0540]

[Table 30]

[0541]

[Table 31]

[0542]

[Table 32]

[0543]

[Table 33]

[0544]

[Table 34]

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Emiko Ejiri 5-3-5 Wakamatsu, Sagamihara City, Kanagawa Prefecture (72) Inventor Kiyomi Aizawa 322-1 Unomori, Sagamihara City, Kanagawa Prefecture (72) Inventor Koichi Kakura Sagamihara, Kanagawa Prefecture City Oshima 3231-1 (72) Inventor Sadayuki Ukai 4-15-12 Minamisurugadai, Fujieda City, Shizuoka Prefecture (72) Inventor Tomoko Yoshii 3-7-10 Tanaka, Fujieda City, Shizuoka Prefecture (72) Osamu Yamada Shita Shizuoka Prefecture 2777-8 Fujimori, Oigawa-cho, Gunma

Claims (6)

[Claims] 1. A compound represented by the general formula (I): [In the formula, X ¹ represents a halogen atom, and X ² represents a hydrogen atom or a halogen atom. R ¹ represents an optionally substituted cycloalkyl group having 3 to 8 carbon atoms, R ² is a hydrogen atom,
Represents a chlorine atom or a methyl group. R ³ and R ⁴ are each independently a hydrogen atom, which may be substituted, having 1 to 1 carbon atoms.
12 alkyl groups, C3-9 cycloalkyl groups,
It represents an aryl group having 6 to 10 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, or an alkynyl group having 3 to 5 carbon atoms, or R ³ and R ⁴ are substituted or unsubstituted fats together with the nitrogen atom to which they are bonded. A cyclic heterocyclic ring may be formed. ] Indicated by 3,
4,5,6-Tetrahydrophthalamide derivative. 2. The 3,4,5,6-tetrahydrophthalamide derivative according to claim 1, wherein X ¹ is a fluorine atom and X ² is a chlorine atom. 3. R ¹ is a cyclopentyl group.
The 3,4,5,6-tetrahydrophthalamide derivative described. 4. A compound represented by the general formula (II): [In the formula, X ¹ represents a halogen atom, and X ² represents a hydrogen atom or a halogen atom. R ¹ represents an optionally substituted cycloalkyl group having 3 to 8 carbon atoms, R ² is a hydrogen atom,
Represents a chlorine atom or a methyl group. ] 3, 4,
A 5,6-tetrahydrophthalimide derivative and a compound represented by the general formula (III): [In the formula, R ³ and R ⁴ are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 9 carbon atoms, or an aryl group having 6 to 10 carbon atoms. Represents an alkenyl group having 3 to 5 carbon atoms or an alkynyl group having 3 to 5 carbon atoms, or R ³ and R ⁴ together with the bonded nitrogen atom form a substituted or unsubstituted alicyclic heterocyclic ring. May be. ] The compound represented by the general formula (I): [In the formula, X ¹ represents a halogen atom, and X ² represents a hydrogen atom or a halogen atom. R ¹ represents an optionally substituted cycloalkyl group having 3 to 8 carbon atoms, R ² is a hydrogen atom,
Represents a chlorine atom or a methyl group. R ³ and R ⁴ are each independently a hydrogen atom, which may be substituted, having 1 to 1 carbon atoms.
12 alkyl groups, C3-9 cycloalkyl groups,
It represents an aryl group having 6 to 10 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, or an alkynyl group having 3 to 5 carbon atoms, or R ³ and R ⁴ are substituted or unsubstituted fats together with the nitrogen atom to which they are bonded. A cyclic heterocyclic ring may be formed. ] Indicated by 3,
A method for producing a 4,5,6-tetrahydrophthalamide derivative. 5. A compound represented by the general formula (IV): [In the formula, X ¹ represents a halogen atom, and X ² represents a hydrogen atom or a halogen atom. R ¹ represents an optionally substituted cycloalkyl group having 3 to 8 carbon atoms, R ² is a hydrogen atom,
Represents a chlorine atom or a methyl group. ] And a tetrahydroisophthalimide derivative represented by the general formula (III): [In the formula, R ³ and R ⁴ are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 9 carbon atoms, or an aryl group having 6 to 10 carbon atoms. Represents an alkenyl group having 3 to 5 carbon atoms or an alkynyl group having 3 to 5 carbon atoms, or R ³ and R ⁴ together with the bonded nitrogen atom form a substituted or unsubstituted alicyclic heterocyclic ring. May be. ] The compound represented by the general formula (I): [In the formula, X ¹ represents a halogen atom, and X ² represents a hydrogen atom or a halogen atom. R ¹ represents an optionally substituted cycloalkyl group having 3 to 8 carbon atoms, R ² is a hydrogen atom,
Represents a chlorine atom or a methyl group. R ³ and R ⁴ are each independently a hydrogen atom, which may be substituted, having 1 to 1 carbon atoms.
12 alkyl groups, C3-9 cycloalkyl groups,
It represents an aryl group having 6 to 10 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, or an alkynyl group having 3 to 5 carbon atoms, or R ³ and R ⁴ are substituted or unsubstituted fats together with the nitrogen atom to which they are bonded. A cyclic heterocyclic ring may be formed. ] Indicated by 3,
A method for producing a 4,5,6-tetrahydrophthalamide derivative. 6. A compound represented by the general formula (I): [In the formula, X ¹ represents a halogen atom, and X ² represents a hydrogen atom or a halogen atom. R ¹ represents an optionally substituted cycloalkyl group having 3 to 8 carbon atoms, R ² is a hydrogen atom,
Represents a chlorine atom or a methyl group. R ³ and R ⁴ are each independently a hydrogen atom, which may be substituted, having 1 to 1 carbon atoms.
12 alkyl groups, C3-9 cycloalkyl groups,
It represents an aryl group having 6 to 10 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, or an alkynyl group having 3 to 5 carbon atoms, or R ³ and R ⁴ are substituted or unsubstituted fats together with the nitrogen atom to which they are bonded. A cyclic heterocyclic ring may be formed. ] Indicated by 3,
A herbicide containing a 4,5,6-tetrahydrophthalamide derivative as an active ingredient.