DESC:Field of the Invention:
The present application relates to an improved process for the preparation of
Divalproex Sodium, which is represented by the following structural formula-1.
5
Formula-1
Background of the Invention:
Divalproex sodium chemically known as sodium hydrogen bis (2-propyl
pentanoate) or Sodium 2-propyl pentanoate 2-propyl pentanoic 10 acid (1:1) molar ratio.
Divalproex sodium is approved in US in 1989 for the treatment of epilepsy and bipolar
disorder, developed by Abbott Laboratories, with the brand name of Depakote.
The patent US4988731 first reported divalproex sodium and its process. The process involves
15 reacting valproic acid with sodium valproate in equimolar quantities.
The IN1754/DEL/2005 reported a process for preparation of divalproex sodium, by
dissolving equimolar quantities of sodium valproate & valproic acid in a single solvent or
mixture of solvents.
The US6667420B2 reported a process for preparation of divalproex sodium, by
20 reacting valproic acid with sodium methoxide.
The IN1618/MUM/2006 disclosed a process for preparation of valproic acid
derivatives such as sodium salt or potassium salt. The process involves, reacting dialkyl
malonate with n- propyl halide in presence of alkali metal alkoxide to obtain ester of dialkyl
malonic acid, subjecting the said dialkyl malonicacid ester with alkali hydrolysis followed by
25 decarboxylation in a conventional manner to produce valproic acid. The obtained valproic
acid is converted to its sodium/ potassium salt using sodium or potassium hydroxide.
The CN102241582B reported a process for preparation of divalproex sodium,
characterized in that diethyl malonate and 1-bromo-n-propane are dissolved in sodium
ethoxide in ethanol to get dipropylmalonic ester. The dipropylmalonic ester is hydrolyzed
3
with aq. sodium hydroxide followed by acidification with dil. hydrochloric acid to get 2,2-
dipropyl malonic acid, followed by decarboxylation to get valproic acid. Valproic acid is
converted into divalproex sodium by using sodium hydroxide, water in toluene.
Based on the prior art processes, there is a continuous need to develop a process for
the preparation of divalproex sodium, valproic acid suitable for commercial 5 manufacturing
with high yields and purity.
The present invention provides an improved process for preparation of Divalproex
sodium, valproic acid which is efficient, industrially viable and cost effective.
Brief Description :
10 The first aspect of the present invention is to provide an improved process for the
preparation of divalproex sodium compound of formula-1.
The second aspect of the present invention is to provide an improved process for the
preparation of divalproex sodium compound of formula-1.
The third aspect of the present invention is to provide an improved process for the
15 preparation of the valproic acid compound of formula-5.
The fourth aspect of the present invention is to provide an improved process for the
preparation of the Magnesium valproate salt compound of formula-6.
Brief description of the drawings:
20 Figure 1: Illustrates the PXRD pattern of compound of formula-1 according to example 2.
Figure 2: Illustrates the PXRD pattern of compound of formula-6 according to example 3.
Detailed Description:
The present invention is related to an improved process for preparation of Divalproex sodium
25 and Valproic acid.
As used herein the term “suitable solvent” used in the present invention refers to
“hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane,
cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as
dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene
30 glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,
4
diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl
ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl
acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as
dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), Nmethylpyrrolidone
(NMP) and the like; “chloro solvents” such 5 as dichloromethane,
dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as
acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as
acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol,
ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-
10 fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol,
diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol
monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar
solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or organic
15 base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium
carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium
bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium
hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides”
such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide,
20 sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal
hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali
metal amides such as sodium amide, potassium amide, lithium amide and the like; and
organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine,
diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N25
methyl morpholine (NMM), or mixtures thereof.
The term “phase transfer catalyst (PTC)” used in the present invention refers are selected
from triethylbenzyl ammonium chloride, tetrabutyl ammoniumbromide, tetrabutyl
ammonium chloride, tetrabutyl ammonium acetate, methyl tributyl ammonium chloride,
tetrabutylammonium hydroxide, tributylbenzylammonium chloride thereof.
