JP5029000B2 - Production method of halogen-substituted benzenedimethanol - Google Patents

Description

  The present invention relates to a method for producing a halogen-substituted benzene dimethanol.

  Halogen-substituted benzenedimethanol is an important compound as a raw material and intermediate for medicines and agricultural chemicals. In particular, 2,3,5,6-tetrafluorobenzenedimethanol is known to be useful as an intermediate for household insecticides (see, for example, Patent Document 1).

  As a method for synthesizing such a halogen-substituted benzenedimethanol, for example, a method of reducing 2,3,5,6-tetrafluoroterephthalic acid ester using a borohydride compound (for example, see Patent Document 2) is known. It has been.

However, this method is not industrially satisfactory in terms of yield.
Japanese Patent No. 2606892 Chinese Patent Publication No. 1458137

  Under such circumstances, the present inventor has intensively studied to develop a further industrially advantageous method for producing halogen-substituted benzene dimethanol. As a result, the reaction between the halogen-substituted terephthalic acid diester and the borohydride compound is carried out. As a result, it was found that the halogen-substituted benzene dimethanol can be efficiently produced by carrying out the reaction in the presence of the present invention.

（式中、Ｘ^１〜Ｘ^４はそれぞれ同一または相異なって、水素原子またはハロゲン原子を表す。ただし、少なくとも一つはハロゲン原子である。）
で示されるハロゲン置換テレフタル酸のジエステルと水素化ホウ素化合物とを、水素化ホウ素化合物に対して０．５〜１０モル倍の水の存在下に反応させる式（２）

（式中、Ｘ^１〜Ｘ^４は上記と同じ意味を表す。）
で示されるハロゲン置換ベンゼンジメタノールの製造法を提供するものである。 That is, the present invention provides a compound of formula (1) in the presence of an organic solvent.

(Wherein, X ¹ to X ⁴ are each the same or different, represent a hydrogen atom or a halogen atom., Provided that at least one is a halogen atom.)
Formula (2) in which a diester of a halogen-substituted terephthalic acid represented by formula (II) and a borohydride compound are reacted in the presence of 0.5 to 10 moles of water with respect to the borohydride compound.

^(Wherein, X 1 to X ⁴ are as defined above.)
A process for producing a halogen-substituted benzenedimethanol represented by the formula:

  According to the present invention, halogen-substituted benzenedimethanol, which is important as an intermediate for medicines and agricultural chemicals, and the like can be produced with high yield, which is industrially useful.

  Hereinafter, the present invention will be described in detail.

In the diester of halogen-substituted terephthalic acid represented by the above formula (1) (hereinafter abbreviated as halogen-substituted terephthalic acid diester),
Examples of the halogen atom represented by X ^{1 to} X ⁴ include a fluorine atom, a chlorine atom, and a bromine atom.

（式中、Ｘ^１〜Ｘ^４は上記と同じ意味を表し、Ｒは炭素数１〜６のアルキル基を表す。）
で示されるハロゲン置換テレフタル酸ジエステルが挙げられる。 The two alcohol residues of the halogen-substituted terephthalic acid diester are not particularly limited, and may be the same or different from each other. Preferably, Formula (3)

^(Wherein, X 1 to X ⁴ are as defined above, R represents an alkyl group having 1 to 6 carbon atoms.)
And halogen-substituted terephthalic acid diesters represented by the formula:

  In the formula (3), examples of the alkyl group having 1 to 6 carbon atoms represented by R include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert, Examples include linear, branched or cyclic alkyl groups such as -butyl group, n-pentyl group, cyclopropyl group, 2,2-dimethylcyclopropyl group, cyclopentyl group, and cyclohexyl group.

  Examples of the halogen-substituted terephthalic acid diester include dimethyl 2-fluoroterephthalate, dimethyl 2-chloroterephthalate, dimethyl 2,5-difluoroterephthalate, dimethyl 2,6-difluoroterephthalate, and dimethyl 2,3-difluoroterephthalate. Dimethyl 2,5-dichloroterephthalate, dimethyl 2,6-dichloroterephthalate, dimethyl 2,3-dichloroterephthalate, dimethyl 2,3,5-trifluoroterephthalate, dimethyl 2,3,5-trichloroterephthalate Dimethyl 2,3,5,6-tetrafluoroterephthalate, diethyl 2,3,5,6-tetrafluoroterephthalate, di (n-propyl) 2,3,5,6-tetrafluoroterephthalate, 2, 3,5,6-tetrafluoroterephthalic acid diisopropyl 2,3,5,6-tetrafluoroterephthalic acid di (n-butyl), 2,3,5,6-tetrafluoroterephthalic acid di (tert-butyl), 2,3,5,6-tetrachloroterephthalic acid Dimethyl acid, diethyl 2,3,5,6-tetrachloroterephthalate, di (n-propyl) 2,3,5,6-tetrachloroterephthalate, diisopropyl 2,3,5,6-tetrachloroterephthalate, 2,3,5,6-tetrachloroterephthalic acid di (n-butyl), 2,3,5,6-tetrachloroterephthalic acid di (tert-butyl), 2,3,5,6-tetrachloroterephthalic acid Examples include di (n-pentyl), 2,3,5,6-tetrachloroterephthalic acid di (n-hexyl), dimethyl 2,3,5-trifluoro-6-chloroterephthalate, and the like.

