FORM 2
THE PATENTS ACT. 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Provisional Specification [See Sections 10 and rule 13]
Title: A process for preparation of choline fenofibrate
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-chlorobenzoyl)phenoxy]-2-methylpropanoate.2-hydroxyelhyl(trimelhyl)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 the following formula (I) is an active metabolite of fenofibrate.

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


Fenofibrate is a drug of fibrate class and is mainly used to reduce cholesterol 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.
Fenofibrate can be used alone or in combination with statins in the treatment of hypercholesterolemia and hypertriglyceridemia.
Fenofibrate and its acid addition salts were first disclosed in US 4:058.552. The process for preparation of Fenofibrate as disclosed in this patent is as follows:

Choline fenofibrate is approved in US under the tradename TRIL1PIX. Choline fenofibrate is a peroxisome proliferator receptor alpha (PPARa) activator used as monotherapy to reduce TG in patients with severe hypertriglyceridemia and to reduce elevated LDL-C and increase HDL-C in patients with primary hyperlipidcmia or mixed dyslipidemia.
The active pharmaceutical ingredient in TRILIPIX is choline salt of fenofibric acid. Choline is a quaternary saturated amine with the chemical formula (CH3)3N+CH2CH2OH.

Choline salt of fenofibric acid is first disclosed in US 7.259.186, This patent reports that novel salts of fenofibric acid including choline salt exhibit photostability when compared to fenofibric acid and other earlier disclosed salts of fenofibric acid. Two alternative processes for preparation of choline salt of fenofibric acid are disclosed in US 7.259,186 in examples 17A and 17B. The processes are summarized as below.

WO 2010/086700 discloses process for the preparation of choline salt of fenofibric acid by reaction of fenofibric acid with choline chloride in presence of organic base and solvent. The reported yield was approximately 75%. The process is summarized as below;

US 7,714.163 discloses process for preparation of choline fenofibrate. which includes reacting isopropyl-2-brorno-2-methylpropanoate and (4-chlorophenyl) (4-hydroxypheny!) methanone in a first step to obtain fenofibric acid (in sifu) and further reacting it with aqueous choline hydroxide in second step.

IN 2461/MUM/2010 discloses process for preparing choline fenofibratc comprising the steps of reacting fenofibric acid with choline hydroxide using single organic solvent (isopropanol) in the absence of a base.
IN 2267/MUM/2010 discloses process for preparation of choline fenotlbrate by reaction of fenofibric acid with choline chloride in presence of non metallic inorganic base.
Choline hydroxide used in some of the above reported processes is not readily available for commercial purpose. Since it is always advisable to use easily available reagents to develop a commercially feasible process, 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.
Some of the reported processes employ metallic bases, such as sodium bicarbonate for reaction of fenofibric acid and choline chloride to give choline fenofibrate as disclosed in US 7,259,186. US 7,714.163 discloses usage of 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. Thus, there is a need to prepare an improved, economical and industrial feasible process for the preparation of choline fenofibrate.

Serendipitously, the inventors of present invention found that the reaction of fenofibric acid with choline chloride in presence of potassium acetate gives choline fenofibrate without having ash content in the final product with higher yield and greater purity. Additionally, in situ purification of choline fenofibrate with isopropanol avoids multiple purification steps which are required to eliminate ash content in the final product, makes the reaction more economical and industrially feasible.
OBJECTS OF THE INVENTION
The main object of the present invention provides a process for preparation of choline fenofibrate comprising a step of condensation of fenofibric acid with choline chloride in the presence of base or buffer.
The base or buffer as mentioned hereinabove includes but not limited to ammonium acetate, zinc acetate or acetate of alkali metal or alkaline earth metal such as sodium acetate, potassium acetate, magnesium acetate and the like or mixtures thereof.
Yet another object of the present invention is to provide a process for preparation of choline fenofibrate comprising a step of condensation of fenofibric acid with choline chloride in the presence of potassium acetate.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of choline fenofibrate comprising a step of condensation of fenofibric acid (I) with choline chloride (II) in the presence of base or buffer.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the invention, the present invention provides a process for the preparation of choline fenofibrate of formula (III) comprising a step of condensation of fenofibric acid (I) with choline chloride (II) in the presence of base or buffer.
In another embodiment of the invention, the present invention provides a process for the preparation of choline fenofibrate of formula (III) comprising a step of condensation of fenofibric acid (I) with choline chloride (II) in the presence of base. The reaction can be summarized as below:

The base used for this reaction includes but not limited to ammonium acetate, zinc acetate or acetate of alkali metal or alkaline earth metal .such as sodium acetate, potassium acetate, magnesium acetate and the like or mixtures thereof. In a preferred embodiment of the invention, the base is potassium acetate.
The base used in the process of present invention in general can also act as buffer.
The solvent used for this reaction can be any suitable solvent, preferably, an alcoholic solvent. Alcoholic solvent includes but not limited to methanol, ethanol. n-propanol. isopropanol butanol, isobutano! or pcntanol. In a preferred embodiment of the invention, the solvent is isopropanol.
The reaction can be carried out at room temperature or at higher temperature. The resultant reaction mixture containing choline fenofibralc can be heated to higher

temperature of about 70-90°C for around 3-4 hours, followed by cooling to 20-30°C. After completion of reaction, the obtained product i.e. choline fenofibrate can be filtered from the reaction mixture. Crude choline fenofibrate filtrate can be taken for further purification without isolation by addition of isopropanol and water. The reaction mass thus obtained was heated, followed by cooling. The obtained precipitated product i.e. pure choline fenofibrate can be filtered and dried under
vacuum (Yield 80% w/w & purity 99.97% by HPLC).
Fenofibric acid, which is used as starting material for the preparation of choline fenofibrate in the present invention can be prepared by any known prior art process.
The following examples are intended to illustrate the present invention. It should be understood that the invention is not limited to those specific examples. Numerous changes and modifications may be made to the embodiments of the invention without departing from actual scope of the invention.
EXAMPLE 1: Preparation of choline fenofibrate from fenofibric acid
Fenofibric acid (100 cm) and isopropanol (2000 ml) were charged in a RBF. The reaction mixture thus obtained was heated to 40-45°C. To this potassium acetate (32.32 gm) was added while stirring, followed by addition of choline chloride (65.70 gm). The reaction mixture was heated at 70-90°C for 3-4 hours. After completion of reaction, reaction mixture was filtered and cooled to 20-35°C. The resultant filtrate was washed with isopropanol (50 ml) to give crude choline fenofibrate.

EXAMPLE 2: Purification of choline fenofibrate
Crude choline fenofibrate (in situ) filtrate obtained in example 1 was taken into flask. Isopropyl alcohol (1455 ml) and purified water (45 ml) were charged to filtrate. The reaction mixture thus obtained was heated lo 70-90°C while stirring followed by cooling to 20-30°C. After completion of reaction, the product thus precipitated was
filtered and dried under vacuum. (Yield 80% w/w & purity 99.97% by HPLC).

We claim:
1. A process for the preparation of choline fcnofibrate comprising a step of reacting fenofibric acid with choline chloride in presence of potassium acetate.
2. The process as claimed in claim 1. wherein the reaction is carried out in presence of an alcoholic solvent.
3. The process as claimed in claim 2. wherein an alcoholic solvent is selected from the group consisting of methanol, ethanol. n-propanol. isopropanot. butanol. isobutanol and pentanol.
4. The process as claimed in claim 1. further comprises in-situ purification of choline fcnofibrate with isopropanol.