AN IMPROVED PROCESS FOR THE PREPARATION OF VALSARTAN
FIELD OF THE INVENTION
This invention relates to an improved process for the preparation of valsartan and pharmaceutically acceptable salts thereof, which is simple, devoid of toxic reagents, environment friendly, economically viable and industrially feasible. The invention further relates to a process for the preparation of valsartan and pharmaceutically acceptable salts thereof having enhanced enantiomeric purity.
BACKGROUND OF THE INVENTION
(5)-N-(l-Carboxy-2-methylprop-l-yl)N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-methyl]amine, commonly known as valsartan is structurally represented as,
(Formula Removed)
Valsartan is a known angiotensin II antagonist and is used for the prophylaxis and the treatment of diseases or conditions, which may be inhibited by blocking the AT1receptor.
U.S. Patent No. 5,399,578 discloses valsartan, its pharmaceutically acceptable salts, pharmaceutical compositions comprising valsartan and their use in treating high blood pressure and cardiac insufficiency. It also discloses a process for the preparation of valsartan, which involves the condensation of N-[2'-cyanobiphenyl-4-yl-(methyl)]-(L)-valine methyl ester with valeryl chloride in the presence of triethylamine and dichloromethane, followed by flash chromatography to give the compound N-[2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester, which is then treated with tributyl tin azide to achieve tetrazole ring formation. The tetrazole compound so obtained
is then hydrolyzed using sodium hydroxide to give valsartan after flash chromatography. The cited US patent further describes a variant of above method with use of benzyl ester. The process disclosed uses highly toxic compounds such as tributyl tin azide in penultimate intermediate of valsartan leading to various organo tin impurities, making the process impractical to obtain a pure valsartan of pharmacopoieal standard. Further, the use of flash chromatography at various stages during the preparation of valsartan makes the process difficult to operate on industrial scale.
U.S. Patent No. 7,659,406 discloses a process for preparing valsartan, comprising condensing N-[2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester, with valeryl chloride in the presence of a reaction medium consisting of sodium carbonate, water and toluene to form N-[2'-cyanobiphenyl-4-yl)methyl-(L)-valine methyl ester of 98.9% purity. The resulting intermediate is further treated with tributyl tin azide for the formation of tetrazole ring, followed by hydrolysis of the resulting compound to obtain valsartan. The process involves the use of highly toxic and expensive reagent tributyl tin azide for tetrazole ring formation, thereby reducing the capability of the disclosed process to be industrially beneficial and safe.
U.S. Patent Application Publication No 20060281801 discloses a process for the preparation of valsartan, which involves a purification method for the removal of organotin impurity form benzyl valsartan. The purification process for the removal of organotin impurity is very elaborate and involves subsequent purifications, which involve first crystallization of benzyl valsartan intermediate from a ternary solvent mixture and then a second crystallization from a binary solvent system to yield benzyl valsartan in oily state. As the disclosed process involves multiple crystallizations, it is very time consuming, involves use of large volume of solvents during crystallization step, while the purity of the valsartan obtained from the resulting intermediate in oil form is highly uncertain, thus the process becomes industrially uneconomical and unacceptable.
U.S. Patent Application Publication No. 20070093542 discloses a process for the preparation of valsartan containing less than about 5000 ppm residual solvent involving the use of humid air in fluidized bed drier and drying by maintaining valsartan at a
temperature from 5 to 60°C under pressure of less than 30 mm Hg for a period of 1 to 5 days. The duration involved in achieving the valsartan of the desired characteristics of pharmacopeial standards is very long for the implementation on industrial scale.
U.S. Patent Application Publication No. 20090192318 discloses a process for the preparation of valsartan, wherein the valsartan methyl ester is converted to its hydrochloride salt in an attempt to purify the said intermediate. The hydrochloride salt formation is carried out at specific pH and precise temperature conditions. Even a slight temperature rise or variation in pH leads to the formation of undesired impurities. Use of such stringent reaction conditions in an industrial process is not feasible in terms of ease of operation of process and also, it is difficult to control the formation of undesired impurity in such a process at large scale. The said limitations render the disclosed process infeasible on industrial scale.
