DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

IMPROVED PROCESS FOR THE PREPARATION OF INTERMEDIATE USED IN THE PREPARATION OF DIPEPTIDYL PEPTIDASE-4 (DPP-4) ENZYME INHIBITOR

We, ARENE LIFE SCIENCES PRIVATE LIMITED,
a company incorporated under the companies act, 1956 having address at
#3 - 58, S.R.Chambers, Ramachandrapuram, Hyderabad - 502 032,
Telangana, INDIA.

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of intermediate compounds used in the preparation of a dipeptidyl peptidase-4 (dpp-4) enzyme inhibitor.

The present invention relates to an improved process for the preparation of intermediate compounds used in the preparation of Sitagliptin.

The present invention specifically relates to an improved process for the preparation of 2,4,5-(trifluorophenyl ) acetic acid compound of formula (I) used in the preparation of Sitagliptin or its pharmaceutically acceptable salts.
Formula I
The present invention also relates to an improved process for the preparation of intermediate compounds of formula (II) used in the preparation of Sitagliptin or its pharmaceutically acceptable salts
Formula (II)
wherein X is halogen.

The present invention also specifically relates to an improved process for the preparation of intermediate compounds of formula (IIa) used in the preparation of Sitagliptin or its pharmaceutically acceptable salts.
Formula (IIa)

BACKGROUND OF THE INVENTION
Sitagliptin phosphate is a dipeptidyl peptidase IV inhibitor and is currently marketed in the United States under the trade name of JANUVIATM in its monohydrate form. JANUVIATM is indicated to improve glycemic control in patients with type2 diabetes mellitus. Its chemical name is 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3,-a]pyrazine phosphate monohydrate and the molecular Formula is C16H15F6N5O.H3PO4.H2O with a molecular weight of 523.32. The structural Formula of Sitagliptin phosphate monohydrate is:

Sitagliptin base and its pharmaceutically acceptable acid addition salts have been described in U.S. Pat. No. 6,699,871. In particular, Example 7 of U.S. Pat. No. 6,699,871 discloses the preparation of Sitagliptin base and its hydrochloride salt.

Sitagliptin phosphate salt and different forms thereof have been disclosed in U.S. Pat. No. 7,326,708.

US 8,835,679 B2 disclose a process of preparing 2,4,5-trifluorophenylacetic acid by acylation of 1,2,4-trifluorobenzene followed by halogenation of the product formed and subsequent operations. The process is shown in the scheme given below:

WO2008/078350 A2, discloses a process for the preparation of 2,4,5-trifluorophenylacetic acid the detailed scheme of which is given below :

This work consists of 6 conversions and 5 stages. The reaction of 1 with dichloroacetyl chloride will takes place by friedel crafts alkylation reaction results in compound 3a which is further converted to 2,4,5-trifluorophenylacetic acid in multiple stage operations. An alternate process disclosed in WO ‘350 is

US 2004/0068141 discloses a process for the preparation of 2,4,5-trifluorophenylacetic acid which is shown in the scheme below :

The prior-art processes hitherto reported suffer from several disadvantages as the processes involves multistage operations from the same starting materials. On the contrary the process of the present invention involves two simple steps, thereby making it easily workable on plant scale and commercially feasible. The process of the present invention involves friedel crafts acylation reaction using trichloroacetyl chloride to get intermediate 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone directly, which will be utilised to get target product in single stage by Wolff Kishner reduction of keto to methylene under basic condition, which enables hydrolysis of trichloromethyl to acid as well to accomplish trifluorophenyl acetic acid.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of intermediate compounds used in the preparation of a dipeptidyl peptidase-4 (dpp-4) enzyme inhibitor.

Another objective of the present invention is provide an improved process for the preparation of intermediate compounds used in the preparation of Sitagliptin.

Yet another objective of the present invention is to provide an improved process for the preparation of intermediate compounds of formula (I) used in the preparation of Sitagliptin or its pharmaceutically acceptable salts.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of intermediate compounds used in the preparation of Sitagliptin.

