An improved process for manufacturing of valproic acid and / or its salt

Abstract

The present invention provides an improved process for manufacturing of Valproic acid, intermediates, and sodium salt of valproic acid (Divalproex sodium). The present invention provides sequential additions of reactants and / or catalyst or reagents and / or solvent(s) which is most effective to achieve maximum conversion efficiency, less or no impurity formation, which overall results in increased yield as well as purity not less than 99%. Furthermore, it involves use of green solvents (recover and / or recycle easily); mild & cheaper catalyst or reagent; reduced reaction time and steps to be performed. In the present invention, synthesis of valproic acid is carried out without isolating any intermediate compound; and divalproex sodium is synthesised by heating valproic acid without use of solvent at about 60°C to about 110°C. The obtained compound of formula (Divalproex sodium) is substantially free of impurities.

Description

AN IMPROVED PROCESS FOR MANUFACTURING OF VALPROIC ACID AND / OR ITS SAUTCROSS-REFERENCE TO REEATED APPLICATION

[0001] The present invention claims benefit of Indian Provisional Application No. IN202321067545 filed on October 06, 2023, the entire contents of which are incorporated by reference herein.TECHNICAL FILED

[0002] The present invention relates to an improved process for manufacturing of Valproic acid, intermediates, and sodium salt of valproic acid (Divalproex sodium).BACKGROUND OF INVENTION

[0003] Divalproex sodium is an oligomer composed of valproic acid and sodium valproate in an equal molar ratio (1: 1). It was first disclosed in US4988731 patent. The chemical name of divalproex sodium is sodium bis(2-propylvalerate) hydrogen. Divalproex sodium’s probable structure is shown in Fig 1.

[0004] Divalproex sodium is one of the most widely used epileptic agents presently available in the market. Both the constituents, valproic acid and sodium valproate themselves have also been used for the treatment of epileptic seizures and convulsions.

[0005] Sodium valproate is the sodium salt of valproic acid. Valproic acid is a liquid at a room temperature and is not suitable for easy-to-take oral solid preparations such as tablets. Sodium valproate is a solid at room temperature and has a high melting point. However, sodium valproate easily absorbs moisture, which not only causes certain difficulties in the preparation process but also causes poor stability of pharmaceutical preparations made from sodium valproate.

[0006] Drug synthesis and / or formulation can generate genotoxic impurities. For instance, alkylating agents are potentially carcinogenic compounds that, due to their electrophilicnature, can introduce lesions at nucleophilic centres of DNA. Industrial syntheses generate these compounds as products or byproducts and human exposure can occur through either direct contact with the product or through environmental contamination. Pharmaceutical companies often formulate therapeutic compounds as salts for better stability and absorption (Glowienke et al; “Structure-activity considerations and in vitro approaches to assess the genotoxicity of 19 methane-, benzene- and toluenesulfonic acid esters”; Mutation Research / Genetic Toxicology and Environmental Mutagenesis, Volume 581, Issues 1-2, 7 March 2005, Pages 23-34).

[0007] The impurities may affect the quality and safety of drug products, henceforth, impurity identification and profiling are an integral part of drug quality control and is particularly important for newly developed medications.

[0008] However, process-related impurities are commonly detected by high-performance liquid chromatography (HPLC) during the synthesis and purification steps. As these impurities may affect the quality and safety of drug products, impurity identification and profiling have received considerable attention from regulatory authorities (Poojashree et al., A review on pharmaceutical impurities and its importance in pharmacy, Am. J. Pharm tech Res. 9 (2019)76e87). The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) states that impurities present in quantities above the identification threshold should be identified and characterized (International Conference on Harmonization, ICH Guidelines, Impurities in new drug substances, Q3A, 2006, (p. R2)). All APIs used in human medication must meet the ICH quality guidelines. The quality of any API depends on its synthetic process, potential degradation pathway, and possible side reactions. Consequently, API manufacturers attempt to minimize impurity levels; nevertheless, the formation of impurities cannot be fully avoided.

[0009] According to the regulatory authorities, such as the FDA, EU authorities, and the ICH, a drug manufacturer must submit data demonstrating that the product intended for marketing complies with the regulations about the content of impurities. The content of an unidentified impurity cannot exceed 0.1% by weight, while the amount of a known impurity cannot exceed 0.2%. The drug manufacturer usually submits analytical data to the regulatory authority demonstrating that the content of each impurity is in accordance with the regulations. The regulatory authority checks the submitted data to ensure that the drug is free of impurities and is suitable for marketing.

[0010] Following are the prior art references discloses processes for preparation of valproic acid or its sodium salt (Divalproex sodium).

[0011] US4988731A describes two alternative processes for the preparation of the oligomer (ratio of sodium valproate: valproic acid (1: 1)). The oligomer is produced by dissolving g sodium valproate and valproic acid in equimolar amount in acetone and crystallizing from chilled acetone at around 0°C.

[0012] Alternatively, sodium valproate is formed in situ by adding NaOH in acetone at a level of one half of a molecular equivalent of the valproic acid present, preferably as a solution in an acetone-miscible solvent, e. g. water. The new compound can be recovered by evaporating the solvent(s) and, if desired, it can be recrystallized from acetone / water, acetonitrile or other solvents or the material may be spray-dried, lyophilized or purified by chromatography.

[0013] However, US’731 involves use of chilled solution of acetone for the crystallization of product. Solubility of Divalproex sodium is higher in acetone at the temperatures above 10°C and therefore extreme care should be taken while performing washing with chilled acetone as any rise in temperature would lead to the loss of yield. On commercial scale production, during centrifugation of the large volume of mixture, the temperature of the mixture rises therefore, acetone must be cooled below 0°C, which require large amount of liquid nitrogen (N2) or dry ice.

[0014] Furthermore, it was also observed that due to the cooled nature of the solvent, the isolated Divalproex sodium absorbs considerable amount of moisture and therefore, it requires longer time to dry eventually leading to longer time cycle for the drying otherwise it is a simple single step process.

[0015] Also, the high moisture content in the recovered acetone makes it unsuitable for reuse. Alternatively, to avoid absorption of water, the centrifugation had to be carried out under a blanket of dry nitrogen gas. These additional infrastructural loads add to input costs eventually making the otherwise single step low-cost process becoming uncompetitive and economically unviable.

[0016] Similarly, the other process involves the addition of half molar equivalent of NaOH dissolved in water to valproic acid and the solvent has to be evaporated to obtain crude product, which must be recrystallized to get Divalproex of the desired specification. The process is operationally tedious and requires the reduction in the level of water in the reaction mass via evaporation of the solvent followed by recrystallization from acetonitrile making the process lengthy and economically unviable.

[0017] US5101070 describes a process for preparation of valproic acid, wherein said preparation is carried out by reacting acetoacetic acid methyl ester with an allyl halide inpresence of NaOH and a phase transfer catalyst (PTC- tetrabutylammonium bromide (TBAB)) followed by reduction of unsaturated double bonds with Raney nickel and then hydrolysis at high temperature gives valproic acid. However, this process involves use of Raney Ni, Hydrogen (H2) gas which are expensive; hydrogen (H2) gas is highly flammable (explosive in nature); allyl halides which are not easily available on commercial scale. Thus, the process involves tedious, difficult to operate and lengthy steps increasing the cost of production of sodium valproate.