The processes disclosed in the prior arts involves one or more disadvantages such as use of hazardous and toxic chemicals like tributyl tin azide, use of large volume of solvents, multiple operations leading to lower yield of valsartan and intermediates of valsartan. Furthermore, use of toxic reagents leads to the formation of mixture of products thereby affecting the purity of the valsartan, which makes the process unsuitable for commercial scale production.
Consequently, there is a long-felt need for a process for the preparation of valsartan and its intermediates, which not only overcomes the problems in the prior art processes as mentioned above, but also is simple, devoid of toxic reagents, environment friendly, economically viable and industrially feasible for the preparation of valsartan and pharmaceutically acceptable salts thereof.
OBJECT AND SUMMARY OF THE INVENTION
The principal object of the present invention is to overcome or alleviate at least one of the deficiencies of prior art and provide a useful alternative for the preparation of valsartan and pharmaceutically acceptable salts thereof.
It is another object of the present invention to provide an industrially feasible process for the preparation of valsartan free from use of highly toxic reagents and thereby producing valsartan and pharmaceutically acceptable salts thereof free of toxic impurities.
It is another object of the present invention to provide a process for the preparation of valsartan and pharmaceutically acceptable salts thereof with enhanced enantiomeric purity.
In accordance with an object of the present invention, there is provided an improved process for the preparation of valsartan and pharmaceutically acceptable salts thereof, the said process comprising the steps of:
(a) reacting 2-[(2'-cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid methyl
ester hydrochloride of Formula I with valeryl chloride in presence of a base and
solvent to obtain 2-[(2'-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-
butyric acid methyl ester of Formula II;
(Formula Removed)
(b) reacting 2-[(2'-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric
acid methyl ester of Formula II with sodium azide in presence of amine in a
solvent to obtain 3-methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-
ylmethyl]-amino}-butyric acid methyl ester of Formula III;
(Formula Removed)
(c) hydrolyzing 3-methyl-2-{pentanoyl-[2'-(lH-tetrazol-5-yl)-biphenyl-4-ylmethyl]-
amino}-butyric acid methyl ester of Formula III in presence of a base, optionally
in a solvent to obtain crude valsartan of Formula IV;
(Formula Removed)
(d) treating crude valsartan of Formula IV with a base and solvent to prepare a salt of
Formula V;
(Formula Removed)
Wherein n = 1, 2 and M = Li, Na, K, Mg, Ca, Ba
(e) converting the salt of Formula V to valsartan and optionally converting the valsartan to its pharmaceutically acceptable salts.
DESCRIPTION OF THE INVENTION
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
According to one embodiment of the present invention, there is provided an improved process for the preparation of valsartan and pharmaceutically acceptable salts thereof the said process comprising the steps of:
(a) reacting 2-[(2'-cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid methyl ester hydrochloride of Formula I with valeryl chloride in presence of a base and solvent to obtain 2-[(2'-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid methyl ester of Formula II;
(Formula Removed)
(b) reacting 2-[(2'-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric
acid methyl ester of Formula II with sodium azide in presence of amine in a
solvent to obtain 3-methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-
ylmethyl]-amino}-butyric acid methyl ester of Formula III;
(Formula Removed)
(c) hydrolyzing 3-methyl-2-{pentanoyl-[2'-(lH-tetrazol-5-yl)-biphenyl-4-ylmethyl]-
amino}-butyric acid methyl ester of Formula III in presence of a base, optionally
in a solvent to obtain crude valsartan of Formula IV;
(Formula Removed)
(d) treating crude valsartan of Formula IV with a base and solvent to prepare a salt of
Formula V;
(Formula Removed)
wherein n = 1, 2, 3 and M = Li, Na, K, Mg, Ca, Ba
(e) converting the salt of Formula V to valsartan and optionally converting the
valsartan to its pharmaceutically acceptable salts.
