JPH0782224A - Production of aniline derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound in a good yield by a process comprising reacting a bis(amino-substituted phenyl)carbonate with an alkylating agent in the presence of a base in an organic solvent under specific conditions without protecting the amino group. CONSTITUTION:A bis(amino-substituted phenyl)carbonate derivative of formula I (X<1>, X<2> are halogen) is reacted with an alkylating agent of formula: R-Y (R is 3-12C cycloalkyl, alkynyl; Y is a releasable group) in the presence of a phase transfer catalyst in a two-layered system comprising aqueous solution of an alkali metal hydroxide and an organic solvent to obtain an aniline derivative of formula II. A quaternary ammonium salt is especially preferable as the phase transfer catalyst. Sodium hydroxide is especially preferable as the alkali metal hydroxide, and the concentration of the aqueous solution is preferably 24-48%. The compound of formula II is useful as an intermediate for oxazolidinedione and tetrahydrophthalimide useful as herbicides and furthermore for tetrahydroindazole derivatives.

Description

Detailed Description of the Invention

[0001]

The present invention relates to the general formula (1)

[0002]

[Chemical 4]

A bis (amino-substituted phenyl) carbonate derivative represented by the formula (wherein X ¹ and X ² represent a halogen atom) is represented by the general formula (2)

[0004]

[Chemical 5]

(Wherein R represents an optionally substituted cycloalkyl group having 3 to 12 carbon atoms or an alkynyl group having 3 to 6 carbon atoms, and Y represents a leaving group). General formula (3), characterized in that the reaction is carried out in a two-layer system of an aqueous alkali metal hydroxide solution and an organic solvent in the presence of an agent and a phase transfer catalyst.

[0006]

[Chemical 6]

(Wherein, X ¹ and X ² represent a halogen atom, and R represents an optionally substituted cycloalkyl group having 3 to 12 carbon atoms or an alkynyl group having 3 to 6 carbon atoms). The present invention relates to a method for producing an aniline derivative. More specifically, the present invention provides an intermediate for the production of oxazolidinedione, tetrahydrophthalimide, and tetrahydroindazole derivative useful as an active ingredient of the herbicides described in JP-A Nos. 62-167713 and 4-145071, 4-164067. A manufacturing method is provided.

[0008]

2. Description of the Related Art In the production of an aniline derivative represented by the general formula (3) using a bis (amino-substituted phenyl) carbonate derivative represented by the general formula (1) as a raw material, it is usually considered that the aniline derivative is harmful to the reaction. Protecting the group with a suitable protecting group, further starting from an aminophenol derivative obtained by hydrolyzing only the carbonate bond without damaging the protecting group, after alkylating on the oxygen atom in the presence of a base, It is produced by removing the protective group (for example, JP-A-5-17411 or JP-A-5-43525). Specifically, for example, as illustrated in the following formula, bis (5-alkoxycarbonylamino-2-chloro-4-fluorophenyl) carbonate (6) having an amino group protected as an alkyl carbamate group is selectively hydrolyzed. Then phenol derivative (7)
Then, after alkylation, the carbamate group is hydrolyzed under basic conditions to produce the aniline derivative (3) (see Reference Examples-1 and 2 below).

[0009]

[Chemical 7]

[0010]

Therefore, in such a conventional method, a step for introducing and removing a protecting group for an amino group is required, the reaction step becomes long, and an auxiliary raw material corresponding to each step is required. Must be used, which is also disadvantageous from the economical point of view.

[0011]

MEANS FOR SOLVING THE PROBLEMS The inventors of the present invention have commercialized an aniline derivative represented by the general formula (3), which is a raw material for producing oxazolidinedione, tetrahydrophthalimide, and tetrahydroindazole derivative useful as an active ingredient of herbicides. As a result of earnestly studying the development of a more advantageous production method, under the specific conditions, the above general formula (1)
The bis (amino-substituted phenyl) carbonate derivative represented by the formula (1) is reacted with the alkylating agent represented by the general formula (2) in the presence of a base in an organic solvent without protecting the amino group. The present invention has been completed by clarifying that the aniline derivative represented by the formula (3) can be produced in a high yield in one step. That is, the present invention provides bis (amino-substituted phenyl) represented by the general formula (1).
The carbonate derivative and the alkylating agent represented by the general formula (2) are reacted in a two-layer system of an aqueous alkali metal hydroxide solution and an organic solvent in the presence of a phase transfer catalyst. A method for producing an aniline derivative represented by the general formula (3) is provided.