[0018] IN201621035966 discloses a process of preparation of valproic acid and / or sodium valproate salt, wherein sodium valproate salt is prepared by treating valproic acid with sodium hydroxide in toluene and / or water at 25-30°C. The salt is isolated by removing water by azeotropically at 90-110°C and / or lyophilisation process. Furthermore, it also describes the isolation of sodium valproate from aq. solution of sodium valproate by concentrating sodium valproate aq. solution in agitated thin film drier (ATFD).

[0019] However, the removal of water by azeotropically or lyophilisation process is high energy consuming process. Furthermore, for drying of sodium valproate, special type dryer is required (ATFD dryer). Therefore, there is requirement of huge investment, which ultimately increases overall production cost. Said process also involves use of solvent which also increases overall production cost. Therefore, the process involves tedious and lengthy steps increasing the cost of production of sodium valproate, henceforth it is not viable on commercial scale.

[0020] CN103183600A discloses a method for preparing divalproex sodium. The said preparation is carried out by reacting valproic acid with sodium hydroxide to obtain divalproex sodium; and precipitating under 20-30°C from the organic solvent selected from acetone and / or acetonitrile thereby obtaining a divalproex sodium crystal. However, this method involves number of steps as well as solvent. Solvent employed by this method are in large amounts, it therefore increases production cost.

[0021] W02007004238 A2 discloses a process for the manufacture of divalproex sodium by using NaOH in a solvent (acetone and / or acetonitrile) followed by decolourisation and recrystallisation. However, employed organic solvent amount may require in large volumes which leads to increased production cost.

[0022] CN101003476A discloses a technique for preparing divalproex sodium, wherein the process is carried out by dissolving valproic acid and sodium valproate at a mol ratio of 1 : 1 in an appropriate solvent selected from ethanol, ethylene glycol, isopropyl alcohol, n-propanol,glycerol, n-butanol, pentanol or a mixed solvent thereof, preferably n-butyl alcohol; and distilling the solvent under vacuum at 55-90°C to obtain sodium divalproex.

[0023] Thus, cost of solvent used, and high energy utilization leads to increased production cost.

[0024] US4127604 discloses a process for preparing divalproex, wherein said process is carried out by condensation of ethyl cyanacetate with propyl bromide in presence of sodium in propanol to get ethyl-di-n-propyl cyanoacetate followed by saponification using aqueous sodium hydroxide in the presence of cetyltrimethylammonium bromide(CTAB) to obtain di- n-propyl cyanacetic acid; b) decarboxylation of neat di-n-propyl cyanoacetic acid at 140- 190°C to obtain di-n-propyl acetonitrile; c) hydrolysis of di-n-propyl acetonitrile with 80% sulphuric acid to get di-n-propyl acetamide which on in situ reaction with sodium nitrite (NaNC ) gives valproic acid, the key precursor of divalproex sodium; d) reaction of valproic acid in presence of sodium methoxide in heptane produces. However, sodium (Na) metal is pyrophoric in nature. It is hazardous & difficult to handle on commercial scale. Hydrolysis of di-n-propyl acetonitrile in presence of sulphuric acid and NaNC takes longer time for completion and releases lots of nitrous oxide gas during reaction. All above mentioned disadvantages limit its commercial scale production.

[0025] Therefore, considering above mentioned problems associated with cited prior arts, there is a need to develop an improved process for production of valproic acid and / or its sodium salt substantially free of impurities, which is easy to operate; catalyst & reagent used are cheaper (less expensive) that can be easily available and safe to handle, environmentally friendly; with short production cycle; improve yield and production quality; suitable for low cost large scale industrialization production, which has good flow properties, and better dissolution and solubility properties to obtain formulations with greater bioavailability to get the regulatory approval and is suitable for marketing. The present invention provides an improved process for manufacturing of valproic acid and / or its sodium salt (Divalproex sodium) substantially free of impurities which has advantageous properties such as easy to operate, catalyst and reagent used are cheaper (less expensive) to save synthesis cost, with short production cycle (minimum number of steps involved), yield and production quality is all improved, suitable for large-scale industrialization production.

[0026] Furthermore, the present invention provides sequential additions and / or combinations of reactants and / or catalyst or reagents and / or solvent(s) which is most effective to achieve maximum conversion efficiency, less or no impurity formation, which overall results in increased yield as well as purity.OBJECTS OF THE INVENTION

[0027] The principal object of the present invention is to provide a techno- economically viable and environmentally friendly an improved process for manufacturing of valproic acid and / or sodium salt of valproic acid which is substantially free of impurities.

[0028] One of the objects of the present invention is to provide an improved process for manufacturing of valproic acid and / or sodium salt of valproic acid (Divalproex sodium) with high yield as well as high purity.

[0029] Another object of the present invention is to provide an improved process for manufacturing of highly pure valproic acid and / or its salt which may involve use of minimum number of green solvents or without use (no use) of solvents, require minimum steps to be performed for said manufacturing the compounds.

[0030] Another object of the present invention is to provide catalysts or reagents that can be easily available and safe to handle, environmentally friendly.

[0031] Another object of the present invention is to provide sequential additions and / or combinations of substrates (or reactants) and / or catalyst (or reagents) and / or solvent(s) which is most effective to achieve maximum conversion efficiency, less or no impurity formation which results in increased yield as well as purity.

[0032] Another object of the present invention is to provide an improved method for manufacturing of highly pure valproic acid and / or sodium salt of valproic acid which is a substantially free of impurity selected from propyl bromide, Valeric acid, di-n-propyl acetonitrile (DVL-IC), 2 -carbamoyl-2 -propylpentanoic acid (DVL-03), di-n-propyl acetamide (DVL-ID) and like or combinations thereof.

[0033] Yet another object of the present invention is to provide an improved method for manufacturing of highly pure valproic acid and / or sodium salt of valproic acid herein said salt is substantially free from impurities having genotoxic effect such as n-propyl bromide and residual solvents known as potential precursors thereof.

[0034] Yet another object of the present invention is to provide an improved method for manufacturing of valproic acid and / or sodium salt of valproic acid which makes possible use of cheaper and easily available alternative raw materials aq. NaOH solution, thereby obviating the need of severe anhydrous conditions, expensive solvents, and dangerous bases, for example use of metal hydrides, and organometallic reagents, toxic alkali metal alkoxides, amides, and hydrides.

[0035] Yet still another object of the present invention is to provide an improved process for manufacturing valproic acid and / or sodium salt of valproic acid that can be precise, reproducible and industrially feasible.

[0036] Yet another object of the present invention is to provide a process for manufacturing of the present invention which is easy to operate; catalyst or reagent used are cheaper (less expensive) to save synthesis cost, with short production cycle; improved production quality and yield and suitable for large-scale production.SUMMARY OF THE INVENTION

[0037] One of the aspects of present invention provides an improved process for manufacturing of highly pure valproic acid and / or sodium salt of valproic acid (Divalproex sodium) substantially free of impurity, the process comprising of following multiple steps carried out in one or other sequence or combinations thereof, wherein said method comprises the steps of: a) preparing a base solution comprising a base and a solvent; b) processing a phase transfer catalyst (PTC) followed by an alkyl halide (R-X) compound of formula 2 with the base solution obtained from step (a) at a temperature ranging from ambient to about 75 °C under constant stirring to obtain a clear biphasic solution; c) contacting alkyl cyanoacetate compound of formula 1 with the clear biphasic solution obtained from step (b) at the temperature ranging from ambient to about 75°C to obtain compound of formula 3b; d) optionally, recovering the alkyl halide compound of formula 2 from the compound of formula 3b; e) treating the compound of formula 3b with an acid in presence of PTC in a solvent at a temperature ranging from about 100°C to about 180°C to obtain a compound of formula 4; f) reacting the compound of formula 4 with a base at a temperature in the range from about 60°C to about 120°C to obtain the compound of formula 5; and g) drying the compound of formula 5 to obtain a dried compound of formula 5; wherein the dried compound of formula 5 is obtained with yield ranging from about 90% to about 100%, moisture content not more than 1% (by KF) and is having purity ranging from about 90% to about 100%.

[0038] Another aspect of the present invention provides an efficient, non-complex, techno- economically viable and eco-friendly process for manufacturing of valproic acid and / or its sodium salt which involves an integrated and use of non-complex and energy efficient unit operation significantly reduces energy, processing cost without any use of expensive, hazardous chemicals and chemical reagent.BRIEF DESCRIPTION OF FIGURES

[0039] Figure 1 shows GC analysis of compound of formula 5 (Divalproex sodium; DVL-II)

[0040] Figure 2 depicts HPLC purity of compound of formula 3b (cyano compound, DVL- IB)

[0041] Figure 3 shows GC purity of compound of formula 4 (valproic acid, DVL-I)

[0042] Figure 4 illustrates reaction monitoring: In-process samples by HPLC (Area %) of synthesis of compound of formula 4 (DVL-I) by using compound formula 3b at Zero (0) hrs.

[0043] Figure 5 shows reaction monitoring: In-process samples by HPLC (Area %) of synthesis of compound of formula 4 (DVL-I) by using compound formula 3b at two (02) hrs.

[0044] Figure 6 depicts reaction monitoring: In-process samples by HPLC (Area %) of synthesis of compound of formula 4 (DVL-I) by using compound formula 3b at four (04) hrs.

[0045] Figure 7 depicts reaction monitoring: In-process samples by HPLC (Area %) of synthesis of compound of formula 4 (DVL-I) by using compound formula 3b at six (06) hrs.

[0046] Figure 8 shows reaction monitoring: In-process samples by HPLC (Area %) of synthesis of compound of formula 4 (DVL-I) by using compound formula 3b at eight (08) hrs.

[0047] Figure 9 depicts reaction monitoring: In-process samples by HPLC (Area %) of synthesis of compound of formula 4 (DVL-I) by using compound formula 3b at ten (10) hrs.

[0048] Figure 10 shows reaction monitoring: In-process samples by HPLC (Area %) of synthesis of compound of formula 4 (DVL-I) by using compound formula 3b at twelve (12) hrs.DETAILED DESCRIPTION OF THE INVENTION

[0049] In the specification, different terms are used for describing the invention. The definitions of the terms have been provided below.

[0050] The term ‘improved process’ or ‘process’ used herein refers to a process that involves sequential additions and / or combinations of substrates (or reactants) and / or catalyst (or reagents) or solvent(s) which is most effective to achieve maximum conversion efficiency,less or no impurity formation which results in increased yield as well as purity; and furthermore it involves use of cheaper and easily available alternative raw materials (e.g. NaOH), thereby obviating the need of severe anhydrous conditions, expensive solvents, and dangerous bases, for example use of metal hydrides and organometallic reagents.

[0051] The terms ‘improved process’ and ‘process’ can be used interchangeably in the specification of the present invention.

[0052] The term ‘highly pure’ used herein refers the valproic acid and / or its sodium salt (Divalproex) obtained by the present invention which having purity not less than (NLT) 95%, preferably NLT 98%, most preferably NLT less than 99%.

[0053] The term ‘highly pure valproic acid and / or its sodium salt substantially free of impurity’ used herein refers to valproic acid and / or its sodium (Na) salt containing impurity / impurities content of 0.2% or not more than (NMT) 0.2% (<0.2%), preferably NMT 0.1% (<0.1%), more preferably NMT 0.05% (<0.05%) as measured by HPLC (by area %); wherein the impurity is selected from propyl bromide, valeric acid, di-n-propyl acetonitrile (DVL-IC), 2-carbamoyl-2-propylpentanoic acid (DVL-03), di-n-propyl acetamide (DVL-ID) and combinations thereof. And / or

[0054] The term ‘highly pure valproic acid and / or its sodium salt substantially free of impurity’ refers to valproic acid and its sodium (Na) salt containing propyl bromide content of lOppm or less (<10ppm), preferably less than 5ppm (<5ppm), more preferably less than 2ppm (<2ppm) and still more preferably less than Ippm (<lppm).

[0055] The term ‘valproic acid and / or its sodium salt’ or ‘compound of formula 5’ or divalproex sodium’ or ‘DVL-II’ used herein refers to sodium salt of valproic acid obtained by the present invention. The terms ‘valproic acid and / or its sodium salt’, ‘compound of formula 5’ or divalproex sodium’ and ‘DVL-II’ can be used interchangeably in the specification.

[0056] The term ‘Alkyl cyano acetate (ACA)” or ‘compound of formula 1’ used herein refers to organic compound that contains a carboxylate ester (-COOR1) and a nitrile (-CN) group, wherein R1 is selected from Cl to C5 alkyl group, preferably methyl, ethyl group. The term ‘Alkyl cyano acetate (ACA) and ‘compound of formula 1’ can be used interchangeably in the specification. In the present invention diethyl malonate compound can be used in replacement of alkyl cyano acetate (ACA).

[0057] The term ‘base solution’ used herein refers to a solution is prepared by dissolving a base in a solvent for maintaining a basic condition. In the present invention, base solution is obtained by dissolving sodium hydroxide (NaOH) in water.

[0058] The term ‘phase transfer catalyst’ or ‘PTC’ used herein refers to a quaternary ammonium salt which facilitate interphase transfer of reactants or reagents / catalyst from one phase into another phase, making reactions between reactants or catalyst / reagents in two immiscible phases possible. Thus, reaction is made possible by bringing together the reagents which are originally in different phases.

[0059] The terms ‘phase transfer catalyst’ and ‘PTC’ can be used interchangeably throughout the specification.

[0060] The term ‘clear biphasic solution’ used herein refers to a solution with two immiscible phases wherein the reactants used are totally or maximum solubilized in that phases to occur the further reaction.

[0061] The term ‘solvent’ used herein refers to a substance that can have maximum capacity to dissolve a solute, resulting in a solution. In the present invention solvent used can be polar and / or non-polar solvent. The solvent may include such as but is not limited to water, ketone, alcohol, ether, acids, ester, amide, halogenated solvents, dimethylformamide (DMF), dimethylsulphoxide (DMSO), nitriles and combinations thereof.

