JP2007191466A - Method for producing 2,4-difluoronitrobenzene - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially advantageous method for producing 2,4-difluoronitrobenzene. <P>SOLUTION: The method for producing the 2,4-difluoronitrobenzene involves reacting 2,4-dichloronitrobenzene with potassium fluoride in the presence of a dialkyl sulfone compound represented by formula (1): RSO<SB>2</SB>R' (wherein, R and R' are the same or different, and each a 1-3C alkyl group). The dialkyl sulfone compound which is the compound of formula (1) in which R is a methyl group is preferably used. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing 2,4-difluoronitrobenzene.

  2,4-Difluoronitrobenzene is an important compound as a synthetic intermediate for medical and agricultural chemicals. As a method for producing 2,4-difluoronitrobenzene, a method is known in which 2,4-dichloronitrobenzene and potassium fluoride are reacted in the presence of sulfolane or dimethyl sulfoxide (for example, Patent Document 1 and Non-Patent Document). 1). However, these methods are not industrially satisfactory in terms of reaction yield.

  Reactions using various phase transfer catalysts are also known (see, for example, Patent Documents 2 to 6 and Non-Patent Document 2). However, it is not yet an industrially satisfactory method in terms of cost and reaction yield of the phase transfer catalyst to be used, and development of an industrially advantageous production method has been demanded.

U.S. Pat. No. 4,164,517 Japanese National Patent Publication No. 5-507689 Japanese Unexamined Patent Publication No. 3-77850 Special table 2003-503467 gazette JP-A-7-145111 JP 2002-515876 A J. Amer. Chem. Soc., 78, 6034 (1956) Tetrahedron, 51, 6363 (1995)

  Under such circumstances, the present inventor has intensively studied to develop a method capable of more advantageously carrying out the reaction between 2,4-dichloronitrobenzene and potassium fluoride, and as a result, a specific acyclic dialkylsulfone When the reaction was carried out in the presence, 2,4-difluoronitrobenzene was found to be obtained in good yield, and the present invention was achieved.

That is, the present invention provides the formula (1)
RSO ₂ R ′ (1)
(In the formula, R and R ′ are the same or different and each represents an alkyl group having 1 to 3 carbon atoms.)
The present invention provides a method for producing 2,4-difluoronitrobenzene, in which 2,4-dichloronitrobenzene and potassium fluoride are reacted in the presence of a dialkylsulfone compound represented by formula (1).

  According to the present invention, 2,4-difluoronitrobenzene that can be used as a raw material for medical and agricultural chemicals can be produced with high yield without using an expensive catalyst, which is industrially advantageous.

  Hereinafter, the present invention will be described in detail.

  As 2,4-dichloronitrobenzene, a commercially available product may be used, or a product produced by a known method such as nitration of metadichlorobenzene may be used.

  A commercially available thing may be used for potassium fluoride, for example, what is obtained by making potassium hydroxide and hydrogen fluoride react may be used. A smaller particle size is preferred, and a smaller water content is preferred. Examples of such preferable potassium fluoride include potassium fluoride obtained by a spray dry method.

  If the amount of potassium fluoride used is usually 2 mol times or more with respect to 2,4-dichloronitrobenzene, the object of the present invention can be achieved, and the upper limit is not particularly limited. It is the range of 2 to 5 mole times.

  In the dialkyl sulfone compound represented by the above formula (1) (hereinafter abbreviated as dialkyl sulfone (1)), the alkyl group having 1 to 3 carbon atoms represented by R and R ′ includes a methyl group, an ethyl group, Examples include a propyl group and an isopropyl group. A dialkyl sulfone (1) in which R is a methyl group is preferred, a dialkyl sulfone (1) in which R is a methyl group, R ′ is a methyl group or an ethyl group, R is a methyl group, and R ′ is More preferred is a dialkylsulfone (1) which is a methyl group.

  Examples of the dialkyl sulfone (1) include dimethyl sulfone, methyl ethyl sulfone, methyl propyl sulfone, methyl isopropyl sulfone, diethyl sulfone, dipropyl sulfone, and the like, and preferably dimethyl sulfone or methyl ethyl sulfone. In terms of availability, dimethyl sulfone is more preferable.

  As the dialkyl sulfone (1), a commercially available product may be used, for example, a product prepared by any method such as oxidation of the corresponding dialkyl sulfide or dialkyl sulfoxide using an oxidizing agent such as hydrogen peroxide. May be.

  Although the usage-amount of dialkyl sulfone (1) is not restrict | limited in particular, It is the range of 0.1-20 weight times with respect to 2, 4- dichloro nitrobenzene practically.

  The reaction temperature is usually 120 to 200 ° C, preferably 150 to 200 ° C.