The bis (amino-substituted phenyl) carbonate derivative represented by the above-mentioned general formula (1), which is a raw material of this production method, is disclosed in, for example, JP-A-5-17411 or 5-43.
It can be produced by the method described in Japanese Patent No. 525.
Examples of the carbonate derivative include bis (5-amino-
2-chloro-4-fluorophenyl) carbonate, bis (5-amino-2-bromo-4-fluorophenyl)
Examples thereof include carbonate, bis (5-amino-2,4-dichlorophenyl) carbonate, and bis (5-amino-2,4-difluorophenyl) carbonate.

The present production method is characterized by reacting in a two-layer system of an aqueous alkali metal hydroxide solution and an organic solvent in the presence of a phase transfer catalyst. Examples of the alkali metal hydroxide include: , Sodium hydroxide, potassium hydroxide and the like. There is no particular limitation on the concentration of the aqueous solution of the alkali metal hydroxide, but for example, a 24-48% aqueous sodium hydroxide solution which is industrially available at low cost can also be used in this reaction. The amount of the aqueous alkali metal hydroxide solution used is converted into the amount of base,
From the viewpoint of good yield, it is preferable to use 1 equivalent or more, preferably 10 equivalents or more based on the reaction substrate.

As the organic solvent used in the reaction, any solvent can be used as long as it does not adversely affect the reaction. For example, tetrahydrofuran, diethyl ether, diisopropyl ether, benzene, toluene, xylene, chlorobenzene, hexane and the like can be used. It can be illustrated. Of these, aromatic solvents such as toluene and chlorobenzene are preferable in terms of good yield.

The amount of the phase transfer catalyst used is not particularly limited, but a so-called catalytic amount may be used, which is 1/1000 of the substrate.
By using 0 to 1/2 equivalent, preferably 1/1000 to 1/10 equivalent, the target product can be obtained in good yield.

As the phase transfer catalyst, quaternary ammonium salts, crown ethers and the like can be used. Examples thereof include tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium chloride, tetraethylammonium bromide, tetrabutylammonium chloride, Tetrabutylammonium bromide, trimethylbenzylammonium chloride, trimethylbenzylammonium bromide, triethylbenzylammonium chloride, triethylbenzylammonium bromide, cetyltrimethylammonium chloride, trioctylmethylbenzylammonium chloride, tetrabutylammonium hydrogen sulfate, tetraethylammonium p-toluenesulfonate, Tetrapropylammonium hydride Quaternary ammonium salts such as loxide and trimethylbenzylammonium hydroxide, and 1
5-crown-5, 18-crown-6, benzo-15
Examples thereof include crown ethers such as -crown-5, dibenzo-18-crown-6, and dicyclohexano-18-crown-6.

In the alkylating agent represented by the general formula (2), examples of the cycloalkyl group represented by R include cyclopropyl group, cyclopentyl group, cyclohexyl group, cyclooctyl group, cyclododecyl group and the like. However, these cycloalkyl groups may be substituted with an alkyl group having 1 to 4 carbon atoms. Further, as the alkynyl group, a propargyl group, a 1-butyn-3-yl group, a 3-
Butyn-1-yl group, 2-butyn-1-yl group, 1-pentyn-2-yl group, 1-pentyn-3-yl group, 2-
Pentin-1-yl group, 3-hexyn-1-yl group, 5
-Hexyn-1-yl group etc. can be illustrated.

The leaving group represented by Y is a chlorine atom,
Examples thereof include halogen atoms such as bromine atom and iodine atom, and sulfonyloxy groups such as p-toluenesulfonyloxy group, benzenesulfonyloxy group, methanesulfonyloxy group and trifluoromethanesulfonyloxy group.

