MXPA00000861A - Method for preparing 3-cyano-2,4-dihalogen-5-fluor-benzoic acid - Google Patents

Abstract

The invention concerns a method for preparing 3-cyano-2,4-dihalogen-5-fluor-benzoic acid, intermediate products for implementing the method and a method for preparing said intermediate products.

Description

PROCEDURE FOR THE OBTAINING OF THE ACIDS 3-CYANO-2,4-DIHALOGENO-5-FLUOR-BENZOICOS.

Field of the invention. The present invention relates to a process for the preparation of 3-cyano-2,4-di-halogeno-5-fluoro-benzoic acids, intermediates for carrying out this process and processes for obtaining these intermediates.

Description of the prior art. 3-Cyano-2,4-dichloro-5-fluoro-benzoic acid is known from DE-A-3 702 393. This is prepared from 3-amino-2-dichloro-5-fluoro-benzoic acid by diazotization and reaction of the diazonium salt with cyanide salts. This procedure is unfavorable first of all when it is carried out on a large scale.

Description of the invention The object of the present invention is 1. Process for the preparation of 3-cyano-2,4-dihalogeno-5-fluorobenzoic acids of the formula (I) Ref.: 32579 in which X and Y signify, independently of one another, halogen, by hydrolytic cleavage of a) 3-cyano-2,4-dihalogeno-5-fluorobenzoic acid amides of the formula (II) wherein X and Y stand for halogen independently, or b) 1,3-dicyano-2, -dihalogen-5-fluorobenzenes of the formula (III) wherein X and Y signify, independently of each other, halogen, c) esters of the 3-cyano-2,4-dihalogeno-5-fluorobenzoic acids of the formula (IV) where X and Y mean, independently of each other, halogen and R means alkyl having 1 to 4 carbon atoms, which may be substituted if appropriate. 2. The new compounds of the formulas (II i and (iv) in which X and Y stand for each other independently, halogen and R means alkyl with 1 to 4 carbon atoms, which may be substituted, if appropriate, with the exception of methyl 3-cyano-2,4,5-trifluoro-berzoate . 3. Process for obtaining the amides of 3-cyano-2,4-dihalogen, 5-fluoro-benzoic acids of the formula (II) or of the esters of the formula (IV) characterized in that 1, 3-dicyano-2,4-dihalogeno-5-fluoro-benzenes of the formula (III) are hydrolyzed wherein X and Y have the meaning indicated above, in the presence of water or in the presence of alcohols.

The new compounds of the formula (III) wherein X and Y mean different residues of the group consisting of fluorine or chlorine or both residues mean chlorine.

. Process for obtaining the compounds of the formula (III) wherein X and Y mean different residues of the group consisting of fluorine or chlorine, characterized in that 1, 2, 4-trifluoro-3,5-dicyanobenzene (2,4,5-trifluoro-isofalodinitrile) is reacted with a metal halide.

The 1,2,4-trifluoro-3,5-dicyanobenzene and their preparation are known from EP-A-307 897.

In the above formulas, X and Y preferably mean fluorine or chlorine. Particularly preferred in the compounds of the formulas (II) and (IV) are identical residues consisting of fluorine or chlorine.

In the compounds of the formula (III), 2,4-dichloro-5-fluoro-isophthalodinitrile is particularly preferred.

Preferably R means methyl, ethyl, propyl or benzyl.

If 3-cyano-2,4,4-trifluorobenzamide is used as starting material in process a) for the preparation of 3-cyano-2,4,4-trifluorobenzoic acid, the reaction can be represented by means of the formula following; The amides of the formula (II) to be used as starting materials are new. Obtaining it is described later.

The hydrolysis is carried out in the presence of acids and water. As acids, strong organic and inorganic acids can be used. As such, mention may be made of HCl, HBr, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and strong acid ion exchangers in the presence of water.

