FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
[See section 10 and rule 13]
1. TITLE OF THE INVENTION:
"ONE POT PROCESS FOR THE PREPARATION OF DIALKYLATED
MALONIC ACID"
2. APPLICANT(S):
(a) NAME: HARMAN FINOCHEM LIMITED
(b) NATIONALITY: Indian Company incorporated under The
Companies Act, 1956
(c) ADDRESS: 107, Vinay Bhavya Complex, 159-A, C.S.T. Road,
Kalina, Mumbai-400098, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes this invention and the manner in which it is to be performed:

ONE POT PROCESS FOR THE PREPARATION OF DIALKYLATED MALONIC ACID
Field of the invention:
The present invention relates in general to a chemical process for the preparation of dialkyl derivative of malonic acid. More particularly the present invention relates to a process for the preparation of di-n-propyl malonic acid, a valuable intermediate of valproic acid synthesis.
Background of the invention:
Valproic acid, salts and derivatives thereof have long since been utilized in the therapy as anti-convulsant and anti-epileptic drugs. Various processes are available in the literature for the preparation of valproic acid and derivatives thereof. However the impurity issues remained associated with the prior art processes as valproic acid is liquid at room temperature and the riddance of impurities gets difficult. A high vacuum distillation method can be employed for the purification of valproic acid but some impurities may also get distilled alongwith the desired product and hence the product obtained is not suitable for pharmaceutical preparations.
This problem can be overcome by utilizing substantially pure reaction intermediate for the synthesis of valproic acid, salts and derivatives thereof.
Di-n-propyl malonic acid, chemically known as dipropylpropanedioic acid (Formula I) is a key intermediate of valproic acid synthesis.


Formula I
The preparation of highly pure di-n-propyl malonic acid can effectively address the above problem and provide substantially pure valproic acid more suitable for pharmaceutical preparations.
Conventionally di-n-propyl malonic acid is prepared by multi step process, also reported in CS249863, JP56010134, DE2853732 and DE2853998 wherein, firstly, diethyl malonate (Formula II) is reacted with propyl halide in presence of a base in organic solvent. The inorganic salt generated during the reaction is removed from the reaction mixture by filtration and the reaction intermediate formed i.e. diethyl-2,2-di-n-propyl malonate (Formula III) is isolated by distillation. These additional steps are increasing the time cycle and cost of the reaction. Thereafter, the isolated intermediate (Formula III) is hydrolyzed using suitable inorganic base and acidified in subsequent steps. The precipitate obtained is filtered and washed with cold water to give di-n-propyl malonic acid (Formula I). A similar approach has been reported in JP56010135 wherein, ethyl 2-cyanoacetate was used as a starting material instead of diethyl malonate.
Thus, a multi-step preparation of di-n-propyl malonic acid is lengthy, time consuming and resulted in poor yield of final product. Moreover it is observed that, no other process except disclosed in DE'998, discussed the purity of product which is very much requisite for the further use in pharmaceutical preparations. The titrimatic purity of product reported in DE'998 is also not satisfactory as the chances of presence of monoalkylated impurity can not be ruled out in the disclosed process.

Alternatively, CS2171210 and AT365554 reported the preparation of di-n-propyl malonic acid by hydrolyzing diethyl-2,2-di-n-propyl malonate in presence of phase transfer catalyst like quaternary ammonium chloride salt. However, the use of expensive reagent like phase transfer catalyst makes the otherwise simple process uncompetitive and economically unviable.
Journal of Chemical Research, Synopses (3), 174-175, (2003) described the microwave assisted preparation of di-n-propyl malonic acid which is not feasible for industrial application.
In view of the above discussion, the prior art processes for di-n-propyl malonic acid preparation has many disadvantages, like
- the yield and purity of the product obtained from above procedures is not satisfactory from pharmaceutical preparation point of view,
- majority of the processes have multi step approach and involves isolation of reaction intermediate,
- difficult to reproduce on large scale,
require expensive reagents e.g. phase transfer catalyst,
- monoalkylated malonic acid contributes to the final yield of product
decreasing the commercial productivity of the process.
Thus finding a simple, efficient and commercially viable process for the preparation of di-n-propyl malonic acid (Formula I) where the process provides an enhanced conversion of diethyl malonate as compared to conventional process and ensures higher purity of product suitable for pharmaceutical use is of paramount importance.