Therefore, as the alkylating agent represented by the general formula (2), cyclopropyl bromide, cyclopentyl bromide, cyclopentyl iodide, cyclohexyl bromide, cyclooctyl bromide, cyclododecyl bromide, cyclopentyl p-toluene sulfonate,
Cyclopentylbenzene sulfonate, cyclopentyl methane sulfonate, cyclopentyl trifluoromethane sulfonate, (3-methylcyclopentyl) p-toluene sulfonate, (3-methylcyclopentyl) benzene sulfonate, (3-methylcyclopentyl) methane sulfonate, (2-methylcyclopentyl) p-
Toluene sulfonate, (2-methylcyclopentyl)
Benzene sulfonate, (2-methylcyclopentyl)
Methane sulfonate, cyclohexyl p-toluene sulfonate, cyclohexyl benzene sulfonate, cyclohexyl methane sulfonate, cyclooctyl p-toluene sulfonate, cyclooctyl methane sulfonate, cyclododecyl p-toluene sulfonate, cyclododecyl methane sulfonate, propargyl bromide,
Propargyl iodide, 3-bromo-1-butyne, 1-
Bromo-3-butyne, 1-bromo-2-butyne, 1-chloro-2-butyne, 1-bromo-3-pentyne, 1-bromo-5-hexyne, propargyl p-toluenesulfonate, propargylbenzenesulfonate, propargylmethane Sulfonate, (1-butyn-3-yl) p
-Toluenesulfonate, (1-butyn-3-yl) benzenesulfonate, (1-butyn-3-yl) methanesulfonate, (2-butyn-1-yl) p-toluenesulfonate, (2-butyn-1-yl) ) Methanesulfonate, (3-butyn-1-yl) p-toluenesulfonate, (3-butyn-1-yl) methanesulfonate, (3-pentyn-1-yl) p-toluenesulfonate, (3-pentyne-1) -Yl) methane sulfonate, (1-pentyn-3-yl) p-toluene sulfonate, (1-pentyn-3-yl) methane sulfonate, etc. can be illustrated. Commercially available compounds can be used as they are, but sulfonates can be easily produced by reacting a corresponding cycloalkyl alcohol or alkynyl alcohol with a substituted sulfonyl chloride in the presence of a base. (See Reference Examples 3 to 6 below).

When bromide or sulfonate is used as the alkylating agent, the reaction time can be shortened and the yield can be improved by carrying out the reaction in the presence of iodide such as potassium iodide or sodium iodide. You can also let it.

Further, since the bis (amino-substituted phenyl) carbonate derivative represented by the general formula (1) can react stoichiometrically with two molecules of the alkylating agent (2), the alkylating agent (2) is generally It is preferable to use 2 equivalents or more with respect to the bis (amino-substituted phenyl) carbonate derivative represented by the formula (1) in terms of good yield.

The reaction can usually be carried out at 30 to 120 ° C., but by carrying out the heating at 50 to 100 ° C., the reaction can be completed in a short time and the desired product can be obtained in good yield.

After completion of the reaction, the aniline derivative (3) can be obtained by a usual extraction operation. Furthermore, it is also possible to add concentrated hydrochloric acid to, for example, a toluene solution of the obtained aniline derivative (3) to isolate the aniline derivative (3) as its hydrochloride salt, and the hydrochloride salt can be easily treated by treatment with a base. The aniline derivative (3), which is free, can be returned to.

The aniline derivative thus obtained can be converted into an oxazolidinedione derivative or a tetrahydrophthalimide derivative useful as an active ingredient of a herbicide according to the steps exemplified in the following reaction formula (Reference Example-7 below). ~ 9).

[0025]

[Chemical 8]

[0026]

[Chemical 9]

Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.

