Claims:WE CLAIM:
1. A process for the preparation of methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl propanoate of formula I:

which comprises:
a) reducing the methyl 2-[4-(2-chloroacetyl)-phenyl]-2-methyl-propanoate of formula II:

with a reducing agent in a suitable solvent, to produce methyl 2-[4-(2-chloro-1-hydroxy-ethyl)-phenyl]-2-methyl-propanoate, of formula III:

or a salt thereof; and
b) reacting the compound of formula III with a hydrosilane reducing agent in presence of a Lewis acid in a suitable solvent to produce the compound of formula I.

2. The process of claim 1, wherein the reducing agent used in step-(a) is selected from the group consisting of sodium borohydride, potassium borohydride and diisobutylaluminum hydride; wherein the solvent used in step-(a) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetonitrile, tetrahydrofuran, and mixtures thereof; wherein the reducing agent used in step-(b) is selected from the group consisting of triethylsilane, trimethylsilane, dimethyl phenyl silane, phenyl silane, triphenylsilane and trichlorosilane; wherein the Lewis acid used in step-(b) is selected from the group consisting of boron trifluoride diethyl etherate, titanium tetrachloride, aluminum chloride, aluminum bromide, boron tribromide, tin tetrachloride, tin tetrabromide, stannous chloride, ferric chloride and zinc chloride; and wherein the solvent used in step-(b) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

3. The process of claim 2, wherein the reducing agent used in step-(a) is sodium borohydride; wherein the solvent used in step-(a) is methanol; wherein the hydrosilane reducing agent used in step-(b) is triethylsilane; wherein the Lewis acid used in step-(b) is boron trifluoride diethyl etherate; and wherein the solvent used in step-(b) is dichloroethane.

4. A process for the preparation of methyl 2-[4-(2-chloro-1-hydroxy-ethyl)-phenyl]-2-methyl propanoate of formula III:

comprising reducing methyl 2-[4-(2-chloroacetyl)-phenyl]-2-methyl-propanoate of formula II:

with a reducing agent in a suitable solvent to produce the compound of formula III.
5. The process of claim 4, wherein the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride and diisobutylaluminum hydride; and wherein the solvent used is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetonitrile, tetrahydrofuran, and mixtures thereof.

6. The process of claim 5; wherein the reducing agent used is sodium borohydride; and wherein the solvent used is methanol.

7. A process for the preparation of methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl propanoate of formula I:

comprising reducing methyl 2-[4-(2-chloro-1-hydroxy-ethyl)-phenyl]-2-methyl-propanoate of formula III:

with a hydrosilane reducing agent in presence a Lewis acid in a suitable solvent to produce the compound of formula I.

8. The process of claim 7, wherein the reducing agent is selected from the group consisting of triethylsilane, trimethylsilane, dimethyl phenyl silane, phenyl silane, triphenylsilane and trichlorosilane; wherein the Lewis acid is selected from the group consisting of boron trifluoride diethyl etherate, titanium tetrachloride, aluminum chloride, aluminum bromide, boron tribromide, tin tetrachloride, tin tetrabromide, stannous chloride, ferric chloride and zinc chloride; and wherein the solvent is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

9. The process of claim 8, wherein the reducing agent used is triethylsilane; wherein the Lewis acid used is boron trifluoride diethyl etherate; and wherein the solvent used is dichloroethane.

10. A compound, methyl 2-[4-(2-chloro-1-hydroxy-ethyl)-phenyl]-2-methyl propanoate, of formula III:

, Description:FIELD OF THE INVENTION
The present invention relates to novel, commercially viable and industrially advantageous process for the preparation of Bilastine intermediate, methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate, in high yield.

