Field of the invention
The present invention relates to a process for the preparation of 2-propylvaleric acid or valproic acid. Background and prior art
Valproic acid is widely used in the pharmaceutical industry for its anticonvulsant and antiepileptic properties. Several synthetic methods have been described for the preparation of valproic acid.
A well-known process for preparing alkanoic acids involves the hydrolysis and decarboxylation of malonic esters. The malonic ester is saponified with aqueous sodium hydroxide to form an aqueous solution of the disodium salt and ethanol. The salt solution is treated with a strong mineral acid to produce a mineral acid sodium salt and solid dicarboxylic acid is precipitated. The dicarboxylic acid is isolated from the solution by conventional separation procedures, such as filtration or extraction and the sodium salt is discarded as waste. The isolated acid is dried and heated to a sufficient temperature to undergo decarboxylation.
The process for the preparation of di-isopropylacetic acid has been described by Sarel, J. Am. Chem.Soc. 78, 5416-5420 (1956). In this process, cyanoacetic acid ester is alkylated in the presence of sodium isopropylate by means of isopropyl iodide. This results in the formation of diisopropylcyanoacetic acid ester, which is decarboxylated to form diisopropylacetonitrile. In further steps, the diisopropylacetonitrile is converted into diisopropylacetic acid via diisopropylacetic acid amide. The application of this reaction route to the synthesis of di-n-propylacetic acid results in total yield of 10 to 40% and therefore this process is commercially unattractive.
East German (DDR) 129776 discloses a process for the preparation of di-n-propylacetic acid which comprises reacting ester of cyanoacetic acid with n-propyl bromide or iodide in the presence of sodium-n-propylate, saponification of the di-n-propylacetic acid ester by means of caustic lye and followed by acidification result in 2,2-di-n-propylcyanoaceticacid which is decarboxylated to form di-n-propylacetonitrile. The acetonitrile is subsequently converted with aqueous sulfuric acid via the acetamide into di-n-propylacetic acid. This process uses expensive n-propyl bromide and sodium-n-propylate and therefore is commercially not viable.
Japanese unexamined patent publication 156638/1985 discloses a process for preparing valproic acid which comprises reacting an acetoacetic acid ester with an allyl halide to give a 2,2-diallylacetoacetic acid ester, followed by reacting with an alcohol to

give a diallylacetic acid and reducing the diallylacetic acid to give valproic acid. This process yields valproic acid with small amount of a-propyl-p-ethyl-acrylic ester as a by-product. Although the amount of the by-product is small, it remarkably lowers the quality of the product, since it cannot be easily removed by usual purification processes. Therefore, the above mentioned process requires an additional step for removing said by-product.
GB2068962 discloses a process for preparing valproic acid which comprises hydrolyzing di-n-propylacetonitrile with 75 to 85% by weight sulphuric acid at a temperature from 80 to 120°C to form di-n-propylacetamide. In this process, a large volume of water is added to the reaction mixture to reduce the sulphuric acid concentration to 55-65% by weight and thereafter heating the diluted reaction mixture under reflux until conversion of the di-n-propylacetamide to di-n-propylacetic acid has been completed. Di-n-propylacetic acid thus obtained is then recovered from the reaction mixture. Recovery of the acid product is carried out by passage of a steam jet through the reaction mixture. This process uses expensive reagent n-butyl lithium for the preparation of di-n-propyl acetonitrile and the valproic acid so obtained contains a smaller quantity of valeric acid as impurity.
US 5101070 discloses a process for producing valproic acid from an acetoacetic acid ester by a three-step process. The first step involves producing a 2,2-dipropyl acetoacetic acid ester from an acetoacetic acid ester in the presence of a base and a phase transfer catalyst. In the second step the 2,2-dipropyl acetoacetic acid ester is deacetylated with an alcohol in the presence of a basic catalyst to give a valproic acid ester. The third step involves hydrolyzing the valproic acid ester to obtain valproic acid.
US 5856569 describes a process for preparing valproic acid from alkyl alkanoylacetatc. The process comprises, dialkylating a p-ketoester with a propyl halogenide by contacting an aqueous phase comprising water, a base and a phase-transfer catalyst and an organic phase comprising the p-ketoester and the propyl halogenide at 60-80°C for at least 25 hours to produce a reaction mixture comprising said aqueous phase and said organic phase, wherein said organic phase contains a dialkyl-P-ketoester; contacting the reaction mixture comprising said aqueous phase and said organic phase with an alkali at 70-90°C for at least 20 hours, to produce in said aqueous phase an alkali salt of valproic acid; and acidifying said aqueous phase to produce valproic acid. The main disadvantage of the process is prolonged reaction time to obtain valproic acid.

J. Org. Chem, Vol. 67, No. 15, 5440-5443, 2002 discloses a two step process for the conversion of both aliphatic and aromatic ketones to the corresponding carboxylic acid. In the first step ketones are converted to epoxynitriles with the darzens reaction. Second step, involves rearrangement of these epoxynitriles wherein epoxynitrile, lithium bromide, acetonitrile, DMF and water were heated and stirred overnight at 91°C to give alkanoic acids. This process uses expensive lithium bromide in stoichiometric quantity.
The prior art processes use hazardous reagents and costly raw materials and therefore, there is a need for developing simple processes for preparing valproic acid. Objects of the invention
An object of the present invention is to provide a commercially scalable process for the preparation of valproic acid in the presence of a phase transfer catalyst. Summary of the invention
The present invention provides a process for preparation of valproic acid of Formula-1, said process comprising;

hydrolyzing epoxy nitrile of Formula-II,

in presence of a phase transfer catalyst, water, and optionally an alkali or alkaline earth metal halide at a temperature in the range of 120°C to 130°C to obtain a mixture; separating an aqueous layer from said mixture; and isolating valproic acid of Formula-I from said aqueous layer. Detailed description of invention
Accordingly, the present invention provides a process for preparation of valproic acid of Formula-!, said process comprising;


a) hydrolyzing epoxy nitrile of Formula-II,

in presence of a phase transfer catalyst and water, at a temperature in the range of 120°C to 130°C to obtain a mixture,
b) separating an aqueous layer from said mixture, and
c) isolating valproic acid of Formula-I from said aqueous layer.
An embodiment of the present invention, the process wherein the phase transfer catalyst is a quaternary ammonium salt.
Another embodiment of the present invention, the process wherein the quaternary ammonium salt is selected from the group consisting of tetramethylammonium chloride, tetramethylammonium bromide, tctraethylammonium chloride, tetraethylammonium bromide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bromide, preferably tetrabutylammonium bromide.
Further embodiment of the present invention, a process wherein hydrolysis of epoxy nitrile of Formula-II is performed optionally in the presence of an alkali or alkaline earth metal halide.
Further embodiment of the present invention provides a process, wherein the alkali or alkaline earth metal halide is selected from the group consisting of lithium bromide, lithium chloride, sodium bromide, sodium chloride, potassium bromide, potassium chloride, calcium chloride, and magnesium bromide.
Yet another embodiment of the present invention provides a process, wherein the alkali earth metal halide is lithium bromide.
Still another embodiment of the present invention provides a process, wherein the phase transfer catalyst is employed in the range of 0.01 to 1 molar equivalent, preferably 0.3 molar equivalents, per 0.1 molar equivalent of alkali or alkaline earth metal halide.
The process of the present invention is depicted in the form of the following scheme-I:


The reaction mechanism for the preparation of valproic acid in presence of a phase transfer catalyst such as TBAB is depicted in the following scheme:

In the present invention, epoxy nitrile of Formula-II, is prepared in the following steps. However, epoxy nitrile of Formula-II can also be prepared in other known methods .
a) adding a strong base to chloroacetonitrile in an organic solvent to obtain a
reaction mixture; and
b) reacting said reaction mixture with 4-heptanone at a temperature in the
range of -78°C to 27°C to obtain epoxy nitrile of Formula-II.
An embodiment of the present invention provides a process, wherein the strong base is alkali or alkaline earth metal alkoxide, hydroxide or hydride.