  Such a halogen-substituted terephthalic acid diester can be produced, for example, by a known method such as reacting a corresponding acid halide with an alcohol (see, for example, Japanese Patent Publication No. 4-66220).

  Examples of the borohydride compound include alkali metal borohydrides such as sodium borohydride, lithium borohydride, potassium borohydride, and alkaline earth metals such as calcium borohydride and magnesium borohydride. Examples include salt. From the viewpoint of availability, alkali metal borohydride is preferably used, and sodium borohydride is more preferable.

  As such a borohydride compound, a commercially available product may be used, or it may be prepared and used. For example, sodium borohydride can be readily prepared from borate esters and sodium hydride. In addition, other borohydride compounds can be prepared by a reaction between sodium borohydride and a corresponding metal halide. For example, calcium borohydride is obtained by a reaction between sodium borohydride and calcium chloride. When a borohydride compound is prepared and used, one prepared in advance may be added to the reaction system, or it may be prepared in the reaction system and used as it is.

  The amount of the borohydride compound is usually 1 mol times or more with respect to the halogen-substituted terephthalic acid diester, and the object of the present invention can be achieved. 5 mol times or less. Preferably it is the range of 1-2.5 mol times.

  The object of the present invention can be achieved if the amount of water used is 0.5 to 10 mol times the borohydride compound. Preferably it is 0.9-4 mol times.

  The organic solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, ether solvents such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, diisopropyl ether, and dimethoxyethane, such as toluene and xylene. And aromatic hydrocarbon solvents such as chlorobenzene. An ether solvent is preferable.

  The amount of the organic solvent used is not particularly limited, but is usually in the range of 1 to 100 times by weight with respect to the halogen-substituted terephthalic acid diester.

  The reaction temperature is usually in the range of 0 to 150 ° C, preferably 40 to 100 ° C.

  This reaction is carried out by mixing a halogen-substituted terephthalic acid diester, a borohydride compound and water under the reaction temperature conditions, and the order of mixing is not particularly limited. It is carried out by adding water to the mixture of boron compound and solvent. Especially, the aspect which adds water gradually in the said mixture on reaction temperature conditions is preferable. Water may be added as it is or as a mixture with an organic solvent compatible with water.

  Here, examples of the organic solvent compatible with water include ether solvents such as tetrahydrofuran, dioxane, dimethoxyethane, and ethylene glycol dimethyl ether.

  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.

  After completion of the reaction, for example, by mixing an aqueous solution of a mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the reaction mixture, and performing treatment such as neutralization, extraction, concentration, etc., if necessary, the above formula The halogen-substituted benzene dimethanol represented by (2) (hereinafter abbreviated as halogen-substituted benzene dimethanol) can be isolated. The obtained halogen-substituted benzene dimethanol may be further purified by ordinary purification means such as crystallization and column chromatography.

  Examples of the halogen-substituted benzene dimethanol thus obtained include 2-fluoro-1,4-benzene dimethanol, 2-chloro-1,4-benzene dimethanol, 2,5-difluoro-1,4-benzene dimethanol, 2,6-difluoro-1,4-benzenedimethanol, 2,3-difluoro-1,4-benzenedimethanol, 2,5-dichloro-1,4-benzenedimethanol, 2,6-dichloro-1, 4-benzenedimethanol, 2,3-dichloro-1,4-benzenedimethanol, 2,3,5-trifluoro-1,4-benzenedimethanol, 2,3,5-trichloro-1,4-benzene Dimethanol, 2,3,5,6-tetrafluorobenzene dimethanol, 2,3,5,6-tetrachlorobenzene dimethanol, 2,3,5 Trifluoro-6-chlorobenzene dimethanol, and the like.

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

Example 1
A 200 ml flask was charged with 830 mg of sodium borohydride, 10 g of tetrahydrofuran and 2.66 g of dimethyl 2,3,5,6-tetrafluoroterephthalate at room temperature and heated to 65 ° C. While stirring at the same temperature, a mixture of 395 mg of water and 10 g of tetrahydrofuran was added dropwise over 3 hours, and the mixture was kept warm and stirred for 2 hours, and then cooled to room temperature. To the obtained reaction mixture, 20 g of 10 wt% hydrochloric acid was added dropwise at 25-30 ° C. over 30 minutes, stirred at the same temperature for 1 hour, and extracted twice with 30 g of ethyl acetate. The organic layers were combined and washed with 10 g of water to obtain a solution containing 2,3,5,6-tetrafluorobenzenedimethanol. When the solution was analyzed by a liquid chromatography internal standard method, the yield of 2,3,5,6-tetrafluorobenzenedimethanol was 86%.

