DESC:CROSS REFERENCE TO RELATED APPLICATION
This patent application claims the benefit of priority to Indian Provisional Patent Application No. 201741015924, filed on May 5, 2017, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION
The present invention relates to novel, commercially viable and industrially advantageous processes for the preparation of a benzimidazole derivative and its intermediates, in high yield and purity.

BACKGROUND OF THE INVENTION
U.S. Patent No. 5,877,187 (hereinafter referred to as the US‘187 patent) discloses a variety of benzimidazole derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds have high H1 antihistaminic and antiallergic activity and are devoid of effects on the central nervous and cardiovascular systems. Among them, Bilastine, chemically named 2-[4-[2-[4-[l-(2-ethoxyethyl)-benzimidazol-2-yl]piperidin-1-yl]ethyl]phenyl]-2-methylpropanoic acid, is a selective histamine H1 receptor antagonist used for treatment of allergic rhinoconjunctivitis and urticaria (hives). Bilastine is represented by the following structural formula I:

Bilastine, a novel second-generation H1-antihistamine, is approved for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria in adults and children over 12 years of age. Bilastine has a favourable pharmacokinetic profile, being rapidly absorbed resulting in an onset of clinical effect within one hour of administration, and has a long duration of action, exceeding 24 hours, which allows for once-daily dosing.
Bilastine was developed by FAES Farma and approved in the European Union for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. Bilastine is marketed under the trade names Bilaxten® (in Spain, Colombia, Australia, and several other countries), Ilaxten® (in United Kingdom), and Blexten™ (in Canada).
Various processes for the preparation of Bilastine, its intermediates, and related compounds are described in U.S. Patent Nos. US 5,877,187 and US 8,367,704; PCT Publication Nos. WO 2014/188453, WO2014/026657; Chinese Patent Application Publication No. CN 102675101; and Journal Articles: Syn. Comm., 41(9), 1394-1402, 2011; and Drugs of future 35(2), 98-105, 2010.
The synthesis of Bilastine was first described in the US’187 patent. According
to the US’187 patent, Bilastine is prepared by a process as depicted in scheme 1:

According to the synthetic route described in the US’187 patent, Bilastine is prepared by the following main reaction steps: a) 2-(4-(1-(4,4-dimethyl-?2-oxazoline-2-yl)-1-methylethyl)phenyl)ethylp-toluenesulphonate is reacted with 2-(4-piperidinyl)-1H-benzimidazole in the presence of sodium carbonate to produce 2-[1-(2-(4-(1-(4,4-dimethyl-?2-oxazoline-2-yl)-1-methylethyl)phenyl)ethyl)piperidine-4-yl]-1H-benzimidazole ; b) the resulting dimethyl-oxazoline intermediate is reacted with 2-chloroethyl ethyl ether in dimethylformamide in presence of sodium hydride at a temperature of 80°C, followed by tedious work-up and isolation methods to produce the 1-(2-ethoxyethyl)-2-[1-(2-(4-(1-(4,4-dimethyl-?2-oxazoline-2-yl)-1-methylethyl) phenyl)ethyl)piperidine-4-yl]-1H-benzimidazole; c) the resulting 2-ethoxyethyl compound is reacted with 3N Hydrochloric acid to produce 2-4-(2-(4-(1-(2-ethoxyethyl)benzimidazole-2-yl)piperidine-1-yl)ethyl)phenyl-2-methylpropanoic acid (Bilastine).
The process for the preparation of Bilastine as described in the aforementioned prior art suffers from the following major disadvantages and shortcomings: (a) the introduction of the oxazoline group and its subsequent hydrolysis inevitably comprised in the process leads to the formation of several by-products, thereby resulting in a poor product yields and quality and making the whole process lengthy and cumbersome; b) the reaction between 2-[1-(2-(4-(1-(4,4-dimethyl-?2-oxazoline-2-yl)-1-(methylethyl)phenyl)ethyl)piperidine-4-yl]-1H-benzimidazole and 2-chloroethyl ethyl ether is performed under very stringent reaction condition and involves the use of dangerous, corrosive and explosive alkali metal hydrides such as sodium hydride; c) the use of alkali metal hydrides is not advisable for commercial scale operations from safety point of view.
A need remains for novel, commercially viable and environmentally friendly processes for the preparation of Bilastine and its intermediates with high yields and purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.

