JPH05286912A - Production of aminophenol derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as an intermediate for agricultural chemicals simply, in excellent selectivity and in high yield by hydrolyzing new (5-amino-2-chloro-4-fluorophenylethyl) carbonate. CONSTITUTION:An aniline derivative of formula I, namely new (5-amino-2- chloro-4-fluorophenylethyl) carbonate, is hydrolyzed to give 5-amino-2-chloro-4- fluorophenol. The compound of formula I is produced in high yield by reacting 2-chloro-4-fluorophenol of formula II with ethyl chlorocarbonate in an aqueous solvent to give (2-chloro-4-fluorophenyl)ethyl carbonate of formula III, nitrating the compound of formula III to give (2-chloro-4-fluorophenyl)ethyl) carbonate of formula IV and reducing this compound. The aminophenol derivative of the reaction product has extremely high utility value as an intermediate for agricultural chemicals and an intermediate for medicines, dye and monomers.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing 5-amino-2-chloro-4-fluorophenol, which is useful as an intermediate for agricultural chemicals.

[0002]

2. Description of the Related Art Conventionally, 5-amino-2-chloro-4-fluorophenol is known as 2-chloro-4-fluoro-5-
A method for obtaining nitrophenol by reduction has been known (EP-0,061,741 and JP-A-2-42042). However, in this method 2-chloro-4-fluoro-5-
Since nitrophenol is sparingly soluble in a solvent and the reduction yield is not necessarily good, 5-amino-
It has been desired to develop a more advantageous industrial process for producing 2-chloro-4-fluorophenol.

[0003]

For these reasons, the present inventors have made diligent studies to produce 5-amino-2-chloro-4-fluorophenol with excellent operability and in good yield. As a result of repeated experiments, by hydrolyzing (5-amino-2-chloro-4-fluorophenyl) ethyl carbonate, which is a novel compound previously developed by the present inventors, the yield was simpler and more selective than the conventional method. It was found that 5-amino-2-chloro-4-fluorophenol can be obtained at a high rate, and the present invention has been completed.

[0004]

That is, the present invention provides a compound of the formula [I]

The present invention provides a method for producing 5-amino-2-chloro-4-fluorophenol by hydrolyzing an aniline derivative represented by: Less than,
The present invention will be described in detail.

Carbonic acid of the present invention (5-amino-2-chloro-
A base is usually used in the hydrolysis reaction of 4-fluorophenyl) ethyl, and examples of the base include sodium hydroxide and potassium hydroxide. The base used is 3 times mol to a large excess amount with respect to the aniline derivative [I],
The molar amount is preferably 3 to 5 times.

It is also effective to use a catalyst for the reaction, and examples of the catalyst include quaternary ammonium salts such as tetrabutylammonium bromide and triethylbenzylamine chloride, cetyltributylphosphonium bromide, butyltrioctylphosphonium bromide and the like. Phase transfer catalysts such as quaternary phosphonium salts and tris (3,6-dioxaheptyl) amine (TDA-1) or crown ethers typified by 18-Crown-6 are mentioned.

In the above reaction, a solvent is usually used, and as the solvent, an organic solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, toluene, xylene, hexane, heptane, water or a mixed solvent thereof can be used. .. The reaction temperature is usually in the range of room temperature to the boiling point of the solvent.

During the reaction, in order to prevent coloration of the product,
It is also possible to add a reducing agent such as hydrosulfite or sodium sulfite. The reaction solution after hydrolysis with a base is neutralized with a mineral acid such as sulfuric acid or hydrochloric acid or an organic acid such as acetic acid to adjust the pH to 2 to 10, preferably 5 to 8 to obtain 5-amino-2-chloro. It is possible to isolate -4-fluorophenol.

Next, a method for producing the aniline derivative [I] which is the starting material of the present invention will be described. The aniline derivative is a novel compound, and nitrates (2-chloro-4-fluorophenyl) ethyl carbonate obtained by reacting 2-chloro-4-fluorophenol and ethyl chlorocarbonate in an aqueous solvent. To give (2-chloro-4-fluoro-5-nitrophenyl) ethyl carbonate,
Then, it can be easily produced in good yield by reduction. These series of reactions can be represented by the following formula.

