WO2021156893A1 - Process for preparation of 2,4,6-trifluorobenzoic acid - Google Patents

Process for preparation of 2,4,6-trifluorobenzoic acid Download PDF

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Publication number
WO2021156893A1
WO2021156893A1 PCT/IN2021/050117 IN2021050117W WO2021156893A1 WO 2021156893 A1 WO2021156893 A1 WO 2021156893A1 IN 2021050117 W IN2021050117 W IN 2021050117W WO 2021156893 A1 WO2021156893 A1 WO 2021156893A1
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Prior art keywords
acid
trifluorobenzonitrile
trifluorobenzoic
dichloro
phosphate
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PCT/IN2021/050117
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French (fr)
Inventor
Ram Singh
Rajender Kumar
Ajay CHAUDHARY
Bhupender SINGH
Kapil Kumar
Anurag Jain
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Srf Limited
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Publication of WO2021156893A1 publication Critical patent/WO2021156893A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups

Definitions

  • the present invention provides a process for preparation of 2,4,6-trifluorobenzoic acid, preventing the formation of difluorobenzoic acid impurities.
  • the present invention provides a process to produce halogen-containing benzoic acids. These compounds are important raw material for preparing photosensitizer, medicine and pesticides, and find applications in pharmaceuticals and agrochemical industries.
  • Japanese Patent No. 61036244 describes a process for preparation of 2,4,6- trifluorobenzoic acid comprising the step of hydrolysing 3,5-dichloro-2,4,6- trifluorobenzonitrile to 3,5-dichloro-2,4,6-trifluorobenzoic acid using aqueous sulfuric acid at 160°C, followed by de-chlorinating 3,5-dichloro-2,4,6- trifluorobenzoic acid to 2,4,6-trifluorobenzoic acid using potassium hydroxide in presence of palladium catalyst and hydrogen pressure.
  • the process involves formation of difluorobenzoic acid impurities that are very difficult to separate from 2,4,6-trifluorobenzoic acid.
  • the present invention provides an alternate process for the preparation of 2,4,6- trifluorobenzoic acid with significantly reduced fluorobenzoic acid impurities.
  • the present invention provides an alternate process for preparation of 2,4,6- trifluorobenzoic acid, which prevents the formation of difluorobenzoic acid impurities.
  • the present invention provides a process for preparation of 2,4,6-trifluorobenzoic acid, comprising the steps of: a) de-chlorinating 3,5-dichloro-2,4,6-trifluorobenzonitrile using a transition metal catalyst in presence of an alkanoic acid and water to obtain 2,4,6- trifluorobenzonitrile; and b) hydrolysing 2,4,6-trifluorobenzonitrile using an acid to obtain 2,4,6- trifluorobenzoic acid.
  • alkanoic acid is selected from formic acid, acetic acid, trifluoroacetic acid, or the like.
  • the molar ratio of alkanoic acid w.r.t fluorinated benzonitrile is used in the range from 2-5.
  • alkanoic acid is added continuously in the de-chlorination reaction.
  • the alkanoic acid in de-chlorination reaction is added in 2-5 hours.
  • de-chlorination of 3,5-dichloro-2,4,6-trifluorobenzonitrile is carried out using a transition metal catalyst in presence of alkanoic acid to obtain 2,4,6-trifluorobenzonitrile.
  • the transition metal catalyst is selected from copper, zinc, zinc/copper alloy or the like.
  • the transition metal catalyst for de-chlorination process is used in solid or powder form.
  • the transition metal catalyst contains metal content greater than 99%.
  • the mesh size of metal powder used is less than 100 micron and more preferably between 2-50 and more preferably 2-20 micron.
  • the de-chlorination is carried out at a temperature range of 70°C to 90°C.
  • the low temperature range prevents the degradation of product and improves yield significantly.
  • the impurities in the de-chlorination are formed by de-chlorination of one chlorine only.
  • the de-chlorination step is additionally carried out in presence of an organic solvent selected from a group consisting of hexane, toluene, cyclohexane, ethyl acetate, ethanol, methanol, butanol, propanol, isopropanol, diethyl ether, acetone or a mixture thereof.
  • an organic solvent selected from a group consisting of hexane, toluene, cyclohexane, ethyl acetate, ethanol, methanol, butanol, propanol, isopropanol, diethyl ether, acetone or a mixture thereof.
  • de-chlorination is carried out in absence of organic solvent.
  • 3,5-dichloro-2,4,6-trifluorobenzonitrile is de-chlorinated using zinc and acetic acid to obtain 2,4,6-trifluorobenzonitrile in presence of water as solvent.
  • 3,5-dichloro-2,4,6-trifluorobenzonitrile is de-chlorinated using zinc powder of mesh size between 5-10 micron and acetic acid to obtain 2,4,6- trifluorobenzonitrile in presence of water as solvent.
  • 3,5-dichloro-2,4,6-trifluorobenzonitrile is de-chlorinated using zinc and acetic acid to obtain 2,4,6-trifluorobenzonitrile in absence of an organic solvent.
  • 3,5-dichloro-2,4,6-trifluorobenzonitrile is de- chlorinated using zinc and acetic acid in a mixture of water and an organic solvent to obtain 2,4,6-trifluorobenzonitrile.
  • de-chlorination is carried out using a transition metal catalyst, alkanoic acid and a salt.
  • the salts is selected from phosphate salt such as dipotassium hydrogen phosphate, ammonium dihydrogen phosphate, ammonium hydrogen phosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate, calcium phosphate, potassium dihydrogen phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, acetates salt such as sodium acetate potassium acetate, and ammonium/phosphonium salts such as tetramethylammonium chloride, trioctylmethyl ammonium chloride, tetraphenylphosphonium chloride, tetraphenylphosphonium bromide, tetrabutylammonium chloride, tetrabutylammonium bromide or hydrates thereof.