  This reaction can be carried out without using an organic solvent other than dialkylsulfone (1), or can be carried out in the presence of an organic solvent inert to the reaction. When dimethyl sulfone is used as the dialkyl sulfone (1), this reaction is preferably carried out in the presence of an organic solvent inert to the reaction. Examples of the organic solvent inert to the reaction include ether solvents such as dioxane and diethylene glycol dimethyl ether; N, N-dialkylamide solvents such as N, N-dimethylacetamide; aromatic carbonization such as toluene, xylene, chlorobenzene and benzonitrile. Hydrogen solvents; aliphatic hydrocarbon solvents such as octane and decane; and the like, and aromatic hydrocarbon solvents and aliphatic hydrocarbon solvents are preferred. These may be used alone or in combination of two or more. Especially, the organic solvent whose boiling point is 100-200 degreeC is preferable. The amount of the organic solvent inert to the reaction is usually 0.001 to 0.5 times by weight, preferably 0.001 to 0.2 times by weight, relative to the dialkyl sulfone (1).

  This reaction is carried out by mixing 2,4-dichloronitrobenzene, potassium fluoride, dialkylsulfone (1) and, if necessary, an organic solvent inert to the reaction, and stirring at a predetermined temperature. Although the mixing order is not particularly limited, it is preferable to carry out the reaction after dehydrating the reaction system in advance. As a dehydration method, for example, potassium fluoride and dialkyl sulfone (1) are mixed and heated; using an organic solvent azeotropic with water such as toluene and xylene, potassium fluoride and dialkyl sulfone ( And azeotropic dehydration of the mixture with 1). What is necessary is just to mix the mixture after performing this dehydration process, and 2, 4- dichloro nitrobenzene.

  This reaction is usually performed under normal pressure conditions, but may be performed under pressurized conditions. The progress of the reaction can be confirmed by ordinary analytical means such as gas chromatography or liquid chromatography.

  Inorganic salts such as potassium chloride are usually deposited in the reaction mixture. Therefore, after completion of the reaction, if necessary, a solvent having a low compatibility with water and a reaction mixture are mixed, and after removing inorganic salts by, for example, filtration, etc., the resulting reaction mixture and water are mixed and separated. By performing the treatment, 2,4-difluoronitrobenzene can be taken out as an organic layer. Of course, the reaction mixture and water can be mixed and separated without removing the inorganic salt, but when the dimethylsulfone is recycled as described later, the inorganic salt is removed at this stage. It is preferable. By concentrating the organic layer thus obtained, 2,4-difluoronitrobenzene can be isolated. The obtained 2,4-difluoronitrobenzene may be further purified by ordinary purification means such as crystallization and column chromatography.

  Here, examples of the organic solvent having low compatibility with water include aromatic hydrocarbon solvents such as toluene, xylene and chlorobenzene; aliphatic hydrocarbon solvents such as pentane, hexane and heptane; dichloromethane, dichloroethane and chloroform. Halogenated hydrocarbon solvents; ether solvents such as diethyl ether and methyl tert-butyl ether; ester solvents such as ethyl acetate; and the like.

  The dialkyl sulfone (1) used in this reaction is usually recovered as an aqueous layer in the above isolation treatment, and can be recycled for the reaction of the present invention by removing the water by performing a distillation treatment or the like. . Further, when the aqueous layer containing the recovered dialkylsulfone (1) contains an inorganic salt, the present invention can be carried out by removing the inorganic salt by desalting or filtration or removing water by distillation or the like. Can be recycled for the reaction.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by these Examples.

Example 1
A 50 ml flask equipped with a reflux condenser was charged with 730 mg of potassium fluoride (spray dry product), 5.0 g of dimethyl sulfone and 10 g of toluene. The obtained mixture was heated to an internal temperature of 130 ° C., and water in the mixture was removed as an azeotrope with toluene. Thereafter, substantially all of toluene was distilled off at an internal temperature of 140 ° C., and the resulting mixture was cooled to an internal temperature of 100 ° C. The mixture was charged with 960 mg of 2,4-dichloronitrobenzene and 300 mg of xylene, heated to 170 ° C., and incubated and stirred for 12 hours while stirring at the same temperature. During the reaction, no dimethylsulfone solid adhered to the top of the flask or the cooling tube. After the reaction, the mixture was cooled to 100 ° C., 10 g of xylene and 10 g of water were added and separated to obtain an organic layer containing 2,4-difluoronitrobenzene. When analyzed by gas chromatography internal standard method, the yield of 2,4-difluoronitrobenzene was 94%. Monofluorochloronitrobenzene was a by-product of 5% in total of isomers.

