FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See Section 10)
A PROCESS FOR THE PREPARATION OF ACETIC ACID
DERIVATIVES
HARMAN FINOCHEM LIMITED, 107, Vinay Bhavya Complex, 1st Floor, 159-A, C.S.T. Road, Kalina, Mumbai - 400098, Maharashtra, India, Indian National
The following specification particularly describes the invention and the manner
in which it is to be performed.

1
This invention relates to a process for the preparation of acetic acid derivatives. FIELD OF INVENTION:
The invention particularly relates to a process for the preparation of di-n-propyl acetic acid and its sodium salt.
Still more particularly, the invention relates to a process for the preparation of Valproic acid, sodium valproate and Divalproex sodium of the formula I, II, and III respectively.

CH3CH2CH2
CH3CH2CTI2 ■ Fig. I CH3CH2CH2
CH3CH2CH2.
Fig.II

£HCOOH
£HCOO"Na"

3n7^
3n7
C<*H

-C3H7 C3H7>

■C*H

O'
Na+
O

,0

O'

Na+

O'
HO-

OH
O

3n7
C^H

H7C3

C3H7'

7^3
H7C

Fig.III

2

More particularly, the invention relates to a process for the preparation of acetic acid derivatives with anti-convulsant properties. Still more particularly, the invention relates to a process for the preparation of Divalproex sodium having formula of Fig. III.
Valproic acid having formula of Fig. I has molecular formula C8H16O2 and molecular weight 144.21. It is a liquid at room temperature (20°C to 30°C) and thus it is not suitable for manufacture of solid pharmaceutical dosage forms such as tablets for solid administration. Sodium Valproate having formula of Fig. II is the sodium salt of valproic acid . It has molecular formula C8H15O2 ansd molecular weight 166.19. It is solid at room temperature and does not melt at substantially higher temperatures.
Divalproex sodium having formula of Fig. Ill is an oligomer having about 2 to 20 preferably from 4 to 12 and most probably about 8 of the repeating units. The oligomer is described as a stable crystalline solid.
BACKGROUND OF INVENTION:
Divalproex sodium as indicated herein above 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. But their utility has remained restricted since valproic acid is a liquid and is difficult to formulate for an oral dosage form whereas sodium valproate is a hygroscopic solid with poor stability characteristics. Divalproex sodium is an oligomer having 1:1 molar ratio of valproic acid and sodium valproate.
The relevant prior art known to the inventor includes synthesis of Valproic acid that was first described in the literature by Oberreit in 1896 in 'Berichte der Deutschen Chemischem Gesellschaft Volume 29, page no. 1998. The reference teaches acid catalysed hydrolysis of esters using large amount of acetic acid or formic acid as a solvent in presence of 100 mole % of mineral acid such as methane sulphonic acid. The process poses problems for recovery of product and generation of byproducts. In general the synthesis of Valproic acid was described by three methods
1. Process starting with Ethyl Cyano acetate: This method is reported in
GB1529786, DE 3103776, EP 30528, FR 2496646, US 4155929 and US
4317533.
3

2. Process starting with Ethyl Aceto acetate: This method is reported in DE 3207815, DE 3636818, FR 2599737, JP 60156636, JP 63208552, JP 63122646, US 5101070 and US 5856569.
3. Process starting with Diethyl malonate: This process is reported in DE 2853732, PL 136499, US 4965401, US 5041640 and US 5344975.
GB 2068962 claims a process for preparation valproic acid by acid hydrolysis of di-n-propyl acetonitrile at high temperature using sulphuric acid to produce acetamide, which is further converted to acetic acid.
US 5,041,640 describes a novel process where a carboxylic acid is converted to soluble metalated magnesium or zinc carboxylate followed by subsequent alkylation in presence of alkali amide to get the desired title compound.
US Patent No. 5,101,070 relates to preparation of valproic acid comprising (i) producing a 2,2-dipropyl acetoacetic acid ester from an acetoacetic acid ester using alkalimetal hydroxide, n-propyl halide phase transfer catalyst, (ii) treating with alcohol in presence of alkalimetal hydroxide to give valproic acid ester followed by hydrolysis using sodium hydroxide.
As indicated above the starting material is acetoacetic acid ester and involves three steps to get the end product. Moreover, in addition to being a lengthy process, the process generates large quantity of waste thus impairing environment or require additional steps to manage the waste generated.
US 5,344,975 discloses process for the preparation of lower alkanoic acids including valproic acid comprising acid catalyzed hydrolysis and decarboxylation of substituted malonic esters without using any solvent. The invention claims to overcome the disadvantages associated with the prior art such as requirement of large quantities of reactants, lengthy and time consuming cost extensive procedures, and generation of waste.
Patent No. 732 teaches reacting malonic acid diethyl esters with sodium ethylate and n-propyl bromide to produce dipropyl malonic ester followed by hydrolysis with alkali and then heating at elevated temperature to produce dipropyl acetic acid with splitting of carbon dioxide.
4

