FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
"AN IMPROVED PROCESS FOR THE PREPARATION OF DIVALPROEX SODIUM"
UNICHEM LABORATORIES LIMITED, A
COMPANY REGISTERED UNDER THE INDIAN COMPANY
ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED
AT UNICHEM BHAVAN, PRABHAT ESTATE, OFF S. V.
ROAD, JOGESHWARI (WEST), MUMBAI - 400 102,
MAHARASTRA, INDIA

AN IMPROVED PROCESS FOR THE PREPARATION OF DIVALPROEX SODIUM
TECHNICAL FIELD
The present invention provides an improved process for the synthesis of Sodium 2-propylpentanoate 2-propylpentanoic acid (1:1) (Valproate semisbdium or Divalproex sodium).
BACKGROUND OF THE INVENTION
Valproate semisodium or Divalproex sodium chemically known as sodium hydrogen bis(2-propylpentanoate) or Sqdium 2-propylpentanoate 2-propylpentanoic acid (1:1) or sodium valproate and valproic acid in a 1:1 molar ratio, known from U.S. patent no. 4127604 and is represented by compound of structural Formula I

. Divalproex sodium is used for the treatment of manic episodes of bipolar disorder and in rare case it is also used for major depressive disorder, and depressive phases of bipolar disorder. In US it is used as for the treatment of epilepsy, certain side effects of autism, chronic pain associated with neuropathy, and migraine headaches and is marketed as Depakote.
US patent no. 4127604 describes a process for the preparation of Divalproex sodium, which includes:

a) 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 cyanacetic acid at the temperature between 140-190°C to obtain di-n-propyl acetonitrile;
c) hydrolysis of di-n-propyl acetonitrile in presence of 80% sulphuric acid to get di-n-propyl acetamide which on in situ reaction with sodium nitrite gives valproic acid, the key precursor of divalproex sodium;
d) reaction of valproic acid in presence of sodium methoxide in heptane produces divalproex sodium of structural Formula I as indicated in Scheme I.
Scheme I


The process mentioned in the US patent 4127604 has several disadvantages. The overall yield of the reaction (65%-69%) is low. Typical disadvantages are associated with decarboxylation stage that is carried out at higher temperature such as 140°C-190C. It is an energy intensive step. Hydrolysis of di-n-propyl acetonitrile in presence of sulphuric acid and NaNO2 takes longer time for completion and also releases lots of nitrous oxide gas during reaction which limits its commercial scale production
US Patent no. 5101070 describes a process for the preparation of valproic acid. It includes, allylation of beta keto ester with allyl bromide in presence of sodium hydroxide and tetrabutylammonium bromide as a phase transfer catalyst (PTC) followed by reduction of unsaturated double bonds with Raney nickel and then hydrolysis at high temperature gives valproic acid as indicated in Scheme II

US5101070 also discloses the synthesis of valproic acid by alkylation of beta keto ester with propyl bromide in presence of sodium hydroxide and

tetrabutylammonium bromide as a phase transfer catalyst followed by hydrolysis at higher temperature to get valproic acid as indicated in Scheme III.

Scheme II and III of US5101070 mentioned above have several drawbacks. Overall yield is just (65-70%). Reduction of olefins by using Raney nickel and H2 gas in autoclave is a reaction that is carried out under pressure. To conduct it on commercial scale or plant scale is associated with typical difficulties and limits its application.
US patent 5856569 discloses a process for the preparation of valproic acid. It includes alkylation of beta keto ester with propyl bromide in presence of aqueous sodium hydroxide and tetrabutylammonium bromide as a phase transfer catalyst (PTC) followed by hydrolysis using aqueous sodium hydroxide in tetrabutylammonium bromide at higher temperature (80°C) to get valproic acid as indicated in Scheme IV.


Main disadvantages of the reaction taught by US5856569 are: i. Low (43%) overall yield; ii. In alkylation step approximately 11 equivalents of n-propyl bromide is used
and the reaction takes longer time (45 h) for completion; iii. Hydrolysis step also takes longer time (20 h) for completion.
WO 2008/062471 A2 describes a process for the synthesis of valproic acid from diethyl malonate which includes:
i. alkylation of diethyl malonate using propyl bromide in presence of sodium
methoxide; ii. hydrolysis of dialkyl product using aqueous potassium hydroxide to get di-
acid derivative iii. decarboxylation of di-acid derivative in presence of cuprous (I) oxide in acetonitrile produces valproic acid as indicated in Scheme V.


Main disadvantages and limitations of this multiple step synthesis process are poor overall yield and use of expensive unstable cuprous (I) oxide in the process. WO2007/004238 discloses a process for preparing divalproex sodium from valproic acid using sodium hydroxide to get crude divalproex sodium which on recrystallization from acetonitrile produces pure divalproex sodium. Besides moderate yield (50%-%%) of the final step, the patent did not disclose the synthesis ofvalporicacid.
Therefore the processes taught by prior patents and disclosures have several drawbacks namely expensive nature, not suitable for scale up at plant level, energy intensive, difficult, lower yields, longer duration of corrosive reaction and less user friendly. Use of high temperature and longer time to complete the reaction invites safety risks.
Therefore industry strongly needs a simpler, financially cheaper, energy economic and an environment friendly process. Industry needs a process better than known processes that can be carried out at lower temperatures in shorter durations. Thus, the industry needs a process to produce valproic acid and divalproex sodium that

can be carried out at lower temperatures yet giving good yields. The process should be free from hazards and drawbacks of prior art.
OBJECT OF THE INVENTION
The main object of the present invention is to provide a simpler process to prepare valproic acid and divalproex sodium.
Another object of the invention is to provide a cost effective, environment friendly and energy economic process to prepare valproic acid.
Yet another object of the invention is to provide a process to prepare divalproex sodium with good yield.
SUMMARY OF THE INVENTION:
According to the first aspect of the present invention a process for the preparation of divalproex sodium of the Formula I is provided. The process comprises:
i) condensation of C1-C5 alkyl cyanacetate with propyl bromide in presence of sodium in alcoholic solvent to get alkyl-di-n-propyl cyanacetate followed by saponification of alkyl-di-n-propyl cyanacetate using aqueous base at 60°C-100°C in presence of a Phase Transfer Catalyst (PTC) to obtain di-n-propyl cyanacetic acid;
ii) one step conversion of di-n-propyl cyanacetic acid formed in step i) to valproic acid in presence of an acid and a PTC at 110 C-130 C, optionally isolating di-n-propyl acetonitrile and di-n-propyl acetamide;
iii) reaction of valproic acid formed in step ii) with sodium salt or sodium base in an organic solvent at 50°C-100°C to produce divalproex sodium as indicated in Scheme VI.


DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of divalproex sodium of Formula I from valproic acid, which is prepared form alkyl cyanacetate. The process comprises:
i) condensation of C1-C5 alkyl cyanacetate with propyl bromide in presence of sodium in alcoholic solvent to get alkyl-di-n-propyl cyanacetate followed by saponification of alkyl-di-n-propyl cyanacetate using aqueous

base at 60 C-100 C in presence of a PTC to obtain di-n-propyl cyanacetic acid;
ii) one step conversion of di-n-propyl cyanacetic acid formed in step i) to valproic acid in presence of an acid and a PTC at 110°C-130°C, optionally isolating di-n-propyl acetonitrile and di-n-propyl acetamide;
iii) reaction of valproic acid formed in step ii) with a sodium salt or sodium base in an organic solvent at 50°C-100°C to produce divalproex sodium as indicated in Scheme VI.
Condensation of C1-C5 alkyl cyanacetate, with n-propyl bromide in presence of sodium in alcoholic solvent gives alkyl-di-n-propyl cyanacetate. C1-C5 alkyl cyanacetate envisaged by this invention are methyl cyanacetate, ethyl cyanacetate or propyl cyanacetate; preferred being ethyl cyanacetate to give ethyl-di-n-propyl cyanacetate. Alcoholic solvent can be selected from methanol, ethanol, propanol and isopropanol; more preferably propanol. Ethyl-di-n-propyl cyanacetate, obtained in the previous step, is hydrolyzed to di-n-propyl cyanacetic acid in presence of an aqueous base selected from sodium hydroxide, potassium hydroxide or calcium hydroxide at an ambient temperature such as 60°C-100°C, more preferably 75°C to 85°C in the presence of a phase transfer catalyst (PTC), wherein the PTC is selected from tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide, tetrabutylammonium hydrogen sulphate (TBAHS) and cetyltrimethylammonium bromide more preferably tetrabutylammonium hydrogen sulphate.
Di-n-propyl cyanacetic acid is decarboxylated and hydrolyzed using acid at an ambient temperature such as 100 C-130 C, more preferably 110 C to 120 C in presence of a PTC such as tetrabutylammonium hydrogen sulphate to produce valproic acid via the formation of di-n-propyl acetonitrile and di-n-propyl acetamide, wherein the acid is selected from sulphuric acid, acetic acid,