Objects of the invention:
The principle object of the present invention is to provide a simple, cost effective and easily scalable process for the commercial production of highly pure di-n-propyl malonic acid (Formula I) suitable for pharmaceutical use.
Another object of the present invention is to provide an industrially feasible single-pot process for the preparation of highly pure di-n-propyl malonic acid (Formula I) without isolation and purification of reaction intermediates.
Yet another object of the present invention is to provide an improved process for the preparation of highly pure di-n-propyl malonic acid (Formula I) which overcomes the drawbacks of the prior art processes.
Summary of the invention:
In accordance with the principal aspect of the present invention, there is provided a commercially viable single-pot process for the preparation of highly pure di-n-propyl malonic acid (Formula I) to improve upon limitations of the prior art.
In an embodiment, the single-pot process for the preparation of highly pure di-n-propyl malonic acid (Formula I) comprises alkylation of diethyl malonate with alkylhalide in presence of sodium metal in suitable organic solvent. Thereafter, without isolating the reaction intermediate formed i.e. diethyl-2,2-di-n-propyl malonate (Formula III), the reaction mass is hydrolyzed using caustic solution followed by acidification with mineral acid. The precipitate thus obtained is gradually heated to a high temperature, filtered, washed with hot water and dried to obtain highly pure di-n-propyl malonic acid (Formula I) in good yield.

Detailed description of the invention:
The present invention relates to an improved single-pot process for the preparation of highly pure di-n-propyl malonic acid (Formula I),

Formula I
which is a valuable chemical intermediate and of particular interest for the synthesis of compounds like valproic acid and derivative thereof widely used as anticonvulsant and antiepileptic drugs.
The single-pot process of the present invention for the preparation of di-n-propyl malonic acid (Formula I) overcomes the drawbacks of the prior art processes with a high purity and consistently high yield of product, use of inexpensive and non-hazardous chemical reagents and which is easily employable at industrial scale and produce pharmaceutical grade product.
Accordingly, the process for the preparation of di-n-propyl malonic acid (Formula I)
comprises,
(a) alkylation of diethyl malonate (Formula II) with alkyl halide in presence of
sodium metal in suitable organic solvent to form reaction intermediate i.e.
diethyl-2,2-di-n-propyl malonate (Formula III);


The reaction of diethyl malonate and alkyl halide is carried out at the temperature of 50-70°C, preferably at 60-65°C for 6-8 hrs in presence of sodium metal in suitable organic solvent.
The alkyl halide used for the alkylation reaction is n-propyl bromide or n-propyl iodide, preferably n-propyl bromide. The organic solvent used herein is selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, more preferably n-propanol.
Following the complete removal of solvent under reduced pressure at < 100°C, the reaction mass is made salt free by adding water and separating the aqueous layer containing dissolved inorganic salt.
(b) hydrolysis of organic layer using 25% caustic solution followed by acidification with mineral acid forming precipitate of desired product;
The organic layer from step (a) is directly hydrolyzed using 25% caustic solution at a reflux temperature for 8-10 hrs. Thereafter, the reaction mass is cooled to the temperature 20-25°C and acidified with conc.HCl till the pH of the reaction mass come up to 1-2, stirred for 1 hr to get the precipitate of desired product.

