The present invention provides an improved one pot process for preparation of 2,4,5-trifluorophenylacetic acid and the intermediates thereof.
BACKGROUND OF THE INVENTION
2,4,5-trifluorophenylacetic acid is an important intermediate for preparation of sitagliptin, a drug for treating type II diabetes.
United States Patent No. 6,870,067 provides a process for preparation of 2,4,5-trifluorophenylacetic acid by reacting 2,4,5-trifluorobromobenzene with a Grignard reagent such as isopropylmagnesium chloride and an allylating agent followed by the oxidation of resultant intermediate in presence of periodate and a metal catalyst such as ruthenium. Grignard reagents are very unstable and sensitive therefore mandates an inert atmosphere therefore not a viable commercial option. The process also involves use of expensive metal catalysts that increases the cost of production during commercial scale ups.
Chinese Application No. 111187154 provides a process for preparation of 2,4,5-trifluorophenylacetic acid involving hydrolysis of cyano-substituted derivatives using either sulfuric acid or hydrobromic acid at 100-220°C The process involves different solvents and number of operations to isolate the product. Also, the hydrolysis followed by decarboxylation is carried out at high temperature that can cause run off during larger scale production due to fast release of carbon dioxide.
The process of hydrolysis generates very high amount of acid effluent containing ammonium salt and also results in the formation of toxic ethyl bromide. The treatment and disposal of these toxic effluent is a cost intensive process.

The present invention aims to overcome the above challenges posed by the known process for preparation of 2,4,5-trifluorophenylacetic acid by providing a safer one pot commercial alternative that avoids formation of ethyl bromide and allows controlled release of carbon dioxide.
Additionally, the present process requires less quantity and number of solvents, ensure safer operations, complete recovery of costly reagents and solvents, improved yields and involves low amount of effluent load, therefore offers a cost-effective alternative for preparation of 2,4,5-trifluorophenylacetic acid.
OBJECT OF THE INVENTION
The present process provides a one pot synthesis of 2,4,5-trifluorophenylacetic acid with minimum number of solvents, safer operations, improved yield, and low effluent load.
SUMMARY OF THE INVENTION
The present invention provides a preparation of 2,4,5-trifluorophenylacetic acid, comprising the steps of:
a) condensing 2,3,5,6-tetrafluorobenzonitrile with a nucleophile agent of formula I, in a solvent in presence of a base to obtain a compound of formula II,

RI .R2

Formula I

Formula II

wherein R1 and R2 independently represent CN, COOR and R represents an alkyl group,
b) converting the compound of formula II to a compound of formula IE, and
COOH

■ - COOH
Formula HI
c) decarboxylating the compound of formula HI to obtain 2,4,5-
trifluorophenylacetic acid.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, "nucleophilic agent of formula I" may be selected from a group comprising diethylmalonate, ethylmethylmalonate and dimethylmalonate, methylcyanoacetate, ethylcyanoacetate, propanedinitrile or like.
As used herein, "alkyl group" may be selected from a group consisting of methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl or the like.
As used herein, "base" may be selected from a group comprising alkali carbonates, alkali hydrogen carbonates, alkali hydroxide, alkali alkoxides, metal hydrides, alkali metals, alkyl lithium, metal bis(trimethylsilyl)amides or the like.
The examples of alkali hydroxide include sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide or like. The examples of alkali carbonate include sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate or like. The examples of alkali hydrogen carbonate include sodium hydrogen carbonate, potassium hydrogen carbonate, cesium hydrogen carbonate, and magnesium hydrogen carbonate.

The examples of alkali alkoxides include sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium tert-amyloxide, potassium methoxide, potassium ethoxide, and potassium tert-butoxide, potassium tert-amyloxide or the like.
The examples of metal hydrides include sodium hydride, potassium hydride and
calcium hydride or the like. The examples of alkali metals include lithium, sodium, and
potassium. The examples of alkyl lithium include butyl lithium, diisopropyllithium or
the like. The examples of metal bis(trimethylsilyl)amides include lithium
bis(trimethylsilyl)amides, sodium bis(trimethylsilyl)amides, potassium
bis(trimethylsilyl)amides or the like.
In an embodiment of the present invention, the step of condensation is carried out in an appropriate solvent having polarity index less than 5, more preferably having polarity index in the range of 5 to 2.
In another embodiment of the present invention, the step of condensation is carried in a solvent having polarity index less than 5 and selected from a group consisting of ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate, methyl formate, ethyl formate, toluene, xylene, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane, methyl isobutyl ketone, ethyl methyl ketone, methyl tertiary butyl ether or the mixture thereof.
In another embodiment of the present invention, the molar ratio of nucleophilic agent of formula I with respect to 2,3,5,6-tetrafluorobenzonitrile is in the range of 0.95-2.5 preferably in the range of 1.0 to 1.6, most preferably 1.0 to 1.1.
In another embodiment of the present invention, the molar ratio of base with respect to 2,3,5,6-tetrafluorobenzonitrile is in the range of 0.5-3.0 preferably in the range of 1.0 to 2.0, most preferably 1.0 to 1.5.
In another embodiment, the step of condensation is carried out at a temperature of 50-120°C.

