Title of Invention

METHOD FOR PRODUCING HALOGEN - SUBSTITUTED BENZENEDIMETHANOL

Abstract

A method for producing a halogen-substituted benzenedimethanol represented by the formula (2): wherein X1, X2, X3 and X4 are the same or different and independently represent a hydrogen atom or a halogen atom, provided that X1, X2, X3 and X4 are not hydrogen atoms at the same time, by reacting a diester of a halogen-substituted terephthalic acid represented by the formula (1): wherein X1, X2, X3 and X4 are the same meanings as defined above, with a borohydride compound in an organic solvent in the presence of 0.5 to 10 moles of water per 1 mole of the borohydride compound.

Full Text

DESCRIPTION METHOD FOR PRODUCING HALOGEN-SUBSTITUTED BENZENEDIMETHANOL Technical Field The present invention relates to a method for producing a halogen-substituted benzenedimethanol. Background Art A halogen-substituted benzenedimethanol is an important compound as raw materials and intermediates of Pharmaceuticals and agrichemicals, and especially, US 4927852 discloses 2,3,5,6-tetrafluorobenzenedimethanol is useful SLS an intermediate of household pesticides. While, for example, a method comprising reducing 2,3,5,6-tetrafluoroterephthalic acid diester using borohydride compound or the like has been known (e.g. CN 1458137 A) as a method for producing 2,3,5,6- tetrafluorobenzenedimethanol, the development has been desired in the viewpoint of yield. Disclosure of the Invention The present invention provides a method for producing a halogen-substituted benzenedimethanol represented by the formula (2): wherein X1, X2, X3 and X4 are the same or different and independently represent a hydrogen atom or a halogen atom, provided that X1, X2, X3 and X4 are not hydrogen atoms at the same time, by reacting a diester of a halogen-substituted terephthalic acid represented by the formula (1): wherein X1, X2, X3 and X4 are the same meanings as defined above, with a borohydride compound in an organic solvent in the presence of 0.5 to 10 moles of water per 1 mole of the borohydride compound. Best Mode for Carrying Out the Present Invention In the diester of the halogen-substituted terephthalic acid represented by the formula (1), examples of the halogen atom represented by X1, X2, X3 and X4 include a fluorine atom, a chlorine atom and a bromine atom. The diester of the halogen-substituted terephthalic acid represented by the formula (1) is not particularly limited in so far as it is a compound wherein two carboxyl groups of the halogen-substituted terephthalic acid represented by the formula (1) are esterified, and two ester parts may be same or different each other. As the diester of the halogen-substituted terephthalic acid, a halogen-substituted terephthalic acid diester represented by the formula (3): wherein X1, X2, X3 and X4 are the same meanings as defined above and R represents a C1-C6 alkyl group, is preferable. In the formula (3), examples of the C1-C6 alkyl group represented by R include a straight chain, branched chain or cyclic C1-C6 alkyl group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n- butyl group, an isobutyl group, a sec-butyl group, a tert- butyl group, an n-pentyl group, a cyclopropyl group, a 2,2- dimethylcyclopropyl group, a cyclopentyl group and a cyclohexyl group. Examples of the diester of the halogen-substituted terephthalic acid represented by the formula (1) include dimethyl 2-fluoroterephthalate, dimethyl 2- chloroterephthalate, dimethyl 2,5-difluoroterephthalate, dimethyl 2,6-difluoroterephthalate, 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, diisopropyl 2,3,5,6- tetrafluoroterephthalate, di(n-butyl) 2,3,5,6- tetrafluoroterephthalate, di(tert-butyl) 2,3,5,6- tetrafluoroterephthalate, dimethyl 2,3,5,6- tetrachloroterephthalate, diethyl 2,3,5,6- tetrachloroterephthalate, di(n-propyl) 2,3,5,6- tetrachloroterephthalate, diisopropyl 2,3,5,6- tetrachloroterephthalate, di(n-butyl) 2,3,5,6- tetrachloroterephthalate, di(tert-butyl) 2,3,5,6- tetrachloroterephthalate, di(n-pentyl) 2,3,5,6- tetrachloroterephthalate, di(n-hexyl) 2,3,5,6- tetrachloroterephthalate and dimethyl 2,3,5-trifluoro-6- chloroterephthalate. The diester of the halogen-substituted terephthalic acid represented by the formula (1) can be produced, for example, according to a known method such as a method comprising reacting the corresponding acid halide with an alcohol (e.g. JP 4-66220 B). Examples of the borohydride compound include an alkali metal borohydride such as sodium borohydride, lithium borohydride and potassium borohydride; and an alkaline earth metal borohydride such as calcium borohydride and magnesium borohydride. In the view of availability, the alkali metal borohydride is preferable and sodium borohydride is more preferable. While a commercially available borohydride compound is usually used, those prepared according to a known method may be used. For example, sodium borohydride can be prepared easily from a boric acid ester and sodium hydride. Alternatively, other borohydride compounds can be prepared by a reaction of sodium borohydride and the corresponding metal halide, and for example, calcium borohydride is obtained by a reaction of sodium borohydride and calcium