  • the major difluorobenzonitrile impurities are identified as 2,6-difluorobenzonitrile, 2,4-difluorobenzonitrile or like.
  • 3,5-dichloro-2,4,6-trifluorobenzonitrile is de- chlorinated using zinc and acetic acid in presence of potassium dihydrogen phosphate to obtain 2,4,6-trifluorobenzonitrile.
  • 3,5-dichloro-2,4,6-trifluorobenzonitrile is de- chlorinated using zinc and acetic acid in presence of tetraphenylphosphonium bromide to obtain 2,4,6-trifluorobenzonitrile.
  • 3,5-dichloro-2,4,6-trifluorobenzonitrile is de- chlorinated using zinc and acetic acid in presence of Tetrabutylammonium chloride to obtain 2,4,6-trifluorobenzonitrile.
  • the purity of isolated 2,4,6-trifluorobenzonitrile is greater than 90% and preferably greater than 95% and more preferably greater than 99%.
  • 2,4,6-trifluorobenzonitrile contains impurities less than 2% and more preferably between 0.1-1%.
  • the yield of 2,4,6-trifluorobenzonitrile is greater than 80% and preferably greater than 85%.
  • the present invention involves two de-chlorination steps to form 2,4,6- trifluorobenzonitrile.
  • the intermediate formed i.e., 3-chloro-2,4,6-trifluorobenzonitrile is isolated and recycled to de chlorination step.
  • hydrolysing refers to reacting 2,4,6-trifluorobenzonitrile with an acid to obtain 2,4,6-trifluorobenzoic acid;
  • acid is selected from sulfuric acid, hydrochloric acid or like.
  • hydrolysis is carried out using aqueous acid.
  • concentration of aqueous acid may range from 30-80% by mass of acid.
  • an aqueous acid is continuously added to 2,4,6-trifluorobenzonitrile.
  • hydrolysis is carried out at a temperature of 80-160°C and preferably at a temperature of 100-150°C.
  • the hydrolysis reaction may take 2-7 hours for completion.
  • reaction mixture is filtered to isolate 2,4,6-trifluorobenzoic acid.
  • the present invention is isolating 2,4,6-trifluorobenzoic acid by simple filtration and eliminating multiple workup operations.
  • 2,4,6-trifluorobenzonitrile is hydrolysed using an acid to obtain a reaction mixture containing 2,4,6-trifluorobenzoic acid, which is filtered to obtain a purity of 90% to 95%, which upon recrystallization using a solvent or mixture of solvents gives 2,4,6-trifluorobenzoic acid of higher purity of 98-99%.
  • 2,4,6-trifluorobenzoic acid after filtration is purified by re crystallisation.
  • the re-crystallisation solvent is selected from a group consisting of hexane, toluene, cyclohexane, ethyl acetate, ethanol, methanol, butanol, propanol, isopropanol, diethyl ether, acetone, water or a mixture thereof.
  • the present invention has carried out de-chlorination prior to hydrolysis to prevent formation of difluorobenzoic acid impurities in hydrolysis step.
  • the de-chlorination of present invention gives difluorobenzonitrile impurities that are easy to separate as compared to difluorobenzoic acid impurities.
  • This is an alternate process for preparation of 2,4,6-trifluorobenzoic acid that prevents formation of difluorobenzoic acid impurities.
  • firstly de-chlorination is carried out, followed by separation of difluorobenzonitrile impurities from the reaction mixture and secondly, hydrolysis is carried out using an acid to form 2,4,6-trifluorobenzoic acid.
  • difluorobenzoic acid impurities refers to 2,4-difluorobenzoic acid and 2,6- difluorobenzoic acid, dimers or like and difluorobenzonitrile impurities refers to 2,4- difluorobenzonitrile, 2,6-difluorobenzonitrile, dimers or like.
  • 2,4,6-trifluorobenzoic acid has less than 0.05% of 2,6-difluorobenzoic acid and/or 2,4-difluorobenzoic acid impurities
  • 2,4,6-trifluorobenzoic acid of the present invention have purity greater than 99% with less than 0.05% of 2,6- difluorobenzoic acid and/or 2,4-difluorobenzoic acid impurities.
  • 2,4,6-trifluorobenzoic acid is prepared from 2,4,6- trifluorobenzonitrile using an aqueous sulfuric acid at 150°C.
  • 2,4,6-trifluorobenzoic acid is prepared from 2,4,6- trifluorobenzonitrile using an aqueous hydrochloric acid at refluxing.
  • 2,4,6-trifluorobenzoic acid contains 2,4-difluorobenzoic acid and 2,6-difluorobenzoic acid in the range of 0 to 0.05%.
  • the zero impurity refers to not detectable amount of impurity.
  • the selectivity of formation of 2,4,6-trifluorobenzoic acid is greater than 99%.
  • the yield of hydrolysis step is greater than 96%.
  • present invention provides a process for preparation of 2,4,6-trifluorobenzoic acid, comprising the steps of: a) de-chlorinating 3,5-dichloro-2,4,6-trifluorobenzonitrile using zinc and acetic acid in water to obtain 2,4,6-trifluorobenzonitrile; and b) hydrolysing 2,4,6-trifluorobenzonitrile using aqueous sulfuric acid to obtain 2,4,6- trifluorobenzoic acid.
