DESC:Field of the invention:
The present invention relates to a novel process for preparation of substantially pure valproic acid and it’s sodium salts. The invention particularly relates to preparation of key intermediates, monopropyl and dipropyl malonic esters without using solvent.

Background of Invention:
Valproic acid, which is also chemically designated as 2-propylpentanoic acid or 2-propylvaleric acid and its sodium salts have been known to be active pharmaceutical ingredients for treatment of epileptic seizure, convulsion and migraine.

Preparation of valproic acid was reported first time in American Chemical Journal 3, 385, (1882). This journal discloses treatment of dipropyl ethyl acetoacetate with 15% alcoholic potash followed by treatment with sulphuric acid to obtain Valproic acid.

GB1529786 discloses reaction of ethyl cyanoacetate with n-propyl bromide in presence of n-propylate sodium in n-propanol solvent to obtain dipropyl cyanoethyl acetate which is hydrolysed with sodium hydroxide to obtain di-n-propyl cyanoacetic acid which is further converted to valproic acid and further to sodium valproate using sodium hydroxide in methanol and toluene solvents mixture. However, the process involving ethyl cyanoacetate found to be giving poor yields of valproic acid.

US5101070 discloses reaction of acetoacetic acid methyl ester with an allyl halide in presence of tetrabutylammonium chloride in aqueous sodium hydroxide to form methyl 2,2-diallyl acetoacetate which is further reduced with hydrogen in presence of catalyst to form methyl 2,2-dipropyl acetoacetate which is further hydrolysed with aqueous sodium hydroxide to form valproic acid. This process involves use of allyl halides which are not easily available in commercial scale and this process involves tedious and lengthy steps increasing the cost of production of sodium valproate.

DE2853998 discloses reaction of diethyl malonate with n-propyl bromide in presence of sodium methylate in ethanol solvent. After completion of reaction, distilled ethanol, added aqueous potassium hydroxide solution and refluxed reaction mass to complete hydrolysis. After completion of hydrolysis, neutralized with HCl and filtered to isolate dipropylmalonic acid.

Another patent, DE2853732, also discloses preparation of dipropylmalonic acid as per the process disclosed in ‘998 patent by reacting diethyl malonate with n-propyl bromide in presence of sodium methylate in ethanol solvent. Further, this patent also discloses preparation of valproic acid by heating dipropylmalonic acid above 160°C for decarboxylation.

Yet another patent, CN102241582, also discloses similar process for preparation of valproic acid as mentioned in ‘998 and ‘732 patents. This patent discloses preparation of valproic acid by reacting diethyl malonate with bromo-n-propane in ethanol solvent in presence of sodium ethoxide to obtain dipropyl malonate. Dipropyl malonate is hydrolysed with aqueous sodium hydroxide followed by decarboxylation during refluxing to obtain valproic acid.

The process disclosed in the ‘998, ‘732, ‘582 patents is simpler and easy process, however, this process involves use of solvent for dipropylation reaction. Use of solvent is causing yield loss at di propyl diethylmalonate stage and also increasing time cycle and energy consumption due to distillation of solvent to isolate the product.
Consequently, there is a need for improved process to prepare sodium valproate. Therefore, the object of the invention is to provide an economical and industrially applicable novel and improved process. The present invention addresses this need.

Summary of Invention:
The present inventors have, surprisingly, found a novel process for preparation of valproic acid or it’s sodium salts wherein the reaction of dialkyl malonate with n-propyl bromide, sequentially or concomitantly, to obtain dipropylated malonic esters is conducted without using solvent. This process gives high yield of sodium valproate with reduced time cycle.

Accordingly in one aspect, the invention provides a process for preparation of sodium salts of valproic acid, which comprises;
a) reacting alkyl malonate of formula-I, wherein R1 denotes methyl, ethyl or n-propyl, with n-propyl bromide in presence of sodium methoxide without using solvent to obtain mono n-propyl malonic esters of Formula-III,
b) reacting the mono n-propyl malonic esters with n-propyl bromide in presence of sodium methoxide without using solvent to obtain di propyl malonic esters of Formula-IV;
c) hydrolyzing the di propyl malonic esters of Formula-IV with a base to obtain di-n-propyl malonic acid of Formula-V and
d) converting the di-n-propyl malonic acid of Formula-V into valproic acid followed by conversion into sodium salts of valproic acid.