As the solvent, the acid used as reactant or an organic solvent can be used in excess. Suitable organic solvents are acids such as formic acid, acetic acid, propionic acid, ethers such as dimethoxyethane, dioxane, ketones such as acetone, butanone.

The components of the reaction can be combined in any order. It is then heated to the required temperature.

The temperature of the reaction is in the range from 0 to 200 ° C, preferably from 20 to 150 ° C.

The reaction can be carried out without pressure or under a pressure of from 0 to 50 bar, preferably from 0 to 6 bar.

The products are separated by filtration from the reaction mixture, optionally after dilution with water. If the acid in large excess or a solvent is used, it may be advantageous to remove it by distillation and isolate the product by extraction.

If 4-chloro-2, 5-difluoro-isophthalodinitrile is used as the starting material for the preparation of 4-chloro-2,5-difluoro-3-cyanobenzoic acid according to process Ib), the reaction can be represented by following formulas scheme: 2, 4, 5-trifluoro-isophthalodinitrile is known from the literature (EP-A-307). The 2,4-dichloro-5-fluoro-ixophthalodinitrile is new. Obtaining it is described later.

The hydrolysis is carried out with acids in the presence of water. As acids, strong inorganic and organic acids can be used. As such, mention may be made of HCl, HBr, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and strong ion exchangers in the presence of water. ~~ As the solvent, the acid used as reactant or an organic solvent can be used in excess. Suitable organic solvents are acids such as formic acid, acetic acid, propionic acid, ethers such as dimethoxyethane, dioxane, ketones such as acetone, butanone.

The components of the reaction can be combined in any order. It is then heated to the required temperature.

The reaction temperature is in the range from 0 to 200 ° C, preferably from 20 to 15 ° C.

The reaction can be carried out without pressure or under a pressure of from 0 to 50 bar, preferably from 0 to 6 bar.

The products are separated by filtration from the reaction mixture, optionally after dilution with water. If the acid in large excess or a solvent is used, it may be advantageous to remove it by distillation and isolate the product by extraction.

If methyl 3-cyano-2, 4, 5-trifluorobenzoate is used as the starting material in the process le) for the preparation of 3-cyano-2,4,4-trifluorobenzoic acid, the reaction may be represented by means of the following formulas scheme: The esters of the formula (IV) used as starting products are new. Its obtaining is described further on.

The hydrolysis is carried out in the presence of acids and water. As acids, strong organic and inorganic acids can be used. Such as HCl, HBr, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and strong ion exchangers in the presence of water.

As a solvent, the acid used as reactant or an organic solvent can be used in excess. Suitable organic solvents are acids such as formic acid, acetic acid, propionic acid, ethers such as dimethoxyethane, dioxane, ketones such as acetone, butanone.

The components of the reaction can be combined in any order. It is then heated to the required temperature. The temperature of the reaction is in the range from 0 to 200 ° C, preferably from 20 to 150 ° C.

The reaction can be carried out without pressure or under a pressure of from 0 to 50 bar, preferably from 0 to 6 bar.

The products are extracted from the reaction mixture if necessary after dilution with water. If the acid is used in large excess or a solvent, it may be advantageous to remove it by distillation.

As already indicated, the compounds of the formula (IV) are new.If 2, 4-dichloro-5-fluoro-isophthalodinitrile is used as starting material for its preparation according to process 3), the reaction can be represented by means of the following formula scheme: The reaction proceeds intermediately through the i-ester and its hydrolysis with water. As a secondary reaction, the formation of the corresponding amide is observed. If water is added, the formation of the amide will be the main reaction (see below). 2, 4, 5-trifluor-isophthalodinitrile is known from the literature (EP-A-307897). The 2,4-dichloro-5-fluoro-isophthalodinitrile is new, its obtaining has been written later.

The preparation of the compound of the formula (II) is carried out by hydrolysis of the corresponding dinitriles with acids in the presence of water and alcohols.

