JPH1149715A - Production of difluorophenols - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently produce the subject compound useful as an intermediate for medicines, agrochemicals, liquid crystals or the like by reacting a specific trifluorobenzene with sodium methoxide in an alcoholic solvent, producing a specified difluoroanisole and then hydrolyzing the resultant difluoroanisole. SOLUTION: (A) Trifluorobenzene represented by formula I (1,2,3- trifluorobenzene or the like), (B) sodium methoxide in an amount of 8-3.0 mol based on 1 mol component A and (C) an alcohol (methanol, ethanol or the like) in a volume of 2-10 ml based on 1 g component A are charged into a reactor and reacted at 60 deg.C to the boiling and refluxing temperature for 5-12 hr under stirring. A dilute hydrochloric acid is then added to neutralize the reactional mixture after the reaction. Transparent two phases are obtained and an organic phase is subsequently collected by separation. Difluoroanisole represented by formula II is then hydrolyzed in the organic phase to afford the objective compound represented by formula III (2, 5-difluorophenol or the like).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for efficiently producing difluorophenols which can be important intermediates for pharmaceuticals, 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 diazotizing fluoroaniline followed by hydrolysis [J. Am. Chem. Soc. , 61 . 165
(1939)], 2) A method of obtaining fluoroanisole from aminoanisole by Seaman reaction and then hydrolyzing a methoxy group [Nikka 79 , 1121 (197)
9)], 3) Method of hydrolyzing chlorofluorobenzene with alkali [J. F1uorine Chem. , 5
0 , 377, (1990)]. The method 1) has an advantage that it can be easily used in a laboratory, but it cannot be said that the method is industrially practical, for example, the yield is low and a large amount of waste is generated. The method 2) has long steps and the overall yield is as low as 50% or less. In addition, the thermal decomposition reaction in the Seaman reaction involves a large amount of heat and is difficult to control industrially, and involves such troublesome problems as detoxification of boron trifluoride by-produced. In the method 3), the reaction temperature is 200 to 300.
Since an alkali is used as high as ° C., there is an industrial problem such as corrosion of a reactor. We have also proposed a method in which polyfluorobenzenes are reacted with sodium methoxide in an aprotic polar solvent such as N, N-dimethylformamide to obtain fluoroanisole having one fluorine reduced, and then hydrolyzed. (Japanese Patent Application No. 7-294178) This method is useful because the yield is high and the raw materials are relatively easy to obtain, but non-brotonic polar solvents such as N, N-dimethylformamide are relatively expensive. There is a disadvantage that there is.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel synthetic route capable of efficiently producing difluorophenols useful as intermediate compounds.

[0004] Thus, the present inventors have conducted intensive studies and found a useful manufacturing method different from the conventional method.

[0005]

According to the present invention, a trifluorobenzene represented by the following general formula (I) is reacted with sodium methoxide in an inexpensive alcoholic solvent to obtain a compound represented by the following general formula (II). A process for producing difluorophenols, which comprises obtaining difluoroanisole and then hydrolyzing the difluoroanisole cheek to obtain a difluorophenol represented by the following general formula (III):

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That is, the gist of the present invention resides in a method for producing difluorophenols including a synthesis method of reacting trifluorobenzenes with sodium methoxide in an alcohol solvent to obtain difluoroanisole.

The reaction between halogenated benzenes and sodium methoxide is a so-called aromatic nucleophilic substitution reaction,
This usually does not easily proceed in protic solvents such as alcohols. In fact, the reaction of monofluorobenzene and difluorobenzene hardly proceeds in an alcohol solvent. As a result of our intensive studies, we have surprisingly found that trifluorobenzenes and sodium methoxide react significantly in an alcohol solvent under relatively mild conditions to produce difluoroanisole, and arrived at the present invention. In the present invention, difluorophenols are obtained by further hydrolyzing the reaction product by a known method.

In the concrete implementation of the present invention, trifluorobenzenes represented by the general formula (1), alcohol and sodium methoxide are charged into a reactor and reacted at a predetermined temperature and a predetermined time under stirring. This reaction is central to the present invention. After the reaction, the mixture is neutralized by adding dilute hydrochloric acid to obtain two transparent liquid phases, and then the organic phase is separated. Difluoroanisole in the organic phase can be easily separated and purified by a usual method, for example, distillation. The obtained fluoroanisole is hydrolyzed by a conventional method to obtain the desired compound represented by the general formula (II)
Converted to difluorophenol represented by I).

Examples of the alcohol solvent used in the main reaction (I → II) of the present invention include methanol, ethanol, 1-propanol and 2-propanol.

The preferred amount of the solvent used is 2 to 10 ml per 1 g of the starting trifluorobenzenes.

The preferred amount of sodium methoxide used is 0.8 to 3 per unit mole of trifluorobenzenes.
0 mol.

The reaction temperature of the main reaction of the present invention is preferably from 60 ° C. to the boiling reflux temperature. The reaction time is 5 to 12 hours.

The trifluorobenzenes represented by the general formula (I) of the present invention are 1,2,3-trifluorobenzene,
Any of 2,4-trifluorobenzene and 1,3,5-trifluorobenzene. The difluorophenols which are the desired products of the process of the invention of the general formula (III) are 2,2
Any of 5-difluorophenol, 3,5-difluorophenol, 2,3-difluorophenol and 2,6-difluorophenol.

The hydrolysis step can be carried out by any suitable known method, for example, conveniently by the method described in the following Examples.