(c) heating the reaction mass at a high temperature followed by filtration, washing with hot water and drying to obtain highly pure di-n-propyl malonic acid (Formula I). Further, the temperature of the reaction mass of step (b) is gradually increased to a high temperature preferably up to 70-90°C, more preferably up to 80-85°C and maintained for 30-40 min under constant stirring. The reaction mass is filtered at 40-80°C, preferable at 60°C and the solid obtained is washed with hot water ensuring the complete removal of monoalkylated malonic acid impurity. The wet cake obtained is dried at 90-100°C for 10-12 hrs. to afford 82-87% of di-n-propyl malonic acid (Formula I) having purity > 99.80% measured by Gas Chromatography.
The di-n-propyl malonic acid (Formula I) obtained by the procedure disclosed hereinabove is highly pure and more preferable for conversion in to pharmaceutically active substances like valproic acid. The valproic acid, salts and derivative thereof prepared by using said di-n-propyl malonic acid (Formula I) are substantially pure and hence are more suitable for pharmaceutical preparations.
The advantages of single pot process of the present invention lie in that,
it produces di-n-propyl malonic acid in highly pure form, most suitable for the
preparation of pharmaceutically active substances like valproic acid etc.
it avoids the time consuming isolation of reaction intermediate by distillation
prior to hydrolysis.
ensures the commercial viability of the process with consistently high yield
and purity of product.
The example mentioned below explains all the aspects of the present invention, illustrate the details of the invention and should not be construed to limit the scope of the present invention.

Example: Preparation of di-n-propyl malonic acid
Sodium metal pieces 61.3 g was added slowly in to a stirred vessel containing n-propanol 1000 ml. Immediately after the addition, the reaction mass was heated to reflux and the refluxing was maintained till the metal dissolved completely. The reaction mass was cooled to 50-60°C followed by addition of diethyl malonate 200 g (1.25 M) and n-propyl bromide 335 g (2.72 M) to the reaction mixture at 60-70°C respectively. The reaction mass was stirred for 7 hrs at 60-65°C till the completion of the reaction. The solvent was distilled off under reduced pressure at a temperature below 100°C. The left over mass was cooled to 20-25°C. To this, water (750 ml) was added slowly maintaining the temperature below 30°C, stirred for 30 min and allowed to settle. The lower aqueous layer was discarded and 800 g caustic solution (25%) was added to the organic mass and heated to reflux for 8-10 hrs. After completion of alkali hydrolysis, the reaction mass was cooled to 20-25°C and acidified with conc.HCl to adjust the pH 1-2, stirred for 1 hr. Thereafter, the temperature of the reaction mass was increased gradually up to 80-85°C, maintained for 30-40 min under constant stirring. The reaction mass was filtered at 60°C and the solid obtained was washed with hot water. The wet cake was dried at 90-100°C for 10-12 hrs to afford 195 g (83.15%) of the desired product having purity 99.84%. (By Gas Chromatography).

We Claim,
I. A single-pot process for the preparation of highly pure di-n-propyl malonic acid (Formula I) in a high yield, comprising,
(a) alkylation of diethyl malonate (Formula II) with alkyl halide in presence of sodium metal in suitable organic solvent to form reaction intermediate i.e. diethyl-2,2-di-n-propyl malonate (Formula III);
(b) hydrolysis of organic layer using 25% caustic solution followed by acidification with mineral acid forming precipitate of desired product;
(c) heating the reaction mass at a high temperature followed by filtration, washing with hot water, and drying to obtain highly pure di-n-propyl malonic acid (Formula 1).

2. The process according to claim 1, wherein the alkyl halide used is n-propyl bromide or n-propyl iodide.
3. The process according to claim 1, wherein the organic solvent used is selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, more preferably n-propanol.
4. The process according to claim 1, wherein in step (c), the heating of the reaction mass is carried out at a temperature 70-90°C, preferably at 80-85°C for
30-40 min.
5. The process according to claim 1, wherein in step (c), the filtration is done at a temperature 40-80°C, preferably at 60°C.
6. The process as claimed in any of the preceding claims, wherein purity of di-n-propyl malonic acid (Formula I) produced is above 99.80% by GC.