5
The first aspect of the present invention is to provide an improved process for the
preparation of divalproex sodium compound of formula-1.
5 Formula-1
comprising of:
a) Reacting the compound of formula-2
10 Formula-2
with an alkyl halide in presence of a suitable base, optionally phase transfer catalyst in
suitable solvent to provide compound of formula-3,
Formula-3
15 b) hydrolysing the compound obtained in step-a) with suitable inorganic base in presence of
a suitable alcoholic solvent, followed by acidification with Con. HCl to provide the
compound of formula-4,
Formula-4
20 c) decarboxylating the compound obtained in step-b) at a suitable temperature to provide
the compound of formula-5,
6
Formula-5
d) optionally purifying the compound of formula-5 by high vaccuo distillation,
e) converting the compound obtained in step-c) or d) to sodium salt by reacting with
sodium hydroxide in suitable solvent to provide the 5 compound of formula-1,
Formula-1
f) purifying the compound obtained in step-e) by melting, followed by cooling to get the
10 pure compound of Formula-1.
Wherein in step-a) the suitable inorganic base is selected from lithium hydroxide, sodium
hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide,
barium hydroxide, or mixture thereof; preferably sodium hydroxide; the suitable solvent is
selected from DMF, DMSO, THF, acetonitrile, alcoholic solvent, water and mixture thereof.
15 the suitable phase transfer catalyst is selected from triethylbenzyl ammonium chloride,
tetrabutylammonium bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium acetate,
methyltributyl ammonium chloride, tetrabutyl ammonium hydroxide, tributyl benzyl
ammonium chloride thereof; preferably TBAB;
wherein in step-b) the suitable inorganic base is selected from lithium hydroxide, sodium
20 hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide,
barium hydroxide, or mixture thereof; preferably sodium hydroxide;
The suitable alcoholic solvent methanol, ethanol, n-propanol, isopropanol, n-butanol,
isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol,
2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl
25 alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol,
phenol, glycerol or mixture thereof;
7
wherein in step-c) the suitable temperature is 100-170°C; preferably 150-160°C;
wherein in step-e) the suitable solvent is selected from toluene, xylene; preferably toluene;
suitable temperature is 100-170°C;
wherein in step-f) the suitable melting temperature is 80-110°C; preferably 90-105°C
Preferred embodiment of the present invention is to provide 5 an improved process for
the preparation of the compound of formula-1
Formula-1
Comprising of :
10 a) Reacting the compound of formula-2a
Formula-2a
with n-propylbromide in presence of sodium hydroxide, tetrabutylammonium bromide in
water to provide the compound of formula-3a,
15
Formula-3a
b) hydrolysing the compound obtained in step-a) with sodium hydroxide in presence of
isopropyl alcohol, followed by acidification with Con. hydrochloric acid to provide the
compound of formula-4,
20
Formula-4
8
c) decarboxylating the compound obtained in step-b) at 150-160°C temperature to provide
the compound of formula-5,
Formula-5
d) converting the compound obtained in step-c) to sodium salt 5 by reacting with sodium
hydroxide in toluene to provide the compound of formula-1,
Formula-1
e) purifying the compound obtained in step-d) by melting to 90-105°C, followed by cooling
10 to get the pure compound of formula-1.
The second aspect of the present invention is to provide an improved process for the
preparation of divalproex sodium of formula-1.
comprising of:
a) Reacting the compound of formula-5 (Valproic acid) with sodium hydroxide in toluene to
15 provide the compound of formula-1,
Formula-1
b) purifying the compound obtained in step-a) by melting to 90-105°C, followed by cooling
to get the pure compound of formula-1.