SUMMARY OF THE INVENTION
The object of the present invention is to provide novel, commercially viable and industrially advantageous processes for the preparation of a benzimidazole derivative, specifically Bilastine and its intermediates, in high yields and purity.
The present inventors have found that Bilastine can be prepared in high purity and with high yield, by reacting 2-methyl-2-phenyl-propanoic acid with a mixture of paraformaldehyde, sulphuric acid and 48% aqueous hydrobromic acid to produce 2-[4-(2-bromomethyl)phenyl]-2-methyl-propanoic acid, which is then reacted with sodium cyanide in ethanol and water to produce 2-[4-(2-cyanomethyl)phenyl]-2-methyl-propanoic acid, which undergoes reduction with a suitable reducing agent to produce 2-[4-(2-aminoethyl)phenyl]-2-methyl-propanoic acid, which is further reacted with sodium bromide in presence of sodium nitrite and aqueous sulphuric acid to produce 2-[4-(2-bromoethyl)phenyl]-2-methyl-propanoic acid. The resulting intermediate is further condensed with 1-(2-ethoxyethyl)-2-piperidin-4-yl-1H-benzimidazole in presence of a suitable base to produce Bilastine.
In one aspect, provided herein is an efficient, industrially advantageous and environmentally friendly process for the preparation of Bilastine of formula I, in high yield and high purity. The process disclosed herein avoids the tedious and cumbersome procedures of the prior art processes, thereby resolving the problems associated with the processes described in the prior art, which is more convenient to operate at laboratory scale and on a commercial scale.
The process for the preparation of Bilastine described herein has the following advantages over the processes described in the prior art:
i) the overall process involves a reduced number of process steps, shorter reaction times and less expensive reagents, thereby making the process cost effective;
ii) the process avoids the use of highly inflammable, dangerous and difficult to handle reagents like Sodium hydride;
iii) the process avoids the use of expensive Palladium catalysts like bis (dibenzylidene acetone) palladium (Pd(dba)2); and expensive ligands such as tri-tertiary butyl phosphine (t-Bu3P); and
iv) the process avoids the use of tedious and cumbersome procedures like prolonged reaction time periods, multiple process steps, column chromatographic purifications, multiple isolations, additional and excess amounts of solvents.
The novel process for the preparation of Bilastine disclosed in the present invention may be represented by a schematic diagram as depicted in scheme-2:

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a process for the preparation of highly pure Bilastine of formula I:

or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting 2-methyl-2-phenyl-propanoic acid of formula II:

or a salt thereof,
with paraformaldehyde and a halogenating agent in presence of a suitable acid to produce 2-[4-(2-halomethyl)phenyl]-2-methyl-propanoic acid compound of formula III:

or a salt thereof, wherein the radical ‘X’ represents a halogen atom;
b) cyanation of the compound of formula III obtained in step-(a) with an alkali metal cyanide in presence of a suitable solvent to produce 2-[4-(2-cyanomethyl)phenyl]-2-methyl-propanoic acid compound of formula IV:

or a salt thereof;
c) reducing the compound of formula IV with a suitable reducing agent to produce 2-
[4-(2-aminoethyl)phenyl]-2-methyl-propanoic acid compound of formula V:

or a salt thereof;
d) reacting the compound of formula V with a metal halide in presence of a metal nitrite and a suitable acid to produce 2-[4-(2-haloethyl)phenyl]-2-methyl propanoic acid compound of formula VI:

or a salt thereof, wherein the radical ‘X’ is as defined above; and
e) condensing the compound of formula VI obtained in step-(d) with 1-(2-ethoxyethyl)-2-(piperidin-4-yl)benzimidazole of formula VII:

or an acid addition salt thereof, in presence of a base, optionally in the presence of a phase transfer catalyst, in a suitable solvent to produce Bilastine of formula I or a salt thereof, and optionally purifying the Bilastine obtained using a suitable solvent to produce highly pure Bilastine or a pharmaceutically acceptable salt thereof.
In one embodiment, the halogen atom ‘X’ in the compounds of formulae III and VI is, each independently selected from the group consisting of Cl and Br. Most specifically, the halogen atom ‘X’ in the compounds of formulae III and VI is, each independently Br.
Unless otherwise specified, the solvent used for isolating, purifying and/or recrystallizing the compounds obtained by the processes described in the present invention is selected from the group consisting of water, an alcohol, a ketone, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
Unless otherwise specified, the carbon treatment is carried out by methods known in the art, for example, by stirring the reaction mass/solution with finely powdered carbon at a temperature of about 40°C to the reflux temperature for at least 5 minutes, specifically at the reflux temperature; and filtering the resulting mixture through charcoal bed to obtain a filtrate containing compound by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
Unless otherwise specified, the term ‘base’ as used herein includes, but is not limited to, organic bases and inorganic bases such as carbonates, bicarbonates, hydroxides, alkoxides, acetates and amides of alkali or alkali earth metals.
Specifically, the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, sodium amide, potassium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, and mixtures thereof.
Specifically, the organic base is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n-butylamine, diisobutylamine, triethylamine, tributylamine and tert-butyl amine.
Unless otherwise specified, the term ‘phase transfer catalyst’ as used herein includes, but is not limited to, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, methyltributyl ammonium chloride, crown ethers and the like.
Unless otherwise specified, the term ‘salt’ as used herein may include acid addition salts and base addition salts.
Acid addition salts may be derived from organic and inorganic acids. For example, the acid addition salts are derived from a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, malic acid, ascorbic acid, and the like.
Exemplary acid addition salts include, but are not limited to, hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like. A most specific acid addition salt is hydrochloride salt.
Base addition salts may be derived from an organic or an inorganic base. For example, the base addition salts are derived from alkali or alkaline earth metals such as sodium, calcium, potassium and magnesium, ammonium salt and the like.
The highly pure Bilastine or a pharmaceutically acceptable salt thereof obtained by the process disclosed herein has a purity of greater than about 99.5%, specifically greater than about 99.8%, more specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. For example, the purity of the highly pure Bilastine or a pharmaceutically acceptable salt thereof obtained by the processes disclosed herein is about 99.5% to about 99.99% as measured by HPLC.
As used herein, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
As used herein, the term “room temperature” refers to a temperature of about 20°C to about 35°C. For example, “room temperature” can refer to a temperature of about 25°C to about 30°C.
In one embodiment, the halogenating agent used in step-(a) is selected from the group consisting of aqueous hydrochloric acid and aqueous hydrobromic acid. A most specific halogenating agent used in step-(a) is aqueous hydrobromic acid.
In another embodiment, the acid used in step-(a) is selected from the group consisting of sulphuric acid, phosphoric acid, acetic acid and the like. A most specific acid used in step-(a) is sulphuric acid.
The reaction in step-(a) is carried out in a suitable solvent. Exemplary solvents used in step-(a) include, but are not limited to, water, a halogenated hydrocarbon, a ketone, an ether, an ester, a hydrocarbon, and mixtures thereof.
Specifically, the solvent used in step-(a) is selected from the group consisting of water, dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof. A most specific solvent is water.
Specifically, the reaction in step-(a) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used, specifically at a temperature of about 25°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used. The reaction time may vary between about 2 hours to about 15 hours, specifically about 3 hours to about 12 hours, and more specifically about 4 hours to about 9 hours.
The reaction mass containing the compound of formula III or a salt thereof obtained in step-(a) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, a decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula IV, or the compound of formula III or a salt thereof may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula III or a salt thereof may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation and/or recrystallization of the compound of formula III obtained by the process described herein is selected from the group as described hereinabove.
In one embodiment, the alkali metal cyanide used in step-(b) is selected from the group consisting of sodium cyanide, potassium cyanide, and the like; and a most specific metal cyanide is sodium cyanide.
In one embodiment, the solvent used in step-(b) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof. A most specific solvent is ethanol.
In another embodiment, the reaction in step-(b) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used, specifically at a temperature of about 25°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used. The reaction time may vary between about 30 minutes to about 5 hours, more specifically about 45 minutes to about 4 hours.
The reaction mass containing the compound of formula IV or a salt thereof obtained in step-(b) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula V, or the compound of formula IV or a salt thereof may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula IV or a salt thereof may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for work up, isolation and/or recrystallization of the compound of formula IV obtained by the process described herein is selected from the group as described hereinabove.
In one embodiment, the reducing agent used in step-(c) is selected from the group consisting of platinum, palladium, palladium hydroxide, palladium on carbon, platinum oxide, rhodium, Raney-Nickel, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium bis(2-methoxyethoxy)aluminum hydride (vitride) and the like. A most specific reducing agent is Raney-Nickel.
The reduction in step-(c) is carried out in the presence of ammonia. In one embodiment, ammonia used may be in the form of aqueous ammonia or in the form of ammonia gas or ammonia saturated in an organic solvent. The organic solvent used for saturating ammonia is selected from the group consisting of ethanol, methanol, isopropyl alcohol and ethyl acetate.
In another embodiment, the reaction in step-(c) is carried out at a temperature of about -5°C to about 50°C, more specifically at a temperature of about 0° to about 40°C. The reaction time may vary between about 30 minutes to about 6 hours, more specifically about 45 minutes to about 4 hours.
The reaction mass containing the compound of formula V or a salt thereof obtained in step-(c) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula VI, or the compound of formula V or a salt thereof may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula V or a salt thereof may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for work up, isolation and/or recrystallization of the compound of formula V obtained by the process described herein is selected from the group as described hereinabove.
In one embodiment, the metal nitrite used in step-(d) is selected from the group consisting of sodium nitrite, potassium nitrite, and the like. A most specific metal nitrite is sodium nitrite.
In another embodiment, the metal halide used in step-(d) is selected from the group consisting of sodium bromide, potassium bromide, lithium bromide, copper bromide, sodium chloride, potassium chloride, sodium iodide, potassium iodide, and the like. A most specific metal halide is sodium bromide.
In another embodiment, the acid used in step-(d) is selected from the group consisting of sulphuric acid, hydrobromic acid, phosphoric acid, and the like. A most specific acid is sulphuric acid.
In another embodiment, the reaction in step-(d) is carried out at a temperature of about -5°C to about 50°C, more specifically at a temperature of about -10° to about 40°C. The reaction time may vary between about 30 minutes to about 5 hours, more specifically about 45 minutes to about 4 hours.
The reaction mass containing the compound of formula V or a salt thereof obtained in step-(d) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula VI, or the compound of formula V or a salt thereof may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the base used in step-(e) is an organic base or an inorganic base selected from the group as described hereinabove. Specifically, the base used in step-(e) is an inorganic base. A most specific base used in step-(e) is sodium carbonate or potassium carbonate.
In another embodiment, the reaction in step-(e) is carried out in the presence of a phase transfer catalyst. The phase transfer catalyst can be selected from the group as described hereinabove.
Exemplary solvents used in step-(e) include, but are not limited to, water, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile and mixtures thereof. A most specific solvent used in step-(e) is water.
In one embodiment, the reaction in step-(e) is carried out at a temperature of about 10°C to the reflux temperature of the solvent used, specifically at a temperature of about 30°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used. The reaction time may vary from about 2 hours to 25 hours, more specifically about 3 hours to 24 hours.
The process for the preparation of highly pure Bilastine of formula I can be carried out by the known methods as described herein below.
The reaction mass containing the Bilastine of formula I or a salt thereof obtained in step-(e) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof.
In one embodiment, the Bilastine of formula I or a salt thereof may be isolated, purified and/or recrystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for work up, isolation and/or recrystallization/purification of the Bilastine of formula I or a salt thereof obtained by the process described herein is selected from the group as described hereinabove.
The crude Bilastine obtained in step-(e), optionally subjected to carbon treatment or silica gel treatment. The carbon treatment or silica gel treatment is carried out by the methods known in the art, for example, as per the methods described hereinabove.
In one embodiment, the solvent used for purification of Bilastine obtained in step-(e) is selected from the group consisting of water, acetone, methanol, ethanol, isopropyl alcohol, ethyl acetate, butyl acetate, and mixtures thereof.
Removal of solvent is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution or distillation of solvent, under inert atmosphere to obtain highly pure Bilastine or a salt thereof.
According to another aspect, there is provided a process for the preparation of highly pure Bilastine of formula I:

or a pharmaceutically acceptable salt thereof, which comprises:
condensing the compound of formula VI:

or a salt thereof, wherein the radical ‘X’ represents a halogen atom;
with 1-(2-ethoxyethyl)-2-(piperidin-4-yl)benzimidazole of formula VII:

or an acid addition salt thereof, in presence of a base, optionally in the presence of a phase transfer catalyst, in a suitable solvent to produce Bilastine of formula I or a salt thereof, and optionally purifying the Bilastine obtained using a suitable solvent to produce highly pure Bilastine or a pharmaceutically acceptable salt thereof.
The preparation of the Bilastine of formula I or a pharmaceutically acceptable salt thereof as described in the above process can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
According to another aspect, there is provided a process for the preparation of 2-[4-(2-haloethyl)phenyl]-2-methyl propanoic acid compound of formula VI:

or a salt thereof, which comprises:
a) reacting 2-methyl-2-phenyl-propanoic acid of formula II:

or a salt thereof,
with paraformaldehyde and a suitable halogenating agent in presence of a suitable acid to produce 2-[4-(2-halomethyl)phenyl]-2-methyl-propanoic acid compound of formula III:

or a salt thereof, wherein the radical ‘X’ represents a halogen atom;
b) cyanation of the compound of formula III obtained in step-(a) with an alkali metal cyanide in presence of a suitable solvent to produce 2-[4-(2-cyanomethyl)phenyl]-2-
methylpropanoic acid compound of formula IV:

or a salt thereof;
c) reducing the compound of formula IV with a suitable reducing agent to produce 2-
[4-(2-aminoethyl)phenyl]-2-methyl-propanoic acid compound of formula V:

or a salt thereof; and
d) reacting the compound of formula V with a metal halide in presence of a metal nitrite and a suitable acid to produce 2-[4-(2-haloethyl)phenyl]-2-methyl propanoic acid compound of formula VI or a salt thereof.
The preparation of 2-[4-(2-haloethyl)phenyl]-2-methyl propanoic acid compound of formula VI or a salt thereof as described in the above process can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
According to another aspect, there is provided a process for the preparation of 2-[4-(2-halomethyl)phenyl]-2-methyl propanoic acid compound of formula III:

or a salt thereof, wherein the radical ‘X’ represents a halogen atom, comprising reacting 2-methyl-2-phenyl-propanoic acid of formula II:

or a salt thereof, with paraformaldehyde and a halogenating agent in presence of a suitable acid to produce 2-[4-(2-halomethyl)phenyl]-2-methyl-propanoic acid compound of formula III or a salt thereof.
The preparation of 2-[4-(2-halomethyl)phenyl]-2-methyl-propanoic acid compound of formula III or a salt thereof as described in the above process can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
According to another aspect, there is provided a process for the preparation of 2-[4-(2-cyanomethyl)phenyl]-2-methyl propanoic acid compound of formula IV:

or a salt thereof, comprising cyanation of a compound of formula IIIa:

with an alkali metal cyanide in presence of a suitable solvent to produce 2-[4-(2-cyanomethyl)phenyl]-2-methylpropanoic acid compound of formula IV or a salt thereof.
The preparation of 2-[4-(2-cyanomethyl)phenyl]-2-methylpropanoic acid compound of formula IV or a salt thereof as described in the above process can be carried out by using the suitable solvents, reagents, methods, parameters and conditions
as described hereinabove.
According to another aspect, there is provided a process for the preparation of 2-[4-(2-haloethyl)phenyl]-2-methyl propanoic acid compound of formula VI:

or a salt thereof, comprising reacting the 2-[4-(2-aminoethyl)phenyl]-2-methyl-propanoic acid compound of formula V:

or a salt thereof, with a suitable metal nitrite and a metal halide in presence of a suitable acid to produce 2-[4-(2-haloethyl)phenyl]-2-methyl propanoic acid compound of formula VI or a salt thereof.
The preparation of 2-[4-(2-haloethyl)phenyl]-2-methyl propanoic acid compound of formula VI or a salt thereof as described in the above process can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
The compound of formula VII used herein as the starting material can be prepared by the methods known in the art or as per the process described hereinafter.
The compounds obtained in any of the above process steps may be collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.
The highly pure Bilastine or a salt thereof obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
In one embodiment, the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 25°C to about 95°C, and specifically at about 75°C to about 85°C. The drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours.
Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, and the like.
The following examples are given only to illustrate the present invention. However, they should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES
Example 1
Preparation of 2-(4-Piperidinyl)-1H-benzimidazole
Orthophenylenediamine (20 g), polyphosphoric acid (120 g) and isonipecotic acid (26.5 g) were taken into a reaction flask and the resulting mixture was heated to 115-120°C, followed by stirring for 20 hours at the same temperature. After completion of the reaction, the reaction mass was cooled to 90°C, quenched with distilled water (260 ml) and then cooled to room temperature (25-30°C). The resulting mass was further cooled to 10-15°C, followed by adjusting the pH of the reaction mass to 9-10 with dilute sodium hydroxide solution, and then stirring for 30 minutes at 10-15°C. The separated solid was filtered and washed with distilled water. The wet material was dried at 40-45°C. Methanol (720 ml) was added to the resulting material and stirred for 1 hour at room temperature. The resulting mass was filtered and washed with methanol (250 ml). The resulting filtrate was concentrated under reduced pressure to give 36 g of 2-(4-Piperidinyl)-1H-benzimidazole.

Example 2
Preparation of Ethyl 4-(1H-Benzimidazol-2-yl)-piperidine-1-carboxylate
2-(4-Piperidinyl)-1H-benzimidazole (36 g) and chloroform (720 ml) were taken into a reaction flask and then triethylamine (45 g) was added at room temperature. The resulting mass was cooled to 0-5°C, followed by drop-wise addition of a solution of ethyl chloroformate (21.5 g) in chloroform (80 ml) at the same temperature for 30-45 minutes. After completion of the reaction, water (360 ml) was added to the reaction mass at the same temperature and then stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with chloroform (250 ml). The chloroform layers were combined and then washed twice with water (250 ml x 2). The chloroform was distilled off under reduced pressure from the resulting organic layer to give 46 g of crude 4-(1H-benzimidazol-2-yl)-piperidine-1-carboxylic acid ethyl ester. The crude compound was added to cyclohexane (157.5 ml) and then heated to reflux temperature. The resulting mass was stirred for 30-45 minutes at reflux temperature for 30-45 minutes and then cooled the reaction mass to room temperature, followed by stirring for 1 hour at the same temperature. The separated solid was filtered and washed with cyclohexane (45 ml) to give 44 g of pure ethyl 4-(1H-benzimidazol-2-yl)-piperidine-1-carboxylate.

Example 3
Preparation of Ethyl 4-[1-(2-Ethoxyethyl)-benzimidazol-2-yl]-piperidine-1-carboxylate
Ethyl 4-(1H-benzimidazol-2-yl)-piperidine-1-carboxylate (42 g) and toluene (210 ml) were taken into a reaction flask and then heated to 40-45°C. To the reaction mass, sodium hydroxide (18.5 g), potassium iodide (4.6 g), 2-chloroethyl ethyl ether (25 ml) and tetrabutylammonium bromide (10 g) were added. The resulting mixture was heated to 95-100°C and then stirred for 16 hours at the same temperature. After completion of the reaction, the reaction mass was cooled to room temperature, followed by the addition of water (210 ml) and then stirring for 10 minutes at room temperature. The resulting mass was neutralized with dilute hydrochloric acid. The layers were separated and the aqueous layer was extracted twice with ethyl acetate (200 ml x 2). The toluene layer and ethyl acetate layers were combined and washed with distilled water (250 ml). The solvents were distilled off completely under reduced pressure to give 51 g of ethyl 4-[1-(2-ethoxyethyl)-benzimidazol-2-yl]-piperidine-1-carboxylate.

