Title of Invention	A MILD METHOD FOR THE PRODUCTION OF DI-N-PROPYLACETIC ACID ( VALPROIC ACID)
Abstract	A novel process for the production of valproic acid of Formula I, comprising, heating a reaction mixture comprising di-n-propylmalonic acid of Formula (II), metal catalyst in the form of its salt or oxide, and (3) a polar organic solvent, alone or in combination with one another, at 60° to 100°C for 6 to 15 hours to decarboxylate the di-n-propylmalonic acid of Formula II.

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FORM2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2006 PROVISIONAL SPECIFICATION (See section 10; rule 13) 1. Title of the invention -"A MILD METHOD FOR THE PRODUCTION OF DI-N-PROPYLACETIC ACID (VALPROIC ACID)" 2. Applicant(s) (a) NAME: CALYX CHEMICALS AND PHARMACEUTICALS LTD. (b) NATIONALITY : An Indian Company (c) ADDRESS : 5, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India 3. PREAMBLE TO THE DESCRIPTION The following specification describes the invention. FIELD OF THE INVENTION The present invention relates to a novel and mild process for the manufacture of di-n-propylacetic acid, commonly known as valproic acid having formula I. HOOC H Formula I BACKGROUND OF THE INVENTION Valproic acid (2-n-propylpentanoic acid; di-n-propylacetic acid - represented by formula I) and its sodium and magnesium salts have been used primarily in the treatment of epilepsy, the manic phase of bipolar disorder, and as a migraine prophylaxis. Various processes are available in literature for synthesis of valproic acid. The process may be (a) a process using cyanoacetic acid ester as a starting material, (b) a process using acetoacetic acid as a starting material, or (c) a process using malonic acid ester as a starting material. The conventional process is mentioned in Labaz patents, GB 1522450, GB 1529786 and US 4155929. According to the process, ethyl cyanoacetate is dialkylated with propyl bromide in the presence of sodium ethoxide to give ethyl a, a- dipropyl cyanoacetate which is converted to dipropylacetonitrile under alkaline conditions. Alkaline hydrolysis of the same gives valproic acid. 2 The above mentioned reaction is shown in the scheme below. CN COOEt n-Propyl bromide, NaOEt NC .COOEt l.NaOH 2.H+ COOH l.H20/NaOH 2.H+ CN JP 63122646 discloses the preparation of valproic acid comprising (i) obtaining 2,2-dipropylacetoacetic ester (DPAE) by reacting acetoacetic ester with propyl halide, (ii) obtaining valproic acid by deacetylating the DPAE with alcoholic alkaline alkoxid and (iii) hydrolyzing the valproic ester. US 5,856,569 has improvised the above mentioned process wherein (i) acetoacetic ester is reacted with propyl bromide in a biphasic system in the presence of a base and a phase-transfer catalyst to yield 2,2-dipropylacetoacetic ester (DPAE), (ii) contacting the reaction mixture from (i) with an alkali to yield the alkali metal salt of 2,2-dipropyl acetic acid and (iii) acidifying the aqueous phase to yield valproic acid. The reaction is shown in the scheme below: 3 JP 60156638 has disclosed a process, which comprises: (i) reacting an acetoacetic acid ester with an allyl halide to give 2,2-diallyl acetoacetic acid ester, (ii) reacting an alcohol with the 2,2-diallyl acetic acid ester, and (iii) hydrolyzing the diallyl acetic acid ester to give a diallyl acetic acid and reducing the diallyl acetic acid, or (3)' reducing the diallyl acetic acid ester to give a valproic acid ester and hydrolyzing the valproic acid ester. The reaction scheme is as shown below: COCH, CH2=CHCH2X, Base H3COC COOR COOR COOH Hydrolysis COOR Reduction COOH 4 The hydrolysis and decarboxylation of malonic acid esters is a well-known process for preparing mono- or di-substituted carboxylic acids. The malonic acid ester is saponified with aqueous sodium hydroxide to form an aqueous disodium salt and ethanol. The salt solution is treated with a strong mineral acid to get the solid dicarboxylic acid. The dicarboxylic acid is isolated from the solution by conventional separation methods. Synthetic route is shown in the scheme below. COOEt EtOOC COOEt COOEt T C00H HOOC COOH A method for preparing valproic acid from malonic acid ester is disclosed in DE 2853732. Malonic acid diethyl ester was alkylated with propyl bromide in the presence of sodium methoxide, and then saponified with potassium hydroxide to give 2,2-di-n-propyl malonic acid. The pure dipropylmalonic acid is isolated, purified and dried. Only then it is decarboxylated at temperature between 160°C and 165°C, in other words, above the melting point, to dipropyl acetic acid, which then must be purified by fractional distillation. DE 2854195 describes decarboxylation of the 2,2-di-n-propyl malonic acid to get valproic acid by first drying the acid by heating it with toluene to remove water azeotropically and then heating the residue to 160 °C till evolution of carbon dioxide ceased. The heating process was repeated several times to improve the yield of valproic acid. 5 US 4,417,073 discloses a method of getting dipropylacetic acid from dipropylamlonic acid ester by pyrolysis. According to the said method the dipropylmalonic acid ester and water were metered over a period of 19 hours through an evaporator tube into the reactor, filled with a catalyst containing alumina or silica to give 43.7% ethyl ester of valproic acid and 44.3% of valproic acid. The reaction temperature ranged from 298°C to 315°C. In FR 2496646, decarboxylation of dipropyl malonic acid is carried out at 150-155°C in acidic conditions. Another method for preparing valproic acid is disclosed in PL 136,499. Dipropyl malonic acid is decarboxylated by heating at 140° - 145°C in the presence of 2 wt% valproic acid, the valproic acid acting as a decarboxylation catalyst. The known processes for the production