  • the present invention provides a process for preparation and purification of 2,4,6-trifluorobenzoic acid, comprising the steps of: a) hydrolysing 2,4,6-trifluorobenzonitrile using an aqueous sulfuric acid to obtain a reaction mixture containing 2,4,6-trifluorobenzoic acid with a purity of 90-95%; b) filtering step a) reaction mixture to obtain 2,4,6-trifluorobenzoic acid having purity 90% - 95%; and c) crystallizing 2,4,6-trifluorobenzoic acid obtained from step b) using a mixture of ethyl acetate and hexane to obtain 2,4,6-trifluorobenzoic acid having purity of 99% to 99.8%.
  • 2,4,6-trifluorobenzoic acid is also prepared by the step of de-halogenation of a compound selected from 3,5-dichloro-2,4,6- trifluorobenzonitrile, 3,5-dibromo-2,4,6-trifluorobenzonitrile, 3-bromo-5-chloro- 2,4,6-trifluorobenzonitrile followed by the hydrolysis.
  • 3,5-dichloro-2,4,6-trifluorobenzonitrile is obtained by fluorinating 2,3,4,5,6-pentachlorobenzonitrile using potassium fluoride as a fluorinating agent.
  • a fluorinating agent used in the present invention is selected from a group consisting of alkali metal fluoride such as sodium fluoride, potassium fluoride and cesium fluoride, or ammonium fluoride or the like.
  • the present invention provides a process for preparation of 2,4,6- trifluorobenzoic acid from 2,3,4,5,6-pentachlorobenzonitrile.
  • present invention provides a process for preparation of 2,4,6- trifluorobenzoic acid, comprising the steps of: a) fluorinating 2,3,4,5,6-pentachlorobenzonitrile using an anhydrous potassium fluoride to obtain 3,5-dichloro-2,4,6-trifluorobenzonitrile; a) de-chlorinating 3,5-dichloro-2,4,6-trifluorobenzonitrile using zinc and acetic acid in water to obtain 2,4,6-trifluorobenzonitrile; and b) hydrolysing 2,4,6-trifluorobenzonitrile using an aqueous sulfuric acid to form
  • 3,5-dichloro-2,4,6- trifluorobenzonitrile is obtained by fluorinating 2,3,4,5,6-pentachlorobenzonitrile using a fluorinating agent selected from an alkali metal fluoride
  • present invention provides a process for preparation of
  • 2.4.6-trifuorobenzoic acid comprising fluorinating 2,3,4,5,6-pentachlorobenzonitrile to form 3,5-dichloro-2,4,6-trifluorobenzonitrile, de-chlorinating 3,5-dichloro-2,4,6- trifluorobenzonitrile to 2,4,6-trifluorobenzonitrile and hydrolysing 2,4,6- trifluorobenzonitrile to form 2,4,6-trifluorobenzoic acid.
  • fluorination of 2,3,4,5,6-pentachlorobenzonitrile is carried out using potassium fluoride to form 3,5-dichloro-2,4,6-trifluorobenzonitrile.
  • fluorination of 2,3,4,5,6-pentachlorobenzonitrile is carried out using potassium fluoride at a pressure of 2-3kg/cm2 at a temperature of 250°C.
  • fluorination of 2,3,4,5,6-pentachlorobenzonitrile is carried out using potassium fluoride at a pressure of 2-3kg/cm2 at a temperature of 250°C under an inert atmosphere.
  • the inert atmosphere is maintained using nitrogen, helium or argon.
  • the product may be isolated by any method known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, recrystallization, evaporation, column chromatography and filtration or a mixture thereof.
  • the compound of 2,4,6-trifluorobenzoic acid is isolated by any method known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or a mixture thereof.
  • TLC thin layer chromatography
  • HPLC high pressure liquid chromatography
  • UPLC ultra-pressure liquid chromatography
  • GC Gas chromatography
  • LC liquid chromatography
  • any of the words “comprising”, “comprises” and includes mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
  • Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations.
  • the described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
  • the following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.
  • Example 1 Preparation of 3,5-dichloro-2,4,6-trifluorobenzonitrile 2,3,4,5,6-pentachlorobenzonitrile (200 g), benzonitrile (1200 g) and potassium fluoride (169 g) were added in an autoclave reactor in an inert atmosphere. The reaction mass heated to 250°C. The pressure of the reactor was 2-3kg/cm2 at 250°C during the reaction. The reaction mass analysis was done on gas chromatography. After reaction completed, the reaction mass was cooled to room temperature and filtered. The filtered solid was washed with benzonitrile. The filtrate was fractionally distilled under reduced pressure and product was isolated.
  • Zinc powder (73 g), water (1000 g) and 3,5-dichloro-2,4,6-trifluorobenzonitrile (100 g) were charged in a reactor.
  • Potassium hydrogen phosphate (2 g) were added in the reactor and reaction mass heated to 80°C under stirring.
  • the acetic acid (80 g) was added slowly to the reaction mass in 2-3 hours at 90-95°C.
  • the reaction mass was monitored on gas chromatography. After reaction, the reaction mass cooled to 35°C and dichloromethane (300 g) was added to the reaction mass.
  • the reaction mass was filtered under vacuum and filtrate was separated into organic and aqueous layer. The organic layer was concentrated on rota evaporator and concentrated mass was distilled to isolate 2,4,6-trifluorobenzonitrile.
  • Zinc powder (73 g), a mixture of water and tetrahydrofuran (500 g) and 3,5-dichloro- 2,4,6-trifluorobenzonitrile (100 g) were charged in a reactor.
  • Tetrabutylammonium chloride (2 g) were added in the reactor and reaction mass heated to 80°C under stirring.
  • the acetic acid (80 g) was added slowly to the reaction mass in 2-3 hours at 80°C.
  • the reaction mass was monitored on gas chromatography. After reaction, the reaction mass cooled to 35°C and dichloromethane (300 g) was added to the reaction mass.
  • the reaction mass was filtered under vacuum and filtrate was separated into organic and aqueous layer. The organic layer was concentrated on rota evaporator and concentrated mass was distilled to isolate product.