Example 4
Preparation of 1-(2-Ethoxyethyl)-2-(piperidin-4-yl)-benzimidazole
Ethyl 4-[1-(2-ethoxyethyl)-benzimidazol-2-yl]-piperidine-1-carboxylate (50 g) and isopropyl alcohol (350 ml) were taken into a reaction flask and then potassium hydroxide (100 g) was added at room temperature. The resulting mixture was heated to reflux and then maintained for 10 hours at reflux temperature. The solvent was distilled off completely from the reaction mass under reduced pressure to obtain crude product. Water (850 ml) was added to the crude product and then neutralized with dilute hydrochloric acid. The resulting mass was extracted with 1-butanol (600 ml) and again extracted with 1-butanol (300 ml x 2) twice. The solvent was distilled off under reduced pressure, followed by co-distillation with toluene (100 ml). The resulting crude was cooled to room temperature and then toluene (135 ml) was added, followed by stirring for 20-30 minutes. The separated solid was filtered and washed with toluene (40 ml) to give 41 g of crude 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-benzimidazole. The crude compound was added to isopropyl alcohol (400 ml) and then heated to reflux, followed by stirring the reaction mass at reflux temperature for 30 minutes. The reaction mass was cooled to 25-30°C, filtered the material and then washed with isopropyl alcohol (30 ml) to give 32.5 g of pure 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-benzimidazole.

Example 5
Preparation of 2-[4-(2-Bromomethyl)phenyl]-2-methyl-propanoic acid
Sulphuric acid (100 g) was slowly added to a mixture of 2-methyl-2-phenyl-propanoic acid (40 g) and paraformaldehyde (13.6 g) in 48% aqueous hydrobromic acid (97 g) at room temperature. The resulting mixture was heated to 90-92°C and maintained for 6 hours at the same temperature. The resulting mass was cooled to room temperature and water (200 ml) was added and extracted with dichloromethane (200 ml x 3). The organic layers were combined, washed with water (200 ml) and the solvent was distilled under reduced pressure to produce 60 g of 2-[4-(2-Bromomethyl)phenyl]-2-methyl-propanoic acid.
Example 6
Preparation of 2-[4-(2-Cyanomethyl)phenyl]-2-methyl-propanoic acid
2-[4-(2-Bromomethyl)phenyl]-2-methyl-propanoic acid (40 g) and sodium cyanide (23 g) were added to a mixture of ethanol (250 ml) and water (40 ml) in a pressure reactor. The resulting mixture was heated to 80°C and maintained for 1 hour at the same temperature. After completion of reaction, the resulting mass was cooled to room temperature and the contents were transferred into a reaction flask with ethanol (200 ml) and water (200 ml). 50 ml of solvent was distilled. The resulting mass was cooled to 5-10°C and water (200 ml) was added. The pH of the resulting mass was adjusted to 1-2 with 10% aqueous hydrochloric acid at 5-10°C and extracted with dichloromethane (150 ml x 3). The organic layers were combined and the solvent was distilled-off completely to produce 25 g of 2-[4-(2-Cyanomethyl)phenyl]-2-methyl-propanoic acid.
Example 7
Preparation of 2-[4-(2-Aminomethyl)phenyl]-2-methyl-propanoic acid
2-[4-(2-Cyanomethyl)phenyl]-2-methyl-propanoic acid (25 g) was taken in methanol (625 ml). To the resulting mass, ammonia gas was passed until the weight of the reaction mass was increased by 200 g. The resulting mass was transferred to an autoclave and then Raney-Nickel (10 g) was added and excess of ammonia gas was removed. To the resulting mass, hydrogen pressure of 5 kg/cm2 was applied at 40-42°C for 1-2 hours. After completion of reaction, the resulting mass was cooled to room temperature and the solvent was distilled-off completely to produce 23 g of 2-[4-(2-Aminomethyl)phenyl]-2-methyl-propanoic acid.

Example 8
Preparation of 2-[4-(2-Bromomethyl)phenyl]-2-methyl-propanoic acid
2-[4-(2-Aminomethyl)phenyl]-2-methyl-propanoic acid (16 g) was taken in 1.5 M sulphuric acid (114 ml) at room temperature. To the resulting mixture, sodium bromide (26.5 g) was slowly added. The resulting mass was cooled to -15°C and a mixture of sodium nitrite (6.9 g) in water (10.2 ml) was added at the same temperature. The temperature of the resulting mass was allowed to raise to room temperature and stirred for 30 minutes to 1 hour at the same temperature. Chloroform (40 ml) was added to the resulting mixture and stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with chloroform (40 ml x 2). The solvent was distilled completely to produce 12.6 g of 2-[4-(2-Bromomethyl)phenyl]-2-methyl-propanoic acid.

Example 9
Preparation of Pure Bilastine
Step-(a): Preparation of Crude Bilastine
2-[4-(2-Bromomethyl)phenyl]-2-methyl-propanoic acid (10 g) and 1-(2-ethoxyethyl)-2-piperidin-4-yl-1H-benzimidazole (13 g) were added to a mixture of water (100 ml) and sodium carbonate (14 g) at room temperature. The resulting mixture was heated to reflux temperature and maintained for 21 hours at the same temperature. After completion of reaction, the resulting mass was cooled to room temperature, followed by addition of water (480 ml) at the same temperature. The layers were separated and the aqueous layer was washed with toluene (300 ml x 2). The aqueous layer was separated and then neutralized with acetic acid, followed by extracting thrice with dichloromethane (300 ml x 3). The organic layers were combined and the solvent was distilled produce a crude compound. Acetone (30 ml) was added to the resulting crude compound. The solvent was distilled completely from the resulting mass, acetone (30 ml) was added again and stirred for 30 minutes at room temperature. The separated solid was filtered and washed with acetone (10 ml) to produce 4.3 g of crude Bilastine.