20 Third aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-5 (Valproic acid)
Formula-5
9
comprising of:
a) Reacting the compound of formula-2
Formula-2
with an alkyl halide in presence of a suitable base, optionally phase 5 transfer catalyst in
suitable solvent to provide the compound of formula-3,
Formula-3
b) hydrolysing the compound obtained in step-a) with suitable inorganic base in presence of
10 suitable alcoholic solvent, followed by acidification with Con. HCl to provide the compound
of formula-4,
Formula-4
c) decarboxylating the compound obtained in step-b) with a suitable temperature to provide
15 the compound of formula-5,
Formula-5
d) optionally purifying the compound of formula-5 by high vaccuo distillation.
Wherein in step-a) the suitable inorganic base is selected from lithium hydroxide, sodium
20 hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide,
10
barium hydroxide, or mixture thereof; preferably sodium hydroxide; the suitable solvent is
selected from DMF, DMSO, THF, acetonitrile, alcoholic solvent, water and mixture thereof.
the suitable phase transfer catalyst is selected from triethylbenzyl ammonium chloride,
tetrabutylammonium bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium acetate,
methyltributyl ammonium chloride, tetrabutyl ammonium hydroxide, 5 tributyl benzyl
ammonium chloride thereof; preferably TBAB;
wherein in step-b) the suitable inorganic base is selected from lithium hydroxide, sodium
hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide,
barium hydroxide, or mixture thereof; preferably sodium hydroxide;
10 The suitable alcoholic solvent methanol, ethanol, n-propanol, isopropanol, n-butanol,
isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol,
2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl
alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol,
phenol, glycerol or mixture thereof;
15 wherein in step-c) the suitable temperature is 100-170°C; preferably 150-160°C;
Preferred embodiment of the present invention is to provide an improved process for
the preparation of the compound of formula-5
Formula-5
20 comprising of
a) Reacting the compound of formula-2a
Formula-2a
with n-propylbromide in presence of sodium hydroxide, tetrabutylammonium bromide in
25 water to provide the compound of formula-3a,
11
Formula-3a
b) hydrolysing the compound obtained in step-a) with sodium hydroxide in presence of
isopropyl alcohol, followed by acidification with Con. hydrochloric acid to provide the
5 compound of formula-4,
Formula-4
c) decarboxylating the compound obtained in step-b) at 150-160°C temperature to provide
the compound of formula-5.
10
Formula-5
The process of the present invention can be represented schematically as follows:
15
12
The fourth aspect of the present invention is to provide an improved process for the
preparation of the Magnesium valproate salt.
Formula-6
5 comprising of:
a) Reacting the compound of formula-5 (Valproic acid) with a source of magnesium in
suitable solvent to provide the compound of formula-6.
Wherein in step-a) source of magnesium is magnesium metal, magnesium halides,
magnesium hydroxide, magnesium carbonate, magnesium bicarbonate, magnesium ethoxide,
10 magnesium methoxide; suitable solvent is selected from water, methanol, ethanol,
isopropanol, acetonitrile, dioxane.
The process described in the present invention was demonstrated in examples
illustrated below. These examples are provided as illustration only and therefore should not
15 be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of the compound of formula-5.
A round bottom flask was charged with water (100 mL), slowly added sodium hydroxide
20 (125.36 g) and stirred for 10 min. The reaction mixture was cooled to 25-35°C, added
tetra butyl ammonium bromide (20.12 g), n-Propyl bromide (192.5 g) simultaneously and
heated 50-60°C. To the above reaction mixture diethylmalonate (100 g) was added slowly
for 4-6 hr and maintained at 60-65°C for 2 hr with stirring. The reaction mixture was
cooled to 25-35°C, charged with water (800 mL) stirred for 30 min. The two layers were
25 separated, the organic layer was distilled off completely to get the crude compound. The
crude compound was charged to a solution of sodium hydroxide (75 g in 200 mL water)
and isopropanol (30 mL), heated to 75-85°C and stirred for 12 hr at same temperature.
The reaction mixture was distilled off completely, cooled to 25-35°C charged with water
13
(600 mL) and adjusted the pH to 0.5 to 1.5 with Con. HCl (250 mL), stirred for 60 min.
