FIELD OF THE INVENTION

The present invention provides a 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 the 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 isopropyl magnesium chloride and an alkylating agent followed by 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 and are not viable option at commercial scale. The process also involves use of expensive metal catalysts that increase the cost of production during commercial scaleups.
Chinese Application No. 111187154 provides a process for preparation of 2,4,5-trifluorophenylacetic acid using a cyano-substituted compounds that upon hydrolysis provide 2,4,5-trifluorophenylacetic acid.
Chinese Patent No. 106866406 discloses a process for preparing 2,4,5-trifluorophenylacetic acid by condensing malonic acid derivatives with tetrafluoro terephthalic acid followed by hydrolysis and decarboxylation. Tetrafluoro terephthalic acid used as a starting material is not easily available and so not viable for commercial scale. Beside this the process suffers from lack of selectivity at condensation step that results in the formation of multiple by-products thus requires robust purification steps to obtain pure 2,4,5-trifluorophenylacetic acid.

The present invention provides an economical alternative process for preparation of 2,4,5-trifluorophenyl acetic acid using easily available and cheaper raw material. Additionally, the present process provides 2,4,5-trifluorophenyl acetic acid of high purity without involving excessive purification steps. The present invention involves simple operations and can be easily implemented at industrial scale.
OBJECT OF THE INVENTION
The main object of present invention is to provide an economical and environment friendly process for preparation of 2,4,5-trifluorophenylacetic acid and intermediates thereof.
SUMMARY OF THE INVENTION
In first aspect, the present invention provides a compound of formula I.
COOR R1

Formula-I
wherein, R1 and R2 independently represent H, CN, CONH2, COOH, COOR, wherein both R1 and R2 cannot be H and R represents an alkyl group.
In a second aspect, the present invention provides a process for preparation of 2,4,5-trifluorophenylacetic acid using the compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, "alkyl" may be selected from a group comprising methyl, ethyl, propyl and isopropyl or the like.
A few examples of some of the intermediates of formula I are as provided below:

COOC2H5
COOC2H5
COOCH 3

COOCH.

COOC2H5
COOC2H5

COOC2H5

COOCH3
COOEt
COOMe

COOMe

COOC2H5
F Jk /COOCH 3
COOCH 3

CONH2 COOCH 3
CONH-
COOC2H5

COOC2H5

COOC2H5

COOC2H5
COOC2H5 COOC 2H5

COOC2H5
COOC2H5 COOCH 3

COOMe

As used herein, "nucleophilic agent of formula II" may be selected from a group comprising diethyl malonate, ethylmethyl malonate and dimethylmalonate, methylcyanoacetate, ethylcyanoacetate, propanedinitrile, ethyl acetate, methyl acetate, acetonitrile 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 and metal bis(trimethylsilyl)amides or the like. The examples of alkali hydroxide include sodium hydroxide, potassium hydroxide, cesium hydroxide and magnesium hydroxide or the like. The examples of alkali carbonate include sodium carbonate, potassium carbonate, cesium carbonate and magnesium carbonate or the 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, potassium tert-butoxide and 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 and diisopropyllithium or the like. The examples of metal bis(trimethylsilyl)amides include lithium bis(trimethylsilyl)amides, sodium bis(trimethylsilyl)amides and potassium bis(trimethylsilyl)amides or the like.
As used herein, "acid" used for present invention may be selected from a group consisting of sulphuric acid, hydrochloric acid, hydrobromic acid, acetic acid and trifluoroacetic acid or the like. The acid may be used as an aqueous solution or pure form. The aqueous solutions are preferably more than 40% by weight.
In an embodiment, the present invention provides a process for preparation of a compound of formula I,

COOR R1

Formula-I
wherein, R1 and R2 independently represent H, CN, CONH2, COOH, COOR, wherein both R1 and R2 cannot be H and R represents an alkyl group,
comprising the step of:
a) reacting an alkyl 2,3,5,6-tetrafluorobenzoate and a nucleophilic reagent of formula II in presence of a base to obtain the compound of formula I;
R^R2
Formula-II
wherein, R1 and R2 independently represent H, CN, CONH2, COOH, COOR, wherein
both R1 and R2 cannot be H
In another embodiment, the present invention provides a process for using the process of a compound of formula I for preparation of 2,4,5-trifluorophenylacetic acid, comprising the steps of :
a) reacting an alkyl 2,3,5,6-tetrafluorobenzoate and a nucleophilic reagent of formula II in presence of a base,
R^R2
Formula-II
wherein, R1 and R2 independently represent H, CN, CONH2, COOH, COOR, wherein
both R1 and R2 cannot be H,

to obtain a compound of formula I; and
COOR R1

Formula-I
wherein, R1 and R2 independently represent H, CN, CONH2, COOH, COOR, wherein both R1 and R2 cannot be H and R represents an alkyl group,
b) converting the compound of formula I to 2,4,5-trifluorophenylacetic acid.
In another embodiment, the present invention provides a process for converting a compound of formula I to 2,4,5-trifluorophenylacetic acid, comprising,
a) hydrolysing a compound of formula I with an acid to obtain a reaction mixture; and
b) decarboxylating the reaction mixture using a catalyst to obtain a 2,4,5-
trifluorophenylacetic acid.
In another embodiment, the present invention provides a process for converting a compound of formula I to 2,4,5-trifluorophenylacetic acid, comprising,
a) hydrolysing a compound of formula I with an acid to obtain a reaction mixture; and
b) decarboxylating the reaction mixture using a catalyst to obtain a 2,4,5-
trifluorophenylacetic acid, wherein, the hydrolysis and decarboxylation are carried out
in a single step.
In another embodiment, the step of hydrolysis may include decarboxylation.
In another embodiment, present invention provides a process for preparation of 2,4,5-trifluorophenylacetic acid from alkyl 2,3,5,6-tetrafluorobenzoate.

The molar ratio of nucleophilic reagent of formula II with respect to an alkyl 2,3,5,6-tetrafluorobenzoate is in the range of 0.95-1.05.
In another embodiment, the reaction of alkyl 2,3,5,6-tetrafluorobenzoate with a nucleophilic reagent of formula II is carried out at a temperature of 50-100°C, preferably at a temperature of 60-90°C.
In another embodiment, the reaction of alkyl 2,3,5,6-tetrafluorobenzoate with a
nucleophilic reagent of formula II 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, benzyltriethyl ammonium chloride,
tetrabutylammonium bromide and transition metal catalyst like palladium acetate and {[P(t-Bu)3]PdBr}2
In an embodiment, reaction of alkyl 2,3,5,6-tetrafluorobenzoate with a nucleophilic reagent of formula II is carried out in a polar aprotic solvent selected from a group consisting of acetone, ethylacetate, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), acetonitrile, N-methylpyrrolidone (NMP), tetrahydrofuran, hexamethylphosphoric triamide (HMPT), dichloroethane, N,N-dimethyacetamide, sulfolane, tetrahydrofuran, 1,4-dioxane and l,3-dimethyl-2-imidazolidinone or the like.
The compound of formula I may be isolated or used in-situ for preparation of 2,4,5-trifluorophenylacetic acid.
The compound of formula I, having a purity of 95% to 99.5% may be isolated using solid isolation process involving extraction, crystallization or like.
The yield of the compound of formula I is greater than 80% and preferably greater than 95%.

In an embodiment, a compound of formula I is used in-situ for preparation of 2,4,5-trifluorophenylacetic acid. The isolation of formula I may be avoided to reduce process operation.
In another embodiment, a compound of formula I is isolated and used for preparation of 2,4,5-trifluorophenylacetic acid.
In another embodiment, the step of converting a compound of formula I to 2,4,5-trifluorophenylacetic acid is carried out by firstly hydrolysing the compound of formula I followed by decarboxylation using a decarboxylation catalyst.
The hydrolysis of the compound of formula I with an acid is carried out at a temperature of 100-180°C, preferably at a temperature of 120-140°C.
The hydrolysis of the compound of formula I with an acid may involve simultaneous decarboxylation and is carried out at a temperature of 100-180°C, preferably at a temperature of 120-140°C.
The simultaneous hydrolysis and decarboxylation of the compound of formula I with an acid is carried out at a temperature of 100-180°C, preferably at a temperature of 120-140°C.
The hydrolysis of a compound of formula I is carried out in presence of water to obtain a reaction mixture. The reaction mixture of hydrolysis is directly decarboxylated for preparation of 2,4,5-trifluorophenylacetic acid. The reaction mixture of hydrolysis is directly decarboxylated for preparation of 2,4,5-trifluorophenylacetic acid after recovery of the solvents.
The reaction mixture is decarboxylated using a decarboxylation catalyst to obtain 2,4,5-trifluorophenylacetic acid.

