FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
"BILASTINE SYNTHESIS PROCESS USING PHASE TRANSFER CATALYST"
AJANTA PHARMA LTD.
A company incorporated under the laws of India having their office at
98, Ajanta house, Charkop, Kandivali (West)
Mumbai - 400067, Maharashtra, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 2-[4-(2-{4-[l-(2-Ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinylethyl)phenyI]-2-methyl-propanoic acid represented by Formula-(I) commonly known as Bilastine.

The process provides Bilastine in higher yield and purification technique provides an approach to get rid of impurities effectively compared to the previously known processes.
BACKGROUND OF THE INVENTION
Bilastine, sold under the brand name Bilaxten among others, is a second-generation antihistamine medication which is used in the treatment of allergic rhinoconjunctivitis and urticaria (hives). It exerts its effect as a selective histamine H1 receptor antagonist, and has an effectiveness similar to cetirizine, fexofenadine, and desloratadine. It was developed in Spain by FAES Farma.
Bilastine is approved in the European Union for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria, but it is not approved for any use in the United States. Bilastine meets the current European Academy of Allergy and Clinical Immunology (EAACI) and Allergic Rhinitis and its Impact of Asthma (ARIA) criteria for medication used in the treatment of allergic rhinitis. Bilastine has been effective in the treatment of diseases of allergies, including rhinoconjunctivitis. Additionally, bilastine has been shown to improve quality of life, and all nasal and eye symptoms related to allergic rhinitis.
IN 233119 ("the 119 patent") discloses a variety of benzimidazole derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and

methods of use thereof among them is bilastine. The 119 patent further discloses processes for the preparation of bilastine which is depicted in Scheme 1.

Various other processes for the preparation of Bilastine, its intermediates and related compounds are described in Indian patent application 2799/KOLNP/2010, 2276/CHE/2013; PCT Publication number WO 2014026657; Chinese patent number CN102675101B and various scientific articles such as Synthetic communication 2011, 41(9), 1394-1402, Drugs of the future 2010, 35(2), 98-105.
All these processes described in the prior art for the preparation of bilastine suffer from numerous drawbacks such as formation of by-products affecting the overall yield, making

the process lengthy and cumbersome, harsh reaction conditions, use of metal hydrides which are dangerous and explosive in nature and prevents its commercial scale production. But most pertinent of which is the production of impurities. Thus, it would be advantageous to reduce the level of impurities in the preparation of bilastine.
The present inventors have directed the research work towards preparation of bilastine which not only provides the desired purity but is also devoid of impurities and disadvantages in the prior-art processes. Unexpectedly, when bilastine was purified using neutral alumina column it was observed that the final compound was having better yield and free of impurities with overall process efficacy. Present invention also provides processes for the preparation of various impurities.
The process for the preparation of bilastine is cost effective and avoids the drawback of the prior art processes.
SUMMARY OF THE INVENTION
The present invention provides a process for preparation of Bilastine of Formula I comprising

(a) reacting a compound of Formula II with Compound of Formula III in presence a suitable solvent and an inorganic base and phase transfer catalyst to obtain a compound of formula IV;


(b) reacting the compound of Formula IV with l-chloro-2-ethoxyethane in presence of
suitable solvent, base and phase transfer catalyst to obtain compound of Formula
V.

(c) hydrolysing the compound of Formula V to Bilastine crude in presence of a suitable
reagent.
(d) purifying a crude product by column chromatography with alumina as support.
An object of the present invention provides a process for the preparation of Bilastine using Phase Transfer Catalyst (PTC) which is substantially free from impurity and also
industrially viable.
It has been surprisingly found that the process according to the present invention provides Bilastine having impurities such as BIL-Amide Impurity (Impurity 2), BIL-Butyl ester Impurity (Impurity 3) BIL-Methyl ester Impurity (Impurity 4) below detectable limits. PTC as reagent during reaction increases the rate with minimizing the impurity formation and Alumina bed purification increases the purity further. It was also observed that designing work up of the reaction is so important that it can take care of the impurity formation during conversion of Oxazoline Bilastine to Crude Bilastine except the formation of BIL-Des Ethyl impurity, which is removed by purification using neutral alumina column chromatography.