The use of sodium ethoxide in the formation di-propyl malonic ester gives more
impurities causing loss of yield and quality. Further, sodium ethoxide requires
maintenance of anhydrous conditions that makes the process unfeasible on industrial
scale.
Patent No 569 as a prior art describes dialkylating cyanoacetate with propyl bromide
and sodium ethoxide to produce dipropyl cyanoacetate, which is further converted to
valproic acid in alkaline environment.
Patent No. 420 teaches preparation of sodium divalproate by treating valproic acid with sodium alkoxide particularly methoxide. The reaction is exothermic that requires stringent operational conditions and the yield is only 88%.
Patent No. 850 relates to preparation of magnesium valproate by reacting valproic acid with magnesium alkoxide.
Canadian Patent No. 558 advocates reacting valproic acid and NaOH to produce sodium hydrogen valproate.
Patent No. 542 suggest preparation of divaloprex sodium by adding sodium valproate to valproic acid at temperature of about 50°C or more.
US 4,988,731 ('731) relates to a non-hygroscopic stable sodium hydrogen divalproate oligomer in which one mole each of the valproic acid forms coordinate bonds with the sodium of the sodium valproate molecule, and the valproate ion is ionically bonded to the sodium atom. The structure is thus consistent with the unique characteristic of the compound. However the preferred mode of representing Divalproex sodium is by reference to single compound.
The said patent also describes two alternative processes for the preparation of the oligomer. According to one aspect, the oligomer is produced by dissolving sodium valproate and valproic acid in equimolar amount in acetone and crystallizing from chilled acetone at around 0°C.
Alternatively Divalproex sodium can be isolated from a two component liquid medium, which includes acetone where in half equivalent of NaOH to the valproic acid present, preferable as a solution in an acetone miscible solvent eg. water. The new compound
5