In another embodiment, the present invention provides a process of decarboxylating 2-carboxy-3,4,6-trifluorophenyl acetic acid to 2,4,5-trifluorophenylacetic acid in presence of a decarboxylation catalyst.
The decarboxylation catalyst is selected from a group consisting of hydroxide, carbonate, bicarbonate, sulphates of alkali metals, alkaline earth metals and ammonia and oxides of alkaline earth metals.
The decarboxylation can take place by a method which comprises using simultaneously use of at least one compound selected from the group consisting of sulfates of ammonia, alkali metals, alkaline earth metals, and organic bases and at least one compound selected from the group consisting of hydroxides, carbonates and organic acid salts of alkali metals and alkaline earth metals; oxides of alkaline earth metals.
Optionally the decarboxylation is carried out in presence of an acid selected from sulphuric acid, hydrochloric acid and trifluoroacetic acid or the like along with hydroxide, carbonate, bicarbonate of alkali metal, ammonia and alkaline earth metal and oxide of alkaline earth metals.
The catalyst used for decarboxylation in the present invention is readily available, environment friendly and cheaper compared to transition metal oxides such as copper oxide and silver oxides used in the processes described in literature.
The step of decarboxylation is carried out at a temperature of 100°C-200°C.
The step of decarboxylation is carried out in a polar aprotic solvent preferably N-methyl-pyrrolidone and l,3-dimethyl-2-imidazolidinone or the like.
The 2,4,5-trifluorophenylacetic acid of present invention is isolated in a purity of 95% to 99.8%.
The present invention provides a process for preparing 2,4,5-trifluorophenylacetic acid of purity greater than 99%.

The present invention provides a process for preparation of 2,4,5-trifluorophenylacetic acid having yield of 80% to 95%.
The present invention provides a process for preparation of 2,4,5-trifluorophenylacetic acid from methyl 2,3,5,6-tetrafluorobenzoate.
In another embodiment, present invention provides a process for preparation of 2,4,5-trifluorophenylacetic acid from ethyl 2,3,5,6-tetrafluorobenzoate.
In another embodiment, present invention provides a process for preparation of 2,4,5-trifluorophenylacetic acid, comprising:
a) reacting methyl 2,3,5,6-tetrafluorobenzoate and diethylmalonate in presence of
sodium carbonate to obtain diethyl [3,4,6-trifluoro-2-(methoxycarbonyl)phenyl]
propanedioate;
b) hydrolysing and decarboxylating diethyl [3,4,6-trifluoro-2-
(methoxycarbonyl)phenyl] propanedioate with sulphuric acid to obtain a reaction
mixture; and
c) decarboxylating reaction mixture using calcium hydroxide to obtain 2,4,5-
trifluorophenylacetic acid.
In another embodiment, present invention provides a process for preparation of 2,4,5-trifluorophenylacetic acid, comprising:
a) hydrolysing diethyl [3,4,6-trifluoro-2-(methoxycarbonyl)phenyl] propanedioate with sulphuric acid to obtain a reaction mixture; and
b) decarboxylating reaction mixture using calcium hydroxide to obtain 2,4,5-trifluorophenylacetic acid.
In another embodiment, present invention provides a process for preparation of 2,4,5-trifluorophenylacetic acid, comprising:

a) reacting methyl 2,3,5,6-tetrafluorobenzoate and ethyl cyanoacetate in presence of a base to obtain methyl 2-(l-cyano-2-ethoxy-2-oxoethyl)-3,5,6-trifluorobenzoate;
b) hydrolysing and decarboxylating methyl 2-(l-cyano-2-ethoxy-2-oxoethyl)-3,5,6-trifluorobenzoate with an acid to obtain a reaction mixture; and
c) decarboxylating reaction mixture using calcium hydroxide to obtain 2,4,5-
trifluorophenylacetic acid.
In another embodiment, present invention provides a process for preparation of 2,4,5-trifluorophenylacetic acid, comprising:
a) hydrolysing methyl 2-(l-cyano-2-ethoxy-2-oxoethyl)-3,5,6-trifluorobenzoate with
an acid to obtain a reaction mixture;
b) decarboxylating reaction mixture using calcium hydroxide to obtain 2,4,5-
trifluorophenylacetic acid.
In another embodiment, the present invention provides a process for preparation of 2,4,5-trifluorophenylacetic which is prepared from compound of formula I by the process of present invention and is further converted to sitagliptin by the processes known in the art or as disclosed in EP3424927A1, WO2015162506A1 or the references cited therein.
In an embodiment, the isolation of 2,4,5-trifluorophenylacetic acid and the compound of formula I of the present invention may be carried out by any method selected from evaporation, distillation, extraction, filtration, crystallization or like.
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 methyl 2-(cyanomethyl)-3,5,6-trifluorobenzoate
Anhydrous acetonitrile (1.02 eq.) was added to a solution of n-butyl lithium (2.5 M in hexanes, 1.0 eq.) in dry tetrahydrofuran and the reaction mixture was stirred at -78°C for 45 minutes. A solution of methyl-2,3,5,6-tetrafluoro benzoate (1.0 eq.) in dry tetrahydrofuran was added to the reaction mixture and stirred for additional 2 hours at -78°C and the mixture was allowed to warm at room temperature for over 30 minutes. After completion of the reaction, the reaction mixture was quenched with water and diluted with dichloromethane. The aqueous layer was extracted twice with dichloromethane and the organic filtrate was combined, dried with sodium sulfate and quantified by NMR. The combined filtrate was further concentrated to remove solvent and then the resultant mass was used as such in the next step without any further purification.
Yield: 85%

