The present invention relates to a process for the purification of bilastine.
Background of the Invention Bilastine is chemically known as 2-[4-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)piperidin-1-yl)ethyl)phenyl]-2-methylpropionic acid, and is represented by Formula I.

=v CH3 OH
O
CH3
O
<
CH3
Formula I
Bilastine is a second-generation histamine H1 receptor antagonist developed by the Spanish FAES pharmaceutical company. In 2010, bilastine was approved by the European Union for the treatment of allergic rhinitis and chronic idiopathic urticaria.
Various processes have been disclosed in the literature for the preparation of bilastine.
U.S. Patent No. 5,877,187 discloses a process for the preparation of bilastine, wherein 2-(4-(1-(4,4-dimethyl-A2-oxazoline-2-yl)-1-methylethyl)phenyl)ethyl p-toluenesulphonate of Formula III is reacted with 2-(4-piperidinyl)-1H benzimidazole of Formula II in the presence of sodium carbonate to produce 2-[l-(2-(4-(l-(4,4-dimethyl-A2oxazoline-2-yl)-l-methylethyl)phenyl)ethyl)piperidine-4-yl]-1H-benzimidazole of Formula IV which on further reaction with 2-chloroethyl ethylether of Formula V in the presence of sodium hydride and dimethylformamide produce l-(2-ethoxyethyl)-2-[l-(2-(4-(1-(4,4-dimethyl-A2-oxazoline-2-yl)-1-methylethyl)phenyl)ethyl)piperidine-4-yl-1H-benzimidazole of Formula VI, which subsequently treated with 3N hydrochloric acid produce bilastine.
2



CH3 'CH3
CH3 CH3
+
O~"V,CH3 & CH3 CH3
OH H3C
| T CH3
H
a
N i—y
^—( NH
N >—t
Formula II

O;
'O
0
H3C
H3C
Bilastine
Formula III

H3C

Formula VI

Scheme 1
The inventors of the present invention have observed that during the hydrolysis of the compound of Formula VI using 3N hydrochloric acid, an impurity 2-[4-(2-(4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)piperidin-1-yl)ethyl)phenyl]-2-methylpropionic acid of Formula VII up to a level of 4% is formed, which is difficult to eliminate completely.