In another embodiment of the present invention, the reaction mixture obtained after condensation is acidified to a pH of 2-7 through aqueous or non-aqueous way. The reaction mixture is acidified using an aqueous solution of an acid or passing dry acid through it.
In another embodiment of the present invention, the reaction mixture obtained after condensation and subsequent acidification is made free of fluoride content either by filtration or by washing with appropriate aqueous media preferably brine solution containing 0.5 to 10% of a salt of calcium such as calcium chloride, calcium acetate, calcium carbonate, calcium bicarbonate, calcium sulphate, calcium bisulphate, calcium oxalate, calcium bromide, calcium iodide or hydrate forms thereof and the like.
In another embodiment, the step of condensation is carried out in the presence or absence of a catalyst. The preferred catalyst is selected from a group consisting of phase transfer catalyst like tetraethylammonium chloride, benzyltriethylammonium chloride, tetrabutylammonium bromide and transition metal catalyst like palladium acetate and {[P(t-Bu)3]PdBr}2.
The compound of formula II may be isolated in a purity of 95% to 99.5% in a quantitative yield.
In another embodiment of the present invention, the compound of formula II is used in-situ for one pot preparation of 2,4,5-trifluorophenylacetic acid.
In another embodiment of the present invention, the step of converting a compound of formula II to a compound of formula III, is carried out using an acid selected from a group consisting of sulfuric acid, hydrochloric acid, hydrobromic acid, acetic acid, trifluoroacetic acid or mixture thereof. The acid may be used as an aqueous solution or pure form.
In another embodiment of the present invention, the step of converting a compound of formula II to a compound of formula III is carried out at a temperature of 80-180°C.

In another embodiment, the step of converting a compound of formula II to a compound of formula III is performed under sequential heating by developing heating ramp and carried in multiple stages to control the rate of carbon dioxide evolution to make the process safer. A heating ramp is developed by sequentially increasing the temperature by 5-10°C in a controlled manner.
In another embodiment, the step of converting a compound of formula II to a compound of formula III involves decarboxylation followed by hydrolysis wherein, the decarboxylation is performed using sulfuric acid in the absence of hydrobromic acid to avoid formation of ethyl bromide.
In another embodiment, the step of converting a compound of formula II to a compound of formula III involves decarboxylation followed by hydrolysis wherein, the decarboxylation is performed using sulfuric acid only.
In another embodiment, the strength of sulfuric acid for decarboxylation step is 30 to 80%.
In another embodiment, the step of converting a compound of formula II to a compound of formula III involves sequential addition of sulfuric acid and hydrobromic acid.
In another embodiment, the step of converting the compound of formula II to the compound of formula III comprises the steps of:
a) addition of sulfuric acid to a compound of formula II to obtain a reaction mixture 1;
b) removing ethanol from the reaction mixture 1 to obtain a reaction mixture 2;
c) adding hydrobromic acid to reaction mixture 2 to give the compound of formula III.
In another embodiment, the step of converting a compound of formula II to a compound of formula III, involves removal of any alcohol formed in the step of decarboxylation, prior to the addition of hydrobromic acid.