[0011]

The method for producing the raw material will be described in detail below according to the above formula. First, in the reaction between 2-chloro-4-fluorophenol and ethyl chlorocarbonate, ethyl chlorocarbonate is used in 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 2-chloro-4-fluorophenol.

In this reaction, a base is usually used. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as potassium carbonate and sodium carbonate, triethylamine and pyridine. , N, N-diethylaniline, and other organic amines, and these bases can also be used as a mixture. The amount of these bases used is 1 equivalent to 3 times equivalent, preferably 1 to 2 times equivalent to 2-chloro-4-fluorophenol.

It is also effective to use a catalyst in the above reaction. Quaternary ammonium salts such as tetrabutylammonium bromide and benzyltriethylammonium chloride, crown ethers such as 18-crown-6 and cetyltributylphosphosnium bromide. It is also possible to use a phase transfer catalyst such as a phosphosnium salt typified by or tris (3,6-dioxaheptyl) amine (TDA-1).

This reaction is usually carried out in a water solvent, but it is also possible to use an organic solvent. Reaction temperature is 0-10
It is 0 ° C, preferably 0 to 50 ° C. Change the pH of the reaction solution to
It is desirable to carry out the reaction while controlling the pH to 5 to 12, preferably 7 to 10.

The carbonic acid thus obtained (2-chloro-4-
Examples of the agent for nitrating fluorophenyl) ethyl include nitric acid and the like. The nitric acid used is 1 equivalent to 8 times equivalent, preferably 1 to 2 times equivalent to the carbonate derivative [II].

This reaction is usually carried out in a solvent, and as the solvent, halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, organic solvents such as acetic acid and nitrobenzene, sulfuric acid or a mixed solvent thereof is used. Be done. The reaction temperature is -50 to 100 ° C, preferably -20 to 50 ° C. After completion of the reaction, the target product can be taken out by a usual method.

Examples of the method for reducing the nitrobenzene derivative obtained by the above method include a catalytic reduction method and a chemical reduction method, and any method may be used.

In the catalytic reduction method, platinum carbon, platinum dioxide, palladium carbon or the like is used as a catalyst, and the amount thereof is a catalytic amount with respect to the nitrobenzene derivative [II] as a raw material.

The reaction is usually carried out in a solvent, and examples of the solvent include organic solvents such as methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, toluene and xylene, or water or a mixture thereof. The hydrogen pressure in the reaction may be normal pressure or increased pressure. The reaction temperature is room temperature to 150 ° C.

The chemical reduction method is usually carried out in the presence of iron powder and an acid. In this method, the amount of iron powder used is at least twice the molar amount of the raw material nitrobenzene derivative [II],
It is preferably 2 to 5 times mol.

As the acid, inorganic acids such as hydrochloric acid and sulfuric acid and organic acids such as acetic acid are used. The reaction is generally performed under normal pressure, and the reaction temperature is room temperature to 200 ° C, preferably 40 to
It is 100 ° C.

[0023]

Thus, according to the present invention, 5-amino-2-chloro-4-fluorophenol can be easily obtained in good yield from the raw material aniline derivative [I]. Since it can be easily led to the pesticides described in -38256, it is extremely useful as an intermediate for pesticides, as well as other intermediates for medicines, dyes, and monomers.

[0024]

The present invention will be described in detail below with reference to examples. Example 1 Synthesis of 5-amino-2-chloro-4-fluorophenol 430.0 g of (5-amino-2-chloro-4-fluorophenyl) ethyl carbonate and water 51 were placed in a 3-liter four-necked flask.
0.0g and 15.77 g of hydrosulfite were charged, 976.8 g of 23% aqueous sodium hydroxide solution was added dropwise at a temperature of 35 to 40 ° C over 2 hours, and the mixture was aged for 4 hours. After completion of the reaction, about 440 g of concentrated hydrochloric acid was added dropwise to the reaction solution at 20 to 25 ° C to adjust the pH value to 7. After completion of dropping, the mixture was aged for 1 hour. Thereafter, the precipitated target substance is filtered, washed with water, and then dried.
Amino-2-chloro-4-fluorophenol 277.5g
Got (Yield 95.9%)