can be recovered from the liquid phase by evaporating the solvent(s) and, if desired, the new compound can be recrystallized, for instance from acetonitrile or others or the material may be spay-dried, lyophilized or purified by chromatography. US'731 claims yield of 90% of theory.
Drawbacks of the above mentioned reported methods for the preparation of Divalproex sodium described in US 4988731 are difficult to reproduce on a large scale and provides inconsistent yields and the material obtained is not always free flowing in nature. The process involves the crystallization of a 1:1 mixture of valproic acid and sodium valproate from a chilled solution of acetone, followed by washing with chilled acetone. Divalproex sodium is as such fairly soluble in acetone at temperatures above 10°C and extreme care has to be taken while performing washing with chilled acetone as any rise in temperature would lead to the loss of yield. This problem actually comes to the fore while scaling up the process during commercialization since during centrifugation of the large volume the temperature of the mixture rises and acetone has to be cooled below 0°C, which require large amount of liquid nitrogen or dry ice. Moreover it was also observed that due to the cooled nature of the solvent, the isolated Divalproex sodium absorbs considerable amount of moisture and therefore requires longer time to dry eventually leading to longer time cycle for the otherwise simple single step process. 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.
Similarly the other process involves the addition of half molar equivalent of sodium hydroxide dissolved in water to valproic acid and the solvent has to be evaporated to obtain crude product, which has to 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 re-crystallization from acetonitrile making the process lengthy and economically unviable Thus it is obvious that all the existing processes are associated with one or the other problem with regard to cost, ease for manufacture, and quality or yield of the product. The present invention intends to address to these problems and try to overcome if not eliminate all these problems by judiciously using the reactants and reaction conditions.
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The process of this invention employs bulky alkoxide in order to improve the quality and yield of the product. It also uses diethyl malonate in place of acetic acid ester.
SUMMARY OF THE INVENTION:
The main object of the present invention is to provide a process for the preparation of acetic acid derivatives.
The other object of this invention is to provide a process for the preparation of di-n-propyl acetic acid and its sodium salt.
Another object of this invention is to provide a process for the preparation of Divalproex sodium.
Still other object of this invention is to provide a process that is easy to operate cost effective high yielding overcoming the drawbacks of the existing processes to some extent.
Yet other object of this invention is to provide a process that can produce the title compound with greater purity.
STATEMENT OF THE INVENTION:
Accordingly the present invention provides a process for the preparation of acetic acid derivatives comprising:
(i) producing ester of dialkyl malonic acid by reacting dialkyl malonate with n-
propyl halide in presence of alkali metal alkoxide of formula M+OR- wherein
R is having carbon atoms between 3 and 4 ,
(ii) subjecting the said dialkyl malonic acid ester produced in step (i) to alkali
catalyzed hydrolysis followed by decarboxylation in a conventional manner
such as herein described to produce valproic acid,
(iii) optionally purifying the said valproic acid in a known manner and converting
to its sodium/potassium salt using sodium or potassium hydroxide.
7

According to one of the embodiments of the invention the ester of dialkyl malonic acid produced may be such as ester of diethyl or di-n-propyl malonic ester and the dialkyl malonate used may be such as diethyl malonate, dimethyl malonate, methyl ethyl malonate, di-isopropyl malonate, ethyl butyl malonate.
In accordance with other embodiment of the invention, the propyl halide employed may be n-propyl bromide or n-propyl iodide and alkali metal alkoxide used may be bulky alkoxide preferably be t-butoxide or n-propoxide of alkali metal such as sodium, potassium, or lithium.
In accordance with yet other embodiment of the invention, step (i) may be performed at a temperature ranging from room temperature to reflux temperature, preferably
between 500 C to 600C and using the mole ratio of halide in the range of 2 to 5 preferably 2.5 of malonate.
In accordance with yet another embodiment of the invention, alkali catalyzed hydrolysis in step (ii) is carried out employing sodium or potassium hydroxide in alcohol at a temperature ranging from room temperature to reflux temperature while decarboxylation may be performed at a temperature in the range of 1000C to 2500C preferably 180°Cto 190°C.
In accordance with still other embodiment of the invention, the purification of valproic acid in step (iii) may be conducted by distillation under high vacuum; washing sodium/potassium salt with organic solvent selected from halogenated aliphatic hydrocarbon, aliphatic ethers, esters, and aromatic hydrocarbons; charcolising; and acidifying.
In accordance with still another embodiment of the invention, conversion of acid to salt step (iii) may be carried out in presence of aqueous alcohol, preferably methanol, at a temperature ranging from room temperature to reflux temperature, preferably between 50°C to 60°C.
DETAILED DESCRIPTION:
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As required detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which can be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriately detailed structure. Further, the terms and phrases used herein are not intended to be limiting but rather to provide an understandable description of the invention.
Acordingly, this invention provides the process in which diethyl malonate is reacted with n-propyl halide in the presence of alkali metal alkoxide to give the compound having formula of fig. IV
CH3CH2CH2x C00R CH3CH2CH2/ XCOOR
Wherein R= -propyl or butyl group
The n-propyl halide used are n-propyl bromide or n-propyl iodide. The alkali metal alkoxide used are of formula M+OR- wherein M+ is sodium, potassium or lithium and OR- is t-butoxide, n-propoxide. The prefrebably used is sodium t-butoxide & sodium n-propoxide. The reaction is carried out at room temperature to reflux temperature preferabably between 500C to 60°C. The mole ratio of n-propyl halide used is 2 to 5 moles of diethyl malonate preferabaly 2.5 moles.
The compound of formula having fig. IV is then hydrolysed with alkali metal hydroxide in alcohol at high temperature to give compound of formula having fig. V
CII3CH2CH2\ C00H
CH3CH2CH2/ XCOOH
Fig.V
9