[0015]

EXAMPLES Production of 2,5-difluorophenol Example 1 In a 100 ml glass three-necked flask, 13.2 g (0.100 mol) of 1,2,4-trifluorobenzene and 10.8 g of sodium methoxide (0.10 mol) were added. 200 mol),
35 ml of methanol are charged. The reaction was carried out at a bath temperature of 90 ° C. for 9 hours under magnetic stirring. After the reaction,
The mixture was neutralized by adding dilute hydrochloric acid, and then transferred to a separating funnel to separate the organic phase. According to NMR analysis, the composition of the reaction product was 89.5% of 2,5-difluoroanisole, 0.9% of 2,4-difluoroanisole and 9.6% of 1,2,4-trifluorobenzene. Distill this, 2,5
-11.5 g of difluoroanisole were obtained. Next, 11.5 g of this 2,5-difluoroanisole and 100 g of a 47% hydrobromic acid solution were put into a 200 ml glass three-necked flask, and heated under reflux for 18 hours to carry out a hydrolysis reaction. After allowing to cool, the mixture is extracted with 100 ml of dichloromethane, and then dichloromethane is distilled off. The concentrated residue was distilled to obtain 2,5-difluorophenol. Yield 7.3
g, the yield was 56% (based on trifluorobenzene).

Example 2 Example 1 except that methanol was used as the solvent instead of ethanol.
The same procedure was used.

6. Yield of 2,5-difluorophenol
The yield was 1 g and 55% (based on trifluorobenzene).

Production of 3,5-difluorophenol Example 3 1,2,4-trifluorobenzene as a raw material was converted to 1,3,5
-The procedure was the same as in Example 1, except that trifluorobenzene was used.

5. Yield of 3,5-tolylphenol
The yield was 1 g and 47% (based on trifluorobenzene).

2,3-difluorophenol and 2,
Production of 6-difluorophenol Example 4 Starting material 1,2,4-trifluorobenzene was replaced with 1,2,3
-The procedure was the same as that of Example 1, except that trifluorobenzene was used. However, as a method for isolating anisole, 2,3-difluoroanisole and 2,6
-Divided into difluoroanisole. And hydrolysis reaction was implemented about each anisole.

4. Yield of 2,3-difluorophenol
0 g and 2.8 g of 2,6-difluorophenol were obtained, and the total yield was 7.8 g and the yield was 60% (based on trifluorobenzene).

Example 5 The same procedure as in Example 4 was carried out except that the solvent, methanol, was replaced with 2-propanol.

4. Yield of 2,3-difluorophenol
The total yield was 7.5 g with a yield of 0 g and 2,6-difluorophenol of 2.5 g, and a yield of 58% (based on trifluorobenzene).

Example 6 The same procedure as in Example 4 was carried out except that the solvent, methanol, was replaced with 1-propanol.

4. Yield of 2,3-difluorophenol
The total yield was 2 g, 2.6 g of 2,6-difluorophenol was 7.8 g, and the yield was 60% (based on trifluorobenzene).

According to the method of the present invention, fluorophenols can be advantageously produced under milder conditions than the existing methods and by using an inexpensive solvent.

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[Procedure amendment]

[Submission date] August 29, 1997

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0002

[Correction method] Change

[Correction contents]

[0002]

2. Description of the Related Art Conventionally, as a method for producing fluorophenols, 1) a method of diazotizing fluoroaniline followed by hydrolysis [J. Am. Chem. Soc. , 61 . 165
(1939)], 2) A method of obtaining fluoroanisole from aminoanisole by Seaman reaction and then hydrolyzing a methoxy group [Nikka 79 , 1121 (197)
9)], 3) Method of hydrolyzing chlorofluorobenzene with alkali [J. F1uorine Chem. , 5
0 , 377, (1990)]. The method 1) has an advantage that it can be easily used in a laboratory, but it cannot be said that the method is industrially practical, for example, the yield is low and a large amount of waste is generated. The method 2) has long steps and the overall yield is as low as 50% or less. In addition, the thermal decomposition reaction in the Seaman reaction involves a large amount of heat and is difficult to control industrially, and involves such troublesome problems as detoxification of boron trifluoride by-produced. In the method 3), the reaction temperature is 200 to 300.
Since an alkali is used as high as ° C., there is an industrial problem such as corrosion of a reactor. We have also proposed a method in which polyfluorobenzenes are reacted with sodium methoxide in an aprotic polar solvent such as N, N-dimethylformamide to obtain fluoroanisole having one fluorine reduced, and then hydrolyzed. (Japanese Patent Application No. 7-294178) This method is useful because the yield is high and the raw materials are relatively easy to obtain, but an aprotic polar solvent such as N, N-dimethylformamide is relatively expensive. There is a disadvantage that there is.

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0008

[Correction method] Change

[Correction contents]

In the concrete implementation of the present invention, trifluorobenzenes represented by the general formula (1), alcohol and sodium methoxide are charged into a reactor and reacted at a predetermined temperature and a predetermined time under stirring. This reaction is central to the present invention. After the reaction, the mixture is neutralized by adding dilute hydrochloric acid to obtain two transparent liquid phases, and then the organic phase is separated. Difluoroanisole in the organic phase can be easily separated and purified by a usual method, for example, distillation. The obtained difluoroanisole is hydrolyzed by a conventional method, and is converted into a desired difluorophenol represented by the general formula (III).

[Procedure amendment 3]

[Document name to be amended] Statement

[Correction target item name] 0012

[Correction method] Change

[Correction contents]

[0012] The reaction temperature of the main reaction of the present invention is preferably from 60 ° C to the boiling reflux temperature. The reaction time is 5 to 12 hours.

Claims (1)

[Claims] 1. A difluoroanisole represented by the following general formula (II) is obtained by reacting a trifluorobenzene represented by the following general formula (1) with sodium methoxide in an alcohol solvent. A process for producing difluorophenols, comprising obtaining a difluorophenol represented by the following general formula (III) by a hydrolysis reaction. Embedded image Embedded image Embedded image