Example 2 Synthesis of 5-amino-2-chloro-4-fluorophenol 784.0 g of (5-amino-2-chloro-4-fluorophenyl) ethyl carbonate and water in a 2-liter four-necked flask.
2.0 g was charged therein, and 539.2 g of 23% sodium hydroxide was added dropwise thereto at a temperature of 40 to 45 ° C. over 3 hours, followed by aging for 3 hours. After completion of the reaction, add about 303 g of concentrated hydrochloric acid to the reaction solution.
After dropping at 0 to 25 ° C. and adjusting the pH value to 7, the aqueous layer was extracted twice with methyl isobutyl ketone (total 440 g) and the layers were separated to obtain an organic layer. The obtained organic layer was concentrated to give 5-amino-2-chloro-4-fluorophenol 15
5.1 g was obtained. (Yield 96.1%)

Example 3 Synthesis of 5-amino-2-chloro-4-fluorophenol 22.56 g (5-amino-2-chloro-4-fluorophenyl) ethyl carbonate and toluene in a 500 ml four-necked flask.
112.8 g was charged, and a 10% aqueous potassium hydroxide solution was added dropwise thereto at a temperature of 40 to 50 ° C. for 1 hour, followed by aging for 6.5 hours. After the reaction was completed, the reaction solution was separated, and about 24.5 g of 50% H ₂ SO ₄ was added dropwise to the obtained aqueous layer at 20 to 25 ° C. so that the pH thereof became 5.15. After completion of dropping, at 10 to 20 ° C
Aged for 1.5 hours. Then, the neutralized mass was extracted twice with a total of 388.4 g of methyl isobutyl ketone, and liquid separation was performed to obtain an organic layer. The obtained organic layer was concentrated to obtain 16.99 g of 5-amino-2-chloro-4-fluorophenol. (Yield 97.2%)

Reference Example 1 Synthesis of (5-amino-2-chloro-4-fluorophenyl) ethyl carbonate (20.0 g) of (2-chloro-4-fluoro-5-nitrophenyl) ethyl carbonate and toluene 6 in a 500 ml autoclave.
After charging 0 g and 0.2 g of 5% Pd-C and substituting with nitrogen, hydrogen pressure was 20 kg / cm ² , and reaction temperature was 2.75 under the conditions of 40 ° C.
A time reaction was performed. After completion of the reaction, the reaction solution was cooled, filtered, and concentrated to obtain 17.48 g of (5-amino-2-chloro-4-fluorophenyl) ethyl carbonate. (Yield 95.8
%) Mp 46~48 ℃ FD-MS: 233 ( M +) NMR (CDCl 3) δ: 1.39 (t, 3H, J = 7.0Hz) 3.4~3.7 (b
road, 2H) 4.33 (q, 2H, J = 7.0Hz) 6.62 (d, 1H, J
= 8.2Hz) 7.07 (d, 1H, J = 10.6Hz)

Reference Example 2 Synthesis of (5-amino-2-chloro-4-fluorophenyl) ethyl carbonate 26.36 g of (2-chloro-4-fluoro-5-nitrophenyl) ethyl carbonate and toluene in a 500 ml autoclave.
79.07 g and 1% Pt-C 0.053 g were charged, the atmosphere was replaced with nitrogen, and the hydrogen pressure was 20 kg / cm ² , and the reaction temperature was 80 ° C. 6
Reacted for hours. After the reaction was completed, the reaction solution was cooled and filtered, and the resulting solution was concentrated to give carbonic acid (5-amino-2-chloro-
23.87 g of 4-fluorophenyl) ethyl was obtained. (yield
94.1%)

Reference Example 3 Synthesis of (5-amino-2-chloro-4-fluorophenyl) ethyl carbonate: 1% Pt-C (1.77 g) and toluene (39.5 g) were charged and placed in a nitrogen-substituted 1 l autoclave at a hydrogen pressure of 20 kg / A solution of 79 g of (2-chloro-4-fluoro-5-nitrophenyl) ethyl carbonate in toluene (197.5 g) was injected under pressure over 4 hours under the conditions of cm ² and a reaction temperature of 80 ° C. 4 after press fitting
Aged for hours. After completion of the reaction, the reaction solution was cooled, filtered, and concentrated to obtain 68.89 g of (5-amino-2-chloro-4-fluorophenyl) ethyl carbonate. (Yield 95.0
%)

Reference Example 4 Production of (2-chloro-4-fluorophenyl) ethyl carbonate: A 4-neck flask was charged with 132 g of 2-chloro-4-fluorophenol and 370 g of water, and a small amount of 37.0% sodium hydroxide aqueous solution was added. The pH was adjusted to 7.0. After cooling this in a water bath, 102.6 g of ethyl chlorocarbonate and 102.2 g of 37.0% sodium hydroxide were added over 1 hour at a reaction temperature of 30.
It was poured in parallel at less than ℃. After the reaction solution was stirred at room temperature for 2 hours, a liquid separation operation was performed and the organic layer was separated to obtain 195 g of (2-chloro-4-fluorophenyl) ethyl carbonate.
(Yield 99%) Melting point 28-30 ° C Boiling point 98-100 ° C (1.7mmHg) δ (CDCl ₃ ) 1.40 (3H, t, J = 7.3Hz) 4.34 (2H, q, J = 7.3Hz) 7.00 (1H , M) 7.22 (2H, m) FD-MS M ⁺ 218

Reference Example 5 Synthesis of (2-chloro-4-fluoro-5-nitrophenyl) ethyl carbonate (80 ml) of (2-chloro-4-fluorophenyl) ethyl carbonate and 160 g of 97% sulfuric acid were charged into a four-necked flask. While cooling in an ice bath, 24.5 g of 99% nitric acid was added dropwise over 30 minutes at a reaction temperature of less than 30 ° C. The reaction solution was stirred at room temperature (20.0 ° C) for 2 hours, cooled in an ice bath, and 120 ml of water was added dropwise at less than 30 ° C. Toluene 24
The target substance was extracted by adding 0 g and the layers were separated. Then water 250
ml, the toluene layer obtained by washing with 5% aqueous sodium carbonate solution was washed. Toluene was distilled off from the organic layer obtained by liquid separation under reduced pressure to obtain 93.3 g of (2-chloro-4-fluoro-5-nitrophenyl) ethyl carbonate. (Yield 9
6.7%) Melting point 51-53 ° C NMR δ (CDCl ₃ ) 1.43 (3H, t, J = 7.3H)
z) 4.40 (2H, q, J = 7.3Hz) 7.46 (1H, d, J = 9.90Hz) 8.05 (1H, d, J = 6.9Hz) FD-MS M ⁺ 263

Reference Example 6 Synthesis of (2-chloro-4-fluoro-5-nitrophenyl) ethyl carbonate 280 g of (2-chloro-4-fluorophenyl) ethyl carbonate and 576 g of 97% sulfuric acid were charged into a four-necked flask. While cooling in an ice bath, mixed acid (nitric acid / sulfuric acid 45/5
0) 189 g was added dropwise at a reaction temperature of less than 15 ° C. over 10 hours. The reaction solution was stirred at room temperature (20.0 ° C) for 1 hour and then cooled in an ice bath, to which 300 g of water was added dropwise at less than 15 ° C. To this was added 600 g of toluene to extract the product, which was then separated. Next, the toluene layer was washed with 300 g of water and 300 g of a 5% sodium carbonate aqueous solution, respectively. The organic layer obtained by liquid separation was concentrated under reduced pressure to obtain 294 g of (2-chloro-4-fluoro-5-nitrophenyl) ethyl carbonate. (Yield 91.8%)

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Ritsu Okajima 2-10-1 Tsukahara, Takatsuki City, Osaka Prefecture Sumitomo Chemical Co., Ltd. (72) Inventor Kazuki Takemoto 2-10 Tsukahara, Takatsuki City, Osaka Prefecture No. 1 Sumitomo Chemical Co., Ltd.

Claims (1)

[Claims] 1. Formula 1 A method for producing 5-amino-2-chloro-4-fluorophenol, which comprises hydrolyzing an aniline derivative represented by