[0062] The term ‘dried compound of formula 5’ used herein refers the valproic acid and / or its sodium salt (Divalproex) obtained by the present invention is having moisture content not more than (NMT) 2%(w / w) by Karl -Fisher (KF) method, preferably not more than 1% (w / w) by KF method.

[0063] Furthermore, the term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent, solvent of this invention, ratio, concentration, time, temperature, and the like, is meant to encompass variations of ±10%, ±5%, ±1%, ±0.5%, or even ±0. 1% of the specified amount.

[0064] The present invention provides an improved method for manufacturing highly pure valproic acid and / or its salt, wherein the method is carried out by sequential additions and / or combinations of reactants and / or catalyst or reagents and / or solvent(s) which is most effective to achieve maximum conversion efficiency, less or no impurity formation, which overall results in increased yield as well as purity about not less than 95% by HPLC, preferably about 98%, most preferably about 99%.

[0065] The present invention involves use of green solvents (recover and / or recycle easily), mild & cheaper catalyst or reagent, reduced reaction time and steps to be performed, with improved yield and purity of said compounds.

[0066] One of the embodiments of present invention provides an improved process for manufacturing of valproic acid and / or sodium salt of valproic acid (Divalproex sodium)substantially free of impurity, the process comprising of following multiple steps carried out in one or other sequence or combinations thereof, wherein said method comprises the steps of: a) preparing a base solution comprising a base and a solvent; b) processing a phase transfer catalyst (PTC) followed by an alkyl halide (R-X) compound of formula 2 with the base solution obtained from step (a) at a temperature ranging from ambient to about 75 °C under constant stirring to obtain a clear biphasic solution; c) contacting alkyl cyano acetate compound of formula 1 with the clear biphasic solution obtained from step (b) at the temperature ranging from ambient to about 75°C to obtain compound of formula 3b; d) optionally, recovering the alkyl halide compound of formula 2 from the compound of formula 3b; e) treating the compound of formula 3b with an acid in presence of PTC in a solvent at a temperature ranging from about 100°C to about 180°C to obtain a compound of formula 4; f) reacting the compound of formula 4 with a base at a temperature in the range from about 60°C to about 120°C to obtain the compound of formula 5; and g) drying the compound of formula 5 to obtain a dried compound of formula 5 ; wherein the dried compound of formula 5 is obtained with yield ranging from about 70% to about 100%, moisture content is not more than 1% (by KF) and is having purity ranging from about 90% to about 100%.

[0067] In an embodiment, the manufacturing process is represented as follows.

[0068] Another embodiment of the present invention provides an efficient, non-complex, techno-economically viable and eco-friendly process for manufacturing of valproic acid and / or its sodium salt which involves an integrated and use of non-complex and energy efficient unit operation significantly reduces energy, processing cost without any use of expensive, hazardous chemicals and chemical reagent.

[0069] Another embodiment of the present invention provides an improved process for manufacturing of valproic acid and / or its sodium salt substantially free of impurity, the process comprising: a) treating alkyl cyano acetate compound of formula 1 with alkyl halide compound of formula 2 in presence of a base, a phase transfer catalyst in a solvent to obtain a compound of formula 3b (DVL IB); b) contacting the compound of formula 3b with an acid and PTC in a solvent at a temperature in the range from about 100°C to about 180°C to obtain a compound of formula 4 (DVL-I); c) treating the compound of formula 4 with a base at a temperature in the range from about 60°C to about 120°C to obtain the compound of formula 5; d) drying the compound of formula 5 to obtain a dried compound of formula 5 (DVL-II); wherein the dried compound of formula 5 is obtained with yield ranging from about 70% to about 100%, moisture content not more than 1% (by KF) and is having purity ranging from about 90% to about 100%.

[0070] Another embodiment of the present invention provides an improved method for manufacturing highly pure valproic acid and / or its sodium salt substantially free of impurity, wherein said method further comprises purifying the compound of formula 3b by acid-base treatment.

[0071] Another embodiment of the present invention provides a process for synthesising a compound of formula 4 with impurity not more than (<) 0.05% by HPLC (area %), the process comprising: a. preparing a base solution comprising a base and a solvent; b. processing a phase transfer catalyst (PTC) followed by an alkyl halide (R-X) compound of formula 2 with the base solution obtained from step (a) at a temperature ranging from ambient to about 75°C under constant stirring to obtain a clear biphasic solution;c. contacting alkyl cyano acetate compound of formula 1 with the clear biphasic solution obtained from step (b) at the temperature ranging from ambient to about 75°C to obtain compound of formula 3b; d. optionally, recovering the alkyl halide (R-X) compound of formula 2 from the compound of formula 3b; e. treating the compound of formula 3b with an acid in presence of PTC in a solvent at a temperature ranging from about 100°C to about 180°C to obtain a compound of formula 4 with impurity not more than 0.05%.

[0072] Another embodiment of the present invention provides a process for synthesising compound of formula 4 with impurity not more than (<) 0.05% by HPLC (area %).

[0073] Another embodiment of the present invention provides an improved method for manufacturing of highly pure valproic acid and / or its salt substantially free of impurities, wherein said impurities are selected from n-propyl bromide, valeric acid, di-n-propyl acetonitrile (DVL-IC), 2 -carbamoyl-2 -propylpentanoic acid (DVL-03), di-n-propyl acetamide (DVL-ID), residual solvent and combinations thereof.

[0074] In another embodiment of the present invention there is provided an improved method for manufacturing highly pure valproic acid and / or its salt substantially free of impurity, wherein the impurities are provided as follows:

[0075] In another embodiment of the present invention, there is provided an improved method for manufacturing highly pure valproic acid and / or its sodium salt substantially free of impurity, wherein the obtained valproic acid and / or its sodium salt is free of any traces of impurities, for example n-propyl bromide, valeric acid, di-n-propyl acetonitrile (DVL-IC), 2- carbamoyl-2-propylpentanoic acid (DVL-03), di-n-propyl acetamide (DVL-ID), residual solvent and like or combinations thereof.

[0076] In another embodiment of the present invention there is provided an improved method for manufacturing of highly pure valproic acid and / or its sodium salt substantially free of impurity, wherein total impurities present in the pure valproic acid and / or its sodium salt is not more than (NMT) 0.30% by either HPLC or Gas chromatography (GC).

[0077] In another embodiment of the present invention there is provided an improved method for manufacturing of highly pure valproic acid and / or its sodium salt substantially free of impurity, wherein the impurity is selected from n-propyl bromide, valeric acid, di-n-propyl acetonitrile (DVL-IC), 2 -carbamoyl-2 -propylpentanoic acid (DVL-03), di-n-propyl acetamide (DVL-ID), residual solvent and like or combinations thereof.

[0078] In another embodiment of the present invention there is provided an improved method for manufacturing of highly pure valproic acid and / or its sodium salt substantially free of impurity, wherein the compound of formula 5 obtained is having impurity content of 0.2% or not more than (NMT) 0.2%, preferably NMT 0.1% (<0.1%), more preferably NMT 0.05% (<0.05%) as measured by HPLC (by area %).