In another aspect, the present invention provides an improved process for the preparation of 2,4,5-(trifluorophenyl) acetic acid compound of formula (I) used in the preparation of Sitagliptin or its pharmaceutically acceptable salts.
Formula I

In yet another embodiment the present invention provides an improved process for the preparation of intermediate compounds of formula (II) used in the preparation of Sitagliptin or its pharmaceutically acceptable salts
Formula (II)
wherein X is halogen.

In yet another aspect, the present invention provides an improved process for the preparation of intermediate compounds of formula (IIa) used in the preparation of Sitagliptin or its pharmaceutically acceptable salts.
Formula (IIa)

In yet another aspect, the present invention provides an improved process for the preparation of 2,4,5-(trifluorophenyl) acetic acid compound of formula (I)
Formula I
which comprises the steps of:
i) reacting 1,2,4-trifluorobenzene with trihaloacetyl halide in the presence of lewis acid in the presence or absence of a solvent to obtain compound of formula (II),
Formula (II)
wherein X is halogen,

ii) reacting compound of formula (II) with hydrazine hydrate in the presence of a base in a solvent to produce 2,4,5-(trifluorophenyl) acetic acid compound of formula (I).

In yet another aspect, the present invention provides a process for the preparation of intermediate compounds of formula (II)
Formula (II)

wherein X is halogen which comprises reacting 1,2,4-trifluorobenzene with trihaloacetyl halide in the presence of lewis acid in a solvent to obtain compound of formula (II).

In yet another aspect, the present invention provides an improved process for the preparation of 2,4,5-(trifluorophenyl) acetic acid compound of formula (I)
Formula I
which comprises the steps of:
i) reacting 1,2,4-trifluorobenzene with trichloroacetyl chloride in the presence of lewis acid in a solvent to obtain compound of formula (IIa),
Formula (IIa)

ii) reacting compound of formula (IIa) with hydrazine hydrate in the presence of a base in a solvent to produce 2,4,5-(trifluorophenyl) acetic acid compound of formula (I).

In yet another aspect, the present invention provides an improved process for the preparation of 2,4,5-(trifluorophenyl) acetic acid compound of formula (I)
Formula I
which comprises the steps of:
i) reacting 1,2,4-trifluorobenzene with trichloroacetyl chloride in the presence of aluminium chloride in a solvent to obtain compound of formula (IIa),
Formula (IIa)

ii) reacting compound of formula (IIa) with hydrazine hydrate in the presence of a base in a solvent to produce 2,4,5-(trifluorophenyl) acetic acid compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION
As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

In a specific embodiment, the reaction of 1,2,4-trifluorobenzene with trihaloacetyl halide is carried out in presence of a lewis acid and in suitable solvent. The reaction is carried out at a temperature in the range of 0-25 ºC. After completion of the reaction, the reaction mass is poured into ice cold water and extracted with an appropriate solvent or mixture of solvents. The reaction may be carried out for a duration of 1 to 15 hours.

The Hydrazine hydrate reaction is carried out in the presence of base a temperature in the range of 0-25 ºC, followed by addition of base increasing the temperature to 30-90 ºC and the stirring the reaction mass for a period of 8-15 hrs. After completion of the reaction, the reaction mass is poured into ice cold water and adjusting the pH using an acid to 4-6.

The term Halogen as used herein is selected from chloro, bromo, fluoro.

In yet another embodiment, Trihaloacetyl halide as used herein is selected from trichloroaceyl chloride, trifluoroacetyl chloride, tribromoacetyl bromide and the like.

In yet another embodiment, Lewis acid as used herein is selected from AlCl3 (Aluminium chloride), BF3, BCl3, BBr3, Bl3, SbF5, AlBr3, TiBr4, TiCl4, TiCl3, ZrCl4, PF5, FeCl3, FeBr3, ZnCl2, Cu(OTf)2, Fe(OTf)3, Yb(OTf)3 etc. Preferably Lewis acid is AlCl3 (Aluminium chloride), AlBr3, FeCl3, FeBr3, ZnCl2, Cu(OTf)2, Fe(OTf)3, Yb(OTf)3.

In yet another embodiment, solvents used in the present invention are selected from "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, diethylether, pet-ether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane; amides such as dimethyl formamide, N-methyl acetamide, N,N-dimethyl acetamide; N-methyl pyrrolidone, dimethyl sulfoxide and/or mixtures thereof, preferably the solvent is alcoholic solvent and more preferably methanol.