[0028]

【Example】

 Example-1

[0029]

[Chemical 10]

A eggplant-shaped flask (50 cc) was charged with bis (5-amino-2-chloro-4-fluorophenyl) carbonate.
A solution of (1.50 g, 4.29 mmol), cyclopentyl methanesulfonate (1.50 g, 9.15 mmol) and tetrabutylammonium bromide (70 mg, 0.22 mmol) in toluene (12 mL) was prepared.
Then, 48% aqueous sodium hydroxide solution (6 mL) was slowly added, and the mixture was heated with stirring at 80 ° C. for 3 hours. After the reaction,
The reaction solution was cooled to room temperature, water (15 mL) was added, and toluene (1 mL
It was extracted with 0 mL x 2). The organic layers were combined and washed with water (10 mL x 2). The solvent was distilled off from the obtained toluene solution under reduced pressure to give 4-chloro-5-cyclopentyloxy-2-fluoroaniline (1.94 g, 8.45 mmol, yield 9
8.4%, HPLC purity 94.3%) was obtained. BP: 143-145 ℃ / 1.5mmHg ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.40-2.00 (8H, m), 3.72 (2H,
s), 4.76 (1H, m), 6.39 (1H, d, J = 9.0Hz), 7.04 (1H, d,
J = 11.0Hz) .IR (neat, cm ^-1 ): 3500, 3400, 1630, 1510, 1420, 1245,
1185.

Example-2

[0032]

[Chemical 11]

Eggplant-shaped flask (50 cc) was charged with bis (5-amino-2-chloro-4-fluorophenyl) carbonate.
(1.51g, 4.34mmol), cyclopentyl methanesulfonate (1.51g, 9.21mmol) and tetrabutylammonium bromide (70mg, 0.22mmol) in toluene (8mL) solution, 48% aqueous sodium hydroxide solution (4mL) slowly. In addition, 80 ℃
The mixture was heated and stirred for 1 hour. Then, 48% aqueous sodium hydroxide solution (4 mL) was slowly added, and the mixture was heated with stirring at 80 ° C. for 1 hour. After the reaction is complete, cool the reaction mixture to room temperature and wash with water.
(15 mL) was added, and the mixture was extracted with toluene (10 mL x 2). The organic layers were combined and washed with water (10 mL x 2). The solvent was distilled off from the obtained toluene solution under reduced pressure to give 4-chloro-5-cyclopentyloxy-2-fluoroaniline.
(1.92 g, 8.36 mmol, yield 96.4%, HPLC purity 94.4%) was obtained.

Example-3

[0035]

[Chemical 12]

Eggplant-shaped flask (300 cc) was charged with bis (5-amino-2-chloro-4-fluorophenyl) carbonate.
(10.0 g, 28.6 mmol), cyclopentyl methanesulfonate (10.1 g, 61.3 mmol) and tetrabutylammonium bromide (463 mg, 1.43 mmol) in toluene (55 mL) solution, 48%
Add sodium hydroxide aqueous solution (28 mL) slowly, and add 80
The mixture was heated and stirred at 30 ° C for 30 minutes. Then, 48% aqueous sodium hydroxide solution (27 mL) was slowly added over 30 minutes, and 8
The mixture was further heated and stirred at 0 ° C. for 1.0 hour. After the reaction was completed, the reaction solution was cooled to room temperature, water (100 mL) was added, and toluene (50 mL) was added.
x 2). The organic layers were combined and washed with water (100 mL x 2). The solvent was distilled off from the obtained toluene solution under reduced pressure to give 4-chloro-5-cyclopentyloxy-2-fluoroaniline (12.6 g, 54.7 mmol, yield 95.
4%, HPLC purity 83.8%) was obtained.

Example-4

[0038]

[Chemical 13]

Eggplant-shaped flask (50 cc) was charged with bis (5-amino-2-chloro-4-fluorophenyl) carbonate.
(1.52g, 4.36mmol), cyclopentyl bromide (1.39g,
9.29 mmol) and tetrabutylammonium bromide (74 mg,
To a solution of 0.23 mmol) in toluene (12 mL) was slowly added 48% aqueous sodium hydroxide solution (6 mL), and the mixture was heated with stirring at 80 ° C. for 1 hour. After the reaction is completed, the reaction solution is cooled to room temperature,
Water (15 mL) was added, and the mixture was extracted with toluene (10 mL x 2). The organic layers were combined and washed with water (10 mL x 2). The solvent was distilled off from the obtained toluene solution under reduced pressure to give 4-chloro-5-cyclopentyloxy-2-fluoroaniline (1.93 g, 8.40 mmol, yield 96.3%).