In another embodiment, the step of hydrolysis involves use of hydrobromic acid in 5 to 25 mole equivalents, more preferably 10-15 mole equivalent with respect to compound of formula II.
In another embodiment, after completing the formation of compound of formula III, the total amount of hydrobromic acid is recovered before moving to next step.
In an embodiment the compound of formula III obtained by cooling the reaction mass to 10°C-15°C followed by filtration is washed with water. The water content of compound of formula III is decreased to below 1% by adding an organic solvent followed by azeotropic distillation. The solvent used is selected from high boiling solvents such as N-methylpyrolidone, dimethyl sulfoxide, N,N-dimethyl-formamide, N,N-dimethyl-acetamide and Pyridine, l,3-Dimethyl-2-imidazolidinone, sulpholane, and like or mixture thereof.
The reaction mixture having compound of formula III is decarboxylated using a decarboxylation catalyst to obtain 2,4,5-trifluorophenylacetic acid.
In another embodiment, the present invention provides a process of decarboxylating the compound of formula III to 2,4,5-trifluorophenylacetic acid in presence of a decarboxylation catalyst selected from a group consisting of oxide, carbonates, hydroxides, acetates, halides of noble metals.
Optionally, the step of decarboxylation is carried out in presence of hydroxide, carbonate, bicarbonate, sulphates of alkali metals, alkaline earth metals and ammonia and oxides of alkaline earth metals.
The catalyst used for decarboxylation is transition metal oxides such as copper oxide and silver oxides which is isolated after reaction to avoid their discharge in the aqueous stream as well as to avoid the presence of these metal in the 2,4,5-trifluorophenylacetic acid.

In another embodiment of the present invention, the step of decarboxylation of formula III is carried out at a temperature of 100°C -200°C.
In another embodiment of the present invention, the step of decarboxylation of formula III is carried out using noble metal oxide, in the absence of any ligands such as quinoline, phenanthroline or like.
In another embodiment of the present invention, the step of decarboxylation is carried out in a polar aprotic solvent preferably N-methyl-2-pyrrolidone (NMP) and 1,3-Dimethyl-2-imidazolidinone, dimethylformamide (DMF), dimethylsulfoxide (DMSO), sulpholane, dimethylacetamide or like or mixture thereof.
In another embodiment of the present invention, the noble metal is isolated in the form of hydroxide or oxide by basification of reaction mixture after the reaction.
The reaction solvent is recovered by the extraction of basified reaction mass using an appropriate solvent selected from dichloromethane, chloroform, alky ester (ethyl acetate, isopropyl acetate, tetrahydrofuran (THF), methyl THF, toluene or mixture thereof, to recover the costly polar aprotic solvent such as NMP from the process stream.
The aqueous phase after extraction is acidified to isolate the pure product 2,4,5-trifluorophenylacetic acid using an appropriate acid selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, trifluoroacetic acid or the like. The addition of acid can be done from 10-100°C, more preferably 50-70°C.
The isolation of 2,4,5-trifluorophenylacetic acid may be carried out by any method selected from evaporation, distillation, extraction, filtration, crystallization or like.
2,4,5-trifluorophenylacetic acid of present invention is isolated in a purity of 95% to 99.8% and yield of 95% to 98%.

In another embodiment of the present invention, the step of condensation, hydrolysis and decarboxylation are carried out in a single step, without isolation of the compounds of formula II and formula III.
In another embodiment, present invention provides a process for preparation of 2,4,5-trifluorophenylacetic acid, comprising:
a) reacting 2,3,5,6-tetrafluorobenzonitrile and ethylcyano acetate in presence of a base to obtain ethyl cyano-(2-cyano-3,4,6-trifluorophenyl)acetate;
b) converting ethyl cyano-(2-cyano-3,4,6-trifluorophenyl)acetate to 2-(carboxymethyl)-3,5,6-trifluorobenzoic acid, by sequential addition of sulfuric acid followed by hydrobromic acid and wherein, the conversion is performed under controlled heating conditions;
c) decarboxylating 2-(carboxymethyl)-3,5,6-trifluorobenzoic acid using copper oxide in absence of any ligands to obtain 2,4,5-trifluorophenylacetic acid.
The step of converting ethyl cyano-(2-cyano-3,4,6-trifluorophenyl)acetate to 2-(carboxymethyl)-3,5,6-trifluorobenzoic acid, further involves removal of ethanol, prior to the addition of hydrobromic acid.
In another embodiment, present invention provides a process for preparation of 2,4,5-trifluorophenylacetic acid, comprising:
a) reacting 2,3,5,6-tetrafluorobenzonitrile and diethyl malonate in presence of a base to obtain diethyl (2-cyano-3,4,6-trifluorophenyl)propanedioate;
b) converting diethyl (2-cyano-3,4,6-trifluorophenyl)propanedioate to 2-(carboxymethyl)-3,5,6-trifluorobenzoic acid, by sequential addition of sulfuric acid followed by hydrobromic acid and wherein, the conversion is performed under controlled heating conditions;
c) decarboxylating 2-(carboxymethyl)-3,5,6-trifluorobenzoic acid using copper oxide in absence of any ligands catalyst to obtain 2,4,5-trifluorophenylacetic acid.