[0079] In another embodiment of the present invention, there is provided an improved process for manufacturing of highly pure valproic acid and / or its sodium salt substantially free of impurity, wherein a base solution is prepared by dissolving a base and a solvent at a room temperature (RT).

[0080] In another embodiment of the present invention, there is provided an improved process for manufacturing highly pure valproic acid and / or its sodium salt substantially free of impurity, wherein the base may be organic and / or inorganic base.

[0081] In an embodiment, base is inorganic base.

[0082] In another embodiment of the present invention, there is provided an improved process for manufacturing highly pure valproic acid and / or its sodium salt substantially free of impurity, wherein mole ratio of the base to the compound of formula 4 used in the step (f) is about 0.5: 1.

[0083] In another embodiment of the present invention, there is provided an improved process for manufacturing highly pure valproic acid and / or its sodium salt substantially free of impurity, wherein base used in step (a) and step (f) is selected from sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, hydrogen, Barium monoxide, calcium hydroxide, caesium hydroxide, sodium acid carbonate, potassium carbonate, sodium carbonate, strontium carbonate, Caesium carbonate, vulcanized sodium, sodium hydrogen and like or combinations thereof;

[0084] In an embodiment, base is sodium hydroxide (NaOH).

[0085] In an embodiment, valproic acid and / or its sodium salt produced by the method of present invention is chemically pure having purity greater than about 99%, preferably greater than about 99.5% and containing no single impurity in amounts greater than about 0.2% by HPLC, preferably about 0.15%, more preferably about 0.05% by HPLC.

[0086] In an embodiment of the present invention, wherein the base is inorganic base. The inorganic base may include such as but is not limited to sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, hydrogen, Barium monoxide, calcium hydroxide, caesium hydroxide, sodium acid carbonate, potassium carbonate, sodium carbonate, strontium carbonate, Caesium carbonate, vulcanized sodium, sodium hydrogen and combinations thereof.

[0087] In another embodiment of the present invention, there is provided an improved process for manufacturing of highly pure valproic acid and / or its sodium salt substantial free of impurity, wherein the organic base may include such as but is not limited to metal alkoxide (sodium alkoxide / potassium alkoxide), butyl lithium, pyridine, quinoline, an amine and like or combinations thereof.

[0088] In yet another embodiment of the present invention there is provided an improved process for manufacturing of highly pure valproic acid and / or its salt substantially free of impurity, wherein the sodium alkoxide may be selected from sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropylate, n-butanol sodium or sodium tert-butoxide.

[0089] In yet another embodiment of the present invention there is provided an improved process for manufacturing of highly pure valproic acid and / or its salt substantially free of impurity, wherein the potassium alkoxide can be selected from potassium methoxide,potassium ethoxide, potassium propoxide, potassium isopropoxide, n-butanol potassium or potassium tert-butoxide.

[0090] In another embodiment of the present invention there is provided an improved process for manufacturing of highly pure valproic acid and / or its salt substantially free of impurity, wherein amine can be selected from triethylamine, diethyl amine, tri-n-butylamine, tripropylamine, diisopropylamine or diisopropylethylamine.

[0091] In another embodiment of the present invention, there is provided an improved process for manufacturing of valproic acid and / or its salt, wherein solvent may include polar and / or non-polar solvent.

[0092] In another embodiment of the present invention there is provided an improved process for manufacturing of highly pure valproic acid and / or its salt substantially free of impurity, wherein solvent is selected from water, C1-C5 lower alcohol selected from methanol, ethanol, propyl alcohol, isopropanol, n-butanol, iso-butanol, tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol; ethylene glycol, propane diols, glycerine, n-heptane, N, N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, dioxane, 1 -methyl -2 -pyrrolidinone, methylene dichloride, chloroform, glycol dimethyl ether, diethylene glycol dimethyl ether, glycol mono-ethyl ether and like or combinations thereof.

[0093] In most preferred embodiment of the present invention, the solvent used is water.

[0094] In another embodiment of the present invention there is provided an improved process for manufacturing of highly valproic acid and / or its salt substantially free of impurity, wherein a clear biphasic solution is obtained by adding (processing) phase transfer catalyst followed by an alkyl halide compound of formula 2 into (with) the base solution at a temperature in the range of from ambient to about 60°C under constant stirring.

[0095] In most preferred embodiment of the present invention, wherein the base solution is obtained at the temperature in the range from ambient to about 60°C.

[0096] Another embodiment of the present invention provides an improved method for manufacturing highly pure valproic acid and / or its salt substantially free of impurity, wherein mole ratio of the base to the compound of formula 1 used for preparing the base solution is about 4.5: 1.

[0097] In another embodiment of the present invention there is provided an improved process for manufacturing of highly pure valproic acid and / or its sodium salt substantially free of impurity, wherein the phase transfer catalyst (PTC) is used as quaternary ammonium salt.

[0098] In another embodiment of the present invention there is provided an improved method for manufacturing of valproic acid and / or its salt substantially free of impurity, wherein the phase transfer catalyst (PTC) used in step (b) and / or step (e) is quaternary ammonium salt selected from benzyl trimethylammonium chloride (BTMAC), benzyl trimethylammonium bromide ((BTMAB), benzyl triethylammonium chloride (BTEAC), benzyl triethylammonium bromide (BTEAB), tetramethylammonium chloride (TMAC), Tetrabutylammonium hydrogen-sulfate (TBAHS), tetramethylammonium bromide (TMAB), tetraethylammonium chloride(TEAC), tetraethylammonium bromide (TEAB), tetra-propyl ammonium chloride (TPAC), tetra-propyl ammonium bromide (TPAB), tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), dodecyl trimethylammonium chloride (DTMA-C1), dodecyl trimethylammonium bromide (DTAB / DTMA-Br) and like or combinations thereof.

[0099] In another embodiment of the present invention there is provided an improved method for manufacturing of highly pure valproic acid and / or its salt substantially free of impurity, wherein the phase transfer catalyst (PTC) used in step (b) is tetrabutylammonium bromide (TBAB) used in the ratio of about 10% to the compound of formula 1, and the phase transfer catalyst (PTC) used in step (e) is tetrabutylammonium hydrogen-sulfate (TBAHS) used in the ratio of about 0.7% to the compound of formula 1.

[0100] The quaternary ammonium salt further comprises dodecyl triethylammonium chloride, dodecyl triethylammonium bromide, cetyltrimethylammonium chloride, cetyltrimethylammonium bromide, cetyl triethylammonium chloride, cetyl triethylammonium bromide, and combinations thereof.

[0101] In most preferred embodiment of the present invention, wherein quaternary ammonium salt is tetrabutylammonium bromide (TBAB) or tetrabutylammonium hydrogen- sulfate (TBAHS) and like or combinations thereof.

[0102] In another embodiment of the present invention there is provided an improved process for manufacturing of highly pure valproic acid and / or its salt substantially free of impurity, wherein alkyl halide (R-X) is selected from Ci to C5 alkyl group (R) and X is a halogen selected from the group consisting of fluorine, chlorine, bromine, iodine and combinations thereof.