DETAILED DESCRIPTION OF THE INVENTION
As used throughout the specification, the term "suitable solvent" refers to, but is not limited to halogenated solvents such as methylene chloride (dichloromethane), chloroform, chlorobenzene, trichloroethylene, carbon tetrachloride, chlorinated fluorocarbons, tetrachloroethylene (perchloroethylene), 1,1,1-trichloroethane and the like; halogenated hydrocarbons solvents such as chlorobenzene, dichlorobenzene, trichlorobenzene, and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 4-hydroxy-4-methyl pentanone and the like; water or mixtures thereof.
As used throughout the specification, the term. The term "inorganic base" includes, but is not limited to, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like; alkaline earth metal carbonates; alkali metal carbonates such as sodium carbonate, cesium carbonate, potassium carbonate and the like.
As used throughout the specification, the term "phase transfer catalyst" includes, but is not limited to quaternary ammonium compounds such as tetraethylammonium p-toluenesulfonate, tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate (TBAHS), tetrabutylammonium iodide, and the like, wherein quaternary ammonium salts and particularly tetrabutylammonium hydrogen sulphate and Aliquat 336 (Starks Catalyst) are especially preferred.
The present invention provides a process for preparation of Bilastine of Formula I comprising

(a) reacting a compound of Formula II with Compound of Formula III in presence a suitable solvent and an inorganic base and phase transfer catalyst to obtain a compound of formula IV;


(b) reacting the compound of Formula IV with l-chloro-2-ethoxyethane in presence of
suitable solvent, base and phase transfer catalyst to obtain compound of Formula
V.

(c) hydrolysing the compound of Formula V to Bilastine crude in presence of a suitable
reagent.
(d) purifying a crude product by column chromatography with alumina as support.
In one embodiment, step (a) comprises reacting a compound of Formula II with Compound of Formula III in presence a suitable solvent and an inorganic base and phase transfer catalyst to obtain a compound of formula IV.
The suitable solvent used in step (a) is as defined supra. Preferably, the solvent used for the process in step (a) is ketone solvent and base used is an alkali metal carbonate in presence of Phase transfer catalyst (PTC). More preferably, the solvent used in step (a) is methyl isobutyl ketone (MIBK) and base is sodium carbonate and tetrabutyl-ammonium hydrogensulphate (TBAHS) as PTC. PTC usage improves the overall yield of the reaction while minimizing the formation of impurities.
In one embodiment, the reaction between a compound of Formula II and Formula III is performed using sodium carbonate in MIBK in presence of tetrabutylammonium hydrogensulphate as PTC.
In one embodiment, step (b) comprises reacting compound of Formula IV with 1-chloro-2-ethoxyethane in presence of a suitable solvent, base and phase transfer catalyst to obtain

compound of Formula V.
The suitable solvent used in step (b) may be as defined above. Preferably, the solvent used for step (b) may be selected from amongst halogenated solvents such as methylene chloride (dichloromethane), chloroform, chlorobenzene, trichloroethylene, carbon tetrachloride, chlorinated fluorocarbons, tetrachloroethylene (perchloroethylene), 1,1,1-trichloroethane and the like; and halogenated hydrocarbons solvents such as chlorobenzene, dichlorobenzene, trichlorobenzene. More preferably, the solvent used in step (b) is monochlorobenzene with a PTC and KOH as the base.
In one embodiment, the phase transfer catalyst (PTC) is selected from quaternary ammonium compounds such as tetraethylammonium p-toluenesulfonate, tetrabutyl-ammonium bromide, tetrabutylammonium hydrogensulphate, tetrabutylammonium iodide, and the like, wherein quaternary ammonium salts and particularly tetrabutyl¬ammonium hydrogen sulphate and Aliquat 336 (Starks Catalyst) are preferable.
In one embodiment, step (b) is performed by using KOH and monochlorobenzene in the presence of Aliquat 336 as PTC. Use of PTC in this reaction minimizes the formation of impurities.
In another embodiment, step (c) comprises hydrolysing the compound of Formula V in the presence of suitable reagent to form crude Bilastine.
In another embodiment, step (c) comprises using Hydrochloric acid for hydrolysing of compound of Formula V to form crude Bilastine.
In another embodiment, step (d) comprises purification of crude Bilastine using column chromatography in a suitable solvent.
In another embodiment, the column chromatography in step (d) is carried out using neutral alumina bed. Neutral alumina purification not only removes BIL-Des ethyl impurity but also other minor unknown impurities to give purity of about 99.9%. Other purification techniques such as crystallization using single solvent or mixture of solvents do not remove the impurities to the desired level.
In yet another embodiment, dichloromethane is used as an eluent for chromatography of step (d).

These aspects of the present invention substantially increase the inherent utility of the invention.
Thus present invention is not only novel, non-obvious over prior art but it has tremendous utility and industrial application.
While the present invention has been described in terms of its specific aspects, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Overall yield of the process provided by present invention is better than overall yield of the prior art processes.
Following section describes and illustrates the invention by way of examples. However, these do not limit the scope of the present invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.
The process provided by present invention does not use hazardous, pyrophoric, flammable reagents and cryogenic conditions. The process also does not use sub-zero temperatures and thus supports the large scale production of Bilastine.
The present invention is explained in detail by referring to examples, which are not to be construed as limitative.


To a solution of BIL-Tosylate (100 g) in methyl isobutyl ketone (MIBK) (400 ml) was added BIL-Benz (50.84 g) at 25-30 °C followed by addition of sodium carbonate (63.75 g) and water (500 ml). To this tetra butyl ammonium hydrogen sulfate (TBAHS) (5 g) was added. The reaction mass was heated to 70-75 °C and maintained to 12 h. TLC was used for monitoring the reaction progress. After completion the reaction mass was cooled to 25-30 °C and stirred for 12 h. The reaction mass was filtered and washed with water (slurry wash 2 x 200 ml; running wash 2 x 200 ml) and suck dried well. The wet solid was dried at 55-60 °C till constant weight.
Yield: 90 g (84%)

BIL Condensed (25 g) was taken in monochlorobenzene (250 ml) to this 50% KOH solution (250 ml) was added at 25-30 °C. The reaction mixture was heated to 70-75 °C which results in precipitate. To this Aliquot 336 (10 g) was added and maintained for 46 h. TLC was used for monitoring the reaction. After completion the reaction mixture was cooled to 25-30 °C and layers were separated. Aqueous layer was extracted with dichloromethane (1 x 50 ml). Combined organic layer was washed with water (3 x 100 ml), distilled under vacuum at 70-75 °C resulting in sticky mass. To this hexane (75 ml) was added at 50-55 °C which gives clear solution initially and precipitates immediately,

stirred and maintained for 30 min followed by cooling to 25-30 °C and stirring for 1h. The solid was filtered and washed with hexane (75 ml) and dried at 50-55 °C till constant weight.
Yield: 25 g (86%)

Clear solution of Oxazoline bilastine (180 g) in water: HC1 (1:1, 1800 ml) was refluxed for 4 to 7 h. The progress of the reaction is checked using TLC. After completion of reaction the reaction mass cooled to 10-15 °C followed by addition of n-butanol (900 ml). The pH of the reaction mass was adjusted to 6.5 with 30% NaOH solution. The layers were separated and aqueous layer was extracted with n-butanol (2 x 360 ml). Combined organic layer was distilled at 70-80 °C. The solid obtained was taken in methanol (1800 ml) and heated to 60-70 °C. The clear solution was cooled to 50-55 °C and methanol was

partially removed by distillation and remaining was cooled to 25-30 °C. After 1 h the solid was fileted and washed with methanol (2x 90 ml) and dried at 45-50 °C till constant weight to give bilastine crude.
Yield: 130-140g Purification using Alumina:
Alumina bed was prepared using neutral alumina (270 g) in dichloromethane (540 ml) at ambient temperature. Bilastine crude (135 g) was dissolved in dichloromethane (4500 ml) at 40-45 °C to get a clear solution. The cooled solution of bilastine (to 25-30 °C) in dichloromethane was passed through alumina bed and washed with dichloromethane (3060 ml). The eluted dichloromethane fraction was collected and activated charcoal (36 g) was added and refluxed. After 1 h the reaction mass was cooled to room temperature and filtered through hyflo bed and washed with dichloromethane (2 x 180 ml). The dichloromethane was distilled atmospherically at 40-45 °C till thick slurry is obtained. Methanol (2 x 180 ml) stripping were given and methanol (90 ml) was charged at get slurry at 40-45 °C. The slurry was cooled to room temperature and filtered after 1 h and washed with methanol (90 ml). The solid was dried at 45-50 °C till constant weight.
Yield: 95-104 g (with purity 99.96%).