The step of converting diethyl (2-cyano-3,4,6-trifluorophenyl)propanedioate to 2-(carboxymethyl)-3,5,6-trifluorobenzoic acid, further involves removal of ethanol, prior to the addition of hydrobromic acid.
In another embodiment, after decarboxylation, reaction mass is directly distilled to remove solvent, followed by pH adjustment, carbon treatment, filtration, single extraction and washing with water immiscible organic solvent such as dichloromethane, chloroform, alky ester (ethyl acetate, isopropyl acetate, methyl THF, toluene or mixture thereof, followed by distillation.
In another embodiment, the invention provides a process for preparing 2,4,5-trifluorophenylacetic to make sitagliptin using a compound of formula I. The obtained 2,4,5-trifluorophenylacetic can be converted into sitagliptin by the processes known in the art or as disclosed in EP3424927A1, WO2015162506A1 or the references cited therein.
Unless stated to the contrary, any of the words "comprising", "comprises" 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 completion of the reaction can 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) and alike.

The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.
EXAMPLES
Example 1: Preparation of 2,4,5-trifluorophenyl acetic acid using 2,3,5,6-tetrafluorobenzonitrile and ethylcyano acetate in ethyl acetate solvent and aqueous work-up (in step-1).
A mixture of 2,3,5,6-tetrafluorobenzonitrile (lOOg) in ethyl acetate (200g) was added to a mixture of ethyl acetate (400g), ethylcyano acetate (65g) and potassium carbonate (120g) at a temperature of 75°C and maintained at the same temperature for 10-15 hours. The progress of the reaction was monitored by GC, after completion of the reaction, water (570g) was added to the reaction mixture and was acidified using aqueous hydrochloric acid. The layers were separated to get organic phase and aqueous phase. The organic phase was further washed twice with brine solution, ethyl acetate was recovered from organic phase and an aqueous sulfuric acid was added to the oily product and heated to a temperature of 100°C for an hour, then at 110°C for another hour and then to 120°C till carbon dioxide evolution stopped and parallelly collected ethanol/water distillate. Aqueous 48% HBr (900g) was dropwise added to the reaction mixture at a temperature of 120°C, finally temperature was raised to 125°C and maintained at this temperature for 15-20 hours. The progress of the reaction was monitored through HPLC. After completion of the reaction, HBr (900g) was recovered by distillation. Water (150g) was added and the reaction mixture was cooled to 10-15°C and neutralized using aqueous sodium hydroxide solution. The product was extracted using ethyl acetate at 10-15°C.
After partial recovery of ethyl acetate from organic phase, NMP (150g) was added. After complete recovery of ethyl acetate, copper oxide (4.0 gm) was added, and mixture was heated to a temperature of 150-165°C for 6-8 hours. The reaction progress was monitored by HPLC. After completion of the reaction, aqueous potassium carbonate

solution was added at a temperature of 70°C. The reaction mass was filtered at room temperature. The filtrate was extracted thrice with dichloromethane. The aqueous layer was acidified with an aqueous hydrochloric acid solution to get precipitates. The precipitated product was filtered, washed with water and dried to get 2,4,5-trifluorophenylacetic acid.
Yield: 97.7%; Purity: 99.6%.
Example 2: Preparation of 2,4,5-trifluorophenyl acetic acid using 2,3,5,6-tetrafluorobenzonitrile and ethylcyano acetate in ethyl acetate solvent and non¬aqueous work-up using dry Hydrochloric acid (in step-1).
A mixture of 2,3,5,6-tetrafluorobenzonitrile (lOOg) in ethyl acetate (200g) was added to a mixture of ethyl acetate (400g), ethylcyano acetate (65g) and potassium carbonate (120g) at a temperature of 75°C and maintained at the same temperature for 10-15 hours. The progress of the reaction was monitored by GC, after completion of the reaction, dry hydrochloric acid gas was purged into reaction mixture to acidify it and the mixture was filtered to separate the salts and the filtrate. The filtrate was treated with CaCb and filtered, ethyl acetate was completely recovered from filtrate and an aqueous sulfuric acid was added to the oily product and heated the mixture to a temperature of 100°C for an hour, then at 110°C for another hour and then to 120°C till carbon dioxide evolution stopped and parallelly collected ethanol/water distillate. Aqueous HBr (48%; 900g) was dropwise added at 120°C temperature, finally temperature was raised to 125°C and maintained at this temperature for 15-20 hours. The progress of the reaction was monitored through HPLC. After completion of the reaction, HBr (900g) was recovered by distillation. Water (150g) was added to the reaction mixture, cooled to 10-15°C and neutralized using aqueous sodium hydroxide solution. The product was extracted using ethyl acetate at 10-15°C.
After partial recovery of ethyl acetate from organic phase, NMP (150g) was added. After complete recovery of ethyl acetate, copper oxide (4.0 gm) was added, and mixture