Example 2
A 200 ml flask was charged with 570 mg of sodium borohydride, 20 g of tetrahydrofuran and 2.66 g of dimethyl 2,3,5,6-tetrafluoroterephthalate at room temperature and heated to 65 ° C. While stirring at the same temperature, a mixture of 280 mg of water and 10 g of tetrahydrofuran was added dropwise over 3 hours, and the mixture was kept warm and stirred for 2 hours, and then cooled to room temperature. To the obtained reaction mixture, 20 g of 10 wt% hydrochloric acid was added dropwise at 25-30 ° C. over 30 minutes, stirred at the same temperature for 1 hour, and extracted twice with 30 g of ethyl acetate. The organic layers were combined and washed with 10 g of water to obtain a solution containing 2,3,5,6-tetrafluorobenzenedimethanol. When the solution was analyzed by a liquid chromatography internal standard method, the yield of 2,3,5,6-tetrafluorobenzenedimethanol was 82%.

Example 3
A 200 ml flask was charged with 200 mg of sodium borohydride and 5 g of tetrahydrofuran at room temperature. A mixture of 580 mg of dimethyl 2,3,5,6-tetrafluoroterephthalate and 5 g of tetrahydrofuran was added thereto, and the temperature was raised to 60 ° C. While stirring at the same temperature, a mixture of 400 mg of water and 2.5 g of tetrahydrofuran was added dropwise over 5 hours, and the mixture was kept warm and stirred for 2 hours, and then cooled to room temperature. To the obtained reaction mixture, 20 g of 10 wt% hydrochloric acid was added at 25-30 ° C. over 10 minutes, and the mixture was stirred at the same temperature for 30 minutes. After the resulting treatment liquid was allowed to stand, the aqueous layer was removed by liquid separation treatment, and 20 g of toluene was added to the organic layer, followed by washing twice with 10 g of water. The obtained organic layer was concentrated to obtain 710 mg of a pale yellow oil containing 2,3,5,6-tetrafluorobenzenedimethanol. The oily substance was analyzed by a liquid chromatography internal standard method. As a result, the content of 2,3,5,6-tetrafluorobenzenedimethanol was 50%. Yield 78%

Comparative Example 1
A 200 ml flask was charged with 310 mg of sodium borohydride, 10 g of tetrahydrofuran and 1.0 g of dimethyl 2,3,5,6-tetrafluoroterephthalate at room temperature and heated to 65 ° C. After incubating and stirring at the same temperature for 6 hours, the mixture was cooled to room temperature. To the obtained reaction mixture, 10 g of 10 wt% hydrochloric acid was added dropwise at 25 to 30 ° C. over 30 minutes, stirred at the same temperature for 1 hour, and then extracted twice with 20 g of ethyl acetate. The organic layers were combined and washed with 10 g of water to obtain a solution containing 2,3,5,6-tetrafluorobenzenedimethanol. When the solution was analyzed by a liquid chromatography internal standard method, the yield of 2,3,5,6-tetrafluorobenzenedimethanol was 57%.

Claims (9)

In the presence of an organic solvent, the formula (1)

(Wherein, X ¹ to X ⁴ are each the same or different, represent a hydrogen atom or a halogen atom., Provided that at least one is a halogen atom.)
Formula (2) in which a diester of a halogen-substituted terephthalic acid represented by formula (II) and a borohydride compound are reacted in the presence of 0.5 to 10 moles of water with respect to the borohydride compound.

^(Wherein, X 1 to X ⁴ are as defined above.)
A process for producing a halogen-substituted benzenedimethanol represented by The reaction is carried out by adding 0.5 to 10 moles of water to the borohydride compound in a mixture of the halogen-substituted terephthalic acid diester represented by the formula (1), the borohydride compound and the organic solvent. The method for producing a halogen-substituted benzenedimethanol according to claim 1. The method for producing a halogen-substituted benzene dimethanol according to claim 1 or 2, wherein the borohydride compound is used in an amount of 1 to 2.5 moles relative to the halogen-substituted terephthalic acid diester represented by the formula (1). The method for producing a halogen-substituted benzene dimethanol according to any one of claims 1 to 3, wherein the borohydride compound is an alkali metal borohydride. The method for producing a halogen-substituted benzene dimethanol according to claim 4, wherein the alkali metal borohydride is sodium borohydride. The method for producing a halogen-substituted benzene dimethanol according to any one of claims 1 to 5, wherein the amount of water used is 0.9 to 4 mol times the borohydride compound. The method for producing a halogen-substituted benzene dimethanol according to any one of claims 1 to 6, wherein the reaction temperature is in the range of 40 to 100 ° C. The diester of halogen-substituted terephthalic acid represented by formula (1) is represented by formula (3)

^(Wherein, X 1 to X ⁴ are as defined above, R represents an alkyl group having 1 to 6 carbon atoms.)
The method for producing a halogen-substituted benzene dimethanol according to any one of claims 1 to 7, which is a halogen-substituted terephthalic acid diester represented by the formula: X < ¹ > -X < ⁴ > is all fluorine atoms, The manufacturing method of the halogen substituted benzenedimethanol in any one of Claims 1-8.