According to the present invention, the reaction of 2-[(2'-cyano-biphenyl-4-ylmethyl)-amino] -3 -methyl-butyric acid methyl ester hydrochloride of Formula I with valeryl chloride is carried out in presence of a base and solvent, wherein the base is selected from inorganic or organic base. The inorganic base is selected from a group comprising of
alkali and alkaline earth metal hydroxide, carbonate, hydride and bicarbonate, wherein the alkali and alkaline earth metal is selected from lithium, sodium, potassium, calcium, magnesium, barium and the like. The organic base is selected from a group comprising of N,Nmethylamine, N-ethyl-N-methyl amine, triethylamine, N,N-dimethylbenzylamine, N,N-diethylbenzylamine, N-methyl morpholine, dimethylaminopyridine, pyridine and the like, preferably triethylamine. The solvent used herein is selected from a group comprising of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene, chlorotoluene, 1,2-dichlorobenzene, 1,3-dichlorobenzene and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like or mixtures thereof, preferably chlorobenzene. In accordance with the present invention, the reaction is carried out at temperature from about 0 to 30°C, preferably between 10 to 20°C for 1-5 h preferably 2-3 h.
According to the present invention, the resulting compound 2-[(2'-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric acid methyl ester of Formula II is reacted with metal azide in the presence of amine in a solvent, wherein the metal azide is selected from a group comprising of alkali and alkaline earth-metal azide. The alkali and alkaline earth metal is selected from lithium, sodium, potassium, calcium, magnesium, barium and the like, preferably sodium. The amine used herein is selected from a group comprising of amine hydrochloride, sulphate, oxalate, p-toluenesulphonate, wherein the amine is selected from the group comprising of methylamine, ethylamine, triethylamine, methyl ethylamine, tert-butylamine, trimethylamine and the like, preferably triethylamine hydrochloride. Optionally the amine can be used as a free amine. The solvent used herein is selected from a group comprising of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene, chlorotoluene, 1,2-dichlorobenzene, 1,3-dichlorobenzene and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like or mixtures thereof, preferably chlorobenzene. In accordance with the present invention, the reaction is carried out at temperature from about 60 to 140°C, preferably between 115 to 130°C for 2-15 h preferably 8-10 h.
According to the present invention, the resulting compound of Formula III is hydrolyzed
in presence of a base, wherein the base is selected from inorganic or organic base. The
inorganic base is selected from a group comprising of alkali and alkaline earth metal
hydroxide, carbonate, hydride and bicarbonate, wherein the alkali and alkaline earth
metal is selected from lithium, sodium, potassium, calcium, magnesium, barium and the
like, preferably sodium hydroxide. The organic base is selected from a group comprising
of N,N-dimethylamine, N-ethyl-N-methyl amine, triethylamine, N,N-
dimethylbenzylamine, N,N-diethylbenzylamine, N-methyl morpholine,
dimethylaminopyridine, pyridine and the like. In accordance with the present invention, the hydrolysis is optionally carried out in the presence of a solvent. The solvent used herein is selected from a group comprising of halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene, chlorotoluene, 1,2-dichlorobenzene, 1,3-dichlorobenzene and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like or mixtures thereof, preferably chlorobenzene. In accordance with the present invention, the hydrolysis is carried out at temperature from about 20 to 200°C, preferably between 30 to 50°C for 2-10 h preferably 2-6 h.
According to the present invention, the resulting crude valsartan of Formula IV is treated with a base and solvent to form a salt, wherein the base used is selected from a group comprising of inorganic and organic base. The inorganic base is selected from a group comprising of alkali or alkaline earth metal hydroxide, carbonate, hydride, bicarbonate wherein the alkali and alkaline earth metal is selected from lithium, sodium, potassium, calcium, magnesium, barium and the like, preferably barium hydroxide or barium carbonate. The organic base is selected from a group comprising of N, N-dimethylamine, N-ethyl-N-methyl amine, triethylamine, N,N-dimethylbenzylamine, N,N-diethylbenzylamine, N-methyl morpholine, thiomorpholine, pyridine, dimethylaminopyridine, piperidine, pyrrolidine and the like. The solvent used herein is selected from a group comprising of alcohols such as methanol, ethanol, propanol, butanol and the like; halogenated solvents such as dichloromethane, ethylene dichloride,
chloroform and the like; esters such as ethyl acetate, propyl acetate, butyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; ketones such as diisobutyl ketone, methyl ethyl ketone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, diispropyl ether, dioxane and the like or mixtures thereof, preferably dichloromethane. In accordance with the present invention, the reaction is carried out at temperature from about 10 to 50°C, preferably between 25 to 30°C for 1-5 h preferably 2-3 h.