was heated to a temperature of 150-165°C for 6-8 hours. The reaction progress was monitored by HPLC. After completion of the reaction an aqueous potassium carbonate solution was added to it then reaction mass was filtered at room temperature. The filtrate was extracted thrice with dichloromethane. The aqueous layer was acidified with aqueous hydrochloric acid solution to get precipitates. The precipitated product was filtered, washed with water and dried to get 2,4,5-trifluorophenylacetic acid.
Yield: 97.7%; Purity: 99.6%.
Example 3: Preparation of 2,4,5-trifluorophenyl acetic acid using 2,3,5,6-tetrafluorobenzonitrile and ethylcyano acetate in 2-methyl tetrahydrofuran (Me-THF) solvent (in step-1).
A mixture of 2,3,5,6-tetrafluorobenzonitrile (lOOg) in Me-THF (lOOg) was added to a mixture of Me-THF (500g), Ethylcyano acetate (65g) and potassium carbonate (126g) at 80°C and maintained at the same temperature for 20 hours. The progress of the reaction was monitored by GC. After completion of the reaction, water (570g) was added to the reaction mixture and was acidified using aqueous hydrochloric acid. The layers were separated to get organic phase and aqueous waste. The organic phase was further washed twice with brine solution, methyl THF was recovered from organic phase and an aqueous sulfuric acid (180g) was added to the oily product and heated the mixture to a temperature of 100°C for an hour, then at 110°C for another hour and then at 120°C till carbon dioxide evolution stopped and parallelly collected ethanol/water distillate. An aqueous HBr (900g) was dropwise added at a temperature of 120°C, finally the temperature was raised to 125°C and maintained at this temperature for 15-20 hours. The progress of the reaction was monitored through HPLC. After completion of the reaction, HBr (900g) was recovered by distillation. Water (170g) was added to the reaction mixture and the mixture was cooled to 10-15°C and neutralized using aqueous sodium hydroxide solution. The product was extracted using methyl THF at 25°C.

After partial recovery of methyl THF from organic phase, NMP (150g) was added. After complete recovery of Me-THF, copper oxide (4.0 gm), was added and mixture was heated to a temperature of 155-165°C for 6-8 hours. The reaction progress was monitored by HPLC. After completion of the reaction aqueous potassium carbonate solution was added at a temperature of 70°C then reaction mass was filtered at room temperature. The filtrate was extracted thrice with dichloromethane. The aqueous layer was acidified with aqueous hydrochloric acid solution to get precipitates. The precipitated product was filtered, washed with water, and dried to get 2,4,5-trifluorophenylacetic acid.
Yield: 96.8%; Purity: 99.6%.
Example 4: Preparation of 2,4,5-trifluorophenyl acetic acid using 2,3,5,6-tetrafluorobenzonitrile and ethylcyano acetate in toluene solvent (in step-1).
A mixture of 2,3,5,6-tetrafluorobenzonitrile (100g) in toluene (100g) was added to a mixture of toluene (500g), Ethylcyano acetate (65g) and potassium carbonate (142g) at 100°C. The reaction mixture was stirred at the same temperature for 30 hours. The progress of the reaction was monitored on GC. After completion of the reaction, water (53Og) was added to the reaction mixture and was acidified using aqueous hydrochloric acid. The layers were separated to get organic phase and aqueous waste. The organic phase was further washed twice with brine solution. Toluene was recovered from organic phase and aqueous sulfuric acid (180g) was added to the oily product and heated the mixture to a temperature of 100°C for an hour, then at 110°C for another hour and then at 120°C till carbon dioxide evolution stopped and parallelly collected ethanol/water distillate. An aqueous HBr (900g) was dropwise added at a temperature of 120°C. The temperature was finally raised to 125°C and maintained at this temperature for 15-20 hours. The progress of the reaction was monitored through HPLC. After completion of the reaction, HBr (900g) was recovered by distillation. Water (150g) was added to the reaction mixture. The reaction mixture was cooled to