chloride. When the borohydride compound is prepared to use, those previously prepared may be added to the reaction system and it may be prepared in the reaction system. The used amount of the borohydride compound is usually 1 mole or more per 1 mole of the diester of the halogen- substituted terephthalic acid represented by the formula (1). While there is no specific upper limit, it is practically 5 moles or less and preferably 2.5 moles of less in the viewpoint of economic efficiency. The used amount of water is 0.5 to 10 moles per 1 mole of the borohydride compound and preferably 0.9 to 4 moles. While the organic solvent is not particularly limited in so far as it is an inert on the reaction, examples thereof include ether solvents such as diethyl ether,, methyl tert-butyl ether, tetrahydrofuran, dioxane, diisopropyl ether and dimethoxyethane, and aromatic hydrocarbon solvents such as toluene, xylene and chlorobenzene, and ether solvents are preferable. While the used amount of the organic solvent is not particularly limited, it is usually 1 to 100 parts by weight per 1 part by weight of the diester of the halogen- substituted terephthalic acid represented by the formula (1). The reaction temperature is usually 0 to 150°C, and preferably 40 to 100°C. The present reaction is conducted by mixing the diester of the halogen-substituted terephthalic acid represented by the formula (1), the borohydride compound, the organic solvent and the predetermined amount of water. While the mixing order is not particularly limited, usually, the reaction is conducted by adding the predetermined amount of water into a mixture of the diester of the halogen-substituted terephthalic acid represented by the formula (1), the borohydride compound and the organic solvent, and the reaction is preferably conducted by adding the predetermined amount of water gradually into the above- mentioned mixture adjusted at a reaction temperature. The predetermined amount of water may be added into the above- mentioned mixture as it is and may be mixed with an organic solvent which is compatible with water to add. Examples of the organic solvent which is compatible with water include hydrophilic ether solvents such as tetrahydrofuran, dioxane, dimethoxyethane and ethylene glycol dimethyl ether, and the used amount thereof is not particularly limited. While the present reaction is usually carried out at normal pressure, it may be carried out under pressure. The progress of the reaction can be checked by a conventional analytical means such as gas chromatography and high performance liquid chromatography. After completion of the reaction, for example, the halogen-substituted benzenedimethanol represented by the formula (2) can be isolated by mixing the reaction mixture with an aqueous mineral acid solution such as hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid, if necessary, adding a water-insoluble solvent to extract and concentrating the obtained organic layer. The isolated halogen-substituted benzenedimethanol represented by the formula (2) may be further purified by a conventional purification means such as column chromatography. Examples of thus obtained halogen-substituted benzenedimethanol represented by the formula (2) include 2- fluoro-1,4-benzendimethanol, 2-chloro-l,4-benzendimethanol, 2,5-difluoro-1,4-benzendimethanol, 2,6-difluoro-1,4- benzendimethanol, 2,3-difluoro-1,4-benzendimethanol, 2,5- dichloro-1,4-benzendimethanol, 2,6-dichloro-l,4- benzendimethanol, 2,3-dichloro-l,4-benzendimethanol, 2,3,5- trifluoro-1,4-benzendimethanol, 2,3,5-trichloro-l,4- benzendimethanol, 2,3,5,6-tetrafluorobenzendimethanol, 2,3,5,6-tetrachlorobenzendimethanol and 2,3,5-trifluoro-6- chlorobenzendimethanol. Examples The present invention will be illustrated in more detail by Examples below. The present invention is not limited to these Examples. The analysis was conducted by high performance liquid chromatography internal standard method. Example 1 Into a 200 ml flask, 830 mg of sodium borohydride, 10 g of tetrahydrofuran and 2.66 g of dimethyl 2,3,5,6- tetrafluoroterephthalate were charged at room temperature and the obtained mixture was heated to 65°C. A mixed solution of 395 mg of water and 10 g of tetrahydrofuran was added dropwise to the mixture over 3 hours while stirring at the same temperature to effect the reaction for 2 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to room temperature, and 20 g of 10% by weight hydrochloric acid was added thereto dropwise over 30 minutes at 25 to 30°C. After stirring at the same temperature for 1 hour, the mixture was extracted twice with 30 g of ethyl acetate and the obtained organic layers washed with 10 g of water to obtain a solution containing 2,3,5,6-tetrafluorobenzenedimethanol. The yield of 2,3,5,6-tetrafluorobenzenedimethanol was 86%. Example 2 Into a 200 ml flask, 570 mg of sodium borohydride, 20 g of tetrahydrofuran and 2.66 g of dimethyl 2,3,5,6- tetrafluoroterephthalate were charged at room temperature and the obtained mixture was heated to 65°C. A mixed solution of 280 mg of water and 10 g of tetrahydrofuran was added dropwise to the mixture over 3 hours while stirring at the same temperature to effect the reaction for 2 