FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification [See Sections 10 and rule 13]
Title: A process for preparation of choline fenofibrtae
Applicant: (a) INTAS Pharmaceuticals Limited (b) Nationality: Indian (c) 2nd Floor, Chinubhai Centre,
Ashram Road, Ahmedabad 380009. Gujarat. 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 a novel process for preparation of 2-[4-(4-chIorobenzoyI)phenoxy]-2-methylpropanoate;2~hydroxyethyl(trimethyl)azanium commonly known as choline fenofibrate of formula (III).
BACKGROUND OF THE INVENTION
Fenofibric acid, chemically known as 2-[4-(4-chlorobenzoyl) phenoxy]-2-methylpropanoic acid having following formula

is an active metabolite of fenofibrate. Fenofibrate (IV) is isopropyl ester of fenofibric acid and can be depicted by following formula.

It is a drug of fibrate class and is mainly used to reduce cholestrol level in patients at risk of cardiovascular diseases. Like other fibrates it reduces low density and very low density lipoprotein as well as increasing high density lipoprotein and reducing triglyceride level.
The market approved dosage forms contained of choline salt of fenofibric acid and is known as Trilipix. Choline is a quaternary saturated amine with the chemical formula (CH3)3N+CH2CH2OH.

Choline fenofibrate was disclosed in US 7,259,186 (hereinafter referred as '186). This reports that the novel salts including choline are more photo stable as compared to salts disclosed previously. Two alternative preparation methods are reported in '186, the processes disclosed in example 17 A includes reacting fenofibric acid with choline hydroxide in presence of solvent. The alternative process disclosed in example 17B of same patent includes reacting fenofibric acid with choline chloride in presence of sodium bicarbonate as base.
Another process for preparation of choline fenofibrate is reported in US 7,714,163 (hereinafter referred as ' 163) which includes reacting isopropyl-2-bromo-2-methylpropanoate and (4-chlorophenyl) (4-hydroxyphenyl) methanone in a first step to obtain fenofibric acid and further reacting it with aqueous choline hydroxide in second step. The isolation of fenofibric acid is not effected, thus the process is carried out in situ .
Choline hydroxide used in reported processes is not available readily for commercial purpose. Since it is always advisable to use easily available reagents to develop a commercially feasible process therefore choline hydroxide can be substituted with readily available reagent such as choline chloride. However use of choline chloride necessitates utilization of base either organic or inorganic. The choice of base is crucial for such reactions as it effects the purity of final product i.e. choline fenofibrate.
The reported processes employ metallic bases for reaction of fenofibric acid and choline chloride, such as sodium bicarbonate as disclosed in '186. The '163 patent uses potassium carbonate for the first step i.e. preparation of fenofibric acid but there is immense possibility of its being carried forward to second step which is preparation of choline fenofibrate.

A major technical difficulty in using metal containing bases is that the final product fails to comply with pharmacopoeia limits of sulfated ash hence compromising the overall purity of product. This also leads to additional steps in process to reduce the sulfated ash content.
To overcome one or more insufficiencies of prior art processes the present invention aims to provide an improved process for preparation of choline fenofibrate (III)
The current process comprises reacting fenofibric acid with choline chloride in presence of non-metallic inorganic bases. Use of non metallic bases completely eliminates the possibility of having ash content in the final product; hence highly pure product will be obtained. Moreover the base/s used in present process is/are inexpensive making the process more economical. In addition to this easy availability of choline chloride makes the process industrially more feasible.
OBJECTS OF THE INVENTION
The main object of the present invention provides a process for preparation of choline salt of fenofibric acid generally known as choline fenofibrate.
Another object of the present invention is to provide cost effective, non hazardous process for preparing choline fenofibrate.

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of choline fenofibrate comprises reacting fenofibric acid (I) with choline chloride (II) in presence of non-metallic inorganic bases.
DETAILED DESCRIPTION
In accordance, choline fenofibrate (III) is prepared as presented in following scheme

The process of the invention includes reaction of fenofibric acid with choline chloride in presence of non metallic inorganic bases.
The suitable non-metallic bases that can be employed may be selected from but not limited to ammonium carbonate, ammonium bicarbonate, alcoholic ammonia, a specific example of preferred base is ammonium carbonate.
The reaction can be carried out in any of the conventional solvents. The solvents can be selected from aliphatic alcohols, aliphatic ketones, alkyl esters, aliphatic nitriles and mixtures thereof. Preferred solvents are ethanol, methanol, propanol or mixtures thereof.
In a preferred process fenofibric acid is mixed with choline chloride in presence of base and a solvent followed by heating. Suitable temperature for reaction can range

from about 20°C to about 150°C and the time period can be as long as required for completion of reaction. Any other temperature also is acceptable, as long as the outcome of the reaction is not affected.
After the completion of reaction typically for solid product formation, the reaction mixture may be maintained at a temperature lower than the reaction temperature such as for example 0°C to 30°C for periods of time as required for complete precipitation of the product. A person skilled in the art can readily determine the exact cooling temperature and time required for complete precipitation.
On complete fall out, the product i.e. choline fenofibrate (III) can be recovered by
any technique including filtration or centrifugation. The product thus obtained
complies with the pharmacopeial limits and may be directly taken for further
processes. If desired the product can be recrystallised from any conventionally known i
solvent.
In the process of present application polar solvent like acetone, ethanol, isopropanol or mixture thereof are used for purification of choline fenofibrate (III). The process for purification comprises taking choline fenofibrate in solvent, heating the solution followed by cooling to precipitate the pure product.
The starting material fenofibric acid can be prepared by any one of the process reported in literature or obtained commercially. Choline chloride can also be obtained from any conventional source or can be prepared by conventionally known process.

EXAMPLES
The above said invention can be illustrated by but not limited to following example(s)
Example l: Preparation of choline fenofibrate
l0gm of fenofibric acid, 100 ml of ethyl alcohol were charged in reaction flask. The reaction mass was stirred for 15-20 minutes followed by addition of 3.06g of ammonium carbonate. Temperature of reaction mixture was increased to 60-65°C and 4.4 g of choline chloride was added. The reaction mixture was stirred at 60-65°C for 3 h. The reaction mass was filtered hot and then was cooled to 30-40°C followed by filtration to remove undissolved material generated during reaction. The filtrate was cooled to 0-5°C, the reaction mixture was filtered. The product thus obtained was dried to obtain 6.0g of title compound.
Example2: Purification of choline fenofibrate
100 g choline fenofibrate and 400 ml ethyl alcohol were charged in a reaction flask. Reaction mixture thus obtained was heated at about 50°C under stirring for thirty minutes. The reaction mixture was cooled to 5°C, the solid thus precipitated was isolated by flirtation and dried at 50°C to get the title compound. Yield = 75 g, purity is more than 99.00%

Claims:
comprising reaction of fenofibric acid (II)
1. A process for preparing choline fenofibrate


with choline chloride in presence of non metallic inorganic base.
2. A process as claimed in claim 1, wherein the non-metallic inorganic base is selected from ammonium carbonate, ammonium chloride and alcoholic ammonia.
3. A process as claimed in claim 1, wherein the reaction is carried out in presence of solvent.
4. A process as claimed in claim 1, wherein solvent is selected from acetone. isopropanol, ethanol or mixture thereof.

5. A process as claimed in claim 1, wherein choline fenofibrate (III) is further purified from protic solvent or mixture thereof.
6. A process as claimed in claim 1 or claim 5, wherein choline fenofibrate is purified in presence of solvent selected from acetone, methanol, ethanol, isopropanol or mixture thereof.