Example 2: Preparation of methyl 2-(cyanomethyl)-3,5,6-trifluorobenzoate
A solution of lithium hexamethyldisilazide (1M solution in tetrahydrofuran, 0.08 mol) was added dropwise to a solution of methyl-2,3,5,6-tetrafluoro benzoate (10 g, 0.04 mol) and acetonitrile (3.2 g, 0.08 mol) in tetrahydrofuran (100 ml). The reaction mixture was stirred at -78 °C for 2 hours and then the mixture was slowly warmed at room temperature for 2 hours. Thereafter saturated aqueous ammonium chloride (100 ml) and ethyl acetate (150 ml) were added to the reaction mixture. After completion of the reaction, the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The combined filtrate was quantified by NMR and further concentrated to give crude product. Thereafter the crude product used as such in next step without any further purification.
Yield: 87%
Example 3: Preparation of methyl 2-(l-cyano-2-ethoxy-2-oxoethyl)-3,5,6-trifluorobenzoate
Dimethyl formamide (50 ml), ethyl cyanoacetate (5.7 gm) and sodium carbonate (7.63 gm) were added into the round bottle flask and heated to a temperature of 80-85°C. A mixture of methyl-2,3,5,6-tetrafluoro benzoate (10 gm) in dimethyl formamide (10ml) was added dropwise to the reaction mixture in an hour. After complete addition, reaction mixture was stirred at 85°C to achieve >99% conversion of methyl 2,3,5,6-tetrafluorobenzoate. Thereafter the reaction mixture was cooled to 30-35°C and filtered.
The filtered solid was washed with dimethyl formamide (25 ml) and distilled under reduced pressure at 60-80°C to give crude product. The crude product with 10-15% dimethylformamide and then used as such in next step without any further purification.
Yield: 98%

Example 4: Preparation of methyl 2-(l-cyano-2-ethoxy-2-oxoethyl)-3,5,6-trifluorobenzoate
Acetonitrile (100 ml), ethyl cyanoacetate (5.7 gm) and sodium carbonate (7.63 gm) were added into the round bottle flask and heated to a temperature of 80-85°C. A mixture of methyl-2,3,5,6-tetrafluoro benzoate (10 gm) in acetonitrile (10ml) was added dropwise to the reaction mixture in an hour. After complete addition, reaction mixture was stirred at 85°C to achieve >99% conversion of methyl 2,3,5,6-tetrafluorobenzoate. Thereafter the reaction mixture was cooled to 30-35°C and filtered.
The filtered solid was washed with acetonitrile (30 ml) and distilled at 80-110°C to remove maximum acetonitrile. After acetonitrile removal, water was added and mixture was further distilled to ensure complete removal of acetonitrile from crude product. Thereafter crude product was used as such in next step without any further purification
Yield: 95%
Example 5: Preparation of methyl 2-(l-cyano-2-ethoxy-2-oxoethyl)-3,5,6-trifluorobenzoate
Dimethyl formamide (100 ml), ethyl cyanoacetate (11.2 gm) and potassium carbonate (16.0 gm) were added into the round bottle flask and heated to a temperature of 80-85°C. A mixture of methyl-2,3,5,6-tetrafluoro benzoate (20 gm) in dimethyl formamide (20ml) was added dropwise to the reaction mixture in an hour. After complete addition, reaction mixture was stirred at 85°C and monitored the reaction on gas chromatography till the starting material methyl 2,3,5,6-tetrafluorobenzoate appear <0.2%. Thereafter, the reaction mixture was cooled to 30-35°C and filtered. The filtered solid was washed with dimethyl formamide (50 ml) and distilled under reduced pressure at 60-80°C to give residue. The concentrated residue with dimethylformamide (5-10%) and then used as such in next step without any further purification.