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to room temperature, and 20 g of 10% by weight hydrochloric acid was added thereto dropwise over 30 minutes at 25 to 30°C. After stirring at the same temperature for 1 hour, the mixture was extracted twice with 30 g of ethyl acetate and the obtained organic layers washed with 10 g of water to obtain a solution containing 2,3,5,6-tetrafluorobenzenedimethanol. The yield of 2,3,5,6-tetrafluorobenzenedimethanol was 82%. Example 3 Into a 200 ml flask, 200 mg of sodium borohydride and 5 g of tetrahydrofuran were charged at room temperature and a mixed solution of 580 mg of dimethyl 2,3,5,6- tetrafluoroterephthalatethe and 5 g of tetrahydrofuran was added to the obtained mixture. The obtained mixture was heated to 60°C. A mixed solution of 400 mg of water and 2.5 g of tetrahydrofuran was added dropwise to the mixture over 5 hours while stirring at the same temperature to effect the reaction for 2 hours at the same temperature. After completion of the reaction, the reaction mixture was cooled to room temperature, and 20 g of 10% by weight hydrochloric acid was added thereto dropwise over 10 minutes at 25 to 30°C. After stirring at the same temperature for 30 minutes, the mixture was left at rest and the aqueous layer was separated. To the organic layer obtained, 20 g of toluene was added to wash twice with 10 g of water. The organic layer obtained was concentrated to obtain 710 mg of a pale yellow oily matter containing 2,3,5,6-tetrafluorobenzenedimethanol. The content of 2,3,5,6-tetrafluorobenzenedimethanol was 50% and the yield was 78%. Comparative Example 1 Into a 200 ml flask, 310 mg of sodium borohydride, 10 g of tetrahydrofuran and 1.0 g of dimethyl 2,3,5,6- tetrafluoroterephthalate were charged at room temperature and the obtained mixture was heated to 65°C. After reacting for 6 hours at the same temperature, the reaction mixture was cooled to room temperature. To the reaction mixture obtained, 10 g of 10% by weight hydrochloric acid was added thereto dropwise over 30 minutes at 25 to 30°C. After stirring at the same temperature for 1 hour, the mixture was extracted twice with 20 g of ethyl acetate and the obtained organic layers washed with 10 g of water to obtain a solution containing 2,3,5,6- tetrafluorobenzenedimethanol. The yield of 2,3,5,6- tetrafluorobenzenedimethanol was 57%. Industrial Applicability According to the present invention, a halogen- substituted benzenedimethanol which is important as raw materials and intermediates, can be produced in a good yield, and therefore, it is useful industrially. CLAIMS 1. A method for producing a halogen-substituted benzenedimethanol represented by the formula (2): wherein X1, X2, X3 and X4 are the same or different and independently represent a hydrogen atom or a halogen atom, provided that X1, X2, X3 and X4 are not hydrogen atoms at the same time, by reacting a diester of a halogen-substituted terephthalic acid represented by the formula (1): wherein X1, X2, X3 and X4 are the same meanings as defined above, with a borohydride compound in an organic solvent in the presence of 0.5 to 10 moles of water per 1 mole of the borohydride compound. 2. The method according to claim 1, wherein the reaction is conducted by adding 0.5 to 10 moles of water per 1 mole of the borohydride compound into a mixture of the diester of the halogen-substituted terephthalic acid represented by the formula (1), the borohydride compound and the organic solvent. 3. The method according to claim 1 or 2, wherein the used amount of water is 0.9 to 4 moles per 1 mole of the borohydride compound. 4. The method according to claim 1 or 2, wherein the used amount of the borohydride compound is 1 to 2.5 moles per 1 mole of the diester of the halogen-substituted terephthalic acid represented by the formula (1). 5. The method according to claim 1 or 2, wherein the borohydride compound is an alkali metal borohydride. 6. The method according to claim 5, wherein the alkali metal borohydride is sodium borohydride. 7. The method according to claim 1 or 2, wherein the reaction temperature is 40 to 100°C. 8. The method according to claim 1 or 2, wherein the diester of the halogen-substituted terephthalic acid represented by the formula (1) is a halogen-substituted terephthalic acid diester represented by the formula (3): wherein X1, X2, X3 and X4 are the same or different and independently represent a hydrogen atom or a halogen atom, provided that X1, X2, X3 and X4 are not hydrogen atoms at the same time and R represents a C1-C6 alkyl group. 9. The method according to claim 1 or 2, wherein X1, X2, X3 and X4 are fluorine atoms. A method for producing a halogen-substituted benzenedimethanol represented by the formula (2): wherein X1, X2, X3 and X4 are the same or different and independently represent a hydrogen atom or a halogen atom, provided that X1, X2, X3 and X4 are not hydrogen atoms at the same time, by reacting a diester of a halogen-substituted terephthalic acid represented by the formula (1): wherein X1, X2, X3 and X4 are the same meanings as defined above, with a borohydride compound in an organic solvent in the presence of 0.5 to 10 moles of water per 1 mole of the borohydride compound.