Example-5

[0041]

[Chemical 14]

Eggplant-shaped flask (50 cc) was charged with bis (5-amino-2-chloro-4-fluorophenyl) carbonate.
(1.53g, 4.39mmol), propargyl bromide (1.11g, 9.3
6 mmol) and tetrabutylammonium bromide (70 mg, 0.22 m
To a toluene (10 mL) solution of (mol), 48% aqueous sodium hydroxide solution (5 mL) was slowly added, and the mixture was heated with stirring at 80 ° C. for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature and washed with water (15 m
L) was added and extracted with toluene (10 mL x 2). The organic layers were combined and washed with water (10 mL x 2). By distilling off the solvent from the obtained toluene solution under reduced pressure, 4-chloro-
2-fluoro-5-propargyloxyaniline (1.61
g, 8.08 mmol, yield 92.0%) was obtained. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ2.54 (1 H, t, J = 2.3Hz), 3.79
(2H, br s), 4.70 (2H, d, J = 2.3Hz), 6.58 (1H, d, J _HF =
8.9Hz), 7.07 (1H, d, J _HF = 11.2Hz).

Example-6

[0044]

[Chemical 15]

Eggplant-shaped flask (50 cc) was charged with bis (5-amino-2-chloro-4-fluorophenyl) carbonate.
(1.50 g, 4.30 mmol), (1-butyn-3-yl) tosylate (2.03 g, 9.01 mmol) and tetrabutylammonium bromide (71 mg, 0.22 mmol) in toluene (25 mL), 48%
Aqueous sodium hydroxide solution (6 mL) was added slowly, and the temperature was 60 ° C.
The mixture was heated and stirred for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water (15 mL) was added, and the mixture was extracted with toluene (10 mL x 2). The organic layers were combined and washed with water (10 mL x 2). The solvent was distilled off from the obtained toluene solution under reduced pressure to give 4-chloro-2-fluoro-5-{(1-butyne-
3-yl) oxy} aniline (1.12 g, 5.24 mmol, yield 6
1.0%). MP: 74.5-75.5 ℃ ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.60 (3H, d, J = 6.3Hz), 2.48
(1H, d, J = 1.5Hz), 3.46 (2H, br s), 4.72 (1H, d & q, J =
6.3 and 1.5Hz), 6.62 (1H, d, J _HF = 7.5Hz), 7.01 (1H,
d, J _HF = 10.0Hz).

Reference Example-1

[0047]

[Chemical 16]

A 10 L three-necked flask equipped with a stirrer and Dimroth was charged with N- (4-chloro-2-fluoro-5).
-Hydroxyphenyl) methyl carbamate (1.64kg,
7.47 mol), cyclopentyl p-toluenesulfonate (1.
80 kg, 7.48 mol), potassium carbonate (1.03 kg, 7.46 mol), and potassium iodide (12.3 g, 1.0 mol%) were added, acetone (7500 mL) 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 N- (4-chloro-5
White solid of methyl cyclopentyloxy-2-fluorophenyl) carbamate (2.00 kg, 6.95 mol, yield 93.
1%) was isolated by filtration and dried well. MP: 120.0-123.0 ℃ ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.40-2.10 (8H, 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): 1714, 1535, 1500, 1415, 1255, 1
190.

Reference Example-2

[0050]

[Chemical 17]

In a 10 L three-necked flask equipped with a stirrer and a Dimroth, methyl N- (4-chloro-5-cyclopentyloxy-2-fluorophenyl) carbamate was added.
4N- in ethanol (3000mL) solution of (2.25kg, 7.85mol)
An aqueous potassium hydroxide solution (4750 mL) was added, and the mixture was heated under reflux for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and water (5000 m
L) was added, and the mixture was extracted with toluene (5000 mL x 2). The organic layer was washed with water and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off from the filtrate under reduced pressure to give 4-chloro-5-cyclopentyloxy-2-fluoroaniline oil (1.75 kg, 7.62 mol, yield 98.3%).
Got

Reference Example-3

[0053]

[Chemical 18]