Yield: 98.5%
Example 6: Preparation of methyl 2-(l-cyano-2-ethoxy-2-oxoethyl)-3,5,6-trifluorobenzoate
Acetonitrile (60 ml), ethyl cyanoacetate (5.7 gm) and potassium carbonate (8.61 gm) were added into the round bottle flask and heated to a temperature of 80-85°C. A mixture of methyl-2,3,5,6-tetrafluoro benzoate (10 gm) in acetonitrile (10 ml) was added dropwise in the reaction mixture in an hour. After complete addition, reaction mixture was stirred at 85°C for 10 hours and monitored the reaction on gas chromatography till the starting material methyl 2,3,5,6-tetrafluorobenzoate appear <0.5%.
Thereafter the reaction mass was cooled to 30-35°C and filtered. The filtered solid was washed with acetonitrile (45 ml) and distilled at 80-100°C. After acetonitrile removal water is added and mixture was further distilled to ensure complete removal of acetonitrile from crude product.
Yield: 97%
Example 7: Preparation of methyl 2-(l-cyano-2-ethoxy-2-oxoethyl)-3,5,6-trifluorobenzoate
N-methyl-2-pyrrolidone (70 ml), ethyl cyanoacetate (5.7 gm) and potassium carbonate (8.61 gm) were added into the round bottle flask and heated to a temperature of 80-85°C. A mixture of methyl-2,3,5,6-tetrafluoro benzoate (10 gm) in N-methyl-2-pyrrolidone (10ml) was added dropwise in the reaction mixture in an hour. After complete addition, reaction mass was stirred at 85°C and monitored the reaction on gas chromatography till the starting material methyl 2,3,5,6-tetrafluorobenzoate appear <0.5%.

The reaction mass was cooled to 30-35°C and filtered. The filtered solid was washed with dimethyl formamide (25 ml) and distilled under reduced pressure at 60-80°C to give residue.
Yield: 98.0%
Example 8: Preparation of methyl 2-(l-cyano-2-ethoxy-2-oxoethyl)-3,5,6-trifluorobenzoate
Dimethyl acetamide (70 ml), ethyl cyanoacetate (5.7 gm) and potassium carbonate (8.61 gm) were added into the round bottle flask and heated to a temperature of 80-85°C. A mixture of methyl-2,3,5,6-tetrafluoro benzoate (10 gm) in dimethylacetamide (10ml) was added dropwise to the reaction mixture in an hour. After complete addition, reaction mass stirred at 85°C and monitored the reaction on Gas Chromatography till the starting material methyl-2,3,5,6-tetrafluorobenzoate appear <0.5%.
The reaction mass was cooled to 30-35°C and filtered. The filtered solid was washed with dimethyl acetamide (25 ml) and distilled under reduced pressure at 60-80°C to give residue.
Yield: 97%
Example 9: Preparation of methyl 2-(2-ethoxy-2-oxoethyl)-3,5,6-trifluorobenzoate
A solution of sodium bis(trimethylsilyl)amide powder (0.115 mol, 1.2 eq.) in toluene (50 mL) was continuously flushed with dry nitrogen gas to remove moisture. To this sodium amide solution was slowly added ethyl acetate (0.105 mol, 1.1 eq.). The resultant solution was stirred at room temperature for 10 minutes. The solution was added to a mixture of methyl 2,3,5,6-tetrafluorobenzoate (0.096 mol, 1 eq.) and {[P(t-Bu)3]PdBr}2 in another reactor. The reaction mixture was then stirred at room temperature or 60 °C for 4 hours and subsequently diluted with dichloromethane (60 mL). The resulting solution was washed with 0.1 N hydrochloric acid (10 mL), and the

aqueous layer was washed with 2 x 50 mL of dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure.
Yield: 88%
Example 10: Preparation of methyl 2-(dicyanomethyl)-3,5,6-trifluorobenzoate
A solution of anhydrous N-methyl-2-pyrrolidone (20 ml) and sodium hydride (4.8 g, 0.12 mol, 60% oil dispersed) was charged into the round bottle flask, continuously flushed with dry nitrogen gas to remove moisture. Then malononitrile (10.34 g, 0.12 mol) was slowly added into the reaction solution to form an anion solution of malononitrile at a temperature 25-40°C. The resultant anion reaction solution was taken in a pressure equalizing funnel and slowly added to the mixture of methyl 2,3,5,6-tetrafluorobenzoate (0.048 mol) and N-methyl-2-pyrrolidone (40 ml) in an hour at a temperature of 80-90°C. The reaction solution was further stirred and maintained at 110-115°C for 12 hours and progress of reaction was monitored by GC to achieve the conversion >99% of methyl-2,3,5,6-tetrafluorobenzoate. The reaction mixture was cooled and mixed with water (50 ml) and acidified with hydrochloric acid (1 N, 75 ml) to bring the pH of the solution to 2. The mixture was extracted two times with dichloromethane (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuum to get bottom concentrated residue.
Yield: 85%
Example 11: Preparation of methyl 2-(dicyanomethyl)-3,5,6-trifluorobenzoate
Dimethylformamide (60 g), malononitrile (0.053 mol), potassium carbonate (0.096 mol) and benzyltriethyl ammonium chloride (0.005 mol) were added to a round bottle flask and heated to a temperature of 90°C. A mixture of methyl-2,3,5,6-tetrafluorobenzoate (10 gm, 0.048 mol) in dimethyl formamide (10 ml) was added dropwise to the reaction mixture in an hour. The progress of the reaction was monitored