  • Zinc powder (73 g), water (400 g) and 3,5-dichloro-2,4,6-trifluorobenzonitrile (100 g) were charged in a reactor.
  • Tetrabutylammonium chloride (2 g) were added in the reactor and reaction mass heated to 90°C under stirring.
  • the acetic acid (80 g) was added slowly to the reaction mass in 2-3 hours at 90-95°C.
  • the reaction mass was monitored on gas chromatography. After reaction, the reaction mass cooled to 35°C and dichloromethane (300 g) was added to the reaction mass.
  • the reaction mass was filtered under vacuum and filtrate was separated into organic and aqueous layer. The organic layer was concentrated on rota evaporator and concentrated mass was distilled to isolate product.
  • Zinc powder (73 g), water (1000 g), toluene (60 g) and 3,5-dichloro-2,4,6- trifluorobenzonitrile (100 g) were charged in a reactor.
  • Tetraphenylphosphonium bromide (2.5 g) were added in the reactor and reaction mass heated to 80°C under stirring.
  • the acetic acid (80 g) was added slowly to the reaction mass in 2-3 hours at 90-95°C.
  • the reaction mass was monitored on gas chromatography. After reaction, the reaction mass cooled to 35°C.
  • the reaction mass was filtered under vacuum and filtrate was separated into organic and aqueous layer. The organic layer was concentrated on rota evaporator and concentrated mass was fractionally distilled to isolate 2,4,6-trifluorobenzonitrile.
  • Aqueous sulfuric acid 500g, 70% was charged in a reactor and heated to 140°C.
  • 2,4,6-trifluorobenzonitrile (100 g) was added continuously to reactor in 3-4 hours.
  • the reaction mixture stirred for 2 hours and cooled to room temperature.
  • the reaction mixture was filtered and product was isolated.
  • the product was dried under vacuum at 70°C.
  • Aqueous sulfuric acid (500g, 70%) was charged in a reactor and heated to 140°C.

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Abstract

The present invention provides a process for the preparation of 2,4,6-trifluorobenzoic acid, having less than 0.05% of 2,6-difluorobenzoic acid and/or 2,4-difluorobenzoic acid impurities. The 2,4,6-trifluorobenzoic acid is crucial and an important raw material for preparing the photosensitizers, medicines and pesticides, and also finds applications in pharmaceutical and agrochemical industries.

Description

PROCESS FOR PREPARATION OF 2,4,6-TRIFLUOROBENZOIC ACID
FIELD OF THE INVENTION
The present invention provides a process for preparation of 2,4,6-trifluorobenzoic acid, preventing the formation of difluorobenzoic acid impurities.
BACKGROUND OF THE INVENTION
The present invention provides a process to produce halogen-containing benzoic acids. These compounds are important raw material for preparing photosensitizer, medicine and pesticides, and find applications in pharmaceuticals and agrochemical industries.
Japanese Patent No. 61036244 describes a process for preparation of 2,4,6- trifluorobenzoic acid comprising the step of hydrolysing 3,5-dichloro-2,4,6- trifluorobenzonitrile to 3,5-dichloro-2,4,6-trifluorobenzoic acid using aqueous sulfuric acid at 160°C, followed by de-chlorinating 3,5-dichloro-2,4,6- trifluorobenzoic acid to 2,4,6-trifluorobenzoic acid using potassium hydroxide in presence of palladium catalyst and hydrogen pressure. The process involves formation of difluorobenzoic acid impurities that are very difficult to separate from 2,4,6-trifluorobenzoic acid.
Thus, there is a need to develop a process, which may overcome the drawbacks of the known processes.
The present invention provides an alternate process for the preparation of 2,4,6- trifluorobenzoic acid with significantly reduced fluorobenzoic acid impurities. OBJECT OF THE INVENTION
The present invention provides an alternate process for preparation of 2,4,6- trifluorobenzoic acid, which prevents the formation of difluorobenzoic acid impurities. SUMMARY OF THE INVENTION
The present invention provides a process for preparation of 2,4,6-trifluorobenzoic acid, comprising the steps of: a) de-chlorinating 3,5-dichloro-2,4,6-trifluorobenzonitrile using a transition metal catalyst in presence of an alkanoic acid and water to obtain 2,4,6- trifluorobenzonitrile; and b) hydrolysing 2,4,6-trifluorobenzonitrile using an acid to obtain 2,4,6- trifluorobenzoic acid.
DETAILED DESCRIPTION OF THE INVENTION As used herein, the term “alkanoic acid” is selected from formic acid, acetic acid, trifluoroacetic acid, or the like. The molar ratio of alkanoic acid w.r.t fluorinated benzonitrile is used in the range from 2-5.
In an embodiment, alkanoic acid is added continuously in the de-chlorination reaction. The alkanoic acid in de-chlorination reaction is added in 2-5 hours. In another embodiment, de-chlorination of 3,5-dichloro-2,4,6-trifluorobenzonitrile is carried out using a transition metal catalyst in presence of alkanoic acid to obtain 2,4,6-trifluorobenzonitrile.
The transition metal catalyst is selected from copper, zinc, zinc/copper alloy or the like. The transition metal catalyst for de-chlorination process is used in solid or powder form. The transition metal catalyst contains metal content greater than 99%. The mesh size of metal powder used is less than 100 micron and more preferably between 2-50 and more preferably 2-20 micron.
The de-chlorination is carried out at a temperature range of 70°C to 90°C. The low temperature range prevents the degradation of product and improves yield significantly. The impurities in the de-chlorination are formed by de-chlorination of one chlorine only.