The alkali metal hydroxide used is sodium hydroxide, potassium hydroxide. The alcohol used is methanol, ethanol, propanol or any other higher alcohol. The temperature of reaction is room temperature to reflux temperature.
The compound of formula having fig. V is then decarboxylated at high temperature to give compound of formula having fig. I ( Valproic acid). The crude product obtained is first purified by distilling out the product under high vacuum and then optionally purified by dissolving in water with the alkali metal hydroxide. The solution formed is then washed with organic solvent, charcolised and acidified to give highly purified compound of formula having fig. I.
CH3CH2CH2 CH COOH
CH3CH2CH2/
Fig. I (Valproic Acid)
The decarboxylation is carried out at 100-250 °C preferabably between 180-190 °C. The alkali metal hydroxide used is sodium hydroxide, potassium hydroxide. The organic solvent used for washing are halogenated aliphatic hydrocarbon such as methylene dichloride, Ethylene dichloride, chloroform, aliphatic esters such as ethyl acetate, n-butyl acetate, aromatic hydrocarbon such as toluene or aliphatic ether such as di-isopropyl ether, diethyl ether.
10
The compound of formula having fig. I is then reacted with alkali metal hydroxide in water and alcohol to give compound of formula having fig. III.

The reaction is carried out at room temperature to reflux temperature preferably between 50-60 °C. The alkali metal hydroxide used is sodium hydroxide. The alcohol used is methanol, ethanol, propanol or any other higher alcohol preferably methanol.
The compound of formula having fig. Ill is formed as oligomers as reported in literature.
The invention is further illustrated by the process of the examples which do not limit the effective scope of the claims.
Example I:
Preparation of ester of dialkyl di-n-propyl malonic acid (compound of formula
having fig. IV):
Charge tertiary butyl alcohol (6 Kg , 0.081 mole) in a clean and dry flask. Add small pieces of sodium metal (0.25 Kg, 0.011 mole). Heat reaction mass to reflux and maintain reflux till all metals dissolve. Distil a portion of solvent and cool to 60°C.Charge diethyl Malonate (0.692 Kg, 0.0043 mole) at 60-70°C. Cool to 50°C. Add n-propyl bromide (1.3 Kg, 0.0105 mole) at 50-60°C and maintain reaction mixture at 50 to 60°C till completion of reaction on GC. Distil solvent under vacuum up to a maximum temperature of ~100°C. Cool to room temperature, add water to dissolve solid under stirring, acidify liquid mixture with hydrochloric acid, settle for sometime and separate layer. Send sample for analysis. Yield: 0.959 Kg.
Preparation of di-n-propyl malonic acid(compound of formula having fig. V):
In a clean flask, add methanol (5.09 Kg, 0.159 mole). With stirring, add potassium hydroxide flakes (0.909 Kg, 0.016 mole). Cool to room temperature; add ester (0.909 Kg), heat to reflux for completion of hydrolysis. Distil solvent under vacuum. Cool to room temperature, add water to dissolve solid and again distil at atmospheric pressure to ~100°C. Cool and acidify with hydrochloric acid (2.46 Kg) to precipitate di-n-propyl malonic acid. Yield (wet cake): 0.953 Kg.
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Preparation of Valproic Acid (compound of formula having fig. I):
Charge wet di-n-propyl malonic acid (0.903 Kg) in a flask and slowly start heating. Control heating at - 150°C. Continue heating upto ~190°C. Mass will be converted from solid to liquid state. Cool to room temperature. Distill Valproic acid at controlled temperature and pressure. Separately dissolve sodium hydroxide (0.182 Kg, 0.0045 mole) solution in water (2.251 Lt). Dissolve Valproic Acid in aqueous alkali. Add methylene dichloride (1.815 Lt) slowly at 25-30°C and stir. Settle and separate layers. Repeat extraction with methylene dichloride once again. Charcoalise the reaction mixture, filter and wash the charcoal bed. Acidify clear and colorless aqueous filtrate with hydrochloric acid (0.97 Kg). Settle and separate layers to get Valproic Acid. Yield: 0.428 Kg.
Preparation of Divalproex Sodium (compound of formula having fig. Ill):
Charge water (0.118 Lt) and methanol (1.18 Lt) in a clean and dry flask. Charge Valproic acid (0.428 Kg). Start heating slowly and maintain at 50 to 60° C for 4 hr. Add charcoal and stir for some time. Filter and wash charcoal bed with methanol (0.148 Lt). Charge all clear filtrate and washing in distillation flask. Distil under vacuum till mass becomes thick. Remove thick mass from flask and put the material in dryer. Dry material at 70 to 80° C. Yield: 0.419 Kg.
Example II:
Preparation of ester of dialkyl di-n-propyl malonic acid (compound of formula
having fig. IV)-using n-propyl Iodide:
Charge tertiary butyl alcohol (7.5 Lt) in a clean and dry flask. Add small pieces of sodium metal (0.25 Kg). Heat reaction mass to reflux and maintain reflux till all metals dissolve. Distil a portion of solvent and cool to 60°C.Charge diethyl Malonate (0.692 Kg,0.0043 mole) at 60-70°C. Add n-propyl iodide (1.797 Kg) at 50-60°C and maintain reaction mixture at 50 to 60°C till completion of reaction on GC. Distil solvent under vacuum up to a maximum temperature of ~100°C. Cool to room temperature, add
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water to dissolve solid under stirring, acidify liquid mixture with hydrochloric acid, settle for sometime and separate layer. Send sample for analysis. Yield: 0.959 Kg.
Example III:
Preparation of ester of dialkyl di-n-propyl malonic acid (compound of formula
having fig. IV) - Using n-propyl alcohal:
Charge n-Propyl Alcohol (3.75Lt) in a clean and dry flask. Add small pieces of sodium metal (0.25 Kg). Heat reaction mass to reflux and maintain reflux till all metals dissolve. Distil a portion of solvent and cool to 60°C.Charge diethyl Malonate (0.692 Kg, 0.0043 mole) at 60-70°C. Add n-propyl bromide (1.3 Kg, 0.0105 mole) at 50-60°C and maintain reaction mixture at 50 to 60°C till completion of reaction on GC. Distil solvent under vacuum up to a maximum temperature of ~100°C. Cool to room temperature, add water to dissolve solid under stirring, acidify liquid mixture with hydrochloric acid, settle for sometime and separate layer. Send sample for analysis. Yield: 0.959 Kg.
Example IV:
Preparation of ester of dialkyl di-n-propyl malonic acid (compound of formula
having fig. IV)- Reaction at high temperature:
Charge tertiary butyl alcohol (6 Kg ) in a clean and dry flask. Add small pieces of sodium metal (0.25 Kg). Heat reaction mass to reflux and maintain reflux till all metals dissolve. Distil a portion of solvent and cool to 60°C.Charge diethyl Malonate (0.692 Kg, 0.0043 mole) at 60-70°C. Add n-propyl bromide (1.3 Kg) at 50-60°C and maintain reaction mixture at reflux at 80 to 85°C till completion of reaction on GC. Distil solvent under vacuum up to a maximum temperature of ~100°C. Cool to room temperature, add water to dissolve solid under stirring, acidify liquid mixture with hydrochloric acid, settle for sometime and separate layer. Send sample for analysis. Yield: 0.959 Kg.
Example V:
Preparation of di-n-propyl malonic acid(compound of formula having fig. V)-Use
of Aqueous methanol in place of methanol only :
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In a clean flask, add methanol (3.181 Lt) and water 3.18 Lt. With stirring, add potassium hydroxide flakes (0.909 Kg) slowly till dissolution at 30 to 40°C. Cool to room temperature, add ester (0.909 Kg), heat to reflux for completion of hydrolysis. Distil solvent under vacuum. Cool to room temperature, add water to dissolve solid and again distil at atmospheric pressure to ~100°C. Cool and acidify with hydrochloric acid (2.46 Kg) to precipitate di-n-propyl malonic acid. Yield (Wet cake): 0.953 Kg.
Example VI:
Preparation of ester of dialkyl di-n-propyl malonic acid (compound of formula having fig. IV)-change of mole ratio of n-propyl bromide:
Charge tertiary butyl alcohol (7.5 Lt) in a clean and dry flask. Add small pieces of sodium metal (0.25 Kg). Heat reaction mass to reflux and maintain reflux till all metals dissolve. Distil a portion of solvent and cool to 60°C.Charge diethyl Malonate (0.692 Kg, 0.0043 mole) at 60-70°C. Add n-propyl bromide (1.6 Kg, 0.013 mole) at 50-60°C and maintain reaction mixture at 50 to 60°C till completion of reaction on GC. Distil solvent under vacuum up to a maximum temperature of ~100°C. Cool to room temperature, add water to dissolve solid under stirring, acidify liquid mixture with hydrochloric acid, settle for sometime and separate layer. Send sample for analysis. Yield: 0.959 Kg.
Example VII:
Preparation of Valproic Acid (compound of formula having fig. I)-change of decarboxylation temperature (~225°C):
Charge wet di-n-propyl malonic acid (0.903 Kg) in a flask and slowly start heating. Control heating at ~ 150°C. Continue heating upto ~225°C. Mass will be converted from solid to liquid state. Cool to room temperature. Distill Valproic acid at controlled temperature and pressure. Separately dissolve sodium hydroxide (0.182 Kg) solution in water (2.251 Lt). Dissolve Valproic Acid in aqueous alkali. Add methylene dichloride (1.815 Lt) slowly at 25-30°C and stir. Settle and separate layers. Repeat extraction with methylene dichloride once again. Acidify clear and colorless aqueous filtrate with hydrochloric acid (0.97 Kg). Settle and separate layers to get Valproic Acid. Yield: 0.428 Kg.
14