by gas chromatography (GC) till the starting material methyl 2,3,5,6-tetrafluorobenzoate appear <0.5%.
The reaction mass was cooled to 30-35°C and filtered. The filtered solid was washed with dimethyl formamide (30 ml) and distilled under reduced pressure at 60-80°C to give residue.
Yield: 95%
Example 12: Preparation of diethyl [3,4,6-trifluoro-2-
(methoxycarbonyl)phenyl]propanedioate
A solution of anhydrous dimethylformamide (20 ml) and sodium hydride (9.62 g, 0.096 mol, 60% oil dispersed) was added to a round bottle flask. Diethyl malonate (38.49 g, 0.24 mol) was slowly added to the reaction solution at a temperature of 25-40°C to form an anion solution of malonate. The resultant anion solution was taken in a pressure equalizing funnel and slowly added to a mixture of methyl 2,3,5,6-tetrafluorobenzoate (0.096 mol) and dimethylformamide (40 ml) in an hour at a temperature of 80-90°C. The reaction solution was further stirred and maintained at 110-115°C for 10 hours and progress of reaction was monitored by GC to achieve the conversion >99% of methyl-2,3,5,6-tetrafluorobenzoate. The reaction solution was cooled and mixed with water (100 ml) and acidified with hydrochloride (IN, 150 ml) to bring the pH of the solution to 2. The solution was extracted two times with dichloromethane (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuum to get bottom concentrated residue.
Yield: 86%
Example 13: Preparation of diethyl [3,4,6-trifluoro-2-
(methoxycarbonyl)phenyl]propanedioate
A solution of anhydrous dimethylformamide (50 ml) and sodium tert. butoxide (17.31 g, 0.18 mol) was charged into a round bottle flask, continuously flushed with dry

nitrogen gas to remove moisture. Diethyl malonate (28.86 g, 0.18 mol) was slowly added into the reaction solution at a temperature 25-40°C and stirred for 30 minutes to form an anion solution of malonate. The resultant anion solution was taken in a pressure equalizing funnel and then slowly added to the mixture of methyl 2,3,5,6-tetrafluorobenzoate (0.072 mol) and dimethylformamide (40 ml) in an hour at a temperature of 90-95°C. The reaction mixture was further stirred and maintained at 110-115°C for 12 hours and progress of reaction was monitored by GC to achieve the conversion >99% of methyl-2,3,5,6-tetrafluorobenzoate. The reaction mixture was cooled and mixed with water (70 ml) and acidified with hydrochloric acid (1 N, 110 ml) to bring the pH to 2. The mixture was extracted two times with dichloromethane (100 ml), dried over magnesium sulfate, filtered and concentrated to get bottom concentrated residue.
Yield: 87%
Example 14: Preparation of diethyl [3,4,6-trifluoro-2-
(methoxycarbonyl)phenyl]propanedioate
A solution of methyl-2,3,5,6-tetrafluoro benzoate (0.048 mol), diethyl malonate (11.5 g, 0.072 mol), palladium(II)acetate (0.005 mol), l,2-bis(diphenylphosphino)ethane (0.007 mol), tetramethylethylenediamine (0.02 mol), sodium carbonate (0.096 mol) and potassium iodide (0.02 mol) in dimethylformamide (65 ml) was charged into the round bottle flask, continuously flushed with dry nitrogen gas to remove moisture and stirred the reaction solution at 110°C for 15 hours. Reaction conversion was monitored by GC. Thereafter reaction solution was cooled to room temperature and acidified with aqueous hydrochloric (10%) acid solution to pH 2. The acidified mixture was extracted with 200 ml x 2 dichloromethane, layer were separated and the organic phase was taken for complete removal of dichloromethane to leave concentrated residue.
Yield: 93%