Round bottom separable flask equipped with stirrer
(3000cc), cyclopentyl alcohol (500g, 5.80mo
l) and p-toluenesulfonyl chloride (1210 g, 6.35 mol)
Then, pyridine (2000 mL) was added and dissolved under cold ice. The mixture was stirred for 8 hours while gradually warming to room temperature.
After completion of the reaction, the reaction mixture was poured into ice water (3000 mL) and stirred sufficiently. The precipitated solid was collected by filtration, washed thoroughly with water, and dried to give a white crystal of cyclopentyl p-toluenesulfonate (1117 g, yield 80.1%). MP: <30 ℃ ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.23-2.07 (8H, m), 2.45
(3H, s), 4.98 (1H, m), 7.38 (2H, d, J = 9.0Hz), 7.85 (2
H, d, J = 9.0Hz).

Reference Example-4

[0056]

[Chemical 19]

Cyclopentyl alcohol (10.0 g, 0.116 mol), p-toluenesulfonyl chloride (24.3 g, 0.128 mol) and ether (100 mL) were added to an eggplant-shaped flask (200 cc) and dissolved. Then, powdery potassium hydroxide (32.5 g, 0.58 mol) was slowly added while cooling to 10 ° C or lower in a water bath. After the addition, stirring was continued for 2 hours at the same temperature.
After completion of the reaction, the mixture was poured into ice water (20 mL), and the organic layer and the aqueous layer were separated. The organic layer was dried and then concentrated under reduced pressure to obtain a pale yellow viscous liquid of cyclopentyl p-toluenesulfonate (22.0 g, yield 78.9%).

Reference Example-5

[0059]

[Chemical 20]

Round bottom flask (1000 cc) equipped with a stirrer
Cyclopentyl alcohol (51.2 g, 0.595 mol) and methanesulfonyl chloride (75.1 g, 0.656 mol) were put into the flask, and then pyridine (200 mL) was added under ice cooling to dissolve it. The mixture was stirred for 6 hours while gradually warming to room temperature. After the reaction was completed, the reaction mixture was poured into ice water (300 mL), and ether (200 mL) was added.
Extracted with x3). The organic layer was washed with water, 1N hydrochloric acid and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give cyclopentyl methanesulfonate colorless oil (75.2 g, 0.458 mol, yield
77.0%). ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.54-2.03 (8H, m), 3.01
(3H, s), 5.19 (1H, m).

Reference Example-6

[0062]

[Chemical 21]

Round bottom flask (5000 cc) equipped with stirrer
Cyclopentyl alcohol (250 g, 2.90 mol) and methanesulfonyl chloride (350 g, 3.06 mol) were put in and dissolved in toluene (400 mL). Then, pyridine (480 mL) was added dropwise under ice cooling over 1 hour. After the dropping, the mixture was stirred at the same temperature for 3 hours. After the reaction was completed, 2N-hydrochloric acid (1500 mL) was added to the reaction mixture, and the toluene layer was separated. The aqueous layer was extracted with toluene (500 mL), the toluene layers were combined, and 2N-
It was washed with hydrochloric acid (250 mL). The solvent was distilled off from the obtained toluene solution under reduced pressure to give cyclopentyl methanesulfonate colorless oil (433.4 g, 2.64 mol, yield
90.9%).

Reference Example-7

[0065]

[Chemical formula 22]

Trichloromethyl chloroformate (TCF) (1
A toluene (50 mL) solution of 5 mL, 0.123 mol) was cooled in an ice-water bath, and 4-chloro-5-cyclopentyloxy-2 was added thereto.
A solution of fluoroaniline (23.0 g, 0.10 mol) and triethylamine (0.5 mL) in toluene (50 mL) was added dropwise with sufficient stirring. While the ammonium salt was precipitated and became a suspension upon dropping, the mixture was stirred as it was for 1 hour. Then, the mixture was heated to 100 ° C. and further stirred for 1 hour. After completion of the reaction, toluene was distilled off under reduced pressure, whereby a target red-brown oily substance of 4-chloro-5-cyclopentyloxy-2-fluorophenyl isocyanate was able to be obtained almost quantitatively. ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.50-2.10 (8H, m), 4.67
(1H, m), 6.60 (1H, d, J = 7.5Hz), 7.12 (1H, d, J = 10.5H
z) .IR (neat): 2275, 1720, 1615, 1525, 1470, 1195.