[0103] In most preferred embodiment of the present invention, alkyl halide (R-X) is n-propyl bromide.

[0104] In most preferred embodiment of the present invention, the alkyl cyano acetate compound of formula 1 is ethyl cyanoacetate.

[0105] In another embodiment of the present invention there is provided an improved process for manufacturing of valproic acid and / or its salt substantially free of impurity, wherein synthesis of intermediate compound of formula 3a / 3b is carried out by contacting alkyl cyano acetate compound of formula 1, preferably ethyl cyano acetate, compound of formula 2 with the clear biphasic solution at the temperature in the range of from ambient to about 75°C, preferably from about 40°C to about 50°C, for a period in the range of from about 30min to about 200 min, preferably about 75min to about 90min, and maintained for additional period ranging from about 15min to about 120min, preferably about 30min.

[0106] In another embodiment of the present invention there is provided an improved process for manufacturing of valproic acid and / or its salt substantially free of impurity, wherein contacting alkyl cyanoacetate compound of formula 1 with the clear biphasic solution obtained from step (b) at the temperature from ambient to about 75°C for a period ranging from about 75min to about 90min optionally maintaining for additional period about 30min to obtain compound of formula 3b.

[0107] In another embodiment of the present invention, wherein mole ratio of compound of formula 2 to the compound of formula 1 used in the step (b) and / or (c)) is about 1: 1.5 to about 1: 4.

[0108] In an embodiment of the present invention, wherein optionally alkyl halide is recovered from the compound of formula 3a / 3b by any conventional methods known in the prior art.

[0109] In an embodiment of the present invention, wherein compound 3b is optionally isolated.

[0110] In another embodiment of the present invention there is provided an improved process for manufacturing of valproic acid and / or its salt, wherein synthesis of compound of formula 4 is carried out by hydrolysing and followed by decarboxylating the compound of formula 3a / 3b simultaneously.[oni] In another embodiment of the present invention there is provided an improved process for manufacturing of valproic acid and / or its salt, wherein the hydrolysis may be carried out in acid or alkaline condition.

[0112] In yet another embodiment of the present invention, wherein said hydrolysing and decarboxylating is carried out by treating compound of formula 3a / 3b with an acid in presence of PTC, preferably TBAHS, at a temperature in the range of from about 100°C to about 180°C, preferably about 140 to aboutl45°C for a period in the range of from about 8 to about 18 hrs, preferably about 12 hrs.

[0113] In most preferred embodiment of the present invention, the acid is selected from sulfuric acid, hydrochloric acid, hydrogen chloride gas, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, acetic acid, trichloroacetic acid, perchloric acid and combinations thereof.

[0114] In another embodiment of the present invention there is provided an improved process for manufacturing of valproic acid and / or its salt, wherein synthesis of compound of formula 5 may be carried out by reacting the compound of formula 4 with a base at a temperature in the range of from about 60°C to about 120°C, preferably about 80°C, for period in the range of from about 3hrs to about 8 hrs, preferably about 5hrs.

[0115] In yet another embodiment of the present invention base is used for synthesis of compound of formula 5 selected from organic and / or inorganic base. The inorganic base may include such as but is not limited to sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, hydrogen, Barium monoxide, calcium hydroxide, caesium hydroxide, sodium acid carbonate, potassium carbonate, sodium carbonate, strontium carbonate, caesium carbonate, vulcanized sodium, sodium hydrogen and combinations thereof; preferably sodium hydroxide (NaOH).

[0116] In most preferred embodiment, inorganic base is sodium hydroxide (NaOH).

[0117] In another embodiment of the present invention there is provided synthesis of compound of formula 5, wherein a mixture comprising the compound of formula 4 and the base, is heated at a temperature in the range of from about 75°C to about 85°C and maintained at the same temperature for the time period in the range of from about 4 to about 6 hrs, preferably about 5 hrs, to obtain a clear solution of the compound of formula 5. Furthermore, the clear solution of the compound of formula 5 is transferred and dried at about 55°C to about 75°C for from about 5 hr to about 12 hrs, preferably about 8 hrs.

[0118] In an embodiment, the compound of formula 5 is obtained with yield in the range of from about 90% to about 100% and is having purity in the range of from about 90% to about 100%.

[0119] In another embodiment of the present invention there is provided an improved process for manufacturing of valproic acid and / or its salt substantially free of impurity, wherein synthesis of compound of formula 5 is carried out without use (absence) of solvent.

[0120] In an embodiment of the present invention, synthesis of compound of formula 5 is a neat reaction.

[0121] The present invention makes possible use of cheaper and easily available alternative raw materials like NaOH solution, water solvent, thereby obviating the need of severeanhydrous conditions, expensive solvents, and hazardous base catalyst such as metal hydrides and organometallic reagents.

[0122] Present invention also offers the method for preparation of intermediate compounds namely compound of formula 1, compound of formula 2, compound of formula 3a / 3b and compound of formula 4 which is used in the manufacturing of valproic acid and / sodium salt of valproic acid.

[0123] In another embodiment of the present invention there is provided an improved process for manufacturing of valproic acid and / or its salt substantially free of impurity, wherein synthesis of compound of formula 5 is carried out without use (absence) of solvent.

[0124] In an embodiment of the present invention, synthesis of compound of formula 5 is a neat reaction.

[0125] In another embodiment of the present invention there is provided an improved process for manufacturing of valproic acid and / or its salt, wherein said reactions are carried out in the presence of a PTC catalyst in biphasic systems, simple, cheap and mild bases like NaOH can be used instead of toxic alkali metal alkoxides, amides, and hydrides.

[0126] In an embodiment, process for manufacturing valproic acid and / or its sodium salt, wherein said process can be carried out in one or more steps and can be carried out alternatively.ADVANTAGES OF THE PRESENT INVENTION:1. Simple, cheap and mild bases like NaOH can be used instead of toxic alkali metal alkoxides, amides, and hydrides as well as Replacement of sodium metal with sodium hydroxide2. Replacement of alcoholic solvent with water, ultimately reduced solvent cost.3. Steps have been carried out in one or other sequence or combinations thereof, which is most effective to achieve maximum conversion efficiency, less or no impurity formation, which overall results in increased yield as well as purity not less than 95%, preferably 98%, most preferably 99%.4. Synthesis of compound of formula 4 (valproic acid) is carried out without isolating any intermediate formed.5. Synthesis of compound formula 5 (Sodium valproate / Divalproex sodium) is carried out without use of any solvents (neat reaction) therefore, it reduces solvent cost as well as recovery cost of solvents ultimately low energy consumption.6. Compound formula 5 (Sodium valproate / Divalproex sodium) obtained by the present invention is substantially free of impurities.