10-15°C and neutralized using aqueous sodium hydroxide solution. The product was extracted using ethyl acetate at 10-15°C.
After partial recovery of ethyl acetate from organic phase, NMP (150g) was added. After complete recovery of ethyl acetate, copper oxide (3.75 gm) was added, and mixture was heated to a temperature of 155° to 165°C for 6-8 hours. The reaction progress was monitored by HPLC. After completion of the reaction aqueous potassium carbonate solution was added at a temperature of 70°C then reaction mass was filtered at room temperature. The filtrate was extracted thrice with dichloromethane. The aqueous layer was acidified with aqueous hydrochloric acid solution to get precipitates. The precipitated product was filtered, washed with water and dried to 2,4,5-trifluorophenylacetic acid.
Purity: 99.5%. Yield: 94.9%
Example 5: Preparation of 2,4,5-trifluorophenyl acetic acid using 2,3,5,6-tetrafluorobenzonitrile and diethyl malonate in ethyl acetate solvent (in step-1).
A mixture of 2,3,5,6-tetrafluorobenzonitrile (lOOg) in ethyl acetate (200g) was added to a mixture of ethyl acetate (400g), diethyl malonate (100.6g) and potassium carbonate (158g) at a temperature of 78°C and then maintained at the same temperature for 24 hours. The progress of the reaction was monitored through GC. After completion of the reaction, water (570g) was added to the reaction mixture and was acidified using aqueous Hydrochloric acid. The layers were separated to get organic phase and aqueous waste. The organic phase was further washed twice with brine solution, ethyl acetate was recovered from organic phase and 40% aqueous sulfuric acid (170g) was added to the oily product and heated the mixture to a temperature of 100°C for an hour, then at 110°C for another hour and then to 120°C till carbon dioxide evolution stopped and parallelly collected ethanol/water distillate. Aqueous HBr (48%; 900g) was dropwise added at a temperature of 120°C. The temperature was finally raised to 125°C and maintained at this temperature for 15-20 hours. The progress of the reaction was

monitored through HPLC. After completion of the reaction, HBr (900g) was recovered by distillation. Water (150g) was added to the reaction mixture. The reaction was cooled to 10-15°C and neutralized using aqueous sodium hydroxide solution. The product was extracted using ethyl acetate at 10-15 °C.
After partial recovery of ethyl acetate from organic phase, NMP (150g) was added. After recovery of ethyl acetate, copper oxide (4.0 gm) was added, and mixture was heated to a temperature of 150-165°C for 6-8 hours. The reaction progress was monitored by HPLC. After completion of the reaction added aqueous potassium carbonate solution then reaction mass was filtered at room temperature. The filtrate was extracted thrice with dichloromethane. The aqueous layer was acidified with aqueous hydrochloric acid solution to get precipitates. The precipitated product was filtered, washed with water and dried to get 2,4,5-trifluorophenylacetic acid. Purity: 99.6%; Yield: 94%.
Example 6: Preparation of 2,4,5-trifluorophenyl acetic acid using 2,3,5,6-tetrafluorobenzonitrile and ethylcyano acetate
A mixture of 2,3,5,6-tetrafluorobenzonitrile (100g) in ethyl acetate (200g) was added to a mixture of ethyl acetate (400g), Ethylcyano acetate (65g) and potassium carbonate (120g) at a temperature of 75-78°C and the reaction mass was maintained at the same temperature for 10-15 hours. The progress of the reaction was monitored by GC. After completion of the reaction, water (570g) was added to the reaction mixture and was acidified using aqueous hydrochloric acid. The layers were separated to get organic phase and aqueous phase. The organic phase was further treated with brine and ethyl acetate was recovered from organic phase and aqueous sulfuric acid (180g) was added to the oily product and was heated to a temperature of 100°C for an hour, then at 110°C for another hour and then to 120°C till carbon dioxide evolution was stopped and ethanol/water distillate was parallelly collected, aqueous HBr (48%, 900g) was dropwise added to the reaction mixture at a temperature of 120°C, finally temperature

