FIELD OF THE INVENTION:
This invention relates to a novel process for the preparation of ebastine. The invention also relates to process of preparation of 1-[4-(1, l-dimethyl ethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-one (compound II), an intermediate or preparation of ebonite
BACKGROUND OF THE INVENTION:
1-[4-(1,1-Dimethylethyl)-phenyl]-4-[4-(diphenylmethoxy)-1-piperidinyl]-1-butanone, commonly known as Ebastine. Ebastine is discovered and developed by Ordinal. The structure of ebastine is given below.

Ebastine is generally prepared from 1-[4-(1, 1-dimethyl ethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-one and diphenyl methyl bromide. Several methods for the preparation ebastine are known in literature.
United States patent No 4,550,116 which is incorporated herein in its entirety by reference; discloses synthesis of ebastine according to following schemes. The first scheme is as follows:


In the process for the preparation of ebastine fumarate (IV) in above scheme, the refluxing 1-[4-(1, l-dimethyl ethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-one (II) with diphenylmethyl bromide (III) in presence of sodium carbonate and methyl isobutyl ketene as a solvent was done.
The above-disclosed scheme has several disadvantages, which are as follows: The compound (II) is purified in the form of fumarate salt and further it reacts with compound (III). The compound (III) is highly unstable and moisture sensitive. More over the compound (III) is costlier.. Also the process requires refluxing the reaction mixture for more than 36 hours with addition of compound (III) at every 12 hours time interval.


In above scheme the preparation of 1-ethoxycarbonyl-4-dipheylmethoxypiperidine is highly expensive and commercially not viable because of its low yields.
Thus there is need for the simple, cost effective and less time consuming commercially viable process of preparing ebastine.
OBJECTS OF THE INVENTION:
An object of the present invention is to provide a process of preparing ebastine.
Another object of the present invention is to provide a process of preparing ebastine wherein the process requires about 6 hours time.
Yet another object of the present invention is to provide a process of preparing ebastine, which has a minimum of processing steps.
Yet another object, of the present invention is to provide a cost effective process of preparing ebastine with improved yield of ebastine.
Further object of, the present invention is to provide a process of preparing pure ebastine with purity not less than 99.6 %.
Another object is to provide a process for preparation of compound II which is an intermediate for formation of ebastine.
SUMMARY OF THE INVENTION
According one aspect of the present invention there is provided a process for preparation of ebastine, said process comprising reaction of 1-[4-(1, 1-dimethyl ethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-one compound (II) and diphenyl methanol in presence of dehydrating agent in organic solvent system to obtain ebastine fumarate salt (compound IV) in organic solvent.
According to another aspect of the present invention there is provided a process for preparation of 1-[4-(1, 1-dimethyl ethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-one compound (II), said process comprising coupling reaction between compound (1) and 4-
4

hydroxy piper dine in presence of a base in organic solvent system, distilling the solvent under vacuum, dissolving resulting residue in ethyl acetate and water, washing the aqueous is washed in acidic pH with organic solvent to obtain compound II from a mixture of ethyl acetate and n-Hexane directly without any further purification.
DETAILED DESCRIPTION OF THE INVENTION .
The present invention relates to an efficient and cost effective method of synthesis of ebastine comprising the preparation of 1-[4-(1, 1-dimethyl ethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-one by reacting 1-(4-terf-butylphenyl)-4-chlorobutan-1-one and 4-hydroxy piperidine in organic solvent system in basic condition in one aspect and refluxing the 1-[4-(1, 1-dimethyl ethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-one thus obtained with diphenyl methanol in presence of dehydrating agent by removing the generated water as an azeotrope in another aspect. The crude ebastine is purified by making fumarate salt. The Ebastine fumarate salt is suspended in organic solvent in presence of base stirred for 30 minutes and organic layer is separated. Distilled out solvent completely under vacuum and crystallize resulting residue from alcohol.
The present invention relates to a novel process for preparing ebastine that eliminates the disadvantages of prior art processes for the synthesis of 1- [4-(1, 1-dimethyl ethyl) phenyl]-4-{4-hydroxy piperidin-1-yl) butan-1-one (II) and also eliminate extensive purification requirements.
According to one embodiment, the present invention provides a process of preparing the ebastine, which has following synthetic scheme:

out at refluxing temperature of the solvent for about 6-8hours. After the reaction has proceeded to a desired stage as judged by HPLC analysis, the solvent is distilled out under vacuum and the resulting residue is dissolved in ethyl acetate and water. The organic layer pH is adjusted to acidic with mineral acids such as hydrochloric acid, sulphuric acid or acetic acid. The preferred pH is 2-3 and preferred acid is HCI. At acidic pH the aqueous layer is washed with organic solvent to remove impurities, the desired product is obtained from a mixture of ethyl acetate and n-Hexane directly without any further purification.
The present invention provides novel methods for preparing ebastine. According to prior art literature ebastine can be prepared by refluxing compound (II) with diphenyl methyl bromide or chloride in presence of sodium carbonate. According to present invention, the compound (II) and diphenyl methanol are reacted in presence of dehydrating agent in organic solvent system, wherein organic solvent can be selected from high boiling solvent such as toluene, xylene, methyl isobutyl ketone or dichloroethane. The preferred solvent is toluene. The dehydrating agent can be selected from p-toluene sulphonic acid monohydrate (PTSA), sulphuric acid, methane sulphonic acid, phosphorous pentoxide, titanium tetrachloride or Dicyclohexylcarbodiimide (DCC) etc. The preferred dehydrating agent is p-toluene sulphonic acid monohydrate. The reaction can be carried out at refluxing temperature of the solvent to remove water as an azeotrope for about 6-16 hours. Preferably 6-8 hours. After the reaction has proceeded to a desired stage as judged by HPLC analysis. The desired compound (IV) is isolated in the form fumarate salt in organic solvent. The organic solvent can be selected from alcohols such as methanol, ethanol or isoproppanol; nitriles such as acetonitrile or propionitrile; esters such as ethyl acetate, propyl acetate or butyl acetate; toluene, methyl isobutyl ketone and mixtures thereof. The preferred solvent is ethyl acetate.
In another embodiment of this invention, a pure ebastine is obtained by breaking ebastine fumarate salt (IV) using base. The base is selected from alkali metal hydroxides, carbonates or bicarbonates, ammonia, tertiary amines and mixtures thereof. The preferred base is sodium hydroxide.
In another embodiment of this invention, a pure ebastine is crystallized from resulting residue obtained from breaking ebastine fumarate salt (IV) in presence of organic solvent at -5 to +25° C. The organic solvent is selected from CrCe alcohols such as methanol, ethanol, and propanol; hexanes, cyclohexane; diisopropyl ether and mixtures thereof. The preferred solvent is methanol. Thus obtained Ebastine purity is above 96.6% by HPLC.

The present invention can be illustrated in one of its embodiments by the following non-limiting examples.
EXAMPLE-1:
Preparation of 1-[4-(1,1-dimethylethyl) phenyl]-4-(4-hydroxy piperidin-1■yl) butan-1-
one:
A mixture of 4-hydroxy piperidine (50g, 0.49mol), 1-(4-fert-butylphenyl)-4-chlorobutan-1-one (118.5g, 0.49mol) and sodium bicarbonate (83.5g, 0.8mol) in toluene (500ml) is refluxed for 6-8hrs. The progress of the reaction is monitored by HPLC. Distill out the solvent completely under vacuum; the resulting residue is dissolved in ethyl acetate (500ml) and water (500ml). Separate the ethyl acetate layer and wash the organic layer with water. Adjust the pH of the ethyl acetate layer to 2-3 with 3N HCI solution, wash the aqueous layer with ethyl acetate and make the aqueous solution alkaline with aqueous sodium hydroxide and extracts with ethyl acetate. The organic layer is dried with sodium sulphate and solvent removed completely under vacuum. The title compound is isolated from a mixture of 1:5 ethyl acetate and n-hexane. Yield: 105g (70%), Melting Point: 63-65°C.
EXAMPLE-2:
Preparation of 1-[4-(1,1-dimethylethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1*
one:
A mixture of 4-hydroxy piperidine (10.2g, O.lmol), 1-(4-tert-butylphenyl)-4-chlorobutan-1-one (24.1g, O.lmol) and triethyl amine (20.2g, 0.2mol) in methyl isobutyl ketone (100ml) is refluxed for 6-8hrs. The progress of the reaction is monitored by HPLC. The reaction mass is cooled to room temperature and washed with water. The organic layer pH is adjusted to 2-3 with 3N HCI solution; the aqueous layer is washed with methyl isobutyl ketone and makes the aqueous solution alkaline with aqueous sodium hydroxide and extracted with ethyl acetate. The organic layer is dried with sodium sulphate and solvent removed completely under vacuum. The title compound is isolated from a mixture of 1:5 ethyl acetate and n-hexane. Yield: 18g (58%), Melting Point: 63-65°C.
EXAMPLE-3:
Preparation of 1-[4-(1,1-dimethylethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-
one:
A mixture of 4-hydroxy piperidine (14.2g, 0.14mol), 1-(4-tert-butylphenyl)-4-chlorobutan-1-one (33.5g, 0.14mol) and sodium carbonate (29.68g, 0.8mol) in acetonitrile (100ml) is