The reaction is carried out in the presence of 1 to 10 equivalents of water and primary and secondary aliphatic alcohols. Methanol, ethanol, propanol and butanol are preferred. Acids which can be used are strong inorganic and organic acids such as HCl, HBr, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and strong acid ion exchangers.

It is also possible to use 1 mole of dinitrile in addition to 1 to 10 mole of alcohol also of 1 to 10 mole of water.

The reaction can be carried out with or without solvent. As solvent, the alcohol used as reactant or an inert solvent can be used in excess. Suitable inert solvents are: all inert organic solvents such as hydrocarbons, co-ortho-pentane, hexane, heptane, petroleum ether, benzene, ligroin, benzene, toluene; halogenated hydrocarbons such as dichloromethane, chloroform, chlorobenzene, dichlorobenzene, trichloroethane, ethers such as diethyl ether, dipropyl ether, dibutyl ether, ethylene glycol ethyl ether, diethylene glycol diethyl ether.

The dinitrilo and the alcohol are arranged beforehand and the acid is added, then the water is added. The water, necessary for the reaction, can also be arranged directly in advance.

The temperature of the reaction is in the range of -20 to 150 ° C. They are preferred from 10 up 100 ° C.

The reaction can be carried out at normal pressure or at a higher pressure of 0 to 50 bar. Preference is from 0 to 6 bar.

The reaction mixture is diluted with water and extracted. When alcohol has been used in large excess or an inert solvent, the solvent may be previously removed by distillation. The amide, formed as a secondary product of the reaction, can be separated.

As already indicated above, the compounds of the formula (II) are new.

If 2, 4, 5-trifluoro-isophthalodinitrile is used as starting material for its preparation according to process 3), the reaction can be represented by means of the following formula scheme: The reaction proceeds through the intermediate formed iminoesters, from which the imides are formed by dissociation of the alkyl moiety. 2, 4, 5-trifluoro-isophthalodinitrile is known from the literature (EP-A-307 897). The 2,4-dichloro-5-fluoro-isophthalodinitrile is new, and its "e" has been described later.

The reaction is carried out with primary or secondary aliphatic alcohols in the presence of acids. Methanol, ethanol, propanol and butanol are preferred. Methanol is especially preferred. Acids which can be used are strong organic and inorganic acids, such as HCl, HBr.

They can be used per 1 mole of dinitrile of 1 to 10 moles of alcohol.

The reaction can be carried out with or without solvent. As solvent, the alcohol used as reactant or an inert organic solvent can be used in excess. Suitable inert solvents are: all inert organic solvents, such as hydrocarbons such as pentane, hexane, heptane, petroleum ether, benzine, ligroin, benzene, toluene; halogenated hydrocarbons such as dichloromethane, chloroform, chlorobenzene, trichloroethane, ethers such as diethyl ether, dipropyl ether, dibutyl ether, ethylene glycol dimethyl ether, diethylene glycol diethyl ether.

Dinitrile and alcohol are arranged in advance and the acid is added.

The temperature of the reaction is in the range of -20 to 150 ° C. It is preferred from 0 ° C to 100 ° C.

The reaction can be carried out at normal pressure or at a higher pressure of 0 to 50 bar. Preference is from 0 to 6 bar.

The products are separated by filtration from the reaction mixture, optionally after dilution with water. When the alcohol has been used in large excess or an inert solvent, it can be removed by distillation as a previous step.

The compouof the formula (III), in which X and Y do not simultaneously mean S, are new. Its preparation can be represented, from 2, 4, 5-trifluoro-isofalodinitrile, according to process 5), by means of the following formula scheme: 2, 4, 5-trifluoro-isophthalodinitrile is known from the literature (EP-A-307 897).

The exchange of the halogen is carried out by reaction with inorganic chloride salts.

As inorganic chloride salts, MgCl 2 and CaCl 2 can be used. The reaction can also be catalyzed, for example, by means of tetraalkylammonium salts, crown ethers, etc.