hydrochloric acid, trifluoroacetic acid or mixture thereof, more preferably mixture of sulphuric acid and acetic acid and wherein PTC is selected from the catalysts listed above. Novelty and inventive step of the invention resides in one pot transformation of di-n-propyl cyanacetic acid to valproic acid, wherein the intermediates; di-n-propyl acetonitrile and di-n-propyl acetamide can be optionally isolated.
Valproic acid is reacted with a sodium base or sodium salt in an organic solvent at an ambient temperature of 50°C to 100°C and more preferably from 55 °C to 85°C, to produce crude divalproex sodium, wherein the base or salt is selected from sodium hydroxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodium carbonate and sodium bicarbonate, preferably sodium hydroxide and wherein organic solvent is acetone, methanol, ethanol or toluene or mixtures thereof, preferred being acetone. The crude valproic acid is purified by crystallizing it in acetonitrile to get pure ICH quality divalproex sodium (Scheme VII).
The inventive step of the present invention is one step formation of valproic acid from di-n-propyl cyanacetic acid using a mixture of sulphuric acid and acetic acid at 110°C-130°C in presence of tetrabutylammonium hydrogen sulphate (TBAHS). Novelty resides in a single pot transformation reaction optionally isolating di-n-propyl acetonitrile and di-n-propyl acetamide to get valproic acid.
Present invention overcomes the drawbacks of the prior art as process disclosed by the present invention provi'des.
i) higher overall yield (70% - 80%) as compared to the yield obtained in US
4127604 (60%-70%); ii) three step synthesis as compared to four step synthesis of US 4127604; iii) single step, one pot synthesis of valproic acid form Di-n-propyl cyanacetic acid optionally isolating di-n-propyl acetonitrile and di-n-propyl acetamide;

iv) decarboxylation reaction at the temperature of 110°C - 130 C as compared to 140°C - 190°C as in US 4127604; there is no evolution of nitrous oxide gas as in US 4127604.

In C1-C5 alkyl cyanacetate C1-C5 alkyl is to be construed as methyl, ethyl, propyl and remaining straight and branched chain alkyl moieties. Terms Cyanacetate and cyanoacetate are used interchangeably and have same meaning as an ester of 2-cyano-2-propenoic acid. PTC meaning a phase transfer catalyst such as tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide, tetrabutylammonium hydrogen sulphate (TBAHS) and cetyltrimethylammonium bromide.

The term simpler reaction is to be interpreted to mean simplicity of the procedures involved with respect to the use of non-hazardous reactants, shorter duration of the reactions and better scalability at plant level. Improved process is to be construed in the view of better overall yield, less energy intensive and reduced costs of inputs. Better process and or improved process is also to be interpreted as process that enables production of valproic acid from starting materials as described in the invention herein.
EXAMPLES
EXAMPLE 1: Preparation-di-n propyl cyanacetic acid
A) Preparation of sodium propoxide:
n-Propanol (NPA), 1000 mL was taken in a dry 2L, 4-neck round bottom flask equipped with a mechanical stirrer and 50.8 g of sodium metal pieces were slowly added to it. The reaction mixture was then stirred at room temperature for 1.0 h to 1.5 h. After the complete dissolution of sodium, n-propanol was distilled out under vacuum to get sodium propoxide as a solid powder.
B) Preparation of di-n propyl cyanacetic acid:
Ethyl cyanoacetate (ECA) 100 gm and n-propyl bromide (NPB) 239.2 gm was taken in a dry 2L, 4-neck round bottom flask with mechanical stirrer and stirred for 10-15 min at room temperature. Slowly previously prepared sodium propoxide solution (Sodium propoxide in 10 vol of n-propanol) was added to the reaction mixture at room temperature and stirred for 1.0 h to 1.5 h. After the completion of the reaction monitored by GC, n-propanol (NPA) was distilled out at atmospheric pressure. The residual mass was cooled to room temperature. A solution of 44.2 gm of sodium hydroxide in 440 mL water and 0.35 gm of TBAB was added to the reaction mass. The reaction mixture was heated to