of lower alkanoic acids, such as valproic acid from malonic acid ester are generally time consuming procedures, require presence of a strong acid catalyst and very high temperature for decarboxylation. Decarboxylation step is also responsible for the formation of by-products as it is carried out at high temperature (150°-250°C). It is therefore desired to provide a mild and scaleable process for the production of valproic acid from di-n-propylmalonic acid that is cost effective and does not involve drastic conditions for decarboxylation and gives valproic acid, which is devoid of impurities. The problems of the prior art are addressed by the present invention wherein a process for the production of valproic acid is provided. The present inventors have further observed that the decarboxylation takes place in a surprisingly short time. 6 OBJECT OF THE INVENTION It is an object of the present invention to provide a mild process for the production valproic acid. It is a further object of the present invention to provide very mild and easily scaleable process for large scale manufacture of valproic acid. It is another object of the present invention to provide an economically viable process for the production of valproic acid. It is yet another object of the present invention to provide a better yielding process for the production of valproic acid. It is yet another object of the present invention to provide a process for the production of valproic acid with better purity. It is a further object of the present invention to provide an environmentally safe process for the production of valproic acid. SUMMARY OF THE INVENTION According to an aspect of the present invention there is provided a process for the production of valproic acid of formula I comprising decarboxylation of di-n-propylmalonic acid of formula II in a solvent in the presence of a catalyst. HOOC H HOOC yCOCH Formula I Formula II DETAILED DESCRIPTION OF THE PRESENT INVENTION Valproic acid (Formula I) and its sodium and magnesium salts have been used primarily in the treatment of epilepsy, the manic phase of bipolar disorder, and as 7 a migraine prophylaxis. The present invention describes a process for production of valproic acid starting from dipropylmalonic acid of Formula II. The present invention overcomes all the drawbacks of the prior art and is an economically viable, energy saving and less time consuming process. HOOC HOOC ,COOH Formula I Formula II The present inventors have found that valproic acid can be prepared in excellent yield by decarboxylation of dipropylmalonic acid carried out in the presence of a catalyst for instance copper (I) oxide in a solvent under mild conditions. The present invention is carried out at lower temperature and hence does not require special heating system. The present invention also avoids use of strong acid catalyst. The present inventors have observed that the decarboxylation takes place in a surprisingly short time. The reaction is as shown in Scheme-1: HOOC COOH 0.01-0.05 eq Cu(I) CH3CN, 60-100°C ► 95-98% HOOC, Formula II Formula I Scheme-1 The metal catalyst used is in the form of its salt or an oxide for example copper (I) oxide. 8 The molar ratio of the copper (I) catalyst to dipropylmalonic acid is from 0.01:1 to 0.1:1. Preferably the molar ratio of the catalyst to dipropylmalonic acid is from 0.025:1 to 0.05:1, more preferably the molar ratio of the catalyst to the acid is 0.05:1. The solvent used may be a polar organic solvent, water or a combination of the two. Dipropylmalonic acid concentration in the reaction mixture is in the range of 1 to 100% with reference to the solvent, more preferably 25 to 100%, most preferably 50 to 100% with reference to the solvent. The reaction temperature is from 60°C to 100°C, more preferably from 60°C to 90°C, most preferably from 80°C to 90°C. The reaction time is from 6 to 12 hours. The reaction is monitored by TLC and GC. After the reaction is complete, the product is obtained by methods known in literature to get pure valproic acid in greater than 97% yield (GC purity is 99- 100%). The invention is now demonstrated by the following non limiting illustrative example. Example: To the stirred solution of 2,2-di-n-propyl malonic acid (1.0 kg, 5.313 moles) in acetonitrile (2.5 lit) was added copper (I) oxide (38.1gm, 0.266 moles) at room temperature. Brown slurry thus obtained was gradually heated to reflux (oil bath temp = 90°C -100°C). The reaction mixture was allowed to stir continuously at reflux temperature for 12 hrs. Progress of the reaction was monitored by TLC and GC. After 12 hours of heating acetonitrile was distilled off at atmospheric pressure. Traces of remaining solvent from the crude mass were removed under vacuum at 50°C. Thick green mass obtained after drying for 30 minutes was cooled to 25°C and water was added (1.5 lit), followed by 3N aqueous hydrochloric acid (1.0 lit). Reaction mixture was allowed to stir for 30 minutes. It 9 was then extracted with ethyl acetate (3 x 1.0 lit). The combined organic layers were washed with saturated brine solution (2 x 1.0 lit). Ethyl acetate layer was dried over anhydrous sodium sulphate. Solvent was distilled off under reduced pressure. Crude product thus obtained was dried under high vacuum at 50°C for 2 hours to obtain around 800.0 gm of golden yellow liquid. Finally the above product was distilled under high vacuum (10 mm/Hg) at oil bath temp of 145-155 °C (vapor temperature -110 °C-114°C). Yield of the distilled product = 748.2 gm (97.7%, colorless liquid). G.C. Purity = > 99.5%. Above distilled product has similar spectroscopic data (IR, MS, GC) as authentic valproic acid. Dated this 19m day of October 2006 Sonali Bhokarikar (OF S.MAJUMDAR & CO) Applicants' Agent 10

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