In an embodiment, the de-chlorination step is additionally carried out in presence of an organic solvent selected from a group consisting of hexane, toluene, cyclohexane, ethyl acetate, ethanol, methanol, butanol, propanol, isopropanol, diethyl ether, acetone or a mixture thereof.
In another embodiment, de-chlorination is carried out in absence of organic solvent.
In a specific embodiment, 3,5-dichloro-2,4,6-trifluorobenzonitrile is de-chlorinated using zinc and acetic acid to obtain 2,4,6-trifluorobenzonitrile in presence of water as solvent.
In a specific embodiment, 3,5-dichloro-2,4,6-trifluorobenzonitrile is de-chlorinated using zinc powder of mesh size between 5-10 micron and acetic acid to obtain 2,4,6- trifluorobenzonitrile in presence of water as solvent.
In a specific embodiment, 3,5-dichloro-2,4,6-trifluorobenzonitrile is de-chlorinated using zinc and acetic acid to obtain 2,4,6-trifluorobenzonitrile in absence of an organic solvent.
In another specific embodiment, 3,5-dichloro-2,4,6-trifluorobenzonitrile is de- chlorinated using zinc and acetic acid in a mixture of water and an organic solvent to obtain 2,4,6-trifluorobenzonitrile.
In another embodiment, de-chlorination is carried out using a transition metal catalyst, alkanoic acid and a salt. The salts is selected from phosphate salt such as dipotassium hydrogen phosphate, ammonium dihydrogen phosphate, ammonium hydrogen phosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate, calcium phosphate, potassium dihydrogen phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, acetates salt such as sodium acetate potassium acetate, and ammonium/phosphonium salts such as tetramethylammonium chloride, trioctylmethyl ammonium chloride, tetraphenylphosphonium chloride, tetraphenylphosphonium bromide, tetrabutylammonium chloride, tetrabutylammonium bromide or hydrates thereof.
The major difluorobenzonitrile impurities are identified as 2,6-difluorobenzonitrile, 2,4-difluorobenzonitrile or like.
In another specific embodiment, 3,5-dichloro-2,4,6-trifluorobenzonitrile is de- chlorinated using zinc and acetic acid in presence of potassium dihydrogen phosphate to obtain 2,4,6-trifluorobenzonitrile.
In another specific embodiment, 3,5-dichloro-2,4,6-trifluorobenzonitrile is de- chlorinated using zinc and acetic acid in presence of tetraphenylphosphonium bromide to obtain 2,4,6-trifluorobenzonitrile.
In another specific embodiment, 3,5-dichloro-2,4,6-trifluorobenzonitrile is de- chlorinated using zinc and acetic acid in presence of Tetrabutylammonium chloride to obtain 2,4,6-trifluorobenzonitrile.
The purity of isolated 2,4,6-trifluorobenzonitrile is greater than 90% and preferably greater than 95% and more preferably greater than 99%.
In another embodiment, 2,4,6-trifluorobenzonitrile contains impurities less than 2% and more preferably between 0.1-1%.
The yield of 2,4,6-trifluorobenzonitrile is greater than 80% and preferably greater than 85%.
The present invention involves two de-chlorination steps to form 2,4,6- trifluorobenzonitrile. In a case, where only one chlorine is removed, the intermediate formed i.e., 3-chloro-2,4,6-trifluorobenzonitrile is isolated and recycled to de chlorination step.
As used herein, hydrolysing refers to reacting 2,4,6-trifluorobenzonitrile with an acid to obtain 2,4,6-trifluorobenzoic acid; As used herein, “acid” is selected from sulfuric acid, hydrochloric acid or like.
In an embodiment of present invention, hydrolysis is carried out using aqueous acid. The concentration of aqueous acid may range from 30-80% by mass of acid.
In another embodiment of present invention, an aqueous acid is continuously added to 2,4,6-trifluorobenzonitrile.
In another embodiment, hydrolysis is carried out at a temperature of 80-160°C and preferably at a temperature of 100-150°C. The hydrolysis reaction may take 2-7 hours for completion.
In an embodiment, reaction mixture is filtered to isolate 2,4,6-trifluorobenzoic acid. The present invention is isolating 2,4,6-trifluorobenzoic acid by simple filtration and eliminating multiple workup operations.
In an embodiment of the present invention, 2,4,6-trifluorobenzonitrile is hydrolysed using an acid to obtain a reaction mixture containing 2,4,6-trifluorobenzoic acid, which is filtered to obtain a purity of 90% to 95%, which upon recrystallization using a solvent or mixture of solvents gives 2,4,6-trifluorobenzoic acid of higher purity of 98-99%.
In another embodiment, 2,4,6-trifluorobenzoic acid after filtration is purified by re crystallisation. The re-crystallisation solvent is selected from a group consisting of hexane, toluene, cyclohexane, ethyl acetate, ethanol, methanol, butanol, propanol, isopropanol, diethyl ether, acetone, water or a mixture thereof.
The known method performing hydrolysis prior to de-chlorination. The de chlorination of 3,5-dichloro-2,4,6-trifluorobenzoic acid, after hydrolysis step, produces difluorobenzoic acid impurities. These difluorobenzoic acid impurities are very difficult to separate even after multiple crystallization.
The present invention has carried out de-chlorination prior to hydrolysis to prevent formation of difluorobenzoic acid impurities in hydrolysis step. The de-chlorination of present invention gives difluorobenzonitrile impurities that are easy to separate as compared to difluorobenzoic acid impurities. This is an alternate process for preparation of 2,4,6-trifluorobenzoic acid that prevents formation of difluorobenzoic acid impurities.
In an embodiment of present invention, firstly de-chlorination is carried out, followed by separation of difluorobenzonitrile impurities from the reaction mixture and secondly, hydrolysis is carried out using an acid to form 2,4,6-trifluorobenzoic acid.