Example 15: Preparation of diethyl [3,4,6-trifluoro-2-
(methoxycarbonyl)phenyl]propanedioate
A solution of an anhydrous dimethylformamide (50 ml) and sodium metal (3.32 g, 0.144 mol) was charged into the round bottle flask. Then diethyl malonate (23.09 g, 0.144 mol) was slowly added to the reaction solution at a temperature 25-40°C to form a sodium salt of malonate. The resultant salt was taken in a pressure equalizing funnel and then slowly added to the mixture of methyl 2,3,5,6-tetrafluorobenzoate (0.096 mol) and dimethylformamide (50 ml) in 1 hour at a temperature of 80-90°C. The reaction mixture was further stirred and maintained at 110-115°C for 10 hours and progress of reaction was monitored by GC to achieve the conversion >99% of methyl-2,3,5,6-tetrafluorobenzoate. The reaction mixture was cooled and mixed with water (70 ml) and acidified with concentrated hydrochloric acid to bring the pH to 2. The mixture was extracted two times with dichloromethane (100 ml), dried over magnesium sulfate, filtered and concentrated to get bottom concentrated residue.
Yield: 85%
Example 16: Preparation of 2,4,5-trifluorophenyl acetic acid from methyl 2-(cyanomethyl)-3,5,6-trifluorobenzoate
Water (40 g) was added to the residue (from example-1 or 2; 9.3g, 1 eq.), and then concentrated sulphuric acid (5.0 eq.) was added dropwise in it and heated the reaction solution to 120-140°C. Thereafter cooled the reaction solution to room temperature and filtered. The filtered solid (9.5g) was added in N-methyl-2-pyrrolidone (40g), calcium hydroxide (0.6g) and concentrated sulphuric acid (0.35g) and heated the reaction mixture to 150°C. The reaction progress was monitored by HPLC. The reaction mixture was cooled to 30-35°C and then concentrated hydrochloric acid was added dropwise in it and stirred for 30 minutes and then filtered. The filtered solid was washed with water (30 ml). The wet cake was dried at 80°C under vacuum to obtain 2,4,5-trifluorophenyl acetic acid (6.9g).

Purity: 99.1%
Yield: 90.0%
Example 17: Preparation of 2,4,5-trifluorophenyl acetic acid from methyl 2-(l-cyano-2-ethoxy-2-oxoethyl)-3,5,6-trifluorobenzoate
Water (150 g) was added to the residue (from any of the examples-3-8 0.095 mol), and then concentrated sulphuric acid (98%, 92.3g, 0.94mol) was added dropwise in it at room temperature under mechanical stirring. The reaction mixture was heated to 140°C for 2 hours. Thereafter reaction mixture was cooled to 30-35°C and filtered. The filtered solid (21.5g) was added in N-methyl-2-pyrrolidone (60g), calcium hydroxide (1.8g) and concentrated sulphuric acid (1.2g) and heated the reaction mixture to 150°C. The reaction progress was monitored by HPLC. The reaction mixture was cooled to 30-35°C and then concentrated hydrochloric acid was added dropwise in it and stirred for 30 minutes and then filtered. The filtered solid was washed with water (100 ml). The wet cake was dried at 80°C under vacuum to obtain 2,4,5-trifluorophenyl acetic acid (16.3g).
Purity: 99.3%
Yield: 91.0%.
Example 18 Preparation of 2,4,5-trifluorophenyl acetic acid from methyl 2-(2-ethoxy-2-oxoethyl)-3,5,6-trifluorobenzoate
Water (70 g) was added to the residue (from examples-9, 0.084 mol), and then concentrated sulphuric acid (98%, 46.3g, 0.46mol) was added dropwise in it at room temperature under mechanical stirring. The reaction mixture was heated to 140°C for 2 hours. Thereafter reaction mixture was cooled to 30-35°C and filtered. The filtered solid (20g) was added in N-methyl-2-pyrrolidone (60g), calcium hydroxide (1.8g) and concentrated sulphuric acid (1.2g)and heated the reaction mixture to 150°C. The reaction progress was monitored by HPLC. The reaction mixture was cooled to 30-