In a preferred embodiment, the invention provides a process of preparation of sodium valproate which comprises;
a) reacting alkyl malonate of formula-I, wherein R1 denotes ethyl, with n-propyl bromide in presence of sodium methoxide without using solvent to obtain mixture of mono n-propyl malonic esters of Formula-III wherein R1 denotes ethyl,
b) reacting the mixture of mono n-propyl malonic esters of Formula-III wherein R1 denotes ethyl with n-propyl bromide in presence of sodium methoxide without using solvent to obtain mixture of di-n-propyl malonic esters of Formula-IV wherein R1 denotes ethyl;
c) hydrolyzing the mixture of di-n-propyl malonic esters of Formula-IV wherein R1 denotes ethyl with a base to obtain dipropyl malonic acid of Formula-V and
d) converting the di-n-propyl malonic acid of Formula-V into valproic acid followed by conversion into sodium valproate.

According to another aspect of the present invention, the sodium valproate is isolated by concentrating sodium valproate aqueous solution in agitated thin film drier (ATFD).

Description of Invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words, “including”, “includes”, “comprising”, and “comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items.

Accordingly in one aspect, the invention provides a process for preparation of sodium salt of valproic acid which comprises;
a) reacting alkyl malonate of formula-I, wherein R1 denotes methyl, ethyl or n-propyl, with n-propyl bromide in presence of sodium methoxide without using solvent to obtain mono n-propyl malonic esters of Formula-III,
b) reacting the mono n-propyl malonic esters with n-propyl bromide in presence of sodium methoxide without using solvent to obtain di propyl malonic esters of Formula-IV;
c) hydrolyzing the di propyl malonic esters of Formula-IV with a base to obtain di-n-propyl malonic acid of Formula-V and
d) converting the di-n-propyl malonic acid of Formula-V into valproic acid followed by conversion into sodium salts of valproic acid.

Usually sodium methoxide powder is added into dialkyl malonate in absence of any solvent (i.e., without using solvent) and heated the reaction mass to 85°C for half an hour. Then added n-propyl bromide slowly into the reaction mass and the mass is maintained at 65-90°C for 2-3 hours to complete the reaction to obtain monopropylated malonic esters of Formula-III.

Mixtures of mono n-propyl malonic esters of Formula-III are obtained when the alkyl malonate of formula-I, wherein R1 denotes ethyl or n-propyl. For example when ethyl malonate is used as starting material, mixtures of 1) Propanedioic acid, 2-propyl, 1-ethyl 3-ethyl ester; 2) Propanedioic acid, 2-propyl, 1-ethyl 3-methyl ester; and 3) Propanedioic acid, 2-propyl, 1-methyl 3-methyl ester are obtained. However, when the alkyl malonate of formula-I, wherein R1 denotes methyl (i.e., methyl malonate), mono n-propyl methyl malonic ester is obtained. The mono n-propyl malonic esters of Formula-III may be isolated or optionally, without isolation, it may be taken for further reaction.

The monopropylated malonic esters of Formula-III present in the reaction mass, without isolation, is further taken for next step, dipropylation, without addition of any solvent. Next lot of sodium methoxide is added into the reaction mass and heated to about 85°C for 15 minutes. Then added n-propyl bromide slowly into the reaction mass and the reaction mass is maintained at 60-90°C for 2-3 hours to complete the reaction to obtain dipropylated malonic esters of Formula-IV. Typically the product is isolated from reaction mixture by adding water and layer separation as oily layer. Optionally, the product may be taken for next step without isolation.
When the above mentioned mixtures of mono n-propyl malonic esters of Formula-III are subjected for treatment with n-propyl bromide, corresponding mixtures of dipropylated malonic esters of Formula-IV are obtained.

The isolated dipropylated malonic esters of Formula-IV are subjected for hydrolysis with a base such as sodium hydroxide or potassium hydroxide in mixture of methanol and water solvent system. The hydrolysis reaction is conducted at about 80°C for about 3-4 hours. After completion of hydrolysis, solvent is distilled; water added to the concentrated mass and filtered the dipropylated malonic acid of Formula-V after adjusting the pH of the reaction mass to below 1.5.