To a solution of bilastine (10 g) in dichloromethane (50 ml) was added thionyl chloride (10 ml) at stirred for 10 h at 25-30 °C. After completion the reaction mass was distilled completely to yield sticky residue.


BIL-Chloro (11.0 g) was taken in dichloromethane (110 ml) and 2-amino-2-methyl-propan-1-ol (1.5 mol) was added at 25-30 °C. After 12 h water (50 ml) was added. The layers were separated and the organic layer was distilled to give 10.3 g of crude which was purified using silica gel chromatography in dichloromethane: methanol mixture.
Yield: 3.1 g

To a solution of bilastine (1.0 g) in n-butanol was added cone. HC1 (1.0 ml) and heated to 85-90 °C. After 20-25 h the reaction mixture was cooled to 25-30 °C and followed by careful addition of water (10 ml) and n-butanol (10 ml). The pH was adjusted to 6-7 with 30% sodium hydroxide. The layers were separated and organic layer was distilled to yield oil.
Yield: 0.9 g


Bilastine (10 g) was taken in methanol (100 ml) and conc, sulphuric acid (3.4 ml) was charged to the solution. The reaction mass was headed to 65-70 °C for 20-25 h. After cooling the reaction mixture to 25-30 °C, water (100 ml) was added followed by n-butanol (200 ml). The pH was adjusted to 6-7 with 30% sodium hydroxide and the layers were separated. The organic layer was distilled at 75-80 °C under vacuum to give oil.
Yield = 0.9 g

Stage-1: Reaction Scheme:
To a solution of BIL-condensed (10 g) in DMSO (50 ml) was added powdered potassium hydroxide (3.61 g). The reaction mixture was heated to 40-45 °C for 1 h. To the clear solution 2-chloroethanol (3.6 ml) and sodium iodide (0.5 g) was added. The reaction mixture was heated to 85-90 °C. After 6-8 h the reaction mass was cooled to 25-30 °C. Water (50 ml) and dichloromethane (50 ml) was added to the reaction mass and stirred for 30 min. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 20 ml). Combined organic layer was washed with water (3 x 50 ml) and distilled to give oily mass (9.0 g).
Charge hexane (30 ml) to the above isolated oily mass at 40-45 °C to get solid and stirred for 30 min. The reaction mixture was cooled to 25-30 °C for 1 h, the solid was filtered and washed with hexane (10 ml) to give crude solid (7.0 g).

Above crude was taken in MTBE (60 ml) and was heated to 60-65 °C to give clear solution. Distil out MTBE till 1.5 vol. remains. The reaction mixture was cooled to room temperature and stirred for 1 h.
Yield: 4.9 g (44.5%)

Stage I (4.0 g) was taken in 1:1 HC1 solution (40 ml) at room temperature to get clear solution. Heat the reaction mixture to reflux and maintained for 4-7 h. After completion the reaction mixture was cooled to 10-15 °C and n-butanol (50 ml) was added. pH was adjusted to 6.5-7 with 30% sodium hydroxide. Layers were separated and aqueous layer was extracted with n-butanol (2 x 20 ml). Organic layer was distilled under vacuum at 70-80 °C to get solid. Methanol (20 ml) was added to and heated to get clear solution followed by cooling to 50-55 °C and methanol distilled out till 2 volumes methanol remains. Reaction mass cooled to room temperature and stirred for 1 h. The solid was filtered and washed with methanol (2x 90 ml) to give BIL-Des ethyl impurity.
Yield= 2.5 g