It is an embodiment of the present invention to provide a process, wherein the alkali metal alkoxide is selected from the group consisting of sodium methoxide, potassium methoxide, sodium ethoxide, and potassium ethoxide, preferably sodium methoxide.
Another embodiment of the present invention provides a process, wherein the alkali or alkaline earth metal hydroxide is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, and barium hydroxide, preferably sodium hydroxide.
Yet another embodiment of the present invention provides a process, wherein the alkali or alkaline earth metal hydride is selected from the group consisting of lithium hydride, sodium hydride, potassium hydride, calcium hydride, and barium hydride, preferably sodium hydride.
An embodiment of the present invention provides a process, wherein the organic solvent is selected from the group consisting of a branched or straight chain C1-C6 alcohol, branched or straight chain C1-C6 ester, dimethylformamide, N-methyl-2-pyrrolidine, dimethylsulfoxide, dimethylacetamide, hexamethyrphosphoramide, tetrahydrofuran, and methyl tertiarybutyl ether preferably methyl tertiarybutyl ether (MTB1-).
In an embodiment of the present invention, the branched or straight chain C1-C6 alcohol is selected from a group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-1-butanol, 3-methyl-l-butanol, 1-hexanol, and 2-hexanol.
In another embodiment of the present invention, the branched or straight chain C1-C6 ester, is selected from a group consisting of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, and t-butyl acetate.
In a preferred embodiment of the present invention, the reaction between said reaction mixture and 4-heptanone is carried out at 0°C to 27°C.
The process of preparation of epoxynitrile of Formula-II is depicted in the form of the following reaction scheme-II:


Scheme-H
In an embodiment of the present invention, epoxy nitrile of Formula-II is prepared from 4-heptanonc, and chloroacetonitrile, in presence of a strong base in an organic solvent. However, other known suitable processes for the preparation of epoxy nitrile can also be used.
As an exemplary embodiment of the present invention, epoxy nitrile is prepared by a process comprising:
reacting 4-heptanone, chloroacetonitrile, potassium hydroxide, a phase transfer catalyst and tetrahydrofuran at room temperature for overnight, followed by filtering the resulting reaction mixture through hyflo and washing the precipitate thus obtained with ethyl acetate, washing the filtrate twice with water, drying over sodium sulphate and concentrating under vacuum to obtain epoxy nitrile of Formula-II.
The process steps of the present invention are described in the following examples, which are only illustrative in nature and should not be construed as limiting the scope of the invention in any manner.
EXAMPLES Preparation of Epoxynitrile of Formula-II Example-1:
A two necked R.B. flask was charged with sodiumhydride (2.5g, O.lOmole) under nitrogen and methyltertiarybutylether (MT13E) (50 ml) was added and the reaction mixture was cooled. To this reaction mixture chloroacetonitrile (7.2g, 0.095 mole) was added dropwise and stirred for 30 minutes. To the resultant reaction mass 4-heptanone (l0g, 0.088 mole) was added dropwise and it was allowed to reach the room temperature, stirred overnight, filtered and the precipitate thus obtained was washed with MTBE. The filtrate was washed twice with water and MTBE layer was separated, dried over sodium sulphate and concentrated under vacuum to obtain 13g (97% of theory) of epoxy nitrile.