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02626-kolnp-2008-abstract.pdf

02626-kolnp-2008-claims.pdf

02626-kolnp-2008-correspondence others.pdf

02626-kolnp-2008-description complete.pdf

02626-kolnp-2008-form 1.pdf

02626-kolnp-2008-form 2.pdf

02626-kolnp-2008-form 3.pdf

02626-kolnp-2008-form 5.pdf

02626-kolnp-2008-international publication.pdf

02626-kolnp-2008-international search report.pdf

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2626-KOLNP-2008-(05-03-2014)-ABSTRACT.pdf

2626-KOLNP-2008-(05-03-2014)-ANNEXURE TO FORM 3.pdf

2626-KOLNP-2008-(05-03-2014)-CLAIMS.pdf

2626-KOLNP-2008-(05-03-2014)-CORRESPONDENCE.pdf

2626-KOLNP-2008-(11-11-2014)-CLAIMS.pdf

2626-KOLNP-2008-(11-11-2014)-CORRESPONDENCE.pdf

2626-KOLNP-2008-(11-11-2014)-PETITION UNDER RULE 137.pdf

2626-KOLNP-2008-(11-12-2012)-CORRESPONDENCE.pdf

2626-KOLNP-2008-(29-08-2013)-ABSTRACT.pdf

2626-KOLNP-2008-(29-08-2013)-CLAIMS.pdf

2626-KOLNP-2008-(29-08-2013)-CORRESPONDENCE.pdf

2626-KOLNP-2008-(29-08-2013)-FORM-3.pdf

2626-KOLNP-2008-(29-08-2013)-FORM-5.pdf

2626-KOLNP-2008-(29-08-2013)-OTHERS.pdf

2626-KOLNP-2008-CORRESPONDENCE 1.1.pdf

2626-KOLNP-2008-CORRESPONDENCE 1.2.pdf

2626-KOLNP-2008-FORM 18.pdf

2626-KOLNP-2008-OTHERS.pdf

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