80°C-85°C and maintained while stirring at that temperature for 1.0 h. After the completion of the reaction, as monitored by GC analysis, distilled out ethanol that was formed during reaction, and traces of n-propanol under vacuum of 80-100 Torr at 50°C-60°C. The reaction mass was then cooled to 10°C-15°C and acidified using drop wise addition of 125 mL 36% HC1 to make the pH approximately 1-2. Organic phase was separated out and extracted the aqueous layer by using toluene 100 mL (1.0 Vol). After the distillation of toluene under reduced pressure at 45°C-50 C, di-n-propyl cyanacetic acid was obtained as light brown to dark brown colored viscous liquid. Results: % Yield: 90-94%
EXAMPLE II: Preparation of valproic acid
Crushed ice 190 gm was taken in a dry 2L, 4-neck round bottom flask equipped with a mechanical stirrer and stirred for 10-15 min at room temperature. Sulphuric acid (351 gm, 98%) was slowly added to the crushed ice at that temperature and stirred for 15 minutes. Externally cooled the reaction mixture to 25°C-30°C and di-n-propyl cyanacetic acid (136 gm) and acetic acid (200 gm) was added to it. Tetrabutylammonium hydrogen sulphate (TBAHS) (0.68 gm) was added to the reaction mixture at 25°C-30°C. Heated the reaction mixture to 1100C-130°C and stirred it for 15-16 h as required to complete the reaction (monitored by GC). After the completion of reaction the mixture was cooled to 10 C -15°C and brine solution (8.0 Vol) was added to it. The product was then extracted with toluene by using acid base treatment to get crude valproic acid as a light brown to dark brown colored viscous liquid. The crude valproic acid was purified by vacuum distillation under reduced pressure.
Results: Yield : 85-90 %
Purity :98.5%(GC)

EXAMPLE III: Preparation of divalproex sodium
Valproic acid (90 gm) and acetone (270 gm) was taken in a dry 2L, 4-neck round
bottom flask equipped with a mechanical stirrer and stirred for 10-15 min at room
temperature. Sodium hydroxide (12.5 gm) pellets were added to the reaction
mixture in one lot and raised the temperature to 60°C. The reaction mixture was
then stirred for lh to get clear solution. Acetone was distilled out at atmospheric
pressure and acetonitrile (630 mL) was added to it. The reaction mixture was then
heated to 81°C till clear solution was observed. Cooled the reaction mixture to 5°C -
10°C and filtered the solid material under nitrogen atmosphere to get divalproex
sodium as a white solid.
Result: Yield : 92-95 %
Purity : 99.9 % (GC)
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the said invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the true spirit or scope of the present invention as exemplified and claimed herein below.

We claim:
1. A process for the preparation of divalproex sodium of the Formula I,
comprising:
i) condensation of alkyl cyanacetate with n-propyl bromide in presence of sodium in an alcoholic solvent to get alkyl-di-n-propyl cyanacetate followed by saponification using aqueous base at an ambient temperature in presence of a PTC to prepare di-n propyl cyanacetic acid;
ii) one step conversion of di-n-propyl cyanacetic acid prepared in step i) to valproic acid in presence of an acid and a PTC at an ambient temperature, optionally isolating di-n-propyl acetonitrile and di-n-propyl acetamide;
iii) reaction of valproic acid prepared in step ii), with sodium salt or sodium base in an organic solvent at an ambient temperature to produce divalproex sodium.
2. The process according to claim 1 i) wherein the alkyl cyanacetate is selected from group consisting of C1-C5 alkyl cyanacetate such as methyl cyanacetate, ethyl cyanacetate, propyl cyanacetate, and cyanacetate compounds of straight and branched chain alkyl moieties upto C5, more preferably ethyl cyanacetate.
3. The process according to claim 1 i) wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol and more preferably propanol.
4. The process according to claim 1 i) wherein the aqueous base is selected from sodium hydroxide, potassium hydroxide and calcium hydroxide, more preferably sodium hydroxide.

5. The process according to claim 1 i) wherein the ambient temperature is in
the range of 60°C to 100°C, more preferably 75°C to 85°C.
6. The process according to claim 1 ii) wherein the ambient temperature is
' from 100°C to 130°C, more preferably from 110°C -120°C.
7. The process according to claim 1 ii) wherein the PTC is selected from tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulphate and cetyltrimethylammonium bromide, more preferably tetrabutylammonium hydrogen sulphate.
8. The process according to claim 1 ii) wherein the acid is selected from Sulphuric acid, acetic acid, hydrochloric acid, trifluoroacetic acid or mixture thereof, more preferably mixture of sulphuric acid and acetic acid.
9. The process according to claim 1 iii) wherein the sodium salt or sodium base is selected from the group consisting of sodium hydroxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodium carbonate and sodium bicarbonate, more preferably sodium hydroxide and the organic solvent is selected from acetone, methanol, ethanol and toluene or mixtures thereof, more preferably acetone.
10. The process according to claim 1 iii) wherein the ambient temperature is from 50°C to 100°C and more preferably from 55 °C to 85°C.