The difluorobenzoic acid impurities refers to 2,4-difluorobenzoic acid and 2,6- difluorobenzoic acid, dimers or like and difluorobenzonitrile impurities refers to 2,4- difluorobenzonitrile, 2,6-difluorobenzonitrile, dimers or like.
In an embodiment of present invention, 2,4,6-trifluorobenzoic acid has less than 0.05% of 2,6-difluorobenzoic acid and/or 2,4-difluorobenzoic acid impurities
In another embodiment of present invention, 2,4,6-trifluorobenzoic acid of the present invention have purity greater than 99% with less than 0.05% of 2,6- difluorobenzoic acid and/or 2,4-difluorobenzoic acid impurities.
In a specific embodiment, 2,4,6-trifluorobenzoic acid is prepared from 2,4,6- trifluorobenzonitrile using an aqueous sulfuric acid at 150°C.
In a specific embodiment, 2,4,6-trifluorobenzoic acid is prepared from 2,4,6- trifluorobenzonitrile using an aqueous hydrochloric acid at refluxing.
In a specific embodiment, 2,4,6-trifluorobenzoic acid contains 2,4-difluorobenzoic acid and 2,6-difluorobenzoic acid in the range of 0 to 0.05%. The zero impurity refers to not detectable amount of impurity.
In an embodiment, the selectivity of formation of 2,4,6-trifluorobenzoic acid is greater than 99%.
In an embodiment, the yield of hydrolysis step is greater than 96%.
In a preferred embodiment of present invention, de-chlorination is carried out prior to hydrolysis in the preparation of 2,4,6-trifluorobenzoic acid. In a specific embodiment, present invention provides a process for preparation of 2,4,6-trifluorobenzoic acid, comprising the steps of: a) de-chlorinating 3,5-dichloro-2,4,6-trifluorobenzonitrile using zinc and acetic acid in water to obtain 2,4,6-trifluorobenzonitrile; and b) hydrolysing 2,4,6-trifluorobenzonitrile using aqueous sulfuric acid to obtain 2,4,6- trifluorobenzoic acid.
In a specific embodiment, the present invention provides a process for preparation and purification of 2,4,6-trifluorobenzoic acid, comprising the steps of: a) hydrolysing 2,4,6-trifluorobenzonitrile using an aqueous sulfuric acid to obtain a reaction mixture containing 2,4,6-trifluorobenzoic acid with a purity of 90-95%; b) filtering step a) reaction mixture to obtain 2,4,6-trifluorobenzoic acid having purity 90% - 95%; and c) crystallizing 2,4,6-trifluorobenzoic acid obtained from step b) using a mixture of ethyl acetate and hexane to obtain 2,4,6-trifluorobenzoic acid having purity of 99% to 99.8%.
In another embodiment, 2,4,6-trifluorobenzoic acid is also prepared by the step of de-halogenation of a compound selected from 3,5-dichloro-2,4,6- trifluorobenzonitrile, 3,5-dibromo-2,4,6-trifluorobenzonitrile, 3-bromo-5-chloro- 2,4,6-trifluorobenzonitrile followed by the hydrolysis.
In another embodiment, 3,5-dichloro-2,4,6-trifluorobenzonitrile is obtained by fluorinating 2,3,4,5,6-pentachlorobenzonitrile using potassium fluoride as a fluorinating agent.
A fluorinating agent used in the present invention is selected from a group consisting of alkali metal fluoride such as sodium fluoride, potassium fluoride and cesium fluoride, or ammonium fluoride or the like.
In an embodiment, the present invention provides a process for preparation of 2,4,6- trifluorobenzoic acid from 2,3,4,5,6-pentachlorobenzonitrile. In an embodiment, present invention provides a process for preparation of 2,4,6- trifluorobenzoic acid, comprising the steps of: a) fluorinating 2,3,4,5,6-pentachlorobenzonitrile using an anhydrous potassium fluoride to obtain 3,5-dichloro-2,4,6-trifluorobenzonitrile; a) de-chlorinating 3,5-dichloro-2,4,6-trifluorobenzonitrile using zinc and acetic acid in water to obtain 2,4,6-trifluorobenzonitrile; and b) hydrolysing 2,4,6-trifluorobenzonitrile using an aqueous sulfuric acid to form
2.4.6-trifluorobenzoic acid.
In another embodiment of the present invention, 3,5-dichloro-2,4,6- trifluorobenzonitrile is obtained by fluorinating 2,3,4,5,6-pentachlorobenzonitrile using a fluorinating agent selected from an alkali metal fluoride
In another embodiment, present invention provides a process for preparation of
2.4.6-trifuorobenzoic acid comprising fluorinating 2,3,4,5,6-pentachlorobenzonitrile to form 3,5-dichloro-2,4,6-trifluorobenzonitrile, de-chlorinating 3,5-dichloro-2,4,6- trifluorobenzonitrile to 2,4,6-trifluorobenzonitrile and hydrolysing 2,4,6- trifluorobenzonitrile to form 2,4,6-trifluorobenzoic acid.
In an embodiment, fluorination of 2,3,4,5,6-pentachlorobenzonitrile is carried out using potassium fluoride to form 3,5-dichloro-2,4,6-trifluorobenzonitrile.
In an embodiment, fluorination of 2,3,4,5,6-pentachlorobenzonitrile is carried out using potassium fluoride at a pressure of 2-3kg/cm2 at a temperature of 250°C.
In an embodiment, fluorination of 2,3,4,5,6-pentachlorobenzonitrile is carried out using potassium fluoride at a pressure of 2-3kg/cm2 at a temperature of 250°C under an inert atmosphere. The inert atmosphere is maintained using nitrogen, helium or argon.