BIL-Protected (50 g) in 1:1 HCl (1000 ml) was stirred at room temperature to get clear solution and then heated for 4-6 h at 55-60 °C. Followed by increasing the temperature to 80-85 °C. After reaction completion the reaction mixture cooled to room temperature and n-butanol (300 ml) was added. pH was adjusted to 7 using 30% sodium hydroxide. The layers were separated and aqueous layer was extracted with n-butanol (1 x 200 ml). Combined organic layer were combined and washed with water (1 x 200 ml). n-Butanol was distilled under vacuum at 70-75 °C until constant weight. To the oily residue 30% sodium hydroxide (300 ml) and methanol (300 ml) and heated at 60-65 °C for 4-6 h. The reaction mass was distilled under vacuum at 50-55 °C to get oily mass and aqueous layer. Water (100 ml) was added to get biphasic mixture and extracted with methyl tertiary butyl ether (5 x 250 ml). Organic layer was distilled under vacuum to get slurry. The slurry was cooled to room temperature and solid was filtered and washed with methyl tertiary butyl ether (25 ml) to give 10-15 g of weight solid. pH of the aqueous layer was adjusted to 7 with HCl and extracted with dichloromethane (3 x 200 ml). During extraction solid emulsion formed between the two layers was filtered and washed with water (50 ml) and dichloromethane (25 ml). Organic layer was washed again with water (500 ml, formed solid emulsion was filtered). Solid was combined and dried at 45-50 °C till constant weight.
Yield = 15-25 g

To a solution of bilastine (10 g) in ethanol (200 ml) hydrogen peroxide (8.8 g) was added at once at 25-30 °C and stirred. After completion of reaction 10% sodium thiosulfate solution (50 ml) is added followed by extraction with n-butanol (100 ml). Organic layer was distilled under vacuum at 70-75 °C. To the residue obtained toluene

(100 ml) was added and distilled at atmospheric pressure to remove moisture. The reactioOn mass was cooled to room temperature and the solid was isolated by filtration.
Yield: 0.9 g

We claim:
1) A process for the preparation of Bilastine of Formula I comprising

(a) reacting a compound of Formula II with Compound of Formula III in presence of a
suitable solvent and an inorganic base and phase transfer catalyst to obtain a
compound of formula IV;

(b) reacting the compound of Formula IV with l-chloro-2-ethoxyethane in presence of
suitable solvent, base and phase transfer catalyst to obtain compound of Formula
V.

(c) hydrolysing the compound of Formula V to Bilastine crude in presence of a suitable reagent.
(d) purifying a crude product by column chromatography with alumina as support.
2) A process according to claim 1, wherein the suitable solvent of step (a) is a ketone
solvent selected from the group consisting of acetone, methyl ethyl ketone, methyl
isobutyl ketone and 4-hydroxy-4-methyl pentanone preferably methyl isobutyl
ketone.

3) A process according to claim 1, wherein the inorganic base of step (a) is selected from group consisting of sodium carbonate, cesium carbonate, potassium carbonate preferably sodium carbonate.
4) A process according to claim 1, wherein the phase transfer catalyst of step (a) is selected from tetraethylammonium p-toluenesulfonate, tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate, tetrabutylammonium iodide preferably tetrabutylammonium hydrogensulphate.
5) A process according to claim 1, wherein the suitable solvent of step (b) is a solvent selected from the group consisting of dichloromethane, chloroform, monochlorobenzene, trichloroethylene, carbon tetrachloride, chlorinated fluorocarbons, tetrachloroethylene (perchloroethylene), 1,1,1 -trichloroethane preferably monochlorobenzene.
6) A process according to claim 1, wherein the base of step (b) is selected from group consisting of alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide preferably potassium hydroxide.
7) A process according to claim 1, wherein the phase transfer catalyst of step (b) is selected from quaternary ammonium salts, particularly Aliquat 336 (Starks Catalyst) is preferred.
8) A process according to claim 1, wherein the compound of Formula V obtained by step (b) is hydrolysed in the presence of HC1.
9) A process according to claim 1, wherein crude Bilastine obtained in step (c) is purified using alumina bed as support and dichloromethane as an eluent.
10) A process for the preparation of Bilastine of Formula I comprising