The obtained dipropylated malonic acid of Formula-V is further subjected for decarboxylation to obtain valproic acid. The dipropylated malonic acid is heated to 140-155°C for about 5 hours till completion of decarboxylation to obtain valproic acid. The valproic acid may be purified using suitable solvent or optionally it may be dissolved in suitable solvent such as toluene, hexane or water, and the obtained valproic acid solution is treated with sodium hydroxide to obtain sodium salts of valproic acid i.e., sodium valproate or divalproex sodium. Usually, sodium valproate is prepared in presence of water at ambient temperature. After formation of sodium valproate, the solvent is removed by distillation and the obtained slurry is filtered to isolate the product, sodium valproate.

In an alternative method, the sodium valproate present in aqueous solution may be isolated by lyophilization.

In another aspect of the present invention, the sodium valproate present in aqueous solution is isolated using agitated thin film drier (ATFD) having an evaporation area of 0.05m2 and a condenser area of 0.6m2 at 70-90°C at a feeding rate of 6.25 mL per minute under vacuum. White powder of sodium valproate is obtained by this agitated thin film drying (ATFD) method.
In a preferred embodiment, the invention provides a process for preparation of sodium valproate which comprises;
a) reacting alkyl malonate of formula-I, wherein R1 denotes ethyl, with n-propyl bromide in presence of sodium methoxide without using solvent to obtain mixture of mono n-propyl malonic esters of Formula-III, wherein, R1 denotes ethyl,
b) reacting the mixture of mono n-propyl malonic esters of Formula-III, wherein, R1 denotes ethyl, with n-propyl bromide in presence of sodium methoxide without using solvent to obtain mixture of di-n-propyl malonic esters of Formula-IV, wherein, R1 denotes ethyl;
c) hydrolyzing the mixture of di-n-propyl malonic esters of Formula-IV, wherein R1 denotes ethyl, with a base to obtain dipropyl malonic acid of Formula-V and
d) converting the di-n-propyl malonic acid of Formula-V into valproic acid followed by conversion into sodium valproate.
The present invention is depicted in Scheme-1 using alkyl malonate of formula-I, wherein R1 denotes ethyl.

The following examples are presented to further explain the invention with experimental conditions, which are purely illustrative and are not intended to limit the scope of the invention.

Examples:
Example 1
Preparation of monopropylated malonic ester (III)
Sodium methoxide powder (40.5g, 0.75moles) was charged under nitrogen into diethylmalonate (100g, 0.624mole) at room temperature exotherm was observed wherein the temperature of mass increased to ~85° C. The reaction mass was then maintained at 85-90° C for 30minutes and cooled to 50-55° C after which n-propyl bromide (84.5g, 0.687moles) was added in 45minutes. After addition was complete the reaction mass was heated and maintained at 75-80° C for 2-3 hours and cooled to 30-35° C to provide a mixture of crude monopropylated malonic ester (MPME) III in almost quantitative yield
Analytical Details
Purity by GC: Diethyl monopropyl malonate (IIIa): 31.05 %
Ethyl methyl monopropyl malonate (IIIb): 29.50 %
Dimethyl monopropyl malonate (IIIc): 6.86 %

GC-MS data: (sample fractionally distilled for identification)

GC Analysis Major Mass Fragments Observed
Fragment ion type (+ve mode)
Derived Mol.Wt

Compound

RT Area
(%)

12.8

14.78 143.14 [M-CH3O]+

174.2
Monopropylated dimethyl malonate (IIIc)
132.14 [M-CH3CH2CH2+1]+
100.09 [M-CH3CH2CH2-CH3O]+

13.1

54.77 157.17 [M-CH3O]+

188.22 Monopropylated methyl ethyl malonate
(IIIb)
146.13 [M-CH3CH2CH2+1]+
143.13 [M-CH3CH2O]+

13.6

24.75 173 [M-CH3CH2]+

202.25
Monopropylated diethyl malonate (IIIa)
160.12 [M-CH3CH2CH2+1]+
157.12 [M-CH3CH2O]+
Analysis of crude monopropylated malonic ester (MPME).
1H-NMR in CDCl3 at 300MHz (ppm): 0.97 (t, 3H), 1.23-1.40 (m, 5H), 1.85-1.94 (m, 2H), 3.32-3.42 (m, 1H), 3.75 (s, 3H), 4.17-4.24 (m, 2H)