Example 2
A 50 ml flask equipped with a reflux condenser was charged with 730 mg of the same potassium fluoride used in Example 1, 5.0 g of methyl ethyl sulfone and 10 g of toluene. The obtained mixture was heated to an internal temperature of 130 ° C., and water in the mixture was removed as an azeotrope with toluene. Thereafter, substantially all of toluene was distilled off at an internal temperature of 140 ° C., and the resulting mixture was cooled to an internal temperature of 100 ° C. To this mixture, 960 mg of 2,4-dichloronitrobenzene was charged, the temperature was raised to 170 ° C., and the mixture was kept warm and stirred for 12 hours while stirring at the same temperature. After the reaction, the mixture was cooled to 60 ° C., 10 g of toluene and 10 g of water were added, and liquid separation was performed to obtain an organic layer containing 2,4-difluoronitrobenzene. When analyzed by gas chromatography internal standard method, the yield of 2,4-difluoronitrobenzene was 90%. Monofluorochloronitrobenzene was a by-product of 9% in total of isomers.

Example 3
A 50 ml flask equipped with a reflux condenser was charged with 730 mg of potassium fluoride (powder product), 5.0 g of dimethyl sulfone and 10 g of toluene. The obtained mixture was heated to an internal temperature of 130 ° C., and water in the mixture was removed as an azeotrope with toluene. Thereafter, substantially all of toluene was distilled off at an internal temperature of 140 ° C., and the resulting mixture was cooled to an internal temperature of 100 ° C. The mixture was charged with 960 mg of 2,4-dichloronitrobenzene and 300 mg of xylene, heated to 170 ° C., and kept warm and stirred for 8 hours while stirring at the same temperature. During the reaction, no dimethylsulfone solid adhered to the top of the flask or the cooling tube. After the reaction, the mixture was cooled to 100 ° C., 10 g of xylene and 10 g of water were added and separated to obtain an organic layer containing 2,4-difluoronitrobenzene. When analyzed by gas chromatography internal standard method, the yield of 2,4-difluoronitrobenzene was 89%. Monofluorochloronitrobenzene was a by-product of 9% in total of isomers.

Example 4
A 50 ml flask equipped with a reflux condenser was charged with 730 mg of potassium fluoride, 5.0 g of dimethyl sulfone and 10 g of toluene used in Example 1. The obtained mixture was heated to an internal temperature of 130 ° C., and water in the mixture was removed as an azeotrope with toluene. Thereafter, substantially all of toluene was distilled off at an internal temperature of 140 ° C., and the resulting mixture was cooled to an internal temperature of 100 ° C. To this mixture, 960 mg of 2,4-dichloronitrobenzene was charged, the temperature was raised to 170 ° C., and the mixture was kept warm and stirred for 12 hours while stirring at the same temperature. During the reaction, solid dimethyl sulfone was observed on the top of the flask and the cooling tube. After the reaction, the mixture was cooled to 60 ° C., 10 g of toluene and 10 g of water were added, and liquid separation was performed to obtain an organic layer containing 2,4-difluoronitrobenzene. As a result of analysis by gas chromatography internal standard method, the yield of 2,4-difluoronitrobenzene was 88%. Monofluorochloronitrobenzene was a by-product of 5% in total of isomers.

  2,4-difluoronitrobenzene is a useful compound as a synthetic intermediate for medical and agricultural chemicals. For example, a synthetic intermediate of 2 ′, 4′-difluoro-4-hydroxy- (1,1′-biphenyl) -3-carboxylic acid (generic name: diflunisal), an anti-inflammatory agent (eg, US Pat. No. 4,164,517) The present invention has industrial applicability in that such compounds can be produced industrially advantageously.

Claims (8)

Formula (1)
RSO ₂ R ′ (1)
(In the formula, R and R ′ are the same or different and each represents an alkyl group having 1 to 3 carbon atoms.)
A process for producing 2,4-difluoronitrobenzene, in which 2,4-dichloronitrobenzene and potassium fluoride are reacted in the presence of a dialkylsulfone compound represented by the formula: The production method according to claim 1, wherein R in the formula (1) is a methyl group. The production method according to claim 1, wherein R in the formula (1) is a methyl group, and R 'is a methyl group. The production method according to claim 1, wherein R in the formula (1) is a methyl group, and R 'is an ethyl group. The process according to claim 3, wherein the reaction is carried out in the presence of an organic solvent inert to the reaction. The organic solvent inert to the reaction is at least one organic solvent selected from the group consisting of ether solvents, N, N-dialkylamide solvents, aromatic hydrocarbon solvents, and aliphatic hydrocarbon solvents. Production method. The production method according to claim 6, wherein the boiling point of the organic solvent inert to the reaction is in the range of 100 to 200 ° C. The production method according to any one of claims 5 to 7, wherein the amount of the organic solvent inert to the reaction is 0.001 to 0.5 times by weight with respect to dimethylsulfone.