Title of Invention	A PROCESS FOR PREPARATION OF FENOFIBRATE
Abstract	A process for producing Fenofibrate Comprising: reacting a phenol derivative represented by formula (II), wherein R = H or alklai metal with Haloisobutyric acid isopropyl ester for Formula III, in the presence of a phase transfer catalyst is disclosed herein.

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FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rulel3) 1. TITLE OF THE INVENTION: "A NEW PROCESS FOR PREPARATION OF FENOFIBRATE" 2. APPLICANT (a) NAME: IPCA LABORATORIES LIMITED (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India 3.PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed. Technical Field The present invention relates to a novel method for preparation of p-carbonylphenoxy-isobutyric acid ester derivatives having medicinal value and more particularly to a novel process for producing p-carbonyl phenoxy-isobutric acid derivative (commonly known as fenofibrate) represented by the following general Formula I: 0 CH, '3 if JJ H3C O "^CH, CH3 0 Formula I Background of the invention The compound represented by the above-mentioned general Formula I, namely the objective compound of the present invention, is known to be useful as a lipids / cholesterol lowering agent; moreover, ' it acts as normolipidemiant and hypocholesterolemiant agents. The free acid of compound of Formula I is known to induce gastric ulcers .when administered by oral route and therefore product is desired to be of high purity &' free from said acid impurity. For details on the synthesis and pharmaceutical use of the above compounds, please see US4058552, US2004073058, US4739101,etc. US4058552 patent gives two processes for the preparation of p-carbonylphenoxy- isobutyic acid ester derivatives of the general Formula I, which are represented in the following scheme. Scheme A: u r rH CK /> V ...OH —^»' |l J^ 'L J H,c"CH3 Br' II ■0 Formula IV 2 B; o Cl>^ r^Y'OH CHCI3 CN-"^1 (^y°^~~OH ^K_/%y NaOH k^xy^.X H3C 3 o o Formula II Formula IV In the first alternative, the phenol derivative of Formula II is reacted with bromo-isobutyric acid to form a p-carbonylphenoxy-isobutyric acid Formula IV. The p-carbonylphenoxy-isobutyric acid of Formula IV is then isolated and converted to the title compound by first transforming to corresponding acid chloride using thionyl chloride followed by esterification with isoprpanol to obtain fenofibrate. In the second alternative the p-carbonylphenol derivative of Formula II is reacted with acetone and chloroform in presence of sodium hydroxide to form the p-carbonylphenoxy-isobutyric, acid, , which is isolated, converted to its acid chloride using thionyl chloride followed by esterification with isoprpanol to provide fenofibrate in a three step procedure. The patentee had also pointed out that alternative A is not preferred due to lower yields „■■*.■.'■■*■' * ' * and purity. It can be seen that both methods are multi-step process and not suitable to yield high purity Fenofibrate in good yield, as the esterification of p-carbonylphenoxy-isobutyric acid of formula IV via the acid chloride formation affects the purity of the product fenofibrate, since it is known to be contaminated with the traces of SO2 or its byproducts (gives foul smell). Hence both methods are not suitable for the production of high purity fenofibrate from industrial view point. Another serious problem associated with the above process is longer and incomplete reaction of p-carbonylphenol and bromo-isobutyric acid, which finally contaminates the product. Another process disclosed in US2004073058 patent describes the reaction of p-carbonylphenol with bromo-isobutyric acid isopropyl ester in presence of potassium bicarbonate in an alcohol solvent at a temperature ranging from room temperature to 100°C and claimed to have better yield & industrial applicability as compared to the use of base potassium carbonate in US4058552. However it has been found that the process 3 still suffers from the above drawbacks like incomplete reaction and longer duration of reaction and no significant advantage is seen using the base potassium bicarbonate as compared to potassium carbonate. US4739101 patent provides yet another process alternative for Fenofibrate comprising p-carbofiylphenol witlrbromo-isobutyric acid isopropyl ester in presence of base potassium carbonate "under "solvent free conditions. This process may be workable at lab scale, however, is not suitable of industrial application, since both potassium carbonate and p-carbonylphenol are solid compounds and reaction mixture is too viscous to be able to mix properly on large scale. The