refluxed for 10-14hrs. The progress of the reaction is monitored by HPLC. Distill out solvent completely under vacuum; the resulting residue is dissolved in ethyl acetate (100ml) and water (100ml). Separate the ethyl acetate layer and wash the organic layer with water. Adjust pH of the ethyl acetate layer to 2-3 with 3N HCI solution, the aqueous layer is washed with ethyl acetate and make the aqueous solution alkaline with aqueous sodium hydroxide and extracts with ethyl acetate. The organic layer is dried with sodium sulphate, and solvent removed completely under vacuum. The title compound is isolated from a mixture of 1:5 ethyl acetate and n-hexane. Yield: 14g (33%), Melting Point: 61-64°C
EXAIVIPLE-4: Preparation of Ebastine:
A mixture of 1-[4-(1,1-dimethylethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-one (150g, 0.49mol) and p-toluene sulphonic acid monohydrate (103.5g, 0.54mol) in toluene (500ml) is boiled to 100 - 110°C. Add a solution of diphenyl methanol (60g, 0.32mol) in toluene (80ml) to a reaction mixture over 1 hour at refluxing temperature by continuously removing water as an azeotrope. Maintain refluxing temperature for 1.5 hour and then add another solution of diphenyl methanol (60g, 0.32mol) in toluene (80ml) to the reaction mixture over Ihour at refluxing temperature by continuously removing water as an azeotrope, the mixture is boiled under reflux for 1.5hrs. Another solution of diphenyl methanol of the same quantity is added under similar conditions. The reaction mixture is refluxed for 4- 5hrs. The progress of the reaction is monitored by HPLC. Distill out solvent completely under vacuum, the resulting residue is dissolved in ethyl acetate (750ml) and 10% sodium hydroxide solution (600ml) at 45 - 50°C. Separate the organic layer and wash with water. Wash the organic layer with 3N HCI solution and with 10% sodium bicarbonate solution. The ethyl acetate layer is dried with sodium sulphate and refluxed with fanatic acid (85g, 0.73mol). The resulting ebastine fumarate is filtered, washed with ethyl acetate and dried at 80 - 85°C.
The ebastine fumarate salt (240g) is suspended in ethyl acetate (900ml) and 10% sodium hydroxide solution (800ml), stirred for 0.5hours at room temperature to get a clear solution. Separate the organic layer and wash with water till pH comes to neutral. Distill out solvent completely under vacuum and crystallize the resulting residue from methanol. The obtained pure ebastine solid is filtered and dried at 60 - 65°C. Yield: 150g (64%); Melting point: About 86°C.Purity by HPLC: 99.9%