35°C and then concentrated hydrochloric acid was added dropwise in it and stirred for 30 minutes and then filtered. The filtered solid was washed with water (100 ml). The wet cake was dried at 80°C under vacuum to obtain 2,4,5-trifluorophenyl acetic acid (14.5g).
Purity: >99%
Yield: 90.0%.
Example 19: Preparation of 2,4,5-trifluorophenyl acetic acid from methyl 2-(dicyanomethyl)-3,5,6-trifluorobenzoate
Water (60 g) was added to the residue (from example-10 or 11, 0.04 mol) and then concentrated sulphuric acid (98%, 60g, 0.6mol) was added dropwise in it at room temperature under mechanical stirring. The reaction mixture was heated to 140°C for 8 hours. Thereafter reaction mixture was cooled to 30-35°C and filtered. The filtered solid (9.2g) was added in N-methyl-2-pyrrolidone (60g), calcium hydroxide (1. lg) and concentrated sulphuric acid (0.6g) and heated the reaction mixture to 150°C. The reaction progress was monitored by HPLC. The reaction mixture was cooled to 30-35°C and then concentrated hydrochloric acid was added dropwise in it and stirred for 30 minutes and then filtered. The filtered solid was washed with water (100 ml). The wet cake was dried at 80°C under vacuum to obtain 2,4,5-trifluorophenyl acetic acid (7-0g).
Purity: 99.4%
Yield: 90.0%.
Example 20: Preparation of 2,4,5-trifluorophenyl acetic acid from diethyl [3,4,6-trifluoro-2-(methoxycarbonyl)phenyl]propanedioate
Water (60 g) was added to the residue (from any of the examples-13-16, 0.082 mol) and then concentrated sulphuric acid (98%, 50g, 0.5mol) was added dropwise in it at

room temperature under mechanical stirring. The reaction mixture was heated to 140°C for 6 hours. Thereafter reaction mixture was cooled to 30-35°C and filtered. The filtered solid (19.2g) was added in N-methyl-2-pyrrolidone (60g), calcium hydroxide (1.9g) and concentrated sulphuric acid (0.8g) and heated the reaction mixture to 150°C. The reaction progress was monitored by HPLC. The reaction mixture was cooled to 30-35°C and then concentrated hydrochloric acid was added dropwise in it and stirred for 30 minutes and then filtered. The filtered solid was washed with water (100 ml). The wet cake was dried at 80°C under vacuum to obtain 2,4,5-trifluorophenyl acetic acid (14.2g).
Purity: 99.1%
Yield: 90.0%.

WE CLAIM:

1. A compound of formula I,
COOR R

Formula-I
wherein, R1 and R2 independently represent H, CN, CONH2, COOH, COOR, wherein both R1 and R2 cannot be H and R represents an alkyl group.
2. The process for preparation of a compound of formula I,
j
COOR R

Formula-I
wherein, R1 and R2 independently represent H, CN, CONH2, COOH, COOR, wherein both R1 and R2 cannot be H and R represents an alkyl group.
comprising the step of reacting an alkyl 2,3,5,6-tetrafluorobenzoate and a nucleophilic agent of formula II in presence of a base to obtain the compound of formula I,
Formula-II
wherein, R1 and R2 independently represent H, CN, CONH2, COOH, COOR.

3. The process as claimed in claim 2, wherein the process is carried out in a polar aprotic solvent selected from a group consisting of acetone, ethylacetate, dimethylsulfoxide, N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, tetrahydrofuran, hexamethylphosphoric triamide, dichloroethane, N,N-dimethyacetamide, sulfolane, tetrahydrofuran, 1,4-dioxane and l,3-dimethyl-2-imidazolidinone.
4. The process as claimed in claim 2, wherein the nucleophilic agent of formula II is selected from a group consisting of diethyl malonate, ethylmethyl malonate, dimethylmalonate, methylcyanoacetate, ethylcyanoacetate, propanedinitrile, ethyl acetate, methyl acetate and acetonitrile.
5. The process as claimed in claim 2 further comprises converting the compound of formula I to 2,4,5-trifluorophenylacetic acid, comprising the steps of,
a) hydrolysing a compound of formula I,
j
COOR R

Formula-I
wherein, R1 and R2 independently represent H, CN, CONH2, COOH, COOR, wherein both R1 and R2 cannot be H and R represents an alkyl group
with an acid to obtain a reaction mixture; and
b) decarboxylating reaction mixture using a catalyst to obtain 2,4,5-trifluorophenylacetic acid.
6. The process as claimed in claim 2, wherein the base is selected from a group consisting of alkali carbonates, alkali hydrogen carbonates, alkali hydroxide, alkali

alkoxides, metal hydrides, alkali metals, alkyl lithium and metal bis(trimethylsilyl)amides.
7. The process as claimed in claim 5, wherein the acid is selected from a group consisting of sulphuric acid, hydrochloric acid, hydrobromic acid, acetic acid and trifluoroacetic acid.
8. The process as claimed in claim 5, wherein the catalyst is selected from a group consisting of hydroxide, carbonate, bicarbonate, sulphates of alkali metals, alkaline earth metals and oxides of alkaline earth metals.