was raised to 125°C and maintained at this temperature for 15-20 hours. The progress of the reaction was monitored through HPLC. After completion of the reaction, HBr (900g) was recovered by distillation. Water (150g) was added and the reaction mixture was cooled to 10-15°C and filtered. Wet cake was neutralized using aqueous sodium hydroxide solution and was further filtered to get desired wet cake. The obtained mother liquor was recycled in consecutive batches.
After filtration of wet cake, NMP (150g) was added. After recovery, copper oxide (4.0 gm) was added, and mixture was heated to a temperature of 150-165°C for 6-8 hours. The reaction progress was monitored by HPLC. After completion of the reaction, excess NMP (80-90%) was distilled and the pH was made basic using, aqueous potassium carbonate solution. The reaction mass was filtered. The filtrate was extracted once with dichloromethane. The aqueous layer was acidified with aqueous hydrochloric acid solution to get precipitates. The precipitated product was filtered further purified and dried to get 2,4,5-trifluorophenylacetic acid.
Yield: 97.7%; Purity: 99.6%.
Example 7: Preparation of 2,4,5-trifluorophenyl acetic acid using 2,3,5,6-tetrafluorobenzonitrile and ethylcyano acetate
A mixture of 2,3,5,6-tetrafluorobenzonitrile (100g) in ethyl acetate (200g) was added to a mixture of ethyl acetate (400g), Ethylcyano acetate (65g) and potassium carbonate (120g) at a temperature of 75-78°C and was maintained at the same temperature for 10-15 hours. The progress of the reaction was monitored by GC, after completion of the reaction, water (570g) was added to the reaction mixture and was acidified using aqueous hydrochloric acid. The layers were separated to get the organic phase and aqueous phase. The organic phase was further treated with brine having calcium salt and ethyl acetate was recovered from the organic phase and aqueous sulfuric acid (1400g) was added to the oily product and heated to a temperature of 100°C for an hour, then at 110°C for another hour and then to 140°C and parallelly collected

ethanol/water distillate and maintained at this temperature for 15-20 hours. The progress of the reaction was monitored through HPLC. After completion of the reaction, the reaction mixture was cooled to 10-15 °C and filtered. Wet cake was neutralized using aqueous sodium hydroxide solution and was further filtered to get desired wet cake and mother liquor. The mother liquor was recycled in consecutive batches.
After filtration of wet cake, NMP was added. After complete recovery, copper oxide (4.0 gm) was added, and the mixture was heated to a temperature of 150-165°C for 6-8 hours. The reaction progress was monitored by HPLC. After completion of the reaction, pH was adjusted to alkaline using, aqueous potassium carbonate. The reaction mass was filtered at room temperature. The filtrate was extracted once with dichloromethane (300g). The aqueous layer was acidified with aqueous hydrochloric acid solution (10%) to get precipitates. The precipitated product was filtered. Crude product was washed with dichloromethane, filtered and dried to get 2,4,5-trifulorophenylacetic acid.
Yield: 94.7%; Purity: 99.0%.
Comparative Example 1:
Preparation of ethyl cyano(2-cyano-3,4,6-trifluorophenyl)acetate using 2,3,5,6-tetrafluorobenzonitrile and ethylcyano acetate in acetonitrile solvent:
A mixture of ethyl cyanoacetate (31.0 g) and acetonitrile (750 mL) was added dropwise in 2 hours to a refluxed mixture of 2,3,5,6-tetrafluorobenzonitrile (40.0 g), potassium carbonate (63.15 g) and acetonitrile (600 mL). The progress of the reaction was monitored through HPLC. After completion of the reaction, the reaction mixture was cooled to a temperature of about 20 to 25°C. The reaction mixture was filtered, and the cake was rinsed with acetonitrile (100 mL). The filtrate was distilled under reduced pressure at 40-45°C. Dichloromethane (200 mL) was added to the residue, and the