Example VIII:
Preparation of Valproic Acid (compound of formula having fig. I)-change of decarboxylation temperature (~160°C):
Charge wet di-n-propyl malonic acid (0.903 Kg) in a flask and slowly start heating. Control heating at ~ 150°C. Continue heating at ~160°C. Mass will be converted from solid to liquid state. Cool to room temperature. Distill Valproic acid at controlled temperature and pressure. Separately dissolve sodium hydroxide (0.182 Kg) solution in water (2.251 Lt). Dissolve Valproic Acid in aqueous alkali. Add methylene dichloride (1.815 Lt) slowly at 25-30°C and stir. Settle and separate layers. Repeat extraction with methylene dichloride once again. Acidify clear and colorless aqueous filtrate with hydrochloric acid (0.97 Kg). Settle and separate layers to get Valproic Acid. Yield: 0.428 Kg.
Example IX:
Use of Sulphuric acid in place of hydrochloric acid for acidification in various steps
Preparation of ester of dialkyl di-n-propyl malonic acid (compound of formula having fig. IV):
Charge tertiary butyl alcohol (7.5 Lt) in a clean and dry flask. Add small pieces of sodium metal (0.25 Kg). Heat reaction mass to reflux and maintain reflux till all metals dissolve. Distil a portion of solvent and cool to 60°C.Charge diethyl Malonate (0.692 Kg, 0.0043 mole) at 60-70°C. Add n-propyl bromide (1.3 Kg, 0.0105 mole) at 50-60°C and maintain reaction mixture at 50 to 60°C till completion of reaction on GC. Distil solvent under vacuum up to a maximum temperature of ~100°C. Cool to room temperature, add water to dissolve solid under stirring, acidify liquid mixture with sulphuric acid , settle for sometime and separate layer. Send sample for analysis. Yield: 0.959 Kg.
Preparation of di-n-propyl malonic acid (compound of formula having fig. \):
In a clean flask, add methanol (6.36 Lt). With stirring, add potassium hydroxide flakes (0.909 Kg) slowly till dissolution at 30 to 40°C. Cool to room temperature, add ester (0.909 Kg), heat to reflux for completion of hydrolysis. Distil solvent under vacuum. Cool to room temperature, add water to dissolve solid and again distil at atmospheric
15