In yet another embodiment, the base used herein are not limited to inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof and the like.

In yet another embodiment, the acid used herein is selected from inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid and perchloric acid, polyphosphoric acid; organic acid selected from formic acid, acetic acid, propionic acid, citric acid and oxalic acid or mixture thereof.

In an embodiment, the present invention provides process for the preparation of Sitagliptin using 2,4,5-(trifluorophenyl) acetic acid prepared by the process of the present invention.

The advantages of the present invention can be realised by way of reduced number of steps, increasing the overall yield of 2,4,5-(trifluorophenyl) acetic acid with increased purity. The prior-art process yields 60% whereas the process of the present invention yields 79% of 2,4,5-(trifluorophenyl) acetic acid.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore, the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. The present invention is exemplified by the following examples, which are provided for illustration only and should not be construed to limit the scope of the invention.
The following examples describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions which have been particularly effective on a bench scale.

EXAMPLES
Example 1: Preparation of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone
To a stirred solution of 1,2,4-trifluorobenzene (50 g, 0.38 mol) and 2,2,2-trichloro acetyl chloride (68 g, 0.38 mol), 2 at 0-5 ºC, aluminium chloride (51 g, 0.38 mol) was added portion wise for 10-15 min. The resulting reaction mass was stirred at same temperature for 2-3 h. After completion of the reaction, reaction mass was slowly poured into ice cold water (300 mL) dichloromethane (300 mL) mixture. Organic layer was separated and evaporated to obtain product 97 g (93% yield) of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone, 3 as brown colour solid.

Example 2: Preparation of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone
To a stirred solution of 1,2,4-trifluorobenzene (50 g, 0.38 mol) and 2,2,2-trichloro acetyl chloride (68 g, 0.38 mol), 2 at 0-5 ºC, 1.0M Boron trichloride in MDC (0.38 mol) was added drop wise for 10-15 min. The resulting reaction mass was stirred at same temperature for 2-3 h. After completion of the reaction, reaction mass was slowly poured into ice cold water (300 mL) dichloromethane (300 mL) mixture. Organic layer was separated and evaporated to obtain product 94 g (90.1% yield) of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone, 3 as brown colour solid.

Example 3: Preparation of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone
To a stirred solution of 1,2,4-trifluorobenzene (50 g, 0.38 mol) and 2,2,2-trichloro acetyl chloride (68 g, 0.38 mol), 2 at 0-5 ºC, Boron trifluoride Etherate (53.93 g, 0.38 mol) was added portion wise for 10-15 min. The resulting reaction mass was stirred at same temperature for 2-3 h. After completion of the reaction, reaction mass was slowly poured into ice cold water (300 mL) dichloromethane (300 mL) mixture. Organic layer was separated and evaporated to obtain product 98 g (93.9 % yield) of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone, 3 as brown colour solid.

Example 4: Preparation of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone
To a stirred solution of 1,2,4-trifluorobenzene (50 g, 0.38 mol) and 2,2,2-trichloro acetyl chloride (68 g, 0.38 mol), 2 at 0-5 ºC, Boron tribromide (95.19 g, 0.38 mol) was added drop wise for 10-15 min. The resulting reaction mass was stirred at same temperature for 2-3 h. After completion of the reaction, reaction mass was slowly poured into ice cold water (300 mL) dichloromethane (300 mL) mixture. Organic layer was separated and evaporated to obtain product 98 g (93.9 % yield) of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone, 3 as brown colour solid

Example 5 Preparation of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone
To a stirred solution of 1,2,4-trifluorobenzene (50 g, 0.38 mol) and 2,2,2-trichloro acetyl chloride (68 g, 0.38 mol), 2 at 0-5 ºC, Boron triiodide (148.77 g, 0.38 mol) was added portion wise for 10-15 min. The resulting reaction mass was stirred at same temperature for 2-3 h. After completion of the reaction, reaction mass was slowly poured into ice cold water (300 mL) dichloromethane (300 mL) mixture. Organic layer was separated and evaporated to obtain product 98 g (93.9 % yield) of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone, 3 as brown colour solid