Filtered the obtained solid, washed with water (100 mL) and dried. The obtained wet was
compound heated to 150-160°C for 2 hr and distilled the compound under vacuum to get
the title compound as colourless liquid
5 Purity by GC: 99.901.
Yield: 70 g.
Example-2: Preparation of the compound of formula-1
A round bottom flask was charged with toluene (300 mL), compound of formula-5 (100 g)
and sodium hydroxide (13.61 g) at 25-35°C and stirred for 10 min. The reaction mixture was
10 heated to reflux and removed water by azotropically, stirred for 1.5 hr at 110-125°C. The
reaction mixture was cooled to 25-35°C added charcol and stirred for 15 min, filtered the
mass through hyflow and washed with toluene (50 mL). The toluene layer was distilled off
completely under vacuum, the obtained crude compound was heated to melt (90-105°C) , the
material unloaded in hot condition under nitrogen atmosphere and dried to get the title
15 compound.
Yield: 107.63 g
Purity by GC: 99.96 (Valproic acid)
Example-3: Preparation of the compound of formula-6
A round bottom flask was charged with ethanol (100 mL), magnesium ethoxide (39.58 g)
20 and heated to 65-75°C stirred for 30 min To the reaction mixture valproic acid (100 g) was
added and stirred for 1.5 hr at 65-75°C. The reaction mixture was cooled to 25-35°C, diluted
with acetone (50 mL), stirred for 30 min. The obtained solid was filtered and washed with
acetone, dried to get the title compound.
Yield: 82.5 g
25 Purity by GC: 99.94 (Valproic acid) ,CLAIMS:1 . A process for the preparation of divalproex sodium compound of formula-1.
5 Formula-1
comprising of:
a) Reacting the compound of formula-2
10 Formula-2
with an alkyl halide in presence of a suitable base, optionally phase transfer catalyst in
suitable solvent to provide compound of formula-3,
Formula-3
15 b) hydrolysing the compound obtained in step-a) with suitable inorganic base in presence of
a suitable alcoholic solvent, followed by acidification with Conc. HCl to provide the
compound of formula-4,
Formula-4
20 c) decarboxylating the compound obtained in step-b) at a suitable temperature to provide the
compound of formula-5,
15
Formula-5
d) optionally purifying the compound of formula-5 by high vaccuo distillation,
e) converting the compound obtained in step-c) or d) to sodium salt by reacting with sodium
hydroxide in suitable solvent to provide the 5 compound of formula-1,
Formula-1
f) purifying the compound obtained in step-e) by melting, followed by cooling to get the
10 pure compound of Formula-1.
2. The process according to claim 1 wherein in step-a) the suitable inorganic base is selected
from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium
hydroxide, strontium hydroxide, barium hydroxide, or mixture thereof; preferably sodium
hydroxide; the suitable solvent is selected from DMF, DMSO, THF, acetonitrile, alcoholic
15 solvent, water and mixture thereof.