13C-NMR in CDCl3 at 75.45MHz (ppm): 13.57, 13.59, 13.61, 13.99, 14.30, 14.33, 17.31, 17.35, 17.40, 20.51, 30.76, 34.41, 34.53, 34.69, 41.30, 41.58, 51.38, 51.57, 51.74, 52.04, 52.13, 52.26, 52.33, 52.39, 57.49, 60.83, 60.90, 61.16, 61.24, 61.40, 61.48, 76.66, 77.08, 77.51, 166.56, 167.00, 169.42, 169.51, 169.89, 169.99, 171.78, 171.90.
FT-IR as such (cm-1): 2962, 2876, 1732, 1151

Example 2
Preparation of dipropylated malonic ester (IV)
To a mixture of crude monopropylated malonic ester (MPME) III obtained quantitatively as per example 1, a second lot of sodium methoxide powder (40.5g, 0.75moles) was charged in 15 minutes, exotherm was observed wherein the temperature of the reaction mass increased upto ~65° C. The temperature of the reaction mass was further raised to 85-90°C and was maintained at this temperature for 30minutes. Then the reaction mass was cooled to 50-55° C at which n- propyl bromide (88.5g, 0.72moles) was added in 45minutes and the temperature of the reaction mass was further raised to 70-75° C where it was maintained further for 2-3 hours. The reaction mass was then cooled to 55-60° C where upon water (150ml) was added and the contents stirred at 55-60° C for 15minutes. The title compound IV i.e mixture of dipropylated malonic esters (DPME) separated as upper oily layer was collected after layer separation in quantitative yield.

Analytical details
Purity by GC:

GC-MS of crude dipropylated malonic esters (DPME)
GC Analysis Major Mass Fragments Observed
Fragment ion type
(+ve mode)
Derived Mol.Wt.

Compound

RT Area (%)

15.2

27.73 185.19 [M-CH3O]+

216.28
Dimethyl dipropyl malonate (IVc)
174.17 [M-CH3CH2CH2+1]+
145.14 [M-CH3CH2CH2-CH3CH2+1]+

16.0
46.53 188.16 [M-CH3CH2CH2+1]+
230.30 Ethyl methyl dipropyl malonate (IVb)
159.13 [M-CH3CH2CH2-CH3CH2+1]+

16.8
22.36 202.19 [M-CH3CH2CH2+1]+
244.43
Diethyl dipropyl malonate (IVa)
173.14 [M-CH3CH2CH2-CH3CH2+1]+
NMR of crude dipropylated malonic esters (DPME)
1H-NMR in CDCl3 at 300MHz (ppm): 0.97 (t, 18H), 1.1-1.3 (m, 22H), 1.82-1.94 (m, 12H), 3.70 (d, 9H), 4.13 (q, 5H).

Example 3
Preparation of dipropylated malonic acid (V)
Mixture of dipropylated malonic esters (DPME) (IV) as obtained in Example 2 was dissolved in methanol (210ml) at room temperature. Then sodium hydroxide (75g, 1.875moles) followed by water (140ml) was added and the contents were heated and maintained at 80-85° C for 3-4hours. Then the temperature of reaction mass was increased to ~100°C and subjected to atmospheric distillation. Distillation was stopped when ~325ml of distillate was collected. Then water (700ml) was added and the reaction mass was cooled to 30-40°C at which the pH of the reaction mass was adjusted between 1 to 1.5 with concentrated Hydrochloric acid (~155ml). The obtained slurry was further cooled and maintained at 20-25°C for 2 hours. The solid was then filtered, washed with water (3 X 105ml), suck dried for 1-2 hours and dried in VTD at 60-65°C for 6 hours to provide the title compound V as an off-white solid.
Yield: 94g (81% by theory)
Purity by GC: 99.2%
Analytical Details:
1H-NMR in CDCl3 at 300MHz (ppm): d 0.95 (t, 6H), 1.23-1.36 (m, 4H), 1.93-1.98 (m, 4H).
13C-NMR in CDCl3 at 75.45MHz (ppm): d 14.05, 18.44, 29.61, 57.64, 176.85
FT-IR as such (cm-1): 2967, 2939, 2878, 2620, 1698, 1470
Mass Analysis (ESI, -ve mode): Molecular ion peak observed at 187.18 a.m.u which corresponds to [M-H]- peak of title compound.

Example 4
Preparation of Sodium Valproate (VII) (using toluene)
Dipropylated malonic acid (V) (85g, 0.452moles) was charged at room temperature and heated to 140-155° C. The reaction mass was maintained at 140-155°C for 5 hours which after cooling to 40-45°C provided Valproic acid (VI) as an oil. To this obtained oil, toluene (225ml) followed by water (170ml) was added below 45°C and stirred for 15 minutes at 40-45°C. The upper toluene layer was then separated which was treated with activated charcoal (1.7g) for 15minutes at 25- 35° C. The charcoal was then filtered through celite bed with an additional washing of celite bed with toluene (42.5ml). To the obtained total toluene filtrate, sodium hydroxide (18.4g) followed by water (18.5ml) was added at 25-30° C. After stirring the contents for 10-15 minutes at 25-30° C the temperature was increased and water was removed azeotropically at 90-110° C. After complete removal of water additional toluene (~85ml) was distilled off atmospherically at 110- 111° C. The obtained slurry was then cooled to 25-30° C where it was maintained for 1 hour. The solid was then filtered under nitrogen atmosphere, washed with toluene (42.5ml), suck dried for 15minutes and dried under vacuum initially for 1 hour at 25-30° C, 4 hours at 70-80° C and finally for 4 hours at 110-120° C to provide sodium valproate as a white powder.
Yield: 67g (90% by theory)
Purity by GC: 99.9%
LOD: 0.17 %
Analytical Details:
1H-NMR in D2O at 300MHz (ppm): d 0.71 (t, 6H), 1.03-1.31 (m, 8H), 2.03- 2.11 (septet, 1H)
13C-NMR in D2O at 75.45MHz (ppm): d 13.40, 20.53, 35.24, 48.77, 186.71
FT-IR as such (cm-1): 2957, 2927, 2872, 1557, 1443, 1415.
Mass Analysis (ESI, -ve mode): Molecular ion peak observed at 143.11 a.m.u which corresponds to [M – Na] - peak of title compound.

Example 5
Preparation of Sodium Valproate (VII) (using n-Heptane)
Dipropylated malonic acid (V) (85g, 0.452moles) was charged at room temperature and heated to 145-155°C. The reaction mass was maintained at 140-155°C for 5 hours which after cooling to 40-45°C provided Valproic acid (VI) as an oil. To this obtained oil, n-heptane (225ml) followed by water (170ml) was added below 45°C and stirred for 15 minutes at 40-45°C. The upper toluene layer was then separated which was treated with activated charcoal (1.7g) for 15minutes at 25-35°C. The charcoal was then filtered through celite bed with an additional washing of celite bed with n-heptane (42.5ml). To the obtained total toluene filtrate, sodium hydroxide (17g) followed by water (42.5ml) was added at 25-30°C. After stirring the contents for 10-15 minutes at 25-30°C, the temperature was increased and water was removed azeotropically at 90-100°C. After complete removal of water the obtained slurry was then cooled to 25-30°C where it was maintained for 1 hour. The solid was then filtered under nitrogen atmosphere, washed with n- heptane (42.5ml), suck dried for 15minutes and dried under vacuum initially for 1 hour at 25-30°C, 4 hours at 70-80°C and finally for 4 hours at 110-120° C to provide sodium valproate as a white powder.
Yield: 65g (88% by theory)
Purity by GC : 99.8%
LOD: 1%

Example 6
Preparation of Sodium Valproate (VII) (using water)
To valproic acid (VI) (25g, 0.17moles) prepared as per Example 4, sodium hydroxide (7g, 0.17 moles) dissolved in water (140ml) was added at 25-30° C and stirred for 30 minutes at 25-30° C. Then ~128ml of water was distilled under vacuum 60-65° C from the reaction mass. The resulting slurry was then cooled to 25-30° C and dried in a tray dryer at 125° C till constant weight to provide Sodium valproate as a white solid.