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 anti-allergic 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 2018/042305, WO 2014/188453, WO 2014/026657, WO 2009/102155, WO 2005/019175, WO 01/000615; Indian Patent Application Nos. IN 2010KOLNP2799, IN 2011CHE1908, IN 201741015924, IN 2013CHE2276, IN 201641020776, IN 201841008936 and IN 201641038857; and Scientific Journals: Syn. Comm., 41(9), 1394-1402, 2011; and Drugs of future 35(2), 98-105, 2010; and Journal of Heterocyclic Chemistry 26(3), 541-3; 1989.
In the preparation of Bilastine, methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate of formula I:

is a key intermediate.
The synthesis of Bilastine was first described in the US 5,877,187 patent (herein after referred to as US’187 patent).
PCT Publication No. WO 2014/188453 (Applicant: MSN Laboratories; hereinafter referred to as WO’453 publication) discloses a process for the preparation of methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate. As per the process disclosed in WO’453 publication, methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate is prepared by adding Titanium tetrachloride to a pre-cooled mixture of methyl 2-(4-(2-chloroacetyl)-phenyl)-2-methylpropanoate and dichloromethane (200 ml) at 0-5°C. The temperature was raised to 25-30°C, triethylsilane was added and stirred the reaction mixture for 4 hours at the same temperature. The resulting mass was quenched with water at below 10°C followed by usual work-up to produce methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl propanoate.
The process for the preparation of methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate as described in the aforementioned prior art suffers from the following major disadvantages and shortcomings: (a) the process involves the use of highly expensive and corrosive reagents such as titanium tetrachloride in excess amounts (5 times) with respect to the quantity of methyl 2-(4-(2-chloroacetyl)-phenyl)-2-methylpropanoate; (b) the process involves the use of excess amounts of triethylsilane (3.8 times) with respect to the quantity of methyl 2-(4-(2-chloroacetyl)-phenyl)-2-methylpropanoate; (c) the use of titanium tetrachloride is not advisable for commercial scale operations from safety point of view.
A need remains for novel, commercially viable and environmentally friendly process for the preparation of methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate with high yield 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 process for the preparation of methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate.
The present inventors have surprisingly and unexpectedly found that methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate can be prepared in high yield by reducing methyl 2-[4-(2-chloroacetyl)-phenyl]-2-methyl-propanoate using a suitable reducing agent in a solvent to produce methyl 2-[4-(2-chloro-1-hydroxy-ethyl)-phenyl]-2-methyl-propanoate, which is further reacted with a hydrosilane reducing agent in presence of a Lewis acid to produce methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate.
In one aspect, provided herein is an efficient, industrially advantageous and environmentally friendly process for the preparation of methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate, in high yield. The process disclosed herein avoids 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.
In another aspect, provided also herein is a novel compound, methyl 2-[4-(2-chloro-1-hydroxy-ethyl)-phenyl]-2-methyl-propanoate, of formula III:

In another aspect, provided also herein is a process for the preparation of novel compound of formula III.
In another aspect, the methyl 2-[4-(2-chloro-1-hydroxy-ethyl)-phenyl]-2-methyl-propanoate, of formula III is characterized by an infra red (FT-IR) spectrum having main bands at about 3457, 1731, 1608, 1512, 1469, 1434, 1388, 1367, 1261, 1193, 1149, 1076, 1017, 987 and 845 cm-1.
The novel process for the preparation of methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate disclosed in the present invention may be represented by a schematic diagram as depicted in scheme-2:

The process for the preparation of Bilastine described herein has the following advantages over the processes described in the prior art:
i) the process of the present invention involves the use of novel intermediate compound, methyl 2-[4-(2-chloro-1-hydroxy-ethyl)-phenyl]-2-methyl-propanoate, of formula III;
ii) the overall process involves reduced amounts of triethylsilane, thereby making the process cost effective and commercially viable;
iii) the process avoids the use of highly expensive and difficult to handle reagents like Titanium tetrachloride, thereby making the process cost effective and commercially viable; and
iv) the process produces the product with high overall yield.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a process for the preparation of methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate of formula I:

which comprises:
a) reducing the methyl 2-[4-(2-chloroacetyl)-phenyl]-2-methyl-propanoate of formula II:

with a reducing agent in a suitable solvent, to produce methyl 2-[4-(2-chloro-1-hydroxy-ethyl)-phenyl]-2-methyl-propanoate of formula III:

or a salt thereof; and
b) reacting the compound of formula III with a hydrosilane reducing agent in presence of a Lewis acid in a suitable solvent to produce the compound of formula I.
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, 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 25°C to the reflux temperature of the solvent used for at least 5 minutes, specifically at the reflux temperature of the solvent used; 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.
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 reducing agent used in step-(a) is selected from the group consisting of sodium borohydride, potassium borohydride, diisobutylaluminum hydride, and the like; and a most specific reducing agent is sodium borohydride.
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, an alcohol, an ether, a nitrile solvent, and mixtures thereof.
Preferably, the solvent used in step-(a) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetonitrile, tetrahydrofuran, and mixtures thereof. A most preferable solvent used in step-(a) is methanol.
Specifically, the reaction in step-(a) is carried out at a temperature of about 0°C to about 40°C; and more specifically at a temperature of about 0°C to about 20°C, and most specifically at a temperature of about 0°C to about 10°C. The reaction time may vary between about 30 minutes to about 3 hours.
The reaction mass containing the 2-[4-(2-chloro-1-hydroxy-ethyl)phenyl]-2-methyl-propanoic acid compound of formula III 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, 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 I, 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 hydrosilane reducing agent used in step-(b) is selected from the group consisting of triethylsilane, trimethylsilane, dimethyl phenyl silane, phenyl silane, triphenylsilane, trichlorosilane, and the like; and a most specific reducing agent is triethylsilane.
In another embodiment, the Lewis acid used in step-(b) is selected from the group consisting of boron trifluoride diethyl etherate, titanium tetrachloride, aluminum chloride, aluminum bromide, boron tribromide, tin tetrachloride, tin tetrabromide, stannous chloride, ferric chloride and zinc chloride; and a more specific Lewis acid is boron trifluoride diethyl etherate.
Exemplary solvents used in step-(b) include, but are not limited to, a hydrocarbon solvent, a chlorinated hydrocarbon solvent, and mixtures thereof.
Specifically, the solvent used in step-(b) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof; and a most specific solvent is dichloroethane.
In another embodiment, the reaction in step-(b) is carried out at a temperature of about –10°C to 60°C; and more specifically at a temperature of about 0°C to about 50°C.
The reaction mass containing the compound of formula I 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.
In one embodiment, the compound of formula I 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 I obtained by the process described herein is selected from the group as described hereinabove.
According to another aspect, there is provided a novel methyl 2-[4-(2-chloro-1-hydroxy-ethyl)-phenyl]-2-methyl-propanoate, of formula III:

According to another aspect, there is provided a process for the preparation of methyl 2-[4-(2-chloro-1-hydroxy-ethyl)-phenyl]-2-methyl-propanoate of formula III:

comprising reducing methyl 2-[4-(2-chloroacetyl)-phenyl]-2-methyl-propanoate of formula II:

with a reducing agent in a suitable solvent to produce the compound of formula III.
The process for the preparation of methyl 2-[4-(2-chloro-1-hydroxy-ethyl)-phenyl]-2-methyl-propanoate of formula III 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 methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate of formula I:

comprising reducing methyl 2-[4-(2-chloro-1-hydroxy-ethyl)-phenyl]-2-methyl-propanoate of formula III:

with a hydrosilane reducing agent in presence a Lewis acid in a suitable solvent to produce the compound of formula I.
The preparation of methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate of formula I can be carried out by using the solvents, reagents, methods, parameters and conditions as described hereinabove.
Unless otherwise specified, Bilastine or a polymorphic form thereof can be prepared by using the methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate of formula I, obtained by the process described herein, as per the processes known in the art, for example, as per the processes described in the U.S. Patent Nos. US 5,877,187 and US 8,367,704; PCT Publication Nos. WO 2009/102155, WO 2014/188453, WO 2014/026657, WO 2018/042305; Indian Patent Application Nos. IN 201641029306, IN 201641038857, IN 201641020776, IN 201741015924 and IN 201841008936; and Scientific Journals: Syn. Comm., 41(9), 1394-1402, 2011; and Drugs of future 35(2), 98-105, 2010.

INSTRUMENTAL DETAILS:
Infra-Red Spectroscopy (FT-IR):
FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the generation of the IR spectrum the neat sample was suspended uniformly between the KBr/NaCl Cell. The spectra were recorded in transmission mode ranging from 3800 cm-1 to 650 cm-1.
Mass Spectrometry:
Instrument Name:
Agilent 6120 Single quad Mass Spectrometer; Software: Opes Labs
MS Method
Column : Union
Buffer : 1mL Formic acid in 1L of milli-Q water
Mobile Phase-A : Buffer
Mobile Phase-B : Methanol
Diluent : Methanol
Flow rate : 0.5 mL/min
Isocratic Program : Mobile Phase-A and Mobile Phase-B (90:10) (% v/v)
Run time : 0.5 min
Injection Volume : 5µL
Sample Concentration : 1 mg/mL
MS Conditions
Ionization Method : ESI (Positive/Negative)
Capillary voltage : 3500V
Drying Gas Flow : 10 L/min
Nebulizer : 50 psig
Desolvation Temperature : 320°C

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 methyl 2-[4-(2-chloro-1-hydroxy-ethyl)-phenyl]-2-methyl-propanoate
Methyl 2-[4-(2-chloroacetyl)-phenyl]-2-methyl-propanoate (50 g) was added to methanol (125 ml) at room temperature and the resulting mass was cooled to 0-5°C. To the resulting mass, sodium borohydride (4 g) was added slowly at 0-5°C and maintained for 1-2 hours at the same temperature. The resulting mass was added slowly to pre-cooled water (625 ml) at 10-15°C for about 30 minutes. The pH of the resulting mass was adjusted to 3-4 with acetic acid at 10-15°C. The reaction mass was extracted with dichloroethane (150 ml x 2). The layers were separated and the combined organic layer was washed with saturated sodium bicarbonate solution (150 ml x 2) followed by washing with water (150 ml x 2). To the resulting organic layer, carbon (3.8 g) was added and stirred for 10-15 minutes at room temperature. The resulting mass was filtered, washed with dichloroethane (45 ml) and the solvent was distilled completely under vacuum at 60-65°C to produce 43 g of methyl 2-[4-(2-chloro-1-hydroxy-ethyl)-phenyl]-2-methyl propanoate. (Yield: 85%).
FT-IR Bands: 3457, 1731, 1608, 1512, 1469, 1434, 1388, 1367, 1261, 1193, 1149, 1076, 1017, 987 and 845 cm-1; Mass: [M+H]: 257.2.

Example 2
Preparation of methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate
Methyl 2-[4-(2-chloro-1-hydroxy-ethyl)-phenyl]-2-methyl-propanoate (43 g) was added to dichloroethane (860 ml) at room temperature and the resulting mixture was stirred for 10 minutes at the same temperature. The reaction mass was cooled to 0-5°C. Boron trifluoride diethyletherate (62 g) was added to the resulting mass at 0-5°C and maintained for 10 minutes at the same temperature. The temperature of the resulting mass was raised to 17-23°C and triethylsilane (39 g) was slowly added at the same temperature. The resulting mass was stirred for 2 hours at room temperature. The reaction mass was heated to 43-47°C and maintained for 18 hours at the same temperature. Then, the resulting mass was heated to reflux temperature and maintained for 34 hours at the same temperature. The reaction mass was cooled to room temperature and then further cooled to 10-15°C. Water (645 ml) was added to the resulting mass at 10-15°C and maintained for 15 minutes at the same temperature. Then, the temperature of the resulting mass was raised to room temperature. The resulting mass was transferred into a separating funnel and allowed to settle for 20 minutes at room temperature. The layers were separated. The organic layer was kept aside and the aqueous layer was extracted with dichloroethane (110 ml). The layers were separated and the aqueous layer was discarded. The organic layers were combined and washed with water (485 ml). To the resulting organic layer carbon (4.3 g) was added and stirred for 10-15 minutes at room temperature. The resulting mass was filtered, washed with dichloroethane (43 ml) and the solvent was distilled off completely under vacuum at 75-80°C to produce 38 g of methyl 2-[4-(2-chloroethyl)-phenyl]-2-methyl-propanoate. (Yield: 94%).