The inorganic salt is used in an amount of 0.5 to 10 moles per fluorine to be exchanged. Preferred are 0.5 to 2 moles.

The reaction can be carried out with or without solvent. Suitable solvents are all inert organic solvents, for example pentane, hexane, heptane, petroleum ether, benzene, ligroin, benzene, toluene, dichloromethane, chloroform, chlorobenzene, dichlorobenzene, trichloroethane, ethers such as dibutyl ether, ethylene glycol dimethyl ether, diethylene glycol diethyl ether, ketones, such as acetone, methyl ethyl ketone, cyclohexanone, as well as N-methyl pyrrolidone, dimethylsulfone, sulfolane.

The substances are mixed and heated to the desired temperature. The order of addition plays no role. Depending on the conduct of the reaction, 1 or 2 fluorine atoms may be exchanged per chlorine.

The temperature of the reaction is in the range of 50 to 350 ° C. Preference is 90 to 250 ° C.

The reaction can be carried out with or without pressure. When using a low-boiling solvent, conduction under pressure can be favorable. Pressure range from 0 to 100 bar overpressure. Preferably: from 0 to 50 bar.

The products are isolated by filtration separation of the inorganic salts and the filtrate is subjected to fractional distillation. If a solvent miscible with water was used, it can also be mixed with water and extracted. "~~~ 3-Cyano-2,4-dihalogeno-5-fluoro-benzoic acid can be used, for example, to obtain the compou(VIII) known from the following US-P-4 990 517: 7-Chloro-8-cyano-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 7-chloro-8-cyano-l-cyclopropyl-6-fluoro-1 , Methyl 4-dihydro-4-oxo-3-quinolinecaboxylate, 8-cyano-l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 8-cyano-l- ethyl cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, For this purpose, for example, 3-cyano-2,4,5-trifluorobenzoic acid, in the form of its acyl chloride, is reacted with esters of the β-dimethylamino-acrylic acid of the formula (V) and the product obtained of the formula (VI) is further reacted with cyclopropylamino to give a compound of the formula (VII) and then the above-mentioned compound (VIII) is obtained: (IV) (V) (VI) (VII) (VIII) In the previous formula schema X means halogen, especially fluorine or chlorine, R6 means alkyl having 1 to 4 carbon atoms, especially methyl or ethyl.

In the same way it is possible to react a compound of the formula (IV) directly with esters of the β-cyclopropylamino-acrylic acid, (In the formulas X and R have the meaning indicated above). The acid chloride of 3-cyano-2,4,4-trifluorobenzoic acid can be prepared from the esters of the formula (IV) according to the following scheme: (IV) Compounds with antibacterial activity can be prepared from the compounds of the formula (VIII) by reaction with suitable amines.

If they are reacted, for example, 7-chloro-8-cyano-l-cyclopropy1-6-fluoro-1,4-dihydro-4-oxo-3-quinolirboxylic acid and 2, 8-diazabicyclo [.3.0] nonano, the development of the reaction can be represented by means of the following formulas scheme: The preparation of these compounds has been described in DE-A-196 33 805, not previously published, by the applicant.

The following examples show the present invention without limiting it in its scope.

Example 1. (Procedure a) Quantity Moles Text 0.4 g 1.72 m They were heated at reflux for 3 hours 3-cyano-2, 4-dichloro-5-fluoro-benzamide and concentrated hydrochloric acid. It was then concentrated by evaporation and the residue was dried in the desiccator over sulfuric acid. Yield: 370 mg Purity: 84% (HPLC surfaces) of 3-cyano-2, -dichloro-5-fluorobenzoic acid. 12% (HPLC surfaces) of 3-cyano-2,4-dichloro-5-fluoro-benzamide (starting material).