Step-(b): Purification of Crude Bilastine
Crude Bilastine (4 g) was added to butyl acetate (120 ml) and then heated to reflux temperature while stirring, followed by maintaining the reaction mass for 15 minutes at the same temperature. The resulting mass was cooled to room temperature and then stirred for 30 minutes at the same temperature. The separated solid was filtered and washed with butyl acetate (7 ml). Butyl acetate (110 ml) was added to the resulting wet material and then repeated the above re-crystallization process. The resulting wet material was taken in methanol (65 ml) and then heated to reflux, followed by stirring the reaction mass for 30 minutes at reflux temperature. Activated carbon (0.5 g) was added to the reaction mass and then stirred for 10 minutes. The resulting mixture was filtered through hyflo-bed and then washed the bed with hot methanol (5 ml). The resulting filtrate was cooled to 20-22°C and then stirred for 40 minutes at the same temperature. The separated solid was filtered, washed with cold methanol (5 ml) and then dried the material at 60-70°C to give 2.7 g of pure Bilastine (Purity by HPLC: 99.9%).

The description and disClosure are made Witn an Hitention to teach the Invention to the
skilled persons in the art. Accordingly few embodiments and examples and illustrations
have been provided. Otherwise all modifications and variations are known to skilled
persons in the art is well within the scope and sport of the invention
,CLAIMS:1. A process for the preparation of highly pure Bilastine of formula I:

or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting 2-methyl-2-phenyl-propanoic acid of formula II:

or a salt thereof, with paraformaldehyde and a halogenating agent in presence of a suitable acid to produce 2-[4-(2-halomethyl)phenyl]-2-methyl-propanoic acid compound of formula III:

or a salt thereof, wherein the radical ‘X’ represents a halogen atom;
b) cyanation of the compound of formula III obtained in step-(a) with an alkali metal cyanide in presence of a suitable solvent to produce 2-[4-(2-cyanomethyl)phenyl]-2-methyl-propanoic acid compound of formula IV:

or a salt thereof;
c) reducing the compound of formula IV with a reducing agent to produce 2-[4-(2-aminoethyl)phenyl]-2-methyl-propanoic acid compound of formula V:

or a salt thereof;
d) reacting the compound of formula V with an alkali metal halide in presence of a metal nitrite and a suitable acid to produce 2-[4-(2-haloethyl)phenyl]-2-methyl propanoic acid compound of formula VI:

or a salt thereof, wherein the radical ‘X’ is as defined above; and
e) condensing the compound of formula VI obtained in step-(d) with 1-(2-ethoxyethyl)-2-(piperidin-4-yl)benzimidazole of formula VII:

or an acid addition salt thereof, in presence of a base, optionally in the presence of a phase transfer catalyst, in a suitable solvent to produce Bilastine of formula I or a salt thereof, and optionally purifying the Bilastine obtained using a suitable solvent to produce highly pure Bilastine or a pharmaceutically acceptable salt thereof.
2. The process of claim 1, wherein the halogen atom ‘X’ in the compounds of formulae III & VI is, each independently, selected from the group consisting of Cl and Br; wherein the halogenating agent used in step-(a) is selected from the group consisting of aqueous hydrochloric acid and aqueous hydrobromic acid; wherein the acid used in step-(a) is selected from the group consisting of sulphuric acid, phosphoric acid and acetic acid; wherein the metal cyanide used in step-(b) is selected from the group consisting of sodium cyanide and potassium cyanide; wherein the reducing agent used in step-(c) is selected from the group consisting of platinum, palladium, palladium hydroxide, palladium on carbon, platinum oxide, rhodium, Raney-Nickel, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H) and sodium bis(2-methoxyethoxy)aluminum hydride (vitride); wherein the reduction in step-(c) is carried out in the presence of ammonia used in the form of aqueous ammonia or in the form of ammonia gas or ammonia saturated in an organic solvent; wherein the metal nitrite used in step-(d) is selected from the group consisting of sodium nitrite and potassium nitrite; wherein the metal halide used in step-(d) is selected from the group consisting of sodium bromide, potassium bromide, lithium bromide, copper bromide, sodium chloride, potassium chloride, sodium iodide and potassium iodide; wherein the acid used in step-(d) is selected from the group consisting of sulphuric acid, hydrobromic acid and phosphoric acid; and wherein the phase transfer catalyst used in step-(e) is selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, methyltributyl ammonium chloride and crown ethers.
3. A process for the preparation of highly pure Bilastine of formula I:

or a pharmaceutically acceptable salt thereof, comprising condensing the compound of formula VI:

or a salt thereof, wherein the radical ‘X’ represents a halogen atom;
with 1-(2-ethoxyethyl)-2-(piperidin-4-yl)benzimidazole of formula VII:

or an acid addition salt thereof, in presence of a base, optionally in the presence of a phase transfer catalyst, in a suitable solvent to produce Bilastine of formula I or a salt thereof, and optionally purifying the Bilastine obtained using a suitable solvent to produce highly pure Bilastine or a pharmaceutically acceptable salt thereof.
4. The process of claim 3, wherein the base used in the condensation reaction is an inorganic base; and wherein the phase transfer catalysts is selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, methyltributyl ammonium chloride and crown ethers.
5. A process for preparation of 2-[4-(2-haloethyl)phenyl]-2-methyl propanoic acid compound of formula VI:

or a salt thereof, which comprises:
a) reacting 2-methyl-2-phenyl-propanoic acid of formula II:

or a salt thereof, with paraformaldehyde and a halogenating agent in presence of a suitable acid to produce 2-[4-(2-halomethyl)phenyl]-2-methyl-propanoic acid compound of formula III:

or a salt thereof, wherein the radical ‘X’ represents a halogen atom;
b) cyanation of the compound of formula III obtained in step-(a) with a alkali metal cyanide in presence of a suitable solvent to produce 2-[4-(2-cyanomethyl)phenyl]-2-methyl propanoic acid compound of formula IV:

or a salt thereof;
c) reducing the compound of formula IV with a suitable reducing agent to produce 2-[4-(2-aminoethyl)phenyl]-2-methyl-propanoic acid compound of formula V:

or a salt thereof; and
d) reacting the compound of formula V with an alkali metal halide in presence of a metal nitrite and a suitable acid to produce 2-[4-(2-haloethyl)phenyl]-2-methyl propanoic acid compound of formula VI or a salt thereof.
6. The process of claim 5, wherein the halogen atom ‘X’ in the compounds of formulae III & VI is, each independently, selected from the group consisting of Cl and Br; wherein the halogenating agent used in step-(a) is selected from the group consisting of aqueous hydrochloric acid and aqueous hydrobromic acid; wherein the acid used in step-(a) is selected from the group consisting of sulphuric acid, phosphoric acid and acetic acid; wherein the alkali metal cyanide used in step-(b) is selected from the group consisting of sodium cyanide and potassium cyanide; wherein the reducing agent used in step-(c) is selected from the group consisting of platinum, palladium, palladium hydroxide, palladium on carbon, platinum oxide, rhodium, Raney-Nickel, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H) and sodium bis(2-methoxyethoxy)aluminum hydride (vitride); wherein the reduction in step-(c) is carried out in the presence of ammonia used in the form of aqueous ammonia or in the form of ammonia gas or ammonia saturated in an organic solvent; wherein the metal nitrite used in step-(d) is selected from the group consisting of sodium nitrite and potassium nitrite; wherein the alkali metal halide used in step-(d) is selected from the group consisting of sodium bromide, potassium bromide, lithium bromide, copper bromide, sodium chloride, potassium chloride, sodium iodide and potassium iodide; wherein the acid used in step-(d) is selected from the group consisting of sulphuric acid, hydrobromic acid and phosphoric acid.
7. A process for the preparation of 2-[4-(2-halomethyl)phenyl]-2-methylpropanoic acid compound of formula III:

or a salt thereof, comprising reacting 2-methyl-2-phenyl-propanoic acid of formula II:

or a salt thereof, with paraformaldehyde and a halogenating agent in presence of a suitable acid to produce 2-[4-(2-halomethyl)phenyl]-2-methyl-propanoic acid compound of formula III or a salt thereof, wherein the radical ‘X’ represents a halogen atom.
8. The process of claim 7, wherein the halogen atom ‘X’ in the compound of formula III is selected from the group consisting of Cl and Br; wherein the halogenating agent is selected from the group consisting of aqueous hydrochloric acid and aqueous hydrobromic acid; and wherein the acid is selected from the group consisting of sulphuric acid, phosphoric acid and acetic acid.
9. A process for the preparation of 2-[4-(2-cyanomethyl)phenyl]-2-methyl propanoic acid compound of formula IV:

or a salt thereof, comprising cyanation of a compound of formula IIIa:

with an alkali metal cyanide in presence of a suitable solvent to produce 2-[4-(2-cyanomethyl)phenyl]-2-methylpropanoic acid compound of formula IV or a salt thereof.
10. The process according to claim 9, wherein the alkali metal cyanide is selected from the group consisting of sodium cyanide and potassium cyanide.
11. A process for the preparation of 2-[4-(2-haloethyl)phenyl]-2-methyl propanoic acid compound of formula VI:

or a salt thereof, comprising reacting the 2-[4-(2-aminoethyl)phenyl]-2-methyl-propanoic acid compound of formula V:

or a salt thereof, with an alkali metal halide in presence of a metal nitrite and a suitable acid to produce 2-[4-(2-haloethyl)phenyl]-2-methyl propanoic acid compound of formula VI or a salt thereof.
12. The process of claim 11, wherein the metal nitrite is selected from the group consisting of sodium nitrite and potassium nitrite; wherein the alkali metal halide is selected from the group consisting of sodium bromide, potassium bromide, lithium bromide, copper bromide, sodium chloride, potassium chloride, sodium iodide and potassium iodide; and wherein the acid used in step-(d) is selected from the group consisting of sulphuric acid, hydrobromic acid and phosphoric acid.