The product may be isolated by any method known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, recrystallization, evaporation, column chromatography and filtration or a mixture thereof. The compound of 2,4,6-trifluorobenzoic acid is isolated by any method known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or a mixture thereof.
The completion of the reaction may be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), Gas chromatography (GC), liquid chromatography (LC) and alike.
Unless stated to the contrary, any of the words “comprising”, “comprises” and includes mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims. The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.
EXAMPLES
Example 1: Preparation of 3,5-dichloro-2,4,6-trifluorobenzonitrile 2,3,4,5,6-pentachlorobenzonitrile (200 g), benzonitrile (1200 g) and potassium fluoride (169 g) were added in an autoclave reactor in an inert atmosphere. The reaction mass heated to 250°C. The pressure of the reactor was 2-3kg/cm2 at 250°C during the reaction. The reaction mass analysis was done on gas chromatography. After reaction completed, the reaction mass was cooled to room temperature and filtered. The filtered solid was washed with benzonitrile. The filtrate was fractionally distilled under reduced pressure and product was isolated.
Yield: 90%; Purity: 99%. Example 2: Preparation of 2,4,6-trifluorobenzonitrile
Zinc powder (73 g), water (1000 g) and 3,5-dichloro-2,4,6-trifluorobenzonitrile (100 g) were charged in a reactor. Potassium hydrogen phosphate (2 g) were added in the reactor and reaction mass heated to 80°C under stirring. The acetic acid (80 g) was added slowly to the reaction mass in 2-3 hours at 90-95°C. The reaction mass was monitored on gas chromatography. After reaction, the reaction mass cooled to 35°C and dichloromethane (300 g) was added to the reaction mass. The reaction mass was filtered under vacuum and filtrate was separated into organic and aqueous layer. The organic layer was concentrated on rota evaporator and concentrated mass was distilled to isolate 2,4,6-trifluorobenzonitrile.
Yield: 85%; Purity: 99%.
Example 3: Preparation of 2,4,6-trifluorobenzonitrile
Zinc powder (73 g), a mixture of water and tetrahydrofuran (500 g) and 3,5-dichloro- 2,4,6-trifluorobenzonitrile (100 g) were charged in a reactor. Tetrabutylammonium chloride (2 g) were added in the reactor and reaction mass heated to 80°C under stirring. The acetic acid (80 g) was added slowly to the reaction mass in 2-3 hours at 80°C. The reaction mass was monitored on gas chromatography. After reaction, the reaction mass cooled to 35°C and dichloromethane (300 g) was added to the reaction mass. The reaction mass was filtered under vacuum and filtrate was separated into organic and aqueous layer. The organic layer was concentrated on rota evaporator and concentrated mass was distilled to isolate product.
Yield: 85%; Purity: 99%.
Example 4: Preparation of 2,4,6-trifluorobenzonitrile
Zinc powder (73 g), water (400 g) and 3,5-dichloro-2,4,6-trifluorobenzonitrile (100 g) were charged in a reactor. Tetrabutylammonium chloride (2 g) were added in the reactor and reaction mass heated to 90°C under stirring. The acetic acid (80 g) was added slowly to the reaction mass in 2-3 hours at 90-95°C. The reaction mass was monitored on gas chromatography. After reaction, the reaction mass cooled to 35°C and dichloromethane (300 g) was added to the reaction mass. The reaction mass was filtered under vacuum and filtrate was separated into organic and aqueous layer. The organic layer was concentrated on rota evaporator and concentrated mass was distilled to isolate product.
Yield: 70%; Purity: 99%.
Example 5: Preparation of 2,4,6-trifluorobenzonitrile
Zinc powder (73 g), water (1000 g), toluene (60 g) and 3,5-dichloro-2,4,6- trifluorobenzonitrile (100 g) were charged in a reactor. Tetraphenylphosphonium bromide (2.5 g) were added in the reactor and reaction mass heated to 80°C under stirring. The acetic acid (80 g) was added slowly to the reaction mass in 2-3 hours at 90-95°C. The reaction mass was monitored on gas chromatography. After reaction, the reaction mass cooled to 35°C. The reaction mass was filtered under vacuum and filtrate was separated into organic and aqueous layer. The organic layer was concentrated on rota evaporator and concentrated mass was fractionally distilled to isolate 2,4,6-trifluorobenzonitrile.
Yiled-90% and purity is 99%. Example 6: Preparation of 2,4,6-trifluorobenzoic acid
Aqueous sulfuric acid (500g, 70%) was charged in a reactor and heated to 140°C. 2,4,6-trifluorobenzonitrile (100 g) was added continuously to reactor in 3-4 hours. The reaction mixture stirred for 2 hours and cooled to room temperature. The reaction mixture was filtered and product was isolated. The product was dried under vacuum at 70°C.
Yield: 95%; Purity: 95%. 2,6-difluorobenzoic acid- not detectable (less than 0.05%)
2,4-difluorobenzoic acid- not detectable (less than 0.05%)
Example 7: Preparation of 2,4,6-trifluorobenzoic acid
Aqueous sulfuric acid (500g, 70%) was charged in a reactor and heated to 140°C.
2.4.6-trifluorobenzonitrile (100 g) was added continuously to reactor in 3-4 hours. The reaction mixture stirred for 2 hours and cooled to room temperature. The reaction mixture was filtered and washed with distilled water. The filtered solid was added in a mixture of ethyl acetate and hexane. The crystallisation mixture was stirred for 30 minutes and filtered to isolate product. The product was dried under vacuum at 70°C.
Yield: 95%; Purity: 99%.