Example 2 (Procedure Ib) Amount Moles Text 2.5 g 12m 2, 4-dichloro-5-25 my fluorine-isophthalodinitrile was suspended in methanol, refrigerated at 0 ° C and saturated with hydrochloric acid gas. The load was allowed to stand for 60 hours at -16 ° C. It was then concentrated by evaporation. The residue was combined with 38 my concentrated hydrochloric acid and heated to reflux for 3 hours. It was then poured into water, the precipitate was separated by suction filtration and dried in the desiccator over sulfuric acid 120 ml. Yield: 1.86% purity: 87% of 3-cyano-2,4-dichloro-5-fluoro- benzoic 10% of 3-cyano-2,4-dichloro-5-fluorobenzamide.

Example 3 (Procedure Ib). Ñ Quantity Moles Text i g 5. 5 m 2,4, 5-trifluoro-isophthalodinitrile, 6 3 my water 6. 3 my acetic acid and 0. My 96% sulfuric acid was heated for 24 hours under reflux. The mixture was then poured into 50 ml of water and 25 ml of dichloromethane was added. The aqueous phase was now adjusted to pH 9 with 45% NaOH, the organic phase was then separated and extracted further 2 times with dichloromethane. The extracts were removed. The remaining aqueous phase was adjusted to pH 2 with concentrated hydrochloric acid and extracted three times with 25 ml of dichloromethane, respectively. The combined extracts were dried with sodium sulfate and concentrated by evaporation. Residue: 470 mg Purity: 80% (GC / MS surfaces).

Example 4 (Procedure le) Quantity Moles Text 2g 8.7 m 3-cyano-2, 4, 5-trifluoro-benzoate of ethyl (purity 79%) 1.0 ml Glacial acetic acid 10 ml Water and 1 ml Sulfuric acid 96% were heated for 7.5 hours at reflux. It was then cooled, poured over 100 ml of water and extracted three times with dichloromethane. The extract was combined with 100 ml of water and the pH of the aqueous phase was adjusted to 8.5 with stirring. The organic phase is separated, the aqueous phase is extracted further with dichloromethane. The organic extracts are eliminated. 5O my dichloromethane is added to the aqueous phase and acidified with sulfuric acid. The dichloromethane is separated and extracted again with dichloromethane. The combined extracts are then dried with Na 2 SO and concentrated by evaporation. The residue is dried in the desiccator over KOH. Yield: 1.2 g (81% of theory) Purity: 95% (HPLC surface) Melting point: 146 ° C.

Example 5 (Method 3).

Quantity Moles Text 9 g 42 m 2, 4-dichloro-5-fluoro-isophthalodinitrile was suspended in m tanol, refrigerated at 5 ° C and gaseous hydrochloric acid was passed to saturation. A solution was formed which was stirred for 24 hours at room temperature. It was then concentrated by evaporation. The residue was stirred with dichloromethane and separated by suction filtration. Yield: 8.04 g Purity: 95% (HPLC surfaces) Melting point: 178 °.

Example 6 (Procedure 3) Amount Moles Text 5.52 g 30 m 2, 4, 5-trifluoro-isophthalodinitrile (86% purity in 60 ml dry ethanol and is passed through gaseous hydrochloric acid until saturated, under ice-cooling. hours at room temperature, then 4.8 ml 0.266 water is added and heated for 4 hours. hours at reflux, then concentrated by evaporation, the residue is distributed between water and chloroform.The organic phase is separated, the aqueous phase is subsequently extracted further twice with chloroform. The combined extracts are dried with Na 2 SO 4 and concentrated by evaporation. The residue is distilled in the ball tube. 15 Boiling point: 220 ° C (42 mbar) Yield: 4.21 g (55% theory) Purity: 79% (HPLC surfaces) 1 H-NMR (CDC13) 20 8.1 ppm (m, 1 H, Ar-H) 4.4 ppm (q, J = 8Hz, 2H, -0CH-) 1.4 ppm (t, J = 8 Hz, 3H, -CH3).