pressure to ~100°C. Cool and acidify with sulphuric acid (6.66 Kg) to precipitate di-n-propyl malonic acid. Yield (wet cake): 0.953 Kg.
Preparation of Valproic Acid (compound of formula having fig. I):
Charge wet di-n-propyl malonic acid (0.903 Kg) in a flask and slowly start heating. Control heating at ~ 150°C. Continue heating upto ~190°C. Mass will be converted from solid to liquid state. Cool to room temperature. Distill Valproic acid at controlled temperature and pressure. Separately dissolve sodium hydroxide (0.182 Kg) solution in water (2.251 Lt). Dissolve Valproic Acid in aqueous alkali. Add methylene dichloride (1.815 Lt) slowly at 25-30°C and stir. Settle and separate layers.. Repeat extraction with methylene dichloride once again. Acidify clear and colorless aqueous filtrate with sulphuric acid (2.64 Kg). Settle and separate layers to get Valproic Acid. Yield: 0.428 Kg.
Example X:
Preparation of ester of dialkyl di-n-propyl malonic acid (compound of formula having fig. IV)-change of mole ratio of n-propyl bromide ( 2 mole) :
Charge tertiary butyl alcohol (7.5 Lt) in a clean and dry flask. Add small pieces of sodium metal (0.25 Kg). Heat reaction mass to reflux and maintain reflux till all metals dissolve. Distil a portion of solvent and cool to 60°C.Charge diethyl Malonate (0.692 Kg, 0.0043 mole) at 60-70°C. Cool to 50°C. Add n-propyl bromide (1.065 Kg, 0.0086 mole) at 50-60°C and maintain reaction mixture at 50 to 60°C till completion of reaction on GC. Distil solvent under vacuum up to a maximum temperature of ~100°C. Cool to room temperature, add water to dissolve solid under stirring, acidify liquid mixture with hydrochloric acid, settle for sometime and separate layer. Send sample for analysis. Yield: 0.959 Kg.
Example XI:
Preparation of Valproic Acid (compound of formula having fig. I) - use of
Ethylene dichloride in place of methylene chloride for extraction:
Charge wet di-n-propyl malonic acid (0.903 Kg) in a flask and slowly start heating. Control heating at ~ 150°C. Continue heating upto ~190°C. Mass will be converted from solid to liquid state. Cool to room temperature. Distill Valproic acid at controlled
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temperature and pressure. Separately dissolve sodium hydroxide (0.182 Kg) solution in water (2.251 Lt). Dissolve Valproic Acid in aqueous alkali. Add ethylene dichloride (1.815 Lt) slowly at 25-30°C and stir. Settle and separate layers. Repeat extraction with ethylene dichloride once again. Acidify clear and colorless aqueous filtrate with hydrochloric acid (0.97 Kg). Settle and separate layers to get Valproic Acid. Yield: 0.428 Kg.
Example XII:
Preparation of Valproic Acid (compound of formula having fig. I) - use of Ethyl
Acetate in place of methylene chloride for extraction:
Charge wet di-n-propyl malonic acid (0.903 Kg) in a flask and slowly start heating. Control heating at ~ 150°C. Continue heating upto ~190°C. Mass will be converted from solid to liquid state. Cool to room temperature. Distill Valproic acid at controlled temperature and pressure. Separately dissolve sodium hydroxide (0.182 Kg) solution in water (2.251 Lt). Dissolve Valproic Acid in aqueous alkali. Add ethyl acetate (1.815 Lt) slowly at 25-30°C and stir. Settle and separate layers. Repeat extraction with ethyl acetate once again. Acidify clear and colorless aqueous filtrate with hydrochloric acid (0.97 Kg). Settle and separate layers to get Valproic Acid. Yield: 0.428 Kg.
Example XIII:
Preparation of Valproic Acid (compound of formula having fig. I) - use of
Toluene in place of methylene chloride for extraction:
Charge wet di-n-propyl malonic acid (0.903 Kg) in a flask and slowly start heating. Control heating at ~ 150°C. Continue heating upto ~190°C. Mass will be converted from solid to liquid state. Cool to room temperature. Distill Valproic acid at controlled temperature and pressure. Separately dissolve sodium hydroxide (0.182 Kg) solution in water (2.251 Lt). Dissolve Valproic Acid in aqueous alkali. Add toluene (1.815 Lt) slowly at 25-30°C and stir. Settle and separate layers. Repeat extraction with toluene once again. Acidify clear and colorless aqueous filtrate with hydrochloric acid (0.97 Kg). Settle and separate layers to get Valproic Acid. Yield: 0.428 Kg.
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WE CLAIM:
1. A process for the preparation of acetic acid derivatives comprising:
(i) producing ester of dialkyl malonic acid by reacting dialkyl malonate with n-propyl halide in presence of alkali metal alkoxide of formula M+ OR- wherein R is having carbon atoms between 3 and 4,
(ii) subjecting the said dialkyl malonic acid ester produced in step (i) to alkali catalyzed hydrolysis followed by decarboxylation in a conventional manner such as herein described to produce valproic acid,
(iii) optionally purifying the said valproic acid in a known manner and converting to its sodium salt using sodium or potassium hydroxide.
2. A process as claimed in claim 1 wherein, the ester of dialkyl malonic acid produced is ester of diethyl or di-n-propyl malonic ester and the dialkyl malonate used is diethyl malonate, dimethyl malonate, methyl ethyl malonate, di-isopropyl malonate ethyl butyl malonate.
3. A process as claimed in claim 1 wherein, the propyl halide employed is n-propyl bromide or n-propyl iodide and alkali metal alkoxide used is bulky alkoxide preferably t-butoxide or n-propoxide of alkali metal such as sodium, potassium, or lithium.
4. A process as claimed in claim 1 wherein, step (i) is performed at a temperature ranging from room temperature to reflux temperature, preferably between 50 C to 60°C and using the mole ratio of halide in the range of 2 to 5 preferably 2.5 of malonate.
5. A process as claimed in claim 1 wherein, alkali catalyzed hydrolysis in step (ii) is carried out employing sodium or potassium hydroxide in alcohol at a temperature ranging from room temperature to reflux temperature while decarboxylation is performed at a temperature in the range of 100 C to 250 C preferably 180°C to 190°C.
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6. A process as claimed in claim 1 wherein, the purification of valproic acid in step (iii) is conducted by distillation under high vacuum; washing with organic solvent selected from halogenated aliphatic hydrocarbon, aliphatic ethers, esters, and aromatic hydrocarbons; charcolising; and acidifying.
7. A process as claimed in claim 1 wherein, the conversion of acid to salt step (iii) is carried out in presence of aqueous alcohol, preferably methanol, at a temperature ranging from room temperature to reflux temperature, preferably between 50°C to 60°C.
8. A process for the preparation of acetic acid derivatives is substantially as herein described.
Mrs. L. Balasubrahmanyam Applicant's Agent
Dated this 12th day of September 2006
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ABSTRACT
A PROCESS FOR THE PREPARATION OF ACETIC ACID DERIVATIVES
The invention discloses a process for divalproex sodium comprising (i) Producing esters of diethyl/ di-n-propyl malonic acid from diethyl malonate, sodium alkoxide particularly sodium t- butoxide or n-propoxide and n-propyl halide, (ii) hydrolysing the esters of diethyl/ di-n-propyl malonic acid to di-n-propyl malonic acid, subjecting to decarboxylation of di-n-propyl malonic acid to valproic acid and converting valproic acid to divalproex sodium.
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