Example 6: Preparation of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone
To a stirred solution of 1,2,4-trifluorobenzene 1 (50 g, 0.38 mol) and 2,2,2-trichloro acetyl chloride (68 g, 0.38 mol), 2 at 0-5 ºC, Titanium tetrachloride (64.7 g, 0.40 mol) was added drop wise for 10-15 min. The resulting reaction mass was stirred at same temperature for 2-3 h. After completion of the reaction, reaction mass was slowly poured into ice cold water (300 mL) dichloromethane (300 mL) mixture. Organic layer was separated and evaporated to obtain product 94 g (90.1 % yield) of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone, 3 as brown colour solid.

Example 7: Preparation of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone
To a stirred solution of 1,2,4-trifluorobenzene (50 g, 0.38 mol) and 2,2,2-trichloro acetyl chloride (68 g, 0.38 mol), 2 at 0-5 ºC, Titanium tetrabromide (64.7 g, 0.40 mol) was added portion wise for 10-15 min. The resulting reaction mass was stirred at same temperature for 2-3 h. After completion of the reaction, reaction mass was slowly poured into ice cold water (300 mL) dichloromethane (300 mL) mixture. Organic layer was separated and evaporated to obtain product 94 g (90.1 % yield) of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone, 3 as brown colour solid

Example 8: Preparation of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone
To a stirred solution of 1,2,4-trifluorobenzene (50 g, 0.38 mol) and 2,2,2-trichloro acetyl chloride (68 g, 0.38 mol), 2 at 0-5 ºC, Ferric Bromide (112.31 g, 0.38 mol) was added portion wise for 10-15 min. The resulting reaction mass was stirred at same temperature for 2-3 h. After completion of the reaction, reaction mass was slowly poured into ice cold water (300 mL) dichloromethane (300 mL) mixture. Organic layer was separated and evaporated to obtain product 96 g (92 % yield) of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone, 3 as brown colour solid.

Example 9: Preparation of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone
To a stirred solution of 1,2,4-trifluorobenzene (50 g, 0.38 mol) and 2,2,2-trichloro acetyl chloride (68 g, 0.38 mol), 2 at 0-5 ºC, Ferric chloride (61.7 g, 0.38 mol) was added portion wise for 10-15 min. The resulting reaction mass was stirred at same temperature for 2-3 h. After completion of the reaction, reaction mass was slowly poured into ice cold water (300 mL) dichloromethane (300 mL) mixture. Organic layer was separated and evaporated to obtain product 96 g (92 % yield) of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone, 3 as brown colour solid.

Example 10: Preparation of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone
To a stirred solution of 1,2,4-trifluorobenzene, 1 (50 g, 0.38 mol) and 2,2,2-trichloro acetyl chloride (68 g, 0.38 mol), 2 at 0-5 ºC, Zinc chloride (51.8 g, 0.38 mol) was added portion wise for 10-15 min. The resulting reaction mass was stirred at same temperature for 2-3 h. After completion of the reaction, reaction mass was slowly poured into ice cold water (300 mL) dichloromethane (300 mL) mixture. Organic layer was separated and evaporated to obtain product 96 g (92 % yield) of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone, 3 as brown colour solid.

Example 11: Preparation of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone
To a stirred solution of 1,2,4-trifluorobenzene, 1 (50 g, 0.38 mol) and 2,2,2-trichloro acetyl chloride (119 g, 0.38 mol), 2 at 0-5 ºC, Aluminium chloride (51.8 g, 0.38 mol) was added portion wise for 10-15 min. The resulting reaction mass was stirred at same temperature for 2-3 h. After completion of the reaction, reaction mass was slowly poured into ice cold water (300 mL) Chloroform (300 mL) mixture. Organic layer was separated and evaporated to obtain product 96 g (92 % yield) of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone, 3 as brown colour solid.