Yield: 25.27g (87.71% by theory)
Purity by GC: 99.9%
LOD: 0.38%

Example 7
Preparation of Sodium Valproate (VII) (by Lyophillization)
Valproic acid (VI) (20g, 0.138moles) prepared as per Example 4, was suspended in water (120ml) at room temperature. Then the pH of the mass was then adjusted to 7.6-7.8 with a solution of sodium hydroxide (5.6g, 0.14moles) in water (50ml) at 25-30° C and fine filtered. Then the solution so obtained was lyophilized which provided Sodium valproate as a white solid in almost quantitative yield.
Purity by GC: 99.8%
LOD: 0.91%

Example 8
Preparation of Sodium Valproate (VII) (ATFD)
Valproic acid (VI) (100g, 0.69moles) prepared as per Example 4 was suspended in water (600ml) at room temperature. Then the pH of the mass was adjusted to 7.6 - 7.8 with a solution of sodium hydroxide (28g, 0.70moles) in water (280ml) and was fine filtered. The obtained homogeneous solution (~1000ml) was then concentrated completely in a ATFD having an evaporation area of 0.05m2 and a condenser area of 0.6m2 at 80-84°C, at a feeding rate of 6.25ml per minute under 700mmHg of vacuum to afford the title compound (VII) as a white powder.

Purity by GC: 99.8%
LOD: 0.84%
,CLAIMS:
1) A process of preparation of sodium salt of valproic acid, which comprises;
a) reacting alkyl malonate of formula-I, wherein R1 denotes methyl, ethyl or n-propyl, with n-propyl bromide in presence of sodium methoxide without using solvent to obtain mono n-propyl malonic esters of Formula-III, wherein R1 denotes methyl, ethyl or n-propyl;
b) reacting the mono n-propyl malonic esters with n-propyl bromide in presence of sodium methoxide without using solvent to obtain di propyl malonic esters of Formula-IV, wherein R1 denotes methyl, ethyl or n-propyl;
c) hydrolyzing the di propyl malonic esters of Formula-IV with a base to obtain di-n-propyl malonic acid of Formula-V and
d) converting the di-n-propyl malonic acid of Formula-V into valproic acid followed by conversion into sodium salt of valproic acid.

2) The process as mentioned in claim-1, wherein R1 of Formula-I, III and IV is ethyl group.

3) The process as mentioned in claim-1, wherein the reaction of step 1a is conducted at 65-90°C.

4) The process as mentioned in claim-1, wherein the reaction of step 1b is conducted at 60-90°C.

5) The process as mentioned in claim-1, wherein the base of step 1c is sodium hydroxide.

6) A process of preparation of sodium valproate which comprises;
a) reacting alkyl malonate of formula-I, wherein R1 denotes ethyl, with n-propyl bromide in presence of sodium methoxide without using solvent to obtain mixture of mono n-propyl malonic esters of Formula-III, wherein R1 denotes ethyl;
b) reacting the mixture of mono n-propyl malonic esters of Formula-III wherein R1 denotes ethyl with n-propyl bromide in presence of sodium methoxide without using solvent to obtain mixture of di-n-propyl malonic esters of Formula-IV wherein R1 denotes ethyl;
c) hydrolyzing the mixture of di-n-propyl malonic esters of Formula-IV wherein R1 denotes ethyl with a base to obtain dipropyl malonic acid of Formula-V; and
d) converting the di-n-propyl malonic acid of Formula-V into valproic acid followed by conversion into sodium valproate.

7) The process as mentioned in claim-6, wherein the reaction of step 1a is conducted at 75-80°C.

8) The process as mentioned in claim-6, wherein the reaction of step 1b is conducted at 70-80°C.

9) A process for isolation of sodium valproate from aqueous solution of sodium valproate comprises concentration of sodium valproate aqueous solution in agitated thin film drier (ATFD).

10) The process as mentioned in claim 9, wherein the concentration of sodium valproate aqueous solution is carried out at 70-90°C under vacuum.