[0127] The following examples are given by way of illustration of the present invention and should not be construed to limit the scope of present disclosure. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide further explanation of the claimed subject matter.Examples1. Synthesis of valproic acid (compound of formula 4):

[0128] 2L 4-neck RBF was equipped with reflux condenser and addition funnel arranged on water bath. 230 ml water was charged. Thereafter 160 gm NaOH was added into the water under stirring. The reaction mass was cooled to 40-45°C. 10 gm TBAB was charged to the reaction mass at 40-45°C followed by 260.0 gm n-propyl bromide was mixed at same temperature. A clear biphasic solution was obtained. 100 gm ethyl cyano acetate was added through dropping funnel at 40-45 °C in 60min to 90 min and maintained the temperature at 50-60°C. A clear and light brown colour biphasic solution was obtained. After completion of addition, reaction mass was stirred for 30 min at 40-60°C (Light yellow colour slimy reaction mass was observed). The reaction mass was cooled to 25oC to 35oC, and 1000 ml water was added and stirred reaction for 15-20 min. Layers were separated, n-propyl bromide was recovered (Wt.:40-50 gm.). Aqueous layer was extracted with MDC (3x times). Aqueous layer in reactor was cooled to 5°C to 15°C. pH was adjusted by cone. HC1. Compound was precipitated (If solid not observe in reaction mass was then seeded with compound of formula 3a / 3b (0.1 g). Precipitate was filtered. Wet cake obtained was recrystallised with water. Expected wet wt. 110-140 gm.

[0129] 244 gm cone, sulphuric acid was added in 115 ml water through dropping funnel below 40°C. Recrystalised wet cake (compound 3a / 3b / DVL-IB) and 0.7 gm TBAHS were charged in above acid solution at 25°C to 35°C. Reaction mass was heated at 135°C to 145°C for 12 hr. Clear solution was observed. After completion of reaction, reaction mass was cooled to 25°C C to 35°C. 200 ml water was added and stirred for 30 minutes. Layers are separated. The crude product was extracted with solvent (heptane and / or MDC) and further was purified by using acid-base treatment. Oily product was obtained (Wt. 65-85 gm). Reaction scheme:2. Synthesis of valproic acid (compound of formula 4) by using different bases:• By using NaHCCh:To a flask, water 57.5 ml and 55.44g sodium bicarbonate were charged. 67.5 g of n-propyl bromide followed by 2.5 gm TBAB were added under stirring. The reaction mixture was heated at 40°C. 25g of ethyl cyanoacetate was added at 40-50°C. After 2 hrs, TLC was taken. TLC showed no product formation.• By using Na^CO^:

[0130] To a flask, 57.5ml water and 69.94g sodium carbonate were charged. 67.5g of n- propyl bromide followed by 2.5g TBAB were added in the above flask under stirring. Reaction mixture obtained was heated to 40°C. 25g of ethyl cyanoacetate was added at 40- 50°C. TLC was checked after 5 hrs, product formation was not observed.• By using triethyl amine (TEA):

[0131] To a flask, 57.5ml water and 66.78g Triethylamine were charged. 67.5g of n-propyl bromide followed by 2.5g TBAB were added under stirring. The obtained reaction mixture was heated to 40°C. 25g of ethyl cyanoacetate was charged at 40-50°C. TLC was checked after 4 hrs. Product formation was not observed.• By using

[0132] To a flask, 57.5ml water and 91.21g potassium carbonate were charged. 67.5g of n- propyl bromide followed by 2.5g TBAB were added under stirring. Obtained reaction mixture was heated to 40°C. 25g of ethyl cyanoacetate was added at 40-50°C. TLC was checked after 5hrs. Product formation was not observed.• By using KOH

[0133] To a flask, 57.5ml water and 37.2g potassium hydroxide were charged. Under stirring, 65g of n-propyl bromide followed by 2.5g TBAB were added. The obtained reaction mixture was heated to 40°C. 25g of ethyl cyanoacetate was added at 40-50°C. TLC was checked after 2 hrs, product formation was not observed.3. Synthesis of compound of formula 4 (By using 1.5 moles of N-Propyl bromide):

[0134] To a flask, 57.5 ml water and 33.15g sodium hydroxide were charged. Under stirring, 40.74 g of n-propyl bromide and followed by 2.5 gm TBAB were added. The reaction mixture was maintained at 60°C. 25 g of ethyl cyanoacetate was added at 40-50°C. Check TLC was taken after 2 hrs, product formation was observed.

[0135] Reaction mass was cooled to room temperature and added 250ml water. pH 1 was adjusted using dilute HC1. The obtained solid was filtered and washed with 100 ml water & suck dried. Wet intermediate (3b) obtained was 17gm. This intermediate was added to flask containing 129ml water, 56gm sulfuric acid and 0.17gm of TBAHS and heated at 130-145 °C for 12 hours. Product was confirmed by TLC. Reaction mass was cooled to room temperature. 50ml water was added and separate layers, organic layer was washed by 50ml water twice. Oil obtained was degassed at 50°C under vacuum to get valproic acid. Yield: 8.12gm4. Synthesis of compound of formula 4 (By using 3.0 moles of N-Propyl bromide)

[0136] To a flask, 57.5 ml water and 33.15g sodium hydroxide were added. Under stirring, 81.49 g of n-propyl bromide followed by 2.5 gm TBAB were charged. Reaction mixture was heated to 60°C. 25g of ethyl cyanoacetate at was added 40-50°C. TLC was taken after 2 hrs, product formation was observed. Reaction mass was cooled to room temperature. 250ml water was added. The pH 1 was adjusted by using dilute HC1. Solid was filtered and washed with 100 ml water & suck dried. Wet Intermediate compound (3b) obtained was 17gm. Wet intermediate (3b) was added to flask containing 129ml water, 56gm sulfuric acid and 0.17gm of TBAHS. Reaction mixture was heated to 130-145 °C for 12 hours. Reaction was confirmed by TLC. Reaction mass was cooled to room temperature. 50ml water was charged and separated layers. Organic layer was washed by water (2x50ml). The oil was degassed at 50°C under vacuum to get valproic acid. Yield: 16.25 gm, Purity: 99.99%.5. Synthesis of compound of formula 4 (By using 4.0 moles of N-Propyl bromide)

[0137] To a flask, 57.5ml water and 33.15g sodium hydroxide were added. Under stirring, 108.66 gm of n-propyl bromide followed by 2.5gm TBAB were charged. Reaction mixture was heated to 60°C. 25g of ethyl cyanoacetate added at 40-50°C. TLC was checked after 2 hrs, product formation was observed. Reaction mass was cooled to room temperature. 250 ml water was added. The pH 1 was adjusted by using dil. HC1 to get intermediate. The solidobtained was filtered and washed with 100 ml water & suck dried. Wet intermediate obtained was 17gm. This intermediate was added to flask containing 129 ml water, 56 gm sulfuric acid and 0. 17gm TBAHS and heated to 130-145°C for 12 hours. Product formation was confirmed by TLC. Reaction mass was cooled to room temperature. 50ml water was added and separated the layers. Organic layer was washed with water (2X50ml). Oil obtained was degassed at 50°C under vacuum to get valproic acid. Yield. 18gm, Purity: 99.98%.

[0138] The compound of formula 4 synthesised by using compound formula 3b were monitored (In-process) by HPLC. The impurity formed during the said process were provided in the table 1 (Figures 4-10). Table 1: Reaction monitoring: In-process samples by HPLC (Area %) of synthesis of compound of formula 4 (DVL-I) by using compound formula 3b.

[0139] From the above table showed that all the impurities were controlled during the synthesis of compound of formula 4 (DVL-I, valproic acid). The synthesised compound of formula 4 is substantially free from the impurities or impurities formed or within the acceptable limit.6. Synthesis of Divalproex sodium (compound of formula 5):

[0140] 4-neck 0.5L RBF equipped with mechanical stirrer, TP and condenser on oil bath.100 gm (compound 4) was charged and cooled to 30 ± 5°C. 13.86 gm sodium hydroxide powder was added to the above compound at 25°C to 35°C. Reaction mass was heated to75°C to 85°C and maintained for 5 hrs. A clear solution was observed. The solution was poured in a tray. A sticky solid compound was obtained. The compound was dried at 55°C to65°C for 8-10 hrs and / or more additional hrs if required. 114 gm compound 5 was obtained.Yield: 92-100%.Reaction scheme:

[0141] Synthesis of Divalproex sodium (compound of formula 5) was obtained as per UnitedStates Pharmacopeia (USP) standard.

[0142] The characteristic features of the synthesised divalproex sodium were provided in the below table 2.Table 2: Characteristic features of the synthesised divalproex sodium

Claims

We Claim:

1. An improved process for manufacturing of highly pure valproic acid and / or its sodium salt (of compound of formula 5) substantially free of impurity, the process comprising: a) preparing a base solution comprising a base and a solvent; b) processing a phase transfer catalyst (PTC) followed by an alkyl halide (R-X) compound of formula 2 with the base solution obtained from step (a) at a temperature ranging from ambient to about 75°C under constant stirring to obtain a clear biphasic solution; c) contacting alkyl cyano acetate compound of formula 1 with the clear biphasic solution obtained from step (b) at the temperature ranging from about ambient to about 75°C to obtain compound of formula 3b; d) optionally, recovering the alkyl halide (R-X) compound of formula 2 from the compound of formula 3b; e) treating the compound of formula 3b with an acid in presence of PTC in a solvent at a temperature ranging from about 100°C to about 180°C to obtain a compound of formula 4; f) reacting the compound of formula 4 with a base at a temperature in the range from about 60°C to about 120°C to obtain the compound of formula 5; and g) drying the compound of formula 5 to obtain a dried compound of formula 5; wherein the dried compound of formula 5 is obtained with yield ranging from about 70% to about 100%, moisture content not more than 1% (by KF) and is having purity ranging from about 90% to about 100%.

2. A process for synthesising a compound of formula 4 with impurity not more than (<) 0.05% by HPLC (area %), the process comprising: a. preparing a base solution comprising a base and a solvent; b. processing a phase transfer catalyst (PTC) followed by an alkyl halide (R-X) compound of formula 2 with the base solution obtained from step (a) at a temperature ranging from ambient to about 75°C under constant stirring to obtain a clear biphasic solution; c. contacting alkyl cyano acetate compound of formula 1 with the clear biphasic solution obtained from step (b) at the temperature ranging from ambient to about 75°C to obtain compound of formula 3b;d. optionally, recovering the alkyl halide (R-X) compound of formula 2 from the compound of formula 3b; e. treating the compound of formula 3b with an acid in presence of PTC in a solvent at a temperature ranging from about 100°C to about 180°C to obtain a compound of formula 4;3. The process as claimed in claim 1, further comprises purifying the compound of formula 3b by acid-base treatment.

4. The process as claimed in claim 1 & 2, wherein the impurity is selected from n-propyl bromide, Valeric acid, di-n-propyl acetonitrile (DVL-IC), 2-carbamoyl-2- propylpentanoic acid (DVL-03), di-n-propyl acetamide (DVL-ID), residual solvent and like or combinations thereof.

5. The process as claimed in claim 1, wherein the compound of formula 5 obtained is having impurity content of 0.2% or not more than (NMT) 0.2%, preferably not more than 0.1% (<0.1%), more preferably not more than 0.05% (<0.05%) as measured by HPLC (by area %).

6. The process as claimed in claim 1, wherein base used in step (a) and step (f) is selected from sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, hydrogen, Barium monoxide, calcium hydroxide, caesium hydroxide, sodium acid carbonate, potassium carbonate, sodium carbonate, strontium carbonate, Caesium carbonate, vulcanized sodium, sodium hydrogen and like or combinations thereof, preferably sodium hydroxide7. The process as claimed in claim 1, wherein solvent is selected from water, C1-C5 lower alcohol selected from methanol, ethanol, propyl alcohol, isopropanol, n- butanol, iso-butanol, tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, ethylene glycol, propane diols, glycerine and combinations thereof., N, N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, dioxane, 1- methyl-2-pyrrolidinone, methylene dichloride, chloroform, glycol dimethyl ether, diethylene glycol dimethyl ether, glycol mono-ethyl ether and like or combinations thereof.

8. The process as claimed in claim 7, wherein solvent is water.

9. The process as claimed in claim 1, wherein the phase transfer catalyst (PTC) used in step (b) and / or step (e) is quaternary ammonium salt selected from benzyl trimethylammonium chloride (BTMAC), benzyl trimethylammonium bromide ((BTMAB), benzyl triethylammonium chloride (BTEAC), benzyl triethylammoniumbromide (BTEAB), tetramethylammonium chloride (TMAC), Tetrabutylammonium hydrogen-sulfate (TBAHS), tetramethylammonium bromide (TMAB), tetraethylammonium chloride(TEAC), tetraethylammonium bromide (TEAB), tetrapropyl ammonium chloride (TPAC), tetra-propyl ammonium bromide (TPAB), tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), dodecyl trimethylammonium chloride (DTMA-C1), dodecyl trimethylammonium bromide (DTAB / DTMA-Br) and like or combinations thereof.

10. The process as claimed in claim 1 & 9, wherein the phase transfer catalyst (PTC) used in step (b) is tetrabutylammonium bromide (TBAB), and the phase transfer catalyst (PTC) used in step (e) is Tetrabutylammonium hydrogen-sulfate (TBAHS).

11. The process as claimed in claim 1, wherein alkyl cyano acetate compound of formula 1 is ethyl cyanoacetate.

12. The process as claimed in claim 1, wherein alkyl halide (R-X) of compound of formula 2 is n-propyl bromide.

13. The process as claimed in claim 1, wherein mole ratio of compound of formula 2 to the compound of formula 1 used in the step (b) and / or (c)) is about 1 : 1.5 to about 1: 4.

14. The process as claimed in claim 1, wherein contacting alkyl cyano acetate compound of formula 1 with the clear biphasic solution obtained from step (b) at the temperature less than or equal to 75 °C,15. The process as claimed in claim 1, wherein the acid is selected sulfuric acid, hydrochloric acid, hydrogen chloride gas, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, acetic acid, trichloroacetic acid, perchloric acid and like or combinations thereof.

16. The process as claimed in claim 1, wherein reacting the compound of formula 4 with base at the temperature ranging from about 75°C to about 80°C to obtain compound of formula 5.

17. The process as claimed in claim 1, wherein compound 3b is optionally isolated.

18. The process as claimed in claim 1, wherein step (f) of claim 1 is carried out without (absence) use of solvent or is a neat reaction.

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