FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"IMPROVED PROCESS FOR PREPARING CHOLINE FENOFIBRATE"
2. APPLICANT (S):
(a) NAME: TRICHEM LIFE SCIENCES LIMITED
(b),NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: 212, Abhishek Building, C-5 Dalia Indl. Estate, off New Link Road, Andheri (West), Mumbai - 400 053, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the nature of the invention and the manner
in which it is to be performed.

FIELD OF INVENTION:
The invention provides an improved process for preparing Choline Fenofibrate (Choline salt of fenofibric acid) corresponding to formula (I).

BACKGROUND OF THE INVENTION & DECRIPTION OF THE PRIOR ART:
Fenofibrate belongs to class of compounds of fibrate drugs. It is useful to reduce low -density lipoprotein (LDL) and very low density lipoprotein (VLDL) levels, as well as increasing high-density lipoprotein (HDL) levels and reducing triglycerides level. It also has a beneficial effect on the insulin resistance featured by the metabolic syndrome. Fenofibtrate can be used alone or in conjunction with statins in the treatment of hypercholesterolemia and hypertriglyceridemia.
Fenofibric acid of formula (II) is the active metabolite of fenofibrate, which also produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides rich particles (VLDL) in treated patients.
Fenofibrate and its acid were first disclosed in US patent no. 4058552. The process for synthesis was discussed in this said patent.
Further US patent no. 4179515 describes process for preparation of Fenofibrate. The choline salt of Fenofibric acid was first disclosed and claimed in US patent no. 7259186. This patent narrated two methods.

A first method narrates reaction of fenofibric acid with choline hydroxide in methanol using isopropyl alcohol as solvent. This method narrates use of mixture of solvents posing difficulty in recovery, recycle and reuse.
The second method describes reaction between fenofibric acid and choline chloride using sodium carbonate as base in methanol as solvent. In this method, sodium chloride is obtained as by product which inevitably precipitates out from reaction mixture which is filtered.' However, sodium chloride being partially soluble in methanol passes along with choline salt thereby contaminating the final product.

US Patent application no. 20080275270 describes process for preparation of choline fenofibrate involving reaction of (4-chlorophenyl)(4-hydroyPhenyl)methanone with isopropyl-2-bromo-2-methylpropanoate in presence of P'otassium carbonate to give an

intermediate which is in single operation converted to choline salt of Fenofibric acid using choline hydroxide. The overall yield of the reaction" is 67-70%.

WO2010086700 claims an improved process for the preparation of choline fenofibrate and its novel polymorph designated as form A. In this patent application Fenofibric acid of formula (II) is reacted with choline chloride in presence of organic base in an alcoholic solvent. By product which is hydrochloric acid of organic base is claimed to be highly soluble in the organic solvent and passes completely into filtrate. Choline fenofibrate thus obtained is claimed to be devoid of by product.


In light of above mentioned prior arts, there still exists a need to develop a process for preparation of choline fenofibrate devoid of undesired by product.
Therefore, the object of the present invention is to provide an improved process for manufacture of Choline fenofibrate. The method developed needs to address the above problems in prior art and has to be robust and rugged, so. as to be commercially feasible and environmentally safe.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

Accordingly, the present invention provides an improved overall process to prepare Choline fenofibrate of formula (I), by reacting Fenofibric acid in isopropyl alcohol and choline hydroxide in aqueous 1PA, at reflux temperature to yield choline fenofibrate with high yields. The method according to the present invention uses only single organic solvent viz. isopropyl alcohol which can be routinely recovered, recycled and reused.
In the process of present invention, it is important to distill isopropyl alcohol as azeotrope (88:12 IPA: Water) mixture once the reaction is over, by normal distillation. Equal or partial amount of fresh isopropyl alcohol may be added and continued the operation till the distillate is in conformity with pure isopropyl alcohol i.e. devoid of any moisture content.
The process of conversion of fenofibric acid into choline fenofibrate is carried in the absence of a base. Thus the new process avoids use of any inorganic or organic base thereby totally avoiding the formation/presence of byproducts in the final product, choline fenofibrate. This avoids an additional step of purification that is normally required, in the prior art methods, in the course of preparing pure choline fenofibrate.
Thus the increased yield and purity coupled with recovery, recycle and reuse of the solvent makes the process cost effective and aid in green chemistry.


According to the preferred embodiment, fenofibric acid, choline hydroxide in 45%
aqueous isopropyl alcohol and isopropyl alcohol are charged in a clean agitated stainless
steel reactor provided with heating and cooling arrangement. The combined contents were
tirred and refluxed at about 80-85 deg C for 2 to 4 hours. The reaction is instantaneous
out for ensuring completion of formation of product, it is stirred and refluxed for 2 to 4
lours. After the completion, the reaction mass was subjected to normal distillation to
collect distillate; followed by replenishing with fresh isopropyl alcohol. This distillation
operation was allowed to continue till moisture content of final distillate is below 0.5%
thus ensuring reaction mixture devoid of any trace amount of water. The reaction mixture
was allowed to attain temperature of 25-35 deg C and was then cooled to 0-5 deg C and

stirred further for 2 hours. Solids separated was filtered and washed with chilled isopropyl alcohol and dried at 55-60 deg C.
The following example, which include preferred embodiment, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
EXAMPLE 1
Preparation of Choline fenofibrate
In a clean agitated stainless steel reactor provided with heating and cooling arrangement, were placed 25 kg ( 0.07843 kmoles) of fenofibric acid, 21 kg ( 0.07810 kmoles) choline hydroxide dissolved in 45% aqueous solution in 20 L isopropyl alcohol and 170 L isopropyl alcohol.
The contents were combined, stirred and refluxed at about 82 deg C for 2 to 4 hours. After approximately 2 hours the reaction mass was subjected to normal distillation to collect distillate about 120 L. The reaction mass was replenished with 35 L of fresh isopropyl alcohol. This distillation operation was continued till moisture content of final distillate is below 0.5% thus ensuring reaction mixture is devoid of any trace amount of water. The reaction mixture was allowed to attain temperature of 25-35 deg C and was then cooled to 0-5 deg C and stirred further for 2 hours. Solids separated was filtered and washed with chilled isopropyl alcohol (2 x, 12 L). Solid was dried at 55-60 deg C. Dry weight of Choline fenofibrate 29.6 kg. Yield: 90% Purity: 99.86 % (by HPLC)

We Claim,
1. A process for preparing choline fenofibrate comprising the steps of
a) reacting Fenofibric acid with choline hydroxide using single organic solvent in the absence of a base at reflux temperature to yield choline fenofibrate and
b) isolating choline fenofibrate from the reaction mass.
2. The process according to claim 1, wherein the said isolation comprising a step of distillation of IPA as azeotrope till the pure distillate obtained.
3. The process according to claim 1, wherein said organic solvent is isopropyl alcohol.