Example 12: Preparation of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone
To a stirred solution of 1,2,4-trifluorobenzene, 1 (50 g, 0.38 mol) and 2,2,2-tribromo acetyl chloride (68 g, 0.38 mol), 2 at 0-5 ºC, Ferric chloride (51 g, 0.38 mol) was added portion wise for 10-15 min. The resulting reaction mass was stirred at same temperature for 2-3 h. After completion of the reaction, reaction mass was slowly poured into ice cold water (300 mL) dichloromethane (300 mL) mixture. Organic layer was separated and evaporated to obtain product 96 g (92 % yield) of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl) ethanone, 3 as brown colour solid

Example 13: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), ethylene glycol (160 mL) at 20-30 ºC, Charged hydrazine hydrate. To this KOH flakes was added and allowed to stir at 50-60 ºC for 10-12 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 24 g (85%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 99% HPLC purity

Example 14: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), Methanol (200 mL) at 20-30 ºC, Charged hydrazine hydrate. To this KOH flakes was added and allowed to stir at 50-60 ºC for 10-12 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 24 g (85%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 99% HPLC purity

Example 15: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), ethanol (220 mL) at 20-30 ºC, Charged hydrazine hydrate. To this KOH flakes was added and allowed to stir at 60-70 ºC for 8-10 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 23.5 g (83%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 98.6% HPLC purity

Example 16: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), n-Propanol (200 mL) at 20-30 ºC, Charged hydrazine hydrate. To this KOH flakes was added and allowed to stir at 60-65 ºC for 12-15 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 22.8 g (81%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 97.8% HPLC purity

Example 17: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), Iso propanol (200 mL) at 20-30 ºC, Charged hydrazine hydrate. To this KOH flakes was added and allowed to stir at 50-60 ºC for 10-12 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 24 g (85%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 98.2% HPLC purity

Example 18: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), n-Butanol (160 mL) at 20-30 ºC, Charged hydrazine hydrate. To this KOH flakes was added and allowed to stir at 75-85 ºC for 8-10 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 22.5 g (80%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 98.7% HPLC purity

Example 19: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), t-Butanol (160 mL) at 20-30 ºC, Charged hydrazine hydrate. To this KOH flakes was added and allowed to stir at 50-60 ºC for 15-18 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 22.5 g (80%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 98.5% HPLC purity

Example 20: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), Acetone (240 mL) at 20-30 ºC, Charged hydrazine hydrate. To this KOH flakes was added and allowed to stir at 55-58 ºC for 14-18 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 22.8 g (81%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 98.6% HPLC purity

Example 21: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), ethylmethyl ketone (240 mL) at 20-30 ºC, Charged hydrazine hydrate. To this KOH flakes was added and allowed to stir at 50-60 ºC for 15-18 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 21.5 g (76 %) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 97.9% HPLC purity

Example 22: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), Diethyl Ketone (200 mL) at 20-30 ºC, Charged hydrazine hydrate. To this KOH flakes was added and allowed to stir at 50-60 ºC for 15-18 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 21.5 g (76%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 98.2% HPLC purity
Example 23: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), Methyl tert-butyl ketone (200 mL) at 20-30 ºC, Charged hydrazine hydrate. To this KOH flakes was added and allowed to stir at 55-65 ºC for 12-15 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 21.5 g (76%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 98.9% HPLC purity

Example 24: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), Isopropyl ketone (200 mL) at 20-30 ºC, Charged hydrazine hydrate. To this KOH flakes was added and allowed to stir at 55-65 ºC for 12-15 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 24 g (85%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 98.8% HPLC purity

Example 25: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), Acetonitrile (200 mL) at 20-30 ºC, Charged hydrazine hydrate. To this KOH flakes was added and allowed to stir at 50-60 ºC for 10-12 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 23.5 g (83%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 98.9% HPLC purity

Example 26: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), MDC (200 mL) at 20-30 ºC, Charged hydrazine hydrate. To this KOH flakes was added and allowed to stir at 38-42 ºC for 12-15 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 24 g (85%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 99% HPLC purity

Example 27: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), Methanol (200 mL) at 20-30 ºC, Charged hydrazine hydrate. To this Sodium hydroxide flakes was added and allowed to stir at 50-60 ºC for 10-12 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 23.5 g (83%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 99% HPLC purity

Example 28: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), Methanol (200 mL) at 20-30 ºC, Charged hydrazine hydrate. To this Lithium hydroxide flakes was added and allowed to stir at 50-60 ºC for 10-12 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 23.5 g (83%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 99% HPLC purity