Example 7 (Procedure 3) Amount Moles Text 0.5 g 2.3 m 2, 4-dichloro-5-fluoro-10 my isophthalodinitrile was dissolved in methanol and saturated with gaseous HCl under good cooling at 0 ° C. The load was then allowed to stand for 72 hours at -10 ° C. Next, my 96% aqueous methane was added and heated to reflux for 3 hours. It was then concentrated by evaporation in vacuo, the residue was distributed between chloroform and saturated bicarbonate solution, the organic phase was separated, dried with sodium sulfate and concentrated by evaporation.

Residue: 410 mg According to HPLC there is contained in it 10% starting material 7.5% amide 76% methyl ester.

Example 8 (Method 5) H R5025 HLR5270 Quantity Moles Text 13.5 g 74 m 2,4, 5-Trif lúor-isof talodinitrilo. 125 ml sulfolane and 17.7 g fresh powdery calcium chloride is heated for 24 hours at 200 °. Then pour over 1. 200 my water. The fine precipitate is separated by suction filtration and dried. Yield 13.8 g for purification can be filtered through silica gel with toluene / hexane Yield: 12.8 g Purity: 96% HPLC surfaces Melting point: 119 °.

Example 9 (Method 5) Amount Moles Text 0. 55 g 3 m 2,, 5-trifluoro-isophthalodinitrile, my sulfolane and 0. 37 g 3. 3 m fresh powdery calcium chloride were heated for 1.5 hours at 200 ° C. The mixture was then poured into 100 ml of water and extracted twice with ether.

The extract was dried with sodium sulfate and concentrated by evaporation. Yield: 0.56 g Composition: 75% of 4-chloro-2, 5- difluoro-isophthalodinitrile 25% of 5-fluoro-2,4-dichlorosisophthalodinitrile (HPLC surfaces).

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (5)

1. Process for obtaining the 3-cyano-2,4-dihalogeno-5-fluorobenzoic acids of the formula (I) characterized in that X and Y mean, independently of each other, halogen, by hydrolytic dissociation of a) amides of 3-cyano-2,4-dihalogeno-5-fluorobenzoic acids of the formula (II) in which X and Y stand for, independently of one another, halogen, or b) 1,3-dicyano-2, -dihalogen-5-fluorobenzenes of the formula (III) wherein X and Y are, independently of each other, halogen, or c) esters of the 3-cyano-2,4-dihalogeno-5-fluorobenzoic acids of the formula (IV) i COOR (IV) wherein X and Y stand for halogen independently and R means alkyl with 1 to 4 carbon atoms, which may be substituted if appropriate.

2 . Compounds of the formula (II) and (iv) F- ^ í \ / COO? ? (IV) CN characterized because X and Y mean independently of each other, halogen and R represents alkyl with 1 to 4 carbon atoms, which may be substituted, if appropriate, with the exception of methyl 3-cyano-2,4,5-trifluorobenzoate.

3. Process for obtaining the amides of 3-cyano-2,4-dihalogen, 5-fluoro-benzoic acids of the formula (II) (IV) or of the esters of the formula (IV) in which, X and Y independently of each other, represent halogen, and R represents C? -4 alkyl which is optionally substituted, characterized in that 1, 3-dicyano -2, 4-dihalogeno-5-fluorobenzenes of the formula (III), wherein X and Y have the meaning indicated above, are hydrolyzed in the presence of water or in the presence of alcohols.

4. The new compounds of the formula (III) characterized by X and Y meaning different residues of the group consisting of fluorine or chlorine or both residues mean chlorine.

5. Process for obtaining the compounds of the formula (III) in which X and Y mean different residues of the group formed by fluorine or chlorine, characterized in that 1, 2, 4-trifluoro-3,5-dicyanobenzene (2,4,5-trifluoro-isophthalodinitrile) is reacted with a metal halide.