\ I N—\ N

V
CH3 O
H
CH3 OH

OH
Formula VII
There is still a need in the art to develop an improved process for the purification for bilastine.
Summary of the Invention
The present invention relates to a process for the purification of bilastine that can easily remove an impurity of Formula VII and at the same time, provides bilastine in high yield and purity.
The present invention provides an improved, economical, and industrially advantageous process for the purification of bilastine having purity of 99.9% with impurity of Formula VII to about 0.05%.
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Brief Description of the Drawings Figure 1: High Performance Liquid Chromatography (HPLC) chromatogram of bilastine, obtained as per Reference Example.
Figure 2: HPLC chromatogram of bilastine, obtained as per Example 1.
Detailed Description of the Invention The term “about,” as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
The term “ambient temperature,” as used herein, refers to a temperature in the range of 25°C to 35°C.
The term “contacting,” as used herein, refers to dissolving, slurring, stirring, suspending, or combinations thereof.
The term “purified bilastine,” as used herein, refers to a purity of greater than 99.5% as determined by HPLC.
A first aspect of the present invention relates to a process for the purification of bilastine of Formula I comprising
(a) contacting crude bilastine with a solvent to obtain a solution;
(b) adding neutral alumina to the solution obtained in step (a) to obtain a mixture;
(c) stirring and then filtering the mixture of step (b); and
(d) concentrating and then degassing to obtain purified bilastine.
Bilastine to be purified (starting material) can be obtained using known methods, for example, the process described in U.S. Patent No. 5,877,187.
In an embodiment, the solvent used in step (a) is selected from the group consisting of dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
In an embodiment, the neutral alumina is added to the solution of step (a) at ambient temperature.
In an embodiment, the mixture of step (c) is stirred for about 30 minutes to about 5 hours. In another embodiment, the mixture of step (c) is stirred for about one hour to about 3 hours. In yet another embodiment, the mixture of step (c) is stirred for about one hour to about 2 hours.
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In an embodiment, the filtration of the mixture of step (c) is performed through hyflo bed and/or filter paper.
In another embodiment, the concentration of the mixture of step (d) is performed atmospherically.
In an embodiment, the concentration of the mixture of step (d) is performed at temperature of about 40°C to about 50°C. In another embodiment, the concentration of the mixture of step (d) is performed at a temperature of about 40°C to about 45°C.
In an embodiment, the degassing of the mixture of step (d) is performed at a temperature of about 40°C to about 50°C. In another embodiment, the degassing of the mixture of step (d) is performed at a temperature of about 40°C to about 45°C.
Accordingly, a solution of bilastine is prepared by dissolving crude bilastine in dichloromethane while stirring for 30 minutes to one hour to obtain a clear solution. To this solution of bilastine, neutral alumina is added and the resultant mixture is stirred for 30 minutes to one hour and then filtered. The filtration can be performed through a hyflo bed and/or filter paper to obtain a filtrate. The filtrate is concentrated atmospherically to obtain purified bilastine.
This aspect of the present invention provides bilastine with greater than 99.5% HPLC purity.
Bilastine obtained as per present invention is converted into polymorph I of bilastine by following the process as disclosed in the prior art, for example, in U.S. Patent No. 7,612,095.
While the present invention has been described in terms of its specific aspects and embodiments, 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.
Method
Chromatographic Purity was determined using an Agilent 1260 Infinity (HPLC-01). The column used was an Inertsil® ODS 3V (250 x 4.6 mm) 5μm.
The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
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EXAMPLES
Reference Example: Preparation of bilastine as per procedure disclosed in U.S. Patent No. 5,877,187
l-(2-Ethoxyethyl)-2-[l-(2-(4-(1-(4,4-dimethyl-A2-oxazoline-2-yl)-1-methylethyl) phenyl)ethyl)piperidine-4-yl-1H-benzimidazole (6.72 g; Formula VI) was dissolved in 3N HCl (170 mL) at ambient temperature to obtain a mixture. The mixture was heated under stirring at 90°C to 100°C for 2 hours. The reaction mixture was cooled to ambient temperature and sodium hydroxide (50%) was added until pH was adjusted to 7. The solution was extracted with n-butanol (3 x 15 mL) and washed with water (30 mL). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to obtain residue. Methanol (30 mL) and sodium hydroxide (50%; 40 mL) were added to the residue and refluxed at 70°C for 30 minutes. The methanol was distilled off and water (100 mL) was added dropwise. This mixture was extracted with methyl tert-butyl ether (MTBE) (20 mL). The aqueous layer was adjusted to pH 7.3 using 20% HCl (20 mL of 36% HCl in 50 mL water) and washed with saturated sodium chloride. The reaction mixture was stirred for 3 hours to 4 hours at ambient temperature to obtain solid precipitates. The precipitates was filtered and washed repeatedly with water and dried in a vacuum dryer at 50°C to yield bilastine. Yield: 3.5 g HPLC Purity: 92.7%
Example 1: Purification of bilastine
Crude bilastine was added into dichloromethane (40V) at ambient temperature and stirred for 30 minutes to obtain a clear solution. Neutral alumina was added to the solution and stirred for one hour to obtain a reaction mixture. The reaction mixture was filtered through hyflo bed and then concentrated atmospherically at 45°C to 50°C. Isopropyl alcohol (2V) was added to the reaction mixture at 40°C to 45°C, cooled to ambient temperature and then stirred for one hour to obtain a solid. The obtained solid was filtered, washed with isopropyl alcohol and dried in tray drier at 55°C to 65°C for 5 hours to 8 hours to obtain purified bilastine. Yield: 98% HPLC Purity: 99.9 %

WE CLAIMS

A process for the purification of bilastine of Formula I comprising
(a) contacting crude bilastine with a solvent to obtain a solution;
(b) adding neutral alumina to the solution obtained in step (a) to obtain a mixture;
(c) stirring and then filtering the mixture of step (b); and
(d) concentrating and then degassing to obtain purified bilastine.

2. The process according to claim 1, wherein the solvent used in step (a) is selected from the group consisting dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
3. The process according to claim 1, wherein the neutral alumina is added to the solution of step (a) at ambient temperature.
4. The process according to claim 1, wherein the mixture of step (c) is stirred for about 30 minutes to about 5 hours.
5. The process according to claim 1, wherein the mixture of step (d) is concentrated at temperature of 40°C to 50°C.
6. The process according to claim 1, wherein the mixture of step (d) is degassed at temperature of 40°C to 50°C.
7. Bilastine of Formula I, having greater than 99.5% purity obtained according to process claimed in claims 1 to 6.