Example 29: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), Methanol (200 mL) at 20-30 ºC, Charged hydrazine hydrate. To this Sodium carbonate flakes was added and allowed to stir at 50-60 ºC for 10-12 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 21.5 g (76%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 98.5% HPLC purity

Example 30: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), Methanol (200 mL) at 20-30 ºC, Charged hydrazine hydrate. To this Potassium carbonate flakes was added and allowed to stir at 50-60 ºC for 10-12 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 23 g (81%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 99% HPLC purity

Example 31: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), Methanol (200 mL) at 20-30 ºC, Charged hydrazine hydrate. To this Potassium bicarbonate flakes was added and allowed to stir at 50-60 ºC for 10-12 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 23 g (81%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 99% HPLC purity

Example 32: 3,2-(2,4,5-trifluorophenyl)acetic acid
To a stirred solution of 2,2,2-trichloro-1-(2,4,5-trifluorophenyl)ethanone (40 g, 0.15 mol), Methanol (200 mL) at 20-30 ºC, Charged hydrazine hydrate. To this Sodium methoxide flakes was added and allowed to stir at 50-60 ºC for 10-12 h. After completion of the reaction, reaction mass was slowly poured into ice cold water and PH adjusted with con HCl to 5 to 6. Filter the solids to afford 23.5 g (83%) of desired product 3,2-(2,4,5-trifluorophenyl)acetic acid as yellow colour solid with more than 99% HPLC purity ,CLAIMS:We Claim:
1. An improved process for the preparation of 2,4,5-(trifluorophenyl) acetic acid compound of formula (I)
Formula I
which comprises the steps of:
i) reacting 1,2,4-trifluorobenzene with trihaloacetyl halide in the presence of lewis acid in the presence or absence of a solvent to obtain compound of formula (II),
Formula (II)
wherein X is halogen,

ii) reacting compound of formula (II) with hydrazine hydrate in the presence of a base in a solvent to produce 2,4,5-(trifluorophenyl) acetic acid compound of formula (I).
2. The process as claimed in claim 1, the process comprises preparation of intermediate compounds of formula (II)
Formula (II)

wherein X is halogen which comprises reacting 1,2,4-trifluorobenzene with trihaloacetyl halide in the presence of lewis acid in a solvent to obtain compound of formula (II).

3. The process as claimed in claim 1, wherein the process comprises preparation the preparation of 2,4,5-(trifluorophenyl) acetic acid compound of formula (I)
Formula I
which comprises the steps of:
i) reacting 1,2,4-trifluorobenzene with trichloroacetyl chloride in the presence of lewis acid in a solvent to obtain compound of formula (IIa),
Formula (IIa)

(ii) reacting compound of formula (IIa) with hydrazine hydrate in the presence of a base in a solvent to produce 2,4,5-(trifluorophenyl) acetic acid compound of formula (I).
4. The process as claimed in claim 1, wherein the Trihaloacetyl halide is trichloroaceyl chloride, trifluoroacetyl chloride, tribromoacetyl bromide.
5. The process as claimed in claim 1, wherein the Lewis acid is AlCl3 (Aluminium chloride), BF3, BCl3, BBr3, Bl3, SbF5, AlBr3, TiBr4, TiCl4, TiCl3, ZrCl4, PF5, FeCl3, FeBr3, ZnCl2, Cu(OTf)2, Fe(OTf)3, Yb(OTf)3 etc.
6. The process as claimed in claim 1, wherein the solvents are selected from "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, diethylether, pet-ether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane; amides such as dimethyl formamide, N-methyl acetamide, N,N-dimethyl acetamide; N-methyl pyrrolidone, dimethyl sulfoxide and/or mixtures thereof.
7. The process as claimed in claim 1, wherein the the base used herein are not limited to inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof.
8. The process as claimed in claim 1, wherein the acid is selected from inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid and perchloric acid, polyphosphoric acid; organic acid selected from formic acid, acetic acid, propionic acid, citric acid and oxalic acid or mixture thereof.

Dated this Fourteenth (14th) day of September 2023.

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Dr. S. Padmaja
Agent for the Applicant
IN/PA/883