the suitable phase transfer catalyst is selected from triethylbenzyl ammonium chloride,
tetrabutylammonium bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium acetate,
methyltributyl ammonium chloride, tetrabutyl ammonium hydroxide, tributyl benzyl
ammonium chloride thereof; preferably TBAB;
20 wherein in step-b) the suitable inorganic base is selected from lithium hydroxide, sodium
hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide,
barium hydroxide, or mixture thereof; preferably sodium hydroxide;
The suitable alcoholic solvent methanol, ethanol, n-propanol, isopropanol, n-butanol,
isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol,
25 2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl
16
alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol,
phenol, glycerol or mixture thereof;
wherein in step-c) the suitable temperature is 100-170°C; preferably 150-160°C;
wherein in step-e) the suitable solvent is selected from toluene, xylene; preferably toluene;
suitable temperature 5 is 100-170°C;
wherein in step-f) the suitable melting temperature is 80-110°C; preferably 90-105°C
3. A process for the preparation of the compound of formula-1
Formula-1
10 Comprising of :
a) Reacting the compound of formula-2a
Formula-2a
with n-propylbromide in presence of sodium hydroxide, tetrabutylammonium bromide in
15 water to provide the compound of formula-3a,
Formula-3a
b) hydrolysing the compound obtained in step-a) with sodium hydroxide in presence of
isopropyl alcohol, followed by acidification with Con. hydrochloric acid to provide the
20 compound of formula-4,
17
Formula-4
c) decarboxylating the compound obtained in step-b) at 150-160°C temperature to provide
the compound of formula-5,
5 Formula-5
d) converting the compound obtained in step-c) to sodium salt by reacting with sodium
hydroxide in toluene to provide the compound of formula-1,
Formula-1
10 e) purifying the compound obtained in step-d) by melting to 90-105°C, followed by cooling
to get the pure compound of formula-1.
4. A process for the preparation of divalproex sodium of formula-1.
comprising of:
a) Reacting the compound of formula-5 (Valproic acid) with sodium hydroxide in toluene to
15 provide the compound of formula-1,
Formula-1
b) purifying the compound obtained in step-a) by melting to 90-105°C, followed by cooling
20 to get the pure compound of formula-1.
5. A process for the preparation of the compound of formula-5 (Valproic acid)
Formula-5
18
comprising of:
a) Reacting the compound of formula-2
5 Formula-2
with an alkyl halide in presence of a suitable base, optionally phase transfer catalyst in
suitable solvent to provide the compound of formula-3,
Formula-3
10 b) hydrolysing the compound obtained in step-a) with suitable inorganic base in presence of
suitable alcoholic solvent, followed by acidification with Con. HCl to provide the compound
of formula-4,
Formula-4
15 c) decarboxylating the compound obtained in step-b) with a suitable temperature to provide
the compound of formula-5,
Formula-5
d) optionally purifying the compound of formula-5 by high vaccuo distillation.
20 6. The process according to claim 5 wherein in step-a) the suitable inorganic base is selected
from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium
19
hydroxide, strontium hydroxide, barium hydroxide, or mixture thereof; preferably sodium
hydroxide; the suitable solvent is selected from DMF, DMSO, THF, acetonitrile, alcoholic
solvent, water and mixture thereof.
the suitable phase transfer catalyst is selected from triethylbenzyl ammonium chloride,
tetrabutylammonium bromide, tetrabutyl ammonium chloride, tetrabutyl 5 ammonium acetate,
methyltributyl ammonium chloride, tetrabutyl ammonium hydroxide, tributyl benzyl
ammonium chloride thereof; preferably TBAB;
wherein in step-b) the suitable inorganic base is selected from lithium hydroxide, sodium
hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide,
10 barium hydroxide, or mixture thereof; preferably sodium hydroxide;
The suitable alcoholic solvent methanol, ethanol, n-propanol, isopropanol, n-butanol,
isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol,
2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl
alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol,
15 phenol, glycerol or mixture thereof;
wherein in step-c) the suitable temperature is 100-170°C; preferably 150-160°C;
7. A process for the preparation of the compound of formula-5
20 Formula-5
comprising of
a) Reacting the compound of formula-2a
Formula-2a
25 with n-propylbromide in presence of sodium hydroxide, tetrabutylammonium bromide in
water to provide the compound of formula-3a,
20
Formula-3a
b) hydrolysing the compound obtained in step-a) with sodium hydroxide in presence of
isopropyl alcohol, followed by acidification with Con. hydrochloric acid to provide the
5 compound of formula-4,
Formula-4
c) decarboxylating the compound obtained in step-b) at 150-160°C temperature to provide
the compound of formula-5.
10
Formula-5
8. A process for the preparation of valproic acid obtained any of the proceeding claims.
15 9. A process for the preparation of divalproic acid sodium salt obtained any of the proceeding
claims.