According to the present invention, the resulting salt of compound of Formula V is converted to valsartan by addition of an acid, wherein the acid is selected from a group comprising of inorganic and organic acid. The inorganic acid is selected from a group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and the like, preferably hydrochloric acid. The organic acid is selected from a group comprising of formic acid, acetic acid, trifluoroacetic acid, p-toluenesulphonic acid and the like.
According to the present invention, the resulting valsartan can be optionally converted to pharmaceutically acceptable salts by reaction with suitable base well known in prior art.
The valsartan and pharmaceutically acceptable salts thereof obtained by process of the present invention have enantiomeric purity of greater than or equal to 99% and HPLC purity of greater than or equal to 99.5%
The process of present invention has following advantages over prior art processes:
(a) The process is environment friendly in terms of devoid of use of highly toxic reagents like tributyl tin azide.
(b) The process involves the use of inexpensive amine in place of expensive reagents containing heavy metals such as tributyltin halide, which reduces the cost of the process many folds.
(c) The process is operationally very simple, as it does not involve the use of heavy metals, thus the work-up is very much simplified.
(d) The process reduces the generation of toxic waste, thereby making the process environment friendly.
(e) The process utilizes the single solvent such as monochlorobenzene as reaction medium during the various stages for the preparation of crude valsartan from compound of Formula I. Thus, reducing the solvent consumption to make it industrial friendly and cost effective.
(f) The isolation of valsartan via valsartan salts provides valsartan with high enantiomeric and HPLC purity.
Example 1
Preparation of 2-[(2'-cyano-biphenyl-4- ylmethyl)-pentanoyl-amino] -3 -methyl-butyric acid methyl ester
To a solution of 2-[(2'-cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid methyl ester hydrochloride (100 g) in water (300 ml) and chlorobenzene (300 ml), was added sodium bicarbonate (35 g) at 20-25°C. The reaction mixture was stirred for 30 minutes. The organic layer was separated and washed with water (2 x 200 ml). Cooled the organic layer to 10-15°C. Subsequently, valeroyl chloride (50.24 g) and triethylamine (42.11 g) was added. The reaction mass was then stirred for 2-3 h. After the completion of reaction, the reaction mixture was washed with dilute hydrochloric acid. The layers were separated and the organic layer was washed with 5% sodium bicarbonate solution. The solvent was then distilled under vacuum to obtain title compound.
Example 2
Preparation of 3-methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino)-butyric acid methyl ester
To the solution of product obtained in example 1 in chlorobenzene (200 ml), was added sodium azide (35.1 g) and triethylamine hydrochloride (74.33 g) at 20-25 °C. The reaction mixture was then heated to 120-125°C and stirred for 8-10 h. After the completion of reaction, cooled the reaction mixture, washed with water, stirred for 30 minutes and the layers were separated. The title compound so obtained was taken as such for next step.
Example 3
Preparation of crude valsartan
The product obtained in example 2 was added to sodium hydroxide solution (50 g in 950 ml water) at 15-20°C. The reaction mixture was stirred at 35-40°C for 3-4 h. After completion of reaction, cooled the reaction mixture and separated the layers. The separated aqueous layer was washed with toluene and then extracted with methylene chloride at pH 2.5-3.3 and the organic layer was separated. The separated organic lyer was distilled under vacuum to get crude valsartan.
Example 4
Preparation of Barium salt of Valsartan
The crude valsartan obtained in example 3 was dissolved in dichloromethane. Added
water (630 ml) to the solution and adjusted pH of the reaction mixture to 7.0-8.0 using
20% sodium hydroxide solution. The layers were separated. To the aqueous layer,
charged barium hydroxide (75 g) and stirred for 2-3 h. filtered the reaction mixture to
obtain barium salt of valsartan. The barium salt of valsartan was used in next step as wet
cake.
Example 5 Preparation of valsartan from barium salt of valsartan
To the wet cake of barium salt of valsartan prepared in example 4 was added dichloromethane (450 ml) and water (450 ml). The reaction mixture was stirred for 30 minutes. Adjusted the pH of reaction mixture to 2.5-3.3 with dilute hydrochloric acid. The reaction mixture was again stirred for 30 minutes. Separated the layers. The organic layer was washed with water (2 x 250 ml). Distilled the organic solvent under vacuum and added ethyl acetate (300 ml). The reaction mixture was then cooled to 0-5°C and stirred for 3-4 h. Filtered the solid precipitated out and dried under vacuum to afford title compound. HPLC purity: 99.9% Overall yield: 60-65%

CLAIMS
1. An improved process for the preparation of valsartan and pharmaceutically acceptable salts thereof comprising the steps of:
a) reacting 2-[(2'-cyano-biphenyl-4-ylmethyl)-amino]-3-methyl-butyric acid methyl
ester hydrochloride of Formula I with valeryl chloride in presence of a base and
solvent to obtain 2-[(2'-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-
butyric acid methyl ester of Formula II;
(Formula Removed)
b) reacting 2-[(2'-cyano-biphenyl-4-ylmethyl)-pentanoyl-amino]-3-methyl-butyric
acid methyl ester of Formula II with sodium azide in presence of amine in a
solvent to obtain 3-methyl-2-{pentanoyl-[2'-(1H-tetrazol-5-yl)-biphenyl-4-
ylmethyl]-amino}-butyric acid methyl ester of Formula III;
(Formula Removed)
c) hydrolyzing 3-methyl-2-{pentanoyl-[2'-(lH-tetrazol-5-yl)-biphenyl-4-ylmethyl]-
amino}-butyric acid methyl ester of Formula III in presence of a base, optionally
in a solvent to obtain crude valsartan of Formula IV;
(Formula Removed)
d) treating crude valsartan of Formula IV with a base and solvent to prepare a salt of
Formula V;
(Formula Removed)
wherein n = 1,2 and M = Li, Na, K, Mg, Ca, Ba
e) converting the salt of Formula V to valsartan and optionally converting the
valsartan to its pharmaceutically acceptable salts.
2. The process according to claim 1, wherein the base used in step (a) is selected from a group comprising of inorganic or organic.
3. The process according to claim 2, wherein the inorganic base is selected from a group comprising of alkali or alkaline earth metal hydroxide, carbonate, hydride and bicarbonate.
4. The process according to claim 3, wherein the alkali and alkaline earth metal is selected from a group comprising of lithium, sodium, potassium, calcium, magnesium and barium.
5. The process according to claim 2, wherein the organic base is selected from a group comprising of N,N-dimethylamine, N-ethyl-N-methyl amine, triethylamine, N,N-dimethylbenzylamine, N,N-diethylbenzylamine, N-methyl morpholine, dimethylaminopyridine and pyridine.
6. The process according to claim 5, wherein the organic base is triethylamine.
7. The process according to claim 1, wherein the solvent used in step (a) is selected from a group comprising of halogenated solvent, esters, hydrocarbons or mixtures thereof.
8. The process according to claim 7, wherein the solvent is selected from a group comprising of dichloromethane, ethylene dichloride, chloroform, chlorobenzene, chlorotoluene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, toluene, xylene, n-hexane, n-heptane and cyclohexane.
9. The process according to claim 8, wherein the solvent is chlorobenzene.
10. The process according to claim 1, wherein the metal azide used in step (b) is selected from a group comprising of alkali and alkaline earth metal azide.
11. The process according to claim 10, wherein the alkali and alkaline earth metal is selected from a group comprising of lithium, sodium, potassium, calcium, magnesium and barium.
12. The process according to claim 1, wherein the amine used in step (b) is selected from a group comprising of amine hydrochloride, sulphate, oxalate and p-toluenesulphonate.
13. The process according to claim 12, wherein the amine is selected from a group comprising of methylamine, ethylamine, triethylamine, methyl ethylamine, tert-butylamine and trimethylamine.
14. The process according to claim 13, wherein the amine is trimethylamine or its hydrochloride salt.
15. The process according to claim 1, wherein the solvent used in step (b) is selected from a group comprising of halogenated solvent, esters, hydrocarbons or mixtures thereof.
16. The process according to claim 15, wherein the solvent is selected from a group comprising of dichloromethane, ethylene dichloride, chloroform, chlorobenzene, chlorotoluene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, toluene, xylene, n-hexane, n-heptane and cyclohexane.
17. The process according to claim 16, wherein the solvent is chlorobenzene.
18. The process according to claim 1, wherein the base used in step (c) is selected from a group comprising of inorganic and organic.
19. The process according to claim 18, wherein the inorganic base is selected from a group comprising of alkali and alkaline earth metal hydroxide, carbonate, hydride and bicarbonate.
20. The process according to claim 19, wherein the alkali and alkaline earth metal is selected from a group comprising of lithium, sodium, potassium, calcium, magnesium and barium.
21. The process according to claim 18, wherein the organic base is selected from a group comprising of N,N-dimethylamine, N-ethyl-N-methyl amine, triethylamine, N,N-dimethylbenzylamine, N,N-diethylbenzylamine, N-methyl morpholine, dimethylaminopyridine and pyridine.
22. The process according to claim 1, wherein the solvent used in step (c) is selected from a group comprising of halogenated solvent, esters, ketones, hydrocarbons or mixtures thereof.
23. The process according to claim 22, wherein the solvent is selected from a group comprising of dichloromethane, ethylene dichloride, chloroform, chlorobenzene, chlorotoluene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, diisobutyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, toluene, xylene, n-hexane, n-heptane and cyclohexane.
24. The process according to claim 1, wherein the base used in step (d) is selected from a group comprising of inorganic and organic.
25. The process according to claim 24, wherein the inorganic base is selected from a group comprising of alkali or alkaline earth metal hydroxide, carbonate, hydride and bicarbonate
26. The process according to claim 25, wherein the alkali and alkaline earth metal is selected from lithium, sodium, potassium, calcium, magnesium and barium.
27. The process according to claim 26, wherein the inorganic base is barium hydroxide.
28. The process according to claim 24, wherein the organic base is selected from a group comprising of N,N-dimethylamine, N-ethyl-N-methyl amine, triethylamine,
N,N-dimethylbenzylamine, N,N-diethylbenzylamine, N-methyl morpholine, thiomorpholine, pyridine, dimethylaminopyridine, piperidine and pyrrolidine.
29. The process according to claim 1, wherein the solvent used in step (d) is selected
from a group comprising of alcohols, halogenated solvents, esters, nitriles,
ketones, ethers or mixtures thereof.
30. The process according to claim 29, wherein the solvent is selected from a group
comprising of methanol, ethanol, propanol, butanol, dichloromethane, ethylene
dichloride, chloroform, ethyl acetate, propyl acetate, butyl acetate, acetonitrile,
propionitrile, diisobutyl ketone, methyl ethyl ketone, methyl isobutyl ketone,
tetrahydrofuran, diispropyl ether and dioxane.
31. The process according to claim 1, wherein the acid is used in step (e) is selected from a group comprising of inorganic and organic.
32. The process according to claim 31, wherein the inorganic acid is selected from a group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid.
33. The process according to claim 31, wherein the organic acid is selected from a group comprising of formic acid, acetic acid, trifluoroacetic acid and p-toluenesulphonic acid.