EXAMPUE-5: Preparation of Ebastine:
A mixture of 1-[4-(1,1-dimethylethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-one (150g, 0.49mol), p-toluene sulphonic acid monohydrate (103.5g, 0.54mol) and diphenyl methanol (180g, 0.98mol) in toluene (600ml) is refluxed for 12-15hours by continuously removing water as an azeotrope. The progress of the reaction is monitored by HPLC. Distill out solvent completely under vacuum; dissolve the resulting residue in ethyl acetate (750ml) and 10% sodium hydroxide solution (600ml) at 45 - 50°C. Separate the organic layer and wash with water. Wash the organic layer with 3N HCI solution and with 10% sodium bicarbonate solution. The ethyl acetate layer is dried with sodium sulphate and refluxed with fumaric acid (85g, 0.73mol). The resulting ebastine fumarate is filtered, washed with ethyl acetate and dried at 80 - 85°C.
The ebastine fumarate salt (200g) is suspended in ethyl acetate (800ml) and 10% sodium hydroxide solution (700ml), stirred for 0.5hours at room temperature to get a clear solution. Separate the organic layer and washed with water till pH comes too neutral. Distill out solvent completely under vacuum and crystallize the resulting residue is from methanol. The obtained pure ebastine solid is filtered and dried at 60 - 65°C. Yield: 118g (51%); Melting point: About 86°C. Purity by HPLC: 99.85%
EXAMPLE-6: Preparation of Ebastine:
A mixture of 1-[4-(1,1-dimethylethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-one (25g, 0.08mol), sulphuric acid (24.2g, 0.25mol) and diphenyl methanol (30g, 0.16mol) in toluene (100ml) is refluxed for 8-10hours by continuously removing water as an azeotrope. The progress of the reaction is monitored by HPLC. Cool the reaction mixture to room temperature and wash with water till pH comes to neutral. Dry the organic layer with sodium sulphate and removed solvent completely under vacuum. The resulting residue is refluxed with ethyl acetate and fumaric acid (14.3g, 0.12mol). The obtained ebastine fumarate salt is filtered, washed with ethyl acetate and dried at 80-85°C.
The ebastine fumarate salt (25g) is suspended in ethyl acetate (150ml) and'10% sodium hydroxide solution (100ml), stirred for 0.5hours at room temperature to get a clear solution. Separate the organic layer and washed with water till pH comes too neutral. Distill out solvent completely under vacuum and crystallize the resulting residue from methanol. The obtained pure Ebastine solid is filtered and dried at 60 - 65°C. Yield: 12g (31%); Melting point: About 86°C. Purity by HPLC: 99.7%

EXAMPLE-7: Preparation of Ebastine:
A mixture of 1-[4-(1,1-climethylethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-one (100g, 0.33mol) and p-toluene sulphonic acid monohydrate (69.0g, 0.36mol) in methyl isobutyl ketone (500ml) is boiled to 100-110°C. Added lot wise diphenyl methanol (120g, 0.65mol) to the reaction mixture over 3 hours at refluxing temperature by continuously removing water as an azeotrope. Maintain reflux temperature for 6-8 hours. The progress of the reaction mixture is monitored by HPLC. Cool the reaction mixture to 50-55°C, charge 10% sodium hydroxide solution (500ml) and stir for 30 minutes at same temperature. Separate the organic layer and wash with water. Wash the organic layer with 3N HCI solution and with 10% sodium bicarbonate solution. The ethyl acetate layer is dried with sodium sulphate and refluxed with fumaric acid (56g, 0.486mol). The resulting ebastine fumarate is filtered, washed with ethyl acetate and dried at 80 - 85°C
The ebastine fumarate salt (140g) is suspended in ethyl acetate (500ml) and 10% sodium hydroxide solution (350ml), stirred for 0.5hours at room temperature to get a clear solution. Separate the organic layer and washed with water till pH comes too neutral. Distilled out solvent completely under vacuum and crystallize the resulting residue from methanol. The obtained pure ebastine solid is filtered and dried at 60 - 65°C. Yield: 75 g (48%); Melting point: About 86°C. Purity by HPLC: 99.9%