2.6-difluorobenzoic acid- not detectable (less than 0.05%)
2,4-difluorobenzoic acid- not detectable (less than 0.05%)
Example 8: Preparation of 2,4,6-trifluorobenzoic acid
2.4.6-trifluorobenzonitrile (lOOg) and water (300g) were charged in a reactor and heated to reflux temperature. Hydrogen chloride (140g, 35%) was added continuously to reactor in 3-4 hours. The reaction mixture stirred for 2 hours and cooled to room temperature. The reaction mixture was filtered and product was isolated. The product was dried under vacuum at 70°C.
Yield: 90%; Purity: 90%.
2.6-difluorobenzoic acid- not detectable (less than 0.05%)
2,4-difluorobenzoic acid- not detectable (less than 0.05%) Comparative Examples
Example A: 3,5-dichloro-2,4,6-trifluorobenzoic acid
3.5-dichloro-2,4,6-trifluorobenzonitrile (lOOg) and water (300g) were charged in a reactor and heated to temperature. Sulfuric acid (140g, 35%) was added continuously to reactor in 3-4 hours. The reaction mixture stirred for 2 hours and cooled to room temperature. The reaction mixture was filtered and product was isolated. The product was dried under vacuum at 70°C.
Example B: Preparation of 2,4,6-trifluorobenzoic acid
Zinc powder (73 g), water (400 g) and 3,5-dichloro-2,4,6-trifluorobenzoic acid (100 g) were charged in a reactor. Tetrabutylammonium chloride (2 g) were added in the reactor and reaction mass heated to 90°C under stirring. The acetic acid (80 g) was added slowly to the reaction mass in 2-3 hours at 90-95°C. The reaction mass was monitored on gas chromatography. After reaction, the reaction mass cooled to 35°C and dichloromethane (300 g) was added to the reaction mass. The reaction mass was filtered under vacuum and filtrate was separated into organic and aqueous layer. The organic layer was concentrated on rota evaporator and concentrated mass was distilled to isolate product. Yield: 12-15%
2.6-difluorobenzoic acid- 8-10%
2.4-difluorobenzoic acid- 8-10%
Example B: Preparation of 2,4,6-trifluorobenzoic acid
3.5-dichloro-2,4,6-trifluorobenzoic acid was hydrogenated using palladium catalyst in presence of sodium carbonate. Yield: 40%
2.6-difluorobenzoic acid- 5-8%
2,4-difluorobenzoic acid- 5-8%

Claims

WE CLAIM
1. A process for preparation of 2,4,6-trifluorobenzoic acid, comprising the steps of: a) de-chlorinating 3,5-dichloro-2,4,6-trifluorobenzonitrile using a transition metal catalyst in presence of an alkanoic acid and water to obtain 2,4,6- trifluorobenzonitrile; and b) hydrolysing 2,4,6-trifluorobenzonitrile using an acid to obtain 2,4,6- trifluorobenzoic acid.
2. The process as claimed in claim 1, wherein 3,5-dichloro-2,4,6- trifluorobenzonitrile is obtained by fluorinating 2,3,4,5,6-pentachlorobenzonitrile using a fluorinating agent selected from an alkali metal fluoride.
3. The process as claimed in claim 2, wherein the alkali metal fluoride is selected from a group consisting of potassium fluoride, sodium fluoride, and cesium fluoride.
4. The process as claimed in claim 1, wherein the alkanoic acid is selected from a group consisting of formic acid, acetic acid and trifluoroacetic acid.
5. The process as claimed in claim 1, wherein the transition metal catalyst is selected from a group consisting of copper, zinc and zinc/copper alloy.
6. The process as claimed in claim 1, wherein the de-chlorination step is carried out at a temperature selected in the range of 70°C to 90°C.
7. The process as claimed in claim 1, wherein the de-chlorination step is additionally carried out in presence of an organic solvent selected from a group consisting of hexane, toluene, cyclohexane, ethyl acetate, ethanol, methanol, butanol, propanol, isopropanol, diethyl ether, acetone or a mixture thereof.
8. The process as claimed in claim 1, wherein the hydrolysis is carried out in presence of an acid selected from a group consisting of sulfuric acid and hydrochloric acid.
9. The process as claimed in claim 1, wherein 2,4,6-trifluorobenzoic acid has less than 0.05% of 2,6-difluorobenzoic acid and/or 2,4-difluorobenzoic acid impurities.
10. The process as claimed in claim 1, wherein the de-chlorination step is additionally carried out in presence of a salt selected from phosphate salt, acetate salt, ammonium salt and phosphonium salts.
11. The process as claimed in claim 10, wherein the salt is selected from dipotassium hydrogen phosphate, ammonium dihydrogen phosphate, ammonium hydrogen phosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate, calcium phosphate, potassium dihydrogen phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium acetate, potassium acetate, tetramethylammonium chloride, trioctylmethylammonium chloride, tetraphenylphosphonium chloride, tetraphenylphosphonium bromide, tetrabutylammonium chloride, tetrabutylammonium bromide or hydrates thereof.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04224535A (en) * 1990-12-26 1992-08-13 Ishihara Sangyo Kaisha Ltd Production of 1,3,5-trifluorobenzene
CN103012111A (en) * 2012-09-12 2013-04-03 衢州学院 Preparation method 2,4,5-trifluorophenylacetic acid
WO2018163210A2 (en) * 2017-03-08 2018-09-13 Srf Limited Process for preparation of halo substituted benzoic acid compound and intermediates thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04224535A (en) * 1990-12-26 1992-08-13 Ishihara Sangyo Kaisha Ltd Production of 1,3,5-trifluorobenzene
CN103012111A (en) * 2012-09-12 2013-04-03 衢州学院 Preparation method 2,4,5-trifluorophenylacetic acid
WO2018163210A2 (en) * 2017-03-08 2018-09-13 Srf Limited Process for preparation of halo substituted benzoic acid compound and intermediates thereof

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