DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

NOVEL PROCESS FOR PREPARATION OF ANTIHISTAMINE AGENT INTERMEDIATES AND USES THEREOF

We, LEE PHARMA LIMITED,
a company incorporated under the companies act, 1956 having address at Sy.No: 257 & 258/1; Door No: 11-6/56-C; Opp: IDPL Factory; Moosapet; Balanagar (Post); Hyderabad, Telangana; 500037- India.

The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to novel process for the preparation of intermediate compounds used in the preparation of Antihistamine agents.

The present invention particularly relates to novel process for the preparation of Bilastine intermediate compounds.

The present invention more particularly relates to use of intermediate compounds in the preparation of Bilastine or its pharmaceutically acceptable salts having the following structure of Formula A.

Formula A

The present invention also relates to novel process for preparation of Bilastine Form-III.

BACKGROUND OF THE INVENTION
Bilastine is a second generation antihistamine compound for the treatment of allergic rhinoconjunctivitis and urticaria (hives). Bilastine has been effective in the treatment of ocular symptoms and diseases of allergies, including rhinoconjuctivitis. Additionally, Bilastine has been shown to improve quality of life, and all nasal and ocular symptoms related to allergic rhinitis.

Bilastine is characterized by its chemical name 2-[4-[2-[4-[1-(2-ethoxyethyl) benzimidazol-2-yl]piperidin-1-yl]ethyl]phenyl]-2-methylpropionic acid. It has the following chemical structure.

Bilastine was first disclosed in US 5,877,187 and the process for the preparation of Bilastine disclosed in this patent is as shown below:

IN 5394/CHE/2013 discloses the process for the preparation of Bilastine which is shown below:

US 8,367,704 B2 describes a process for preparing 2-methyl-2’-phenylpropionic acid derivatives like Bilastine which is shown below :

US 3,978,071 discloses substituted phenylalkanoic acids and derivatives thereof of the Formula

wherein each of R1 and R2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; each of X1 and X2 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms; and Y is COOH, COOR (wherein R is an alkyl group having 1 to 4 carbon atoms), CONH2, CSNH2, CN or COZ-A-N(R3)(R4) (wherein Z is an oxygen atom or the group = NH, A is an alkylene group having 2 to 4 carbon atoms and each of R3 and R4 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, or R3 and R4 together with the adjacent nitrogen atom form a saturated heterocycle selected from pyrrolidine, piperidine, morpholine, piperazine and piperazine substituted by an alkyl group having 1 to 4 carbon atoms at the 4-position.

Various other processes for the preparation of Bilastine, its intermediates and related compounds are described in WO 2014/188453, CN 102675101 and Drugs of Future 35(2), 98-105, 2010.

US 6,242,606 B1 discloses novel intermediates useful in the preparation of piperidine derivatives which are useful as antihistamines, anti allergy agents and broncholidators. The process generically disclosed for the preparation of these novel intermediates is shown below :

wherein A is hydrogen or hydroxyl, B is halo or hydroxyl, Hal represents Cl, Br or I and n is an integer of from 1 to 5 and R6 and R7 are each independently H, C1-C6 alkyl, C1-C6 alkoxy or R6 and R7, taken together with the nitrogen atom for a pyrrolidine, piperidine or morpholine, with the proviso that R6 and R7, cannot both be represented by C1-C6 alkoxy.

US 7,612,095 B2 discloses that Bilastine can exist in three clearly different polymorphic forms called crystalline Form 1, crystalline Form 2 and crystalline Form 3.This patent describes three crystalline forms of Bilastine. Specifically, it describes the crystalline Forms 1, 2 and 3 of Bilastine, which are characterized by infrared absorption spectrum and crystallographic parameters in the case of Form 1.

There is always a constant need to develop improved process for solid forms, that are suitable for use in the pharmaceutical industry and in particular, to allow easier production of pharmaceutical compositions of Bilastine in crystalline forms which meet strict pharmaceutical standards.

In view of the importance of Antihistaminic agents such as Bilastine and its intermediates, there is a need for developing a relatively simple, commercially feasible process which involves use of inexpensive, environmental friendly reagents which are easily available or prepared from commercially available sources easily.

The present inventors have surprisingly found new improved methods for the preparation of Bilastine intermediates. Bilastine thus prepared according to the present invention is of high yield and purity.
OBJECTIVE OF THE INVENTION
The main objective present invention is to provide novel process for the preparation of intermediate compounds used in the preparation of Antihistamine agents.

Another objective of the present invention is to provide novel process for the preparation of Bilastine Intermediates.

Another preferred objective of the present invention is to provide use of intermediate compounds in the preparation of Bilastine having the following structure of Formula A

Formula A
or its pharmaceutically acceptable salts.

Still another objective of the present invention is to provide novel process for the preparation of Bilastine Form-III.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides novel process for the preparation of compound of Formula (I)

Formula (I)
wherein Lg represents leaving group and R is H, C1-C4 alkyl; wherein the process comprising the steps of:
a) reacting intermediate compound of Formula (II)

Formula (II)
with the compound of Formula (III)

Formula (III)
wherein Lg represents leaving group in presence of a lewis acid in suitable solvent to obtain an intermediate compound of Formula (IV),

Formula (IV)
b) hydrolyzing the intermediate compound of Formula (IV) using an acid in suitable solvent to produce the intermediate compound of Formula (I),

Formula (I)
wherein Lg is as defined above and R represents hydrogen,
c) optionally esterifying the compound of Formula (I)

Formula (I)
where R is hydrogen to produce compound of Formula (I)

Formula (I)
where R is C1-C4 alkyl ; wherein Lg is as defined as above.

In another aspect, the present invention provides novel process for the preparation of compound of Formula (IV)

Formula (IV)
wherein Lg is as defined above, which comprises reacting intermediate compound of Formula (II)

Formula (II)
with compound of Formula (III),

Formula (III)
wherein Lg represents leaving group in presence of a lewis acid in suitable solvent to obtain an intermediate compound of Formula (IV).

In another aspect, the present invention provides novel process for the preparation of compound of Formula (I)

Formula (I)
wherein Lg represents as defined above and R represents hydrogen; which comprises hydrolyzing the intermediate compound of Formula (IV),

Formula (IV)
wherein Lg is as defined above, using an acid in suitable solvent to obtain compound of Formula (I).

In yet another aspect, the present invention provides novel process for the preparation of intermediate compounds of Formula (I), (II), and (IV).

In yet another preferred aspect, the present invention provides use of intermediate compounds of Formula (I), (II), and (IV) in the preparation of Bilastine or its pharmaceutically acceptable salts compound of Formula (A).

Formula A

In yet another aspect, the present invention provides novel process for the preparation of Bilastine Form-III.

In yet another aspect, the present invention provides novel process for the preