JPH09136853A - Production of fluorophenols - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain fluorophenol useful as an intermediate for a medicine, etc., under a milder condition than a conventional method in >=70% high yield (based on polyfluorobenzene). SOLUTION: A polyfluorobenzene of formula I ((n) is an integer of 1-5) is reacted with sodium methoxide in an aprotic polar solvent at 50-160 deg.C to give a fluoroanisole of formula II, which is hydrolyzed to give a fluorophenol of formula III such as 2-fluorophenol.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for efficiently producing fluorophenols which can be important intermediates for medicines, agricultural chemicals, liquid crystals and the like.

[0002]

2. Description of the Related Art Conventionally, as a method for producing fluorophenols, 1) a method of hydrolyzing fluoroaniline after diazotization [J. Am. Chem. Soc. , 61 , 165
(1939)], 2) A method of hydrolyzing a methoxy group after obtaining fluoroanisole from aminoanisole by a Seaman reaction [Nikka 79 , 1121 (197).
9)], 3) Method of hydrolyzing chlorofluorobenzene with alkali [J. Fluorine Chem. , 5
0 , 377, (1990)] and the like are known. The method 1) has an advantage that it can be easily performed in a laboratory, but it is hard to say that it is a method that can be industrially put into practical use because of low yield and large amount of waste. The method 2) has a long process, and the overall yield is low at 50% or less. In addition, the thermal decomposition reaction in the Seaman reaction has a large amount of heat generation and is industrially difficult to control, and it has troublesome problems such as detoxification treatment of boron trifluoride produced as a by-product. In the method 3), the reaction temperature is 200 to 300.
Since alkali is used as high as ℃, there are industrial problems such as corrosion of the reactor.

[0003]

An object of the present invention is to provide a synthetic route capable of efficiently producing fluorophenols useful as intermediate compounds.

As a result of intensive studies, the present inventors have found a new manufacturing method different from the conventional method.

[0005]

The present invention provides a fluoroanisole represented by the following general formula (II) by reacting polyfluorobenzene represented by the following general formula (I) with sodium methoxy. Is a hydrolysis reaction to obtain a fluorophenol represented by the following general formula (III):

Embedded image

Embedded image

[Chemical 6] (In these formulas, n is an integer of 1 to 5.)

That is, the gist of the present invention resides in a method for producing fluorophenols including a novel synthetic method in which polyfluorobenzene and sodium methoxide are reacted to obtain fluoroanisole in which fluorine is reduced by one.

In practicing the present invention, in the reactor, polyfluorobenzene represented by the general formula (I), N,
An aprotic polar solvent such as N-dimethylformamide and sodium methoxide are charged and reacted with stirring at a predetermined temperature for a predetermined time. This reaction is central to the present invention. After the reaction, dichloromethane and water are added and the mixture is stirred, and after standing, the two phases are separated and the aqueous phase is removed. The fluoroanisole in the organic phase can be easily separated and purified by a conventional method such as distillation. The resulting fluoroanisole can be hydrolyzed by a conventional method to produce the desired fluorophenol represented by the general formula (III).

The aprotic polar solvent used in the main reaction (I → II) of the present invention includes N, N-dimethylformamide, tetramethylene sulfone, N-methylpyrrolidone, dimethyl sulfoxide and 1,3-dimethyl-2-. Imidazolidinone or the like can be used.

The preferable amount of the solvent used is 2 to 10 ml per 1 g of polyfluorobenzene as the raw material.

The preferred amount of sodium methoxide used is 0.8 to 1.4 per mol of polyfluorobenzene.
Is a mole.

The reaction temperature of the main reaction of the present invention is 50 to 16
The temperature is 0 ° C, preferably 70 to 140 ° C. If the reaction temperature is too low, the reaction rate will decrease, and if it is too high, side reactions are likely to occur. The reaction time is 1 to 5 hours.

The polyfluorobenzene represented by the general formula (I) of the present invention has a plurality of fluoro groups, and they are 1,2-difluorobenzene, 1,3-difluorobenzene, 1,4-difluorobenzene and 1-difluorobenzene. , 2,3-Trifluorobenzene, 1,2,4-trifluorobenzene, 1,2,5-trifluorobenzene, 1,3,5-
Trifluorobenzene, 1,2,3,4-tetrafluorobenzene, 1,2,3,5-tetrafluorobenzene, 1,2,4,5-tetrafluorobenzene, 1,
They are 2,3,4,5-pentafluorobenzene and hexafluorobenzene. Preferably 1,2-difluorobenzene, 1,3-difluorobenzene, 1,4-difluorobenzene, 1,2,3-trifluorobenzene,
It is 1,3,5-trifluorobenzene.

The hydrolysis step can be carried out by an appropriate known method, and can be conveniently carried out, for example, by the method described in the following examples.

[0014]

Example 1 Production of 2-Fluorophenol Example 1 22.8 g (0.200 mol) of 1,2-difluorobenzene, 12.0 g (0.222 mol) of sodium methoxide, and N, in a 200 ml three-neck glass flask. N
Charge 100 ml of dimethylformamide. The mixture was reacted at 100 ° C. for 3 hours while stirring with a magnetic stirrer. After completion of the reaction, the reaction product is transferred to a separating funnel, and 200 ml each of water and dichloromethane are added and shaken. After the organic phase was separated, it was concentrated by an evaporator and then simple distilled to obtain 20.8 g of 2-fluoroanisole. 200 ml of this
Place in a glass flask and use 47% hydrobromic acid solution 10.
0 ml was added, and the mixture was heated and reacted at 105 ° C for 24 hours. After cooling, the solvent is extracted with 100 ml of dichloromethane, and then the dichloromethane is distilled off. The concentrated residue is distilled to obtain 2
-Fluorophenol was obtained. Yield 16.7g, Yield 7
It was 4.5% (based on difluorobenzene).

Example 2 The procedure of Example 1 was repeated, except that the solvent N, N-dimethylformamide was replaced by tetramethylene sulfone.

Yield of 2-fluorophenol 16.1
The yield was 72.0% (based on difluorobenzene).

Production of 3-Fluorophenol Example 3 The same procedure as in Example 1 was carried out except that 1,3-difluorobenzene was used instead of 1,2-difluorobenzene as a raw material.

Yield of 3-fluorophenol 16.9
The yield was 75.6% (based on difluorobenzene).

Example 4 The same procedure as in Example 1 was repeated except that 1,2-difluorobenzene as a raw material was changed to 1,3-difluorobenzene and N, N-dimethylformamide as a solvent was changed to N-methylpyrrolidone. I did it.

Yield of 3-fluorophenol 16.1
The yield was 72.0% (based on difluorobenzene).

Production Example 4 of 4-Fluorophenol Example 5 Example 1 except that 1,4-difluorobenzene as a raw material was changed to 1,4-difluorobenzene and a reaction temperature of anisole formation which was a reaction in the first step was changed to 130 ° C. The procedure was the same as in 1.

Yield of 4-fluorophenol 15.7
The yield was 70.1% (based on difluorobenzene).

Example 6 The same procedure as in Example 5 was carried out except that dimethylsulfoxide was used instead of N, N-dimethylformamide as a solvent.

Yield of 4-fluorophenol 15.7
The yield was 70.1% (based on difluorobenzene).

2,3-difluorophenol and 2,
Production of 6-difluorophenol Example 7 The same procedure as in Example 1 was carried out by replacing 1,2-difluorobenzene as a raw material with 1,2,3-trifluorobenzene. However, as a method for isolating anisole, 2,3-difluoroanisole and 2,6-difluoroanisole were separated by rectification. And the hydrolysis reaction was implemented about each anisole.

Yield of 2,3-difluorophenol 1
Yield of 0.9 g, 2,6-difluorophenol 5.5
The total yield was 16.4 g and the yield was 73.2% (based on trifluorobenzene).

Production of 3,5-difluorophenol Example 8 Same as Example 1 except that 1,3,5-trifluorobenzene was used as the starting material, 1,2-difluorobenzene, and the reaction temperature was changed to 80 ° C. It was done according to the procedure.

Yield of 3,5-difluorophenol 1
The amount was 6.0 g and the yield was 71.4% (based on trifluorobenzene).

Comparative Example 1 A reaction was carried out in the same manner as in Example 1 except that the solvent N, N-dimethylformamide was replaced with methanol which was a protic polar solvent. When the reaction liquid was analyzed by gas chromatography, the intermediate 2-fluoroanisole was not produced.

Comparative Example 2 A reaction was carried out in the same manner as in Example 1 except that the solvent N, N-dimethylformamide was replaced with xylene which was a non-polar solvent. When the reaction liquid was analyzed by gas chromatography, the intermediate 2-fluoroanisole was not produced.

Comparative Example 3 A reaction was carried out in the same manner as in Example 1 except that the reaction temperature for the anisole formation which was the reaction in the first stage was changed to 40 ° C. When the reaction liquid was analyzed by gas chromatography, the intermediate 2-fluoroanisole was not produced.

Comparative Example 4 The reaction was carried out in the same manner as in Example 2 except that the reaction temperature for the anisole formation, which was the first-stage reaction, was changed to 170 ° C. When the reaction solution was analyzed by gas chromatography, the amount of 1,2-dimethoxybenzene as a byproduct was 2
-Up to 15% relative to fluoroanisole.

EFFECTS OF THE INVENTION According to the method of the present invention, fluorophenols can be produced in a favorable yield of 70% or more (based on polyfluorobenzene) under milder conditions than existing methods.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Mitsuharu Shimoda 1497 Shibukawa City, Gunma Kanto Denka Kogyo Co., Ltd. Shibukawa Factory

Claims (2)

[Claims] 1. A fluoroanisole represented by the following general formula (II) is obtained by reacting polyfluorobenzene represented by the following general formula (I) with sodium methoxide in an aprotic polar solvent. A method for producing a fluorophenol, which comprises obtaining a fluorophenol represented by the following general formula (III) by a hydrolysis reaction. Embedded image Embedded image Embedded image (In these formulas, n is an integer of 1 to 5) 2. The fluorophenol is any of 2-fluorophenol, 3-fluorophenol, 4-fluorophenol, 2,3-difluorophenol, 2,6-difluorophenol and 3,5-difluorophenol, and The production method according to claim 1, wherein the reaction temperature in the first stage is 50 to 160 ° C.