slurry was beaten at 20-25 °C for 4 hours. After filtering, the filter cake was rinsed with dichloromethane (100 mL) and dried to obtain solid with HPLC purity of 90%.
Comparative Example-2 (with DMF)
Preparation of ethyl cyano(2-cyano-3,4,6-trifluorophenyl)acetate using 2,3,5,6-tetrafluorobenzonitrile and ethylcyano acetate in DMF solvent:
A mixture of 2,3,5,6-tetrafluorobenzonitrile (lOOg) in DMF (lOOg) at 80-85°C was added to a mixture of DMF (400g), potassium carbonate (111.3g), and ethylcyano acetate (120. lg). After the addition, the temperature was raised to 120°C and stirred for 12 hours at the same temperature. The progress of reaction was monitored through HPLC. After completion of the reaction, the reaction mixture was cooled to below 50°C and filtered, the filter cake was washed with DMF, the washing liquid was combined into the filtrate. The combined filtrate was acidified with sulfuric acid (40%) to adjust pH to 5, the DMF and excess ethylcyano acetate were recovered under reduced pressure to dryness, and the temperature was lowered. Dichloromethane (300g) was added, and the organic phase was washed twice with water, and after the solvent was recovered from the organic phase to get oil layer containing the product (Yield: 90%).
Comparative Example-3 (decarboxylation and hydrolysis with HBr only)
Preparation of 2-(carboxymethyl)-3,5,6-trifluorobenzoic acid by decarboxylating and hydrolyzing ethyl cyano(2-cyano-3,4,6-trifluorophenyl)acetate with HBr acid only:
Aqueous hydrobromic acid (48%; 232.5.Og) was added to ethyl cyano (2-cyano-3,4,6-trifluorophenyl)acetate (50g). The temperature was raised to 125°C, as the temperature reached from 70-125°C in 30 minutes and further the reaction was maintained at 125°C temperature for 24 hours. During the initial 2-3 hours collected ethylbromide/water distillate. After the reaction was completed, hydrobromic acid (140.0g) was distilled at atmospheric pressure. Isopropanol (200 mL) was added, and the mixture was stirred at

20-30°C for 2 hours. After filtering, the filter cake was rinsed with isopropanol (20 mL), and then dried to obtain solid with HPLC purity of 93.5%.

WE CLAIM:

1. A process for preparation of 2,4,5-trifluorophenylacetic acid, comprising the steps of:
a) condensing 2,3,5,6-tetrafluorobenzonitrile with a nucleophile agent of formula I, in a solvent in presence of a base to obtain a compound of formula II,


RI .R2

CN R

Formula I Formula II
wherein R1 and R2 independently represent CN, COOR and R represents an alkyl group,
b) converting the compound of formula II to a compound of formula III, and
COOH
COOH
F' ^ "F
Formula HI c) decarboxylating the compound of formula HI to obtain 2,4,5-trifluorophenylacetic acid.
2. The process as claimed in claim 1, wherein "nucleophilic agent of formula I" is selected from a group consisting of diethylmalonate, ethylmethylmalonate, dimethylmalonate, methylcyanoacetate, ethylcyanoacetate and propanedinitrile.
3. The process as claimed in claim 1, wherein the steps of condensation, hydrolysis and decarboxylation are carried out in a single step, without isolation of the compounds of formula II and formula III.

4. The process as claimed in claim 1, wherein, the step of condensation is carried in a solvent having polarity index less than 5 and selected from a group consisting of ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate, methyl formate, ethyl formate, toluene, xylene, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane, methyl isobutyl ketone, ethyl methyl ketone, methyl tertiary butyl ether or the mixture thereof.
5. The process as claimed in claim 1, wherein the step of condensation is carried out at a temperature of 50-120°C.
6. The process as claimed in claim 1, wherein the step of converting the compound of formula II to the compound of formula III is carried out using an acid selected from a group consisting of sulfuric acid, hydrochloric acid, hydrobromic acid, acetic acid and trifluoroacetic acid or a mixture thereof.
7. The process as claimed in claim 1, wherein the step of converting the compound of formula II to the compound of formula III comprises the steps of:

a) addition of sulfuric acid to a compound of formula II to obtain a reaction mixture 1;
b) removing ethanol from the reaction mixture 1 to obtain a reaction mixture 2;
c) adding hydrobromic acid to reaction mixture 2 to give the compound of formula III.

8. The process as claimed in claim 1 and 7, wherein the step of converting the compound of formula II to the compound of formula III is carried out at a temperature of 90-140°C.
9. The process as claimed in claim 1 and 7, wherein the step of converting the compound of formula II to the compound of formula III is performed under sequential heating by increasing the temperature by 5-10°C sequentially.

10. The process as claimed in claim 1, wherein the step of decarboxylation is carried out in a polar aprotic solvent selected from a group consisting of N-methylpyrrolidone, l,3-Dimethyl-2-imidazolidinone, N, N-dimethyl formamide, dimethyl sulfoxide, sulpholane, dimethylacetamide or mixture thereof.