We claim;
1. A process for preparation of ebastine, said process comprising reaction of 1-[4-(1, 1-dimethyl ethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-one (compound II) and diphenyl methanol in presence of dehydrating agent in organic solvent system to obtain ebastine fumarate salt (compound IV) in organic solvent.
2. The process as claimed in claim 1 wherein the organic solvent is selected from high boiling solvent such as toluene, xylene, methyl isobutyl ketone and dichloroethane, preferably toluene.
3. The process as claimed in any one of claims 1 or 2 wherein the dehydrating agent is selected from p-toluenesulphonic acid monohydrate (PTSA), sulphuric acid, methane sulphonic acid, phosphorous pentoxide, titanium tetrachloride and Dicyclohexylcarbodiimide (DCC), preferably dehydrating agent is p-toluenesulphonic acid monohydrate.
4. The process as claimed in any preceding claim wherein the reaction is carried out at refluxing temperature of the solvent to remove water as an azeotrope for about 6-16 hours.
5. The process as claimed in claim 4 wherein the reaction is carried out for 6-8 hours.
6. The process as claimed in any preceding claim wherein the organic solvent in which ebastine fumarate salt (compound IV) is isolated is selected from alcohols nitriles, esters, toluene, methyl isobutyl ketone and mixtures thereof..
7. The process as claimed in claim 6 wherein the alcohol is selected from methanol, ethanol and isoproppanol,
8. The process as claimed in claim 6 wherein the nitrile is selected from acetonitrile or propionitrile.
9. The process as claimed in claim 6 wherein the ester is selected from ethyl acetate, propyl acetate, butyl acetate; preferably ethyl acetate.
10. The process as claimed in claim 1 wherein pure ebastine is obtained by breaking ebastine fumarate salt (IV) using base.

ll.The process as claimed in claim 10 wherein the base is selected from alkali metal hydroxides, carbonates, bicarbonates, ammonia, tertiary amines and mixtures thereof, preferably sodium hydroxide.
12. The process as claimed in claim 1 wherein pure ebastine is crystallized by breaking ebastine fumarate salt (IV) in presence of organic solvent at -5 to 25° C.
13. The process as claimed in claim 12 wherein the organic solvent is selected from C1-C6 alcohols, hexanes, cyclohexane; diisopropyl ether and mixtures thereof.
14. The process as claimed in claim 13 wherein the alcohol is selected from methanol, ethanol, and propanol; preferably methanol.
15. The process as claimed in any preceding claim wherein the obtained Ebastine purity is above 96.6% by HPLC.
16. A process for formation of 1-[4-(1, 1-dimethyl ethyl) phenyl]-4-(4-hydroxy piperidin-1-yl) butan-1-one (compound II), said process comprising coupling reaction between compound (I) and 4-hydroxy piperidine in presence of a base in organic solvent system, distilling the solvent under vacuum, dissolving resulting residue in ethyl acetate and water, washing the aqueous is washed in acidic pH with organic solvent to obtain compound II from a mixture of ethyl acetate and n-Hexane directly without any further purification.
17. The process as claimed in claim 16 wherein the organic solvent for coupling reaction is selected from water miscible solvent and water immiscible solvent and mixtures thereof
18. The process as claimed in claim 17 wherein the water miscible solvent is selected from acetonitrile, dioxane. N, N-dimethyl formamide, acetone and the like
19. The process as claimed in claim 17 wherein the water immiscible solvent is selected from toluene, methyl isobutyl ketone, dichlomethane, xylene, chloroform, cyclohexane preferably toluene.
20. The process as claimed in any of claims 16 to 19 wherein the base is selected from organic and inorganic bases.
21. The process as claimed in claim 20 wherein the inorganic base is selected from alkali metal carbonate, bicarbonate and metal hydroxides

■ 22. The process as claimed in claim 21 wherein the metal carbonates are selected from sodium carbonate, potassium carbonate,
23. The process as claimed in claim 21 wherein the metal bicarbonate is selected from
sodium bicarbonate, potassium bicarbonate, preferably sodium bicarbonate.
24. The process as claimed in claim 21 wherein the metal hydroxide is selected from
lithium hydroxide, sodium hydroxide, and potassium hydroxide.
25. The process as claimed in claim 20 wherein organic base is selected from
triethylamine, diisopropyl ethylamine and pyridine.
26. The process as claimed in any of claims 16 to 25 wherein the reaction is carried out
from ambient temperature to reflux temperature of the solvent, preferably at reflux
temperature.
27. The process as claimed in claim in any of claims 16 to 25 wherein the reaction is
completed in 6-12 hours, preferably about 6-8 hours.
28. The process as claimed in any of claims 16 to 27 wherein the pH is adjusted to 2-3
with mineral acids selected from hydrochloric acid, sulphuric acid and acetic acid.