Reference Example-8

[0068]

[Chemical formula 23]

4-chloro-5-cyclopentyloxy-2-fluorophenylisocyanate (4.00 kg, 15.6 m) was placed in a 20 L stainless steel container equipped with a stirrer and a dropping funnel.
ol) and methyl 2-hydroxy-3-methyl-3-butenoate (2.40 kg, about 90% purity, 18.4 mol) in toluene (10 L) solution, while cooling in an ice-water bath, add triethylamine (40 mL) to the solution temperature. Was added slowly so as not to rise. TLC
The mixture was stirred at the same temperature for 3 hours until the raw materials disappeared. Then, potassium carbonate (200 g) was added, and a distillation apparatus was attached to remove the produced methanol, and
The mixture was heated and stirred at (° C) for 5 hours. After the reaction is complete, add 1 to the reaction mixture.
N-hydrochloric acid (10L), 1N-sodium hydroxide (10L), 1N
-Washed with hydrochloric acid (10 L). The toluene layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and then about half amount of hexane of the obtained oily substance was added and the mixture was allowed to stand at room temperature to precipitate 3N- (4-chloro-5-. Cyclopentyloxy-2-fluorophenyl) -5-isopropylidene-2,4-oxazolidinedione white-yellow solid (4.1
9 kg, 11.8 mol, yield 75.7%, primary crystal) was obtained. MP: 104.5-105.0 ℃ ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.49-1.97 (8H, m), 2.03
(3H, s), 2.31 (3H, s), 4.73 (1H, m), 6.88 (1H, d, J _HF
= 6.6Hz), 7.33 (1H, d, J _HF = 8.5Hz). IR (KBr disk, cm ^-1 ): 2970, 1815, 1740, 1500, 1200.

Reference Example-9

[0071]

[Chemical formula 24]

4-chloro-5-cyclopentyloxy-
2-Fluoroaniline (0.50g, 2.18mmol) and 3,4,5,6
A solution of tetrahydrophthalic anhydride (0.398 g, 2.61 mmol) in acetic acid (3.0 mL) was stirred under reflux for 3 hours. Water (20 mL) was added to the reaction mixture obtained after the reaction, and ethyl acetate (20 mL
x 3). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained pale yellow oily product was separated and purified by silica gel column chromatography (ethyl acetate / hexane = 1/8) to give N- (4
A colorless transparent oily substance (0.513 g, 1.41 mmol, yield 65%) of -chloro-5-cyclopentyloxy-2-fluorophenyl) -3,4,5,6-tetrahydrophthalimide was obtained.
Ethanol was added to this product for recrystallization, whereby a white solid could be obtained. MP: 69.0-75.2 ℃ ¹ H-NMR (CDCl ₃ , TMS, ppm): δ1.32-2.10 (12H, 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 (neat, cm ^-1 ): 1725, 1505, 1430, 1385, 1200.

Claims (3)

[Claims] 1. A compound represented by the general formula (1): (In the formula, X ¹ and X ² represent a halogen atom.) The bis (amino-substituted phenyl) carbonate derivative represented by the general formula (2) (In the formula, R represents an optionally substituted cycloalkyl group having 3 to 12 carbon atoms or an alkynyl group having 3 to 6 carbon atoms, and Y represents a leaving group.),
In the presence of a phase transfer catalyst, characterized by reacting in a two-layer system of an alkali metal hydroxide aqueous solution and an organic solvent,
General formula (3) (In the formula, X ¹ and X ² represent a halogen atom, and R represents an optionally substituted cycloalkyl group having a carbon number of 3 to 12 or an alkynyl group having a carbon number of 3 to 6). Manufacturing method. 2. The method according to claim 1, wherein the phase transfer catalyst is a quaternary ammonium salt. 3. The method according to claim 1 or 2, wherein the alkali metal hydroxide is sodium hydroxide, and the concentration of the aqueous solution thereof is 24 to 48%.