Example-2:
A two necked R.B. flask was charged with sodium methoxide (9.4g, 0.17moles) under nitrogen and methyltertiarybutylether (MTBE) (50ml) was added and the reaction mixture was cooled. To this reaction mixture chloroacetonitrile (7.2g, 0.095 mole) was added dropwise and stirred for 30 minutes. To the resultant reaction mass 4-heptanone (l0g, 0.088 mole) was added dropwise and it was allowed to reach the room temperature, stirred overnight, filtered and the precipitate thus obtained was washed with MTBE. The filtrate was washed twice with water and MTBE layer was separated, dried over sodium sulphate and concentrated under vacuum to obtain 1 lg (82% of theory) of epoxy nitrile.
In the above-stated examples, epoxy nitrile was prepared from 4-heptanone, chloroacetonitrile, MTBE and a strong base such as sodium hydride or sodium ethoxide. However, other known suitable processes for the preparation of epoxy nitrile can also be used. Example-3:
4-heptanone (lOg, 0.088 mole), chloroacetonitrile (7.2g, 0.095 mole), potassium hydroxide (5.85g, 0.10 mole), TBAB (2.8g, 0.009 mole) and THF (20ml) were charged in an autoclave. The reaction mixture was stirred overnight at room temperature, and the resulting reaction mixture was filtered through hyflo. The precipitate thus obtained was washed with ethyl acetate. The filtrate was washed twice with water, dried over sodium sulphate and concentrated under vacuum to obtain 8g (60% of theory) of epoxy nitrile. Preparation of Valproic Acid of Formula-] Example-4:
Epoxy nitrile (lOg, 0.065 mole), tetrabutylammonium bromide (TBAB) (2.1g, 0.0065 mole), Lithium bromide (1.13g, 0.012 mole) and water (20ml) were charged into an autoclave and heated overnight at 120°C. After completion of the reaction, aqueous layer was separated and distilled out to yield 6.2g of valproic acid (65% of theory) of Formula-1 with 86% GC purity. Example-5:
Epoxynitrile (lOg, 0.065 mole), tetrabutylammonium bromide (TBAB) (6.3g, 0.02 mole) and water (20ml) were charged into an autoclave and heated overnight at 120°C. After completion of the reaction, aqueous layer was separated and distilled out to yield 6.7g of valproic acid (71% of theory) of Formula-I with 90% GC purity.

Advantages of the invention
The present invention uses water as a single solvent for the hydrolysis.
In the present invention, the product separates out as a layer, which provides easy work up procedure.
The present invention provides a process wherein the phase transfer catalyst and the alkali halide are recovered.

We claim:
I. A process for the preparation of valproic acid of Formula-I, said process
comprising;

a) hydrolyzingepoxy nitrile of Formula-II,

in presence of a phase transfer catalyst, water at a temperature in the range of 120°C to !30°C to obtain a mixture.
b) separating aqueous layer from said mixture, and
c) isolating valproic acid of Formula-I from said aqueous layer.

2. The process as claimed in claim 1, wherein the phase transfer catalyst is a quaternary ammonium salt.
3. The process as claimed in claim 2, wherein the quaternary ammonium salt is selected from the group consisting of tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium chloride, tetraethylammonium bromide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrabutylammonium chloride, and tetrabutylainmonium bromide, preferably tetrabutylammonium bromide.
4. The process as claimed in claim 1, wherein the hydrolysis of epoxy nitrile is performed optionally in the presence of an alkali or alkaline earth metal halide.
5. The process as claimed in claim 4, wherein the alkali or alkaline earth metal halide is selected from the group consisting of lithium bromide, lithium chloride, sodium bromide, sodium chloride, potassium bromide, potassium chloride, calcium chloride, and magnesium bromide, preferably lithium bromide.
6. The process as claimed in claim 1, wherein the phase transfer catalyst is employed in the range of 0.01 to 1 molar equivalent, per 0.1 molar equivalent of alkali or alkaline earth metal halide.

7. The process as claimed in claim 1, where in the phase transfer catalyst is employed in an amount of 0.3 molar equivalent per 0.1 molar equivalent of alkali or alkaline earth metal halide.