process uses comparatively high temperature for reaction (>140°C) and it has, been observed that even at the above temperature reaction is incomplete. This could be due to lack of effective mixing. According to the above-mentioned known processes, the yield of the compound of general Formula I is as low as about 50 to 69%, because there remains the unreacted phenol compound and requires repeated purification of Fenofibrate to remove the unreacted & side products. Since the contaminative impurity is difficult to remove, production of a compound of Formula I having a high purity requires a complicated process of purification. Objects of the invention It is an object of the present invention to provide a process for producing a phenoxyisobutyric acid ester derivative represented by the general Formula I at a low cost and by a simple procedure. It is another object of the present invention to provide a process for producing a phenoxyisobutyric acid ester derivative represented by the Formula I without any complicated process of purification, in a high yield, and in a high purity. It is yet another object of the present invention to provide an industrially advantageous process for producing the fenofibrate, wherein the reaction can be completed to an extent of less than 1% of starting phenol derivative at a faster pace and the time cycle is reduced. 4 Summary of the invention In view of the above-mentioned present situation, the present inventors have conducted various studies with the aim of achieving the above-mentioned objects. As a result, it has been found in the process of the studies surprisingly that, when a phase-transfer catalyst is used as a catalyst, a compound of Formula I, by a reaction between the phenol of Formula II and the haloisobutyric acid isopropyl ester of Formula III is formed in higher yield and purity in shorter period of time. The reaction is fast and substantially complete conversion of phenol intermediate is achieved, and thereby the objects of the present invention can be met. Based on this finding, the present invention has been accomplished. As used herein, 'halo' phrase in haloisobutyric acid isopropyl ester refers to halogen which are selected from chlorine, bromine or iodine. In a second aspect of the present invention an improved process for esterification of bromo-isobutyric acid is provided, in which the acid is treated with molar amounts of isopropropanol in a solvent medium selected from hydrocarbon solvent and in presence of an acid catalyst like Para toluene sulphonic acid and removing the water formed during the reaction by distillation. The dehydration and anhydride impurity formation are minimized by the practice of the modification proposed in the present invention. Therefore a quantitative yield and purity of the required isopropyl ester intermediate can be achieved by following the process of present invention. Detailed description of the invention According to the present invention, the objective phenoxyisobutyric acid ester derivative represented by the Formula I can be obtained in a high yield and a high purity by reacting a phenol derivative or its alkali metal salt represented by the following Formula II with an ester of haloisobutyric acid of Formula III, o Clv/\, ^^^°R CH3 ,CH3 CL ^-^ ^^ ^0K II ^Y^ + x j —- u^rAJJ C£CH3 Formula II Formula III ° Formula, 5 Wherein R = H or an alkali metal preferably Na, K & R1 = CI - C3 alkyl chain preferably an isopropyl group, halo means chloro, bromo & iodo, in the presence of a phase-transfer catalyst. According to the process of the present invention, Phenol derivative of Formula II and the isopropyl ester of the Formula III can be made to react selectively without hydrolysis to free acid and thereby the objective Fenofibrate of Formula I can be produced on an industrial scale, at a low cost, by a simple procedure, in a high yield and in a high purity. In the process, the reaction between a compound of Formula II and a compound of Formula III is carried out in an appropriate solvent in the presence of a phase-transfer catalyst and further a basic compound. It is advantageous to use catalytic amounts of metal iodide like sodium iodide or potassium iodide in addition to the phase-transfer catalyst. As the solvent used herein, all the inert solvents can be used so far as they exercise no adverse influence on the reaction. Examples of the solvent usable include alcohols such as methanol, ethanol, propanol, isopropyl alcohol, butanol, ethylene glycol, and mixture thereof with or without water; ketones such as acetone, methyl ethyl ketone, ethyl isobutyl ketone and the like; aromatic hydrocarbons such as benzene, o-dichlorobenzene, chlorobenzene, toluene, xylene and the like; and mixtures of the above solvent with water in the ratio of 0 - 50 %. Among these solvents, particularly preferred are alcohols or mixtures of water and an alcohol, preferably the alcohol is isopropyl alcohol. As the basic compound, known ones can be used extensively. Examples thereof include inorganic bases such as sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, cesium carbonate, lithium carbonate,-sodium hydrogen carbonate, potassium hydrogen carbonate, and the like; alcoholates such as sodium methylate, sodium ethylate and the like;.metallic salts of organic acids Such as sodium acetate and the like; Among these bases, inorganic bases such as potassium carbonate, or potassium hydrogen carbonate are particularly preferred. 6 As the phase transfer catalyst, mention can be made of, for example, quaternary ammonium salts substituted with a residue selected from the group consisting of straight or branched chain alkyl group having 1-18 carbon atoms, phenyl lower alkyl group and phenyl group, such as tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, tributylrnethylammonium chloride, tributylbenzylammonium chloride, tetrapentylammonium chloride, tetrapentylammonium bromide, tetrahexylammonium chloride, benzyldimethyloctylammonium chloride, methyltrihexylarnrnonium chloride, benzylmethyloctadecanylammonium chloride, methyltridecanylammonium chloride, benzyltripropylammonium chloride, benzyltriethylammonium chloride, phenyltriethylammonium chloride, tetraethylammonium chloride, tetramethylammonium chloride and the like; phosphonium salts substituted with a residue selected from the group consisting of straight or branched chain alkyl groups having 1-18 carbon atoms such as tetrabutylphosphonium chloride and the like;"and pyridinium salts substituted with a straight or branched chain alkyl group having 1-18 carbon atoms such as l-dodecanylpyridinium chloride and the like. Among these phase transfer catalysts, quaternary ammonium salts substituted with a straight or branched chain alkyl group having 1-18 carbon atoms such as tetrabutylammonium bromide are particularly preferred. The reaction is carried out usually at a temperature not lower than ambient temperature and not higher than 150°C, and preferably at a temperature of 50-100°C most preferably at 80 - 90°C. The reaction time is usually ranges from 35 hours to about 45 hours. It is recommended to use the isobutyric acid isopropyl ester in excess, usually in an amount of at least 1.1 - 2.5 moles, preferably 1.90 to 2.1 mol per mol of the phenol compound of Formula II; to use the basic compound usually in an amount of 1 to 5 mol per mol of the phenol compound of Formula II; to use the phase transfer catalyst usually in an amount of 0.01-1 mol and preferably 0.05 - 0.25 mol to per mol of the phenol compound of Formula II; and to use the metal iodide in an amount of 0.01 to 1 mole and preferably in 0.05 to 0.25 mole to per mol of the phenol compound of Formula II. 7 The compound of Formula I obtained by the above-mentioned reaction can easily be isolated by the conventional separating means. As said separating means, mention can be made of, for example, distillation of solvent and excess reactants followed by crystallization, extraction method using a solvent, dilution method, recrystallization method, column chromatography, preparative thin layer chromatography, etc. The preferred solvents used for crystallization of the compound of Formula I is selected from hexane, heptane, cyclohexane, isopropyl alcohol either single or mixture thereof. The result of the product obtained by following the process of the present invention is compared with process of US4058552, US20040073058 and US4739101 in the following table I substantiating the applicability of the current invention. Table I: Reference Reactants/ Reagents Reaction temp °C Reaction time hr Unreacted Phenol (%) Reaction yield (%) (Based on HPLC Assay) Crudepurity% Purified yield % Finalpurity% US4058552 A B A +Bromoisobutyricacid 100 10 12 -65 75.0 A +. Acetone + Chloroform + NaOH Reflux 10 hr -18 -60.0 65.0 - - US20040073058 A + B + KHCO3 /IPA 82-84 50 hr 5.8 86-88 92.78 67-69 99.78 US4739101 A + B + K2CO3/ Neat 140-43 5hr 21.46 - 68.64 40 - .42 99.50 Present Invention 1] A + B + K2C03 /TBAB, IPA 85-90 ~40hr -1 97.98 99.50 80-84 99.89 2] A + B + K2C03 /TBAB, IPA & Kl 85-90 ~40hr -1 96-97 99.4 80-82 99.80 3] A + B + K2C03 /TBAB, IPA& Water 85-90 ~40hr -1 97.98 99.50 80-82 99.90 4] A + B + K2CO3 / TBAB,Toluene -90 , -40 hr -1 96-97 99.30 80 99.76 Note: TBAB: Tetra butyl ammonium bromide; IPA: Isopropyl alcohol. A: Compound of Formula II; B: Compound of Formula III. 8 The ester derivative of bromo isobutyric acid of Formula III is prepared according to the invention as follows: Bromo isobutyric acid is reacted with C| - C3 alcohol in presence of a catalyst selected from paratoluene sulphonic acid, methane sulphonic acid and sulphuric acid in a solvent medium selected from hydrocarbon solvent, the water formed in the reaction is removed as azeotrope with the hydrocarbon solvent used. In the reaction, the CI - C3 alcohol is selected from methyl alcohol, ethyl alcohol and isopropyl alcohol, most preferably the alcohol used is isopropyl alcohol. The alcohol used in molar amounts as a reactant, preferably in excess in the range of 1 to 5 moles, more preferably 1.5 to 3.0 moles per mole of bromo-isobutyric acid. The hydrocarbon solvents are critically selected from toluene, benzene, xylene, cyclohexane, hexane, heptane or the like where effective removal of water formed in the reaction as azeotrope can be accomplished. The reaction is carried out usually at a temperature not lower than 50°C and not higher than reflux temperature of the solvent and preferably at a temperature of formation of azeotrope of water with the hydrocarbon solvent used. The reaction time is usually from about 10 hours to about 15 hours. The ester derivative of isobutyric acid formed in the reaction is isolated by first distilling the solvents and any excess of the alcohol present^ and finally distilling the product isopropyl ester of bromo-isobutyric acid at reduced pressure of 10 - 12 torr and collecting the fractions of varying GC purity and yield at particular vapour temperature as given in table II. Table II: Fractions Vapour Temperature % Yield GC Purity I] 64 - 80°C -5.0 95-96 II] 80 - 85°C 8.0 98-99 III] 85 - 87°C 86 99.5 - 99.90 Overall yield of ester of] Formula III is 96 - 97%. 9 The current process minimizes the formation of anhydride impurity and dehydrohalogenation as mentioned in WO 2004/052818 Al. EXAMPLES: The following examples, which include preferred embodiments, 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 Fenofibrate: 100g (0.43mole) 4 - Chloro - 4'- hydroxyl benzophenone was charged in isopropyl alcohol (200ml). Stirred and charged 71 g potassium carbonate and 2g tetra butyl ammonium bromide. Raised the temperature to reflux and charged 190g (0.90mole) isopropyl - 2> bromo isobutyrate and continued at reflux further for 40 - 45 hrs. After completion of reaction distilled out solvent and charged 400ml toluene, stirred for 1.0 hr. removed the solid.by filtration and the filtrate subjected to charcoal treatment. Filtered and distilled out solvent completely. Crystallized the residue from isonronvl alcohol to isolate fenofibrate. Yield = 1st crop 130g; Purity by HPLC = 99.89%. End crop- > 10 %.; Purity by HPLC = 99.70%. Example 2. Preparation of Fenofibrate: 100g (0.43mole) 4 - Chloro - 4'- hydroxyl benzophenone was charged in isopropyl alcohol (200ml). Stirred and charged 71g potassium carbonate, 2g tetra butyl ammonium bromide and 2g potassium iodide. Raised the temperature to reflux and charged 190g (0.90mole) isopropyl - 2 - bromo isobutyrate and continued at reflux further for 40 - 45 hrs. After completion of reaction distilled out solvent and charged 400ml toluene, stirred for 1.0 hr. removed the solid by filtration and the filtrate subjected to charcoal treatment. Filtered and distilled out solvent completely. Crystallized the residue from isopropyl alcohol to isolate fenofibrate. Yield= 1st crop l28g; Purity by HPLC = 99.89%. Hnd crop = > 10 %; Purity by HPLC = 99.60%. 10 Example 3. Preparation of Fenofibrate: 100g (0.43mole) 4 - Chloro - 4'- hydroxyl,benzophenone was charged in Toluene (400ml). Stirred and charged 71 g potassium carbonate and 2g tetra butyl ammonium bromide. Raised the temperature to reflux and charged 190g (0.90mole) isopropyl - 2 -bromo isobutyrate and continued at reflux further for 40 - 45 hrs. After completion of reaction cooled the reaction mass to 30 - 40°C filtered the solid. The filtrate after charcoalisation concentrated to dryness. Crystallized the residue from isopropyl alcohol to isolate fenofibrate. Yield = 128g; Purity by HPLC = 99.76%. Example 4. Preparation of Fenofibrate: 100g (0.43mole) 4 - Chloro - 4'- hydroxyl benzophenone was charged in 1:1 mixture of isopropyl alcohol and water (200ml). Stirred and charged 71 g potassium carbonate and 2g tetra butyl ammonium bromide. Raised the temperature to reflux and charged 190g (0.90mole) isopropyl - 2 - bromo isobutyrate and continued at reflux further for 40 - 45 hrs. After completion of reaction cooled the reaction mass to 30 - 40°C, filtered the solid. The filtrate after charcoalisation concentrated to dryness. Crystallized the residue from isopropyl alcohol to isolate fenofibrate. Yield = 13lg; Purity by HPLC = 99.80%. Example 5. Preparation of Isopropyl - 2 - bromo butyrate: 2- Bromo isobutyric acid (200g, 1.19moIe) was charged in toluene (400 ml), stirred and charged para toluene sulphonic acid (13g) and isopropyl alcohol (108g, 1.8mole). The temperature of the reaction was raised to reflux and removed water formed azeotropically from the reaction. Maintained the reaction at reflux till water formation is completely stopped. Distilled out solvent completely and the residue obtained was distilled under high vacuum at 10 - 12 torr to get pure Isopropyl - 2 - bromo isobutyrate. 11 Fractions Vapour Temperature Yield in gm GC Purity I] 64 - 80°C 25-28 95-96 H] 80 - 85°C 18-20 98 - 99 III] 85 - 87°C 215-220 99.5 - 99.90 It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. 12 We Claim, 1. A process for producing Fenofibrate represented by the following Formula I: '3 O C-H, Ck /^ /T\ „.C\ , . 0 .• XH3 JH3C CH3- I which comprises reacting a phenol derivative represented by the following formula (II): Formula II, Wherein R - H, alklai metal with Haloisobutyric acid isopropyl ester of Formula III, in the presence of a phase transfer catalyst Formula III 2. The process as claimed in claim 1, wherein the reaction is in presence of a base compound and an inert solvent. 3. The process as claimed in claim 1 wherein the reaction is carried out in presence of an additional metal iodide. 4. The process as claimed in the claim 3, wherein the metal iodide are sodium iodide or potassium iodide. 5. 'A process for producing a fenofibrate according to claim 1, wherein the reaction is carried out at a reaction temperature not lower than the ambient temperature and not higher than 150° C, in a solvent, in the presence of a basic compound. 6. A process for producing Fenofibrate according to claim 5, wherein the reaction temperature is 50°C to 120°C. 13 7. A process for producing a Fenofibrate according to claim 2 to 5, wherein the solvent used is Q to C4 alcohol, mixture of C1 to C4 alcohols with hydrocarbon solvents like toluene, xylene, or mixture with solvents like methylpropyl ketone etc! 8.. A process for producing fenofibrate according to claim7, wherein the solvent *' further comprises water. 9. A process for producing Fenofibrate according to claim 2 to 5, wherein said inorganic base is potassium carbonate, cesium carbonate or lithium carbonate. 10. A process for producing Fenofibrate according to claim 1, wherein halogen in the haloisobutyric acid of formula (IV) is bromo isobutyric acid. 11. A process for producing Fenofibrate according to any one of the preceding claim, wherein said phase transfer catalyst is a quaternary ammonium salt substituted with a residue selected from the group consisting of straight or branched chain * 12. A process for-producing fenofibrate according to claim 11 wherein said phase transfer catalyst is a quaternary ammonium salt substituted with a straight or branched chain alkyl group having 1-18 carbon atoms. 13. A process for producing fenofibrate according to claim 10, wherein said phase transfer catalyst is tetrabutylammoniurn chloride. 14. A process for; producing fenofibrate according to claim 11 to 13, wherein said phase transfer catalyst is used in an amount of 0.1 to 1 mol per mol of the compound of formula (III). 15. A process for producing fenofibrate according to claim 14, wherein said phase transfer catalyst is used in an amount of 0.1 to 0.5 mol per mol of the compound of formula (III). 16. The process according to claim 1, wherein the haloisobutyric acid ester is prepared by the following procedure: a. Combining halo butyric acid with an alcohol and a catalyst in a solvent selected from hydrocarbon solvent to form a mixture b: Refluxing said mixture and removing water c. Isolating the ester derivative of Formula III. 14 17. The process as claimed in claim 16, wherein the hydrocarbon solvent is toluene, benzene, cyclohexane or xylene. 18. The process as claimed in claim 16, wherein the alcohol is isopropanol and halo butyric acid ester is bromoisobutyric acid isopropyl ester. 15 ABSTRACT: A process for producing Fenofibrate comprising: reacting a phenol derivative represented by formula (II), wherein R = H or alklai metal with Haloisobutyric acid isopropyl ester of Formula III, in the presence of a phase transfer,catalyst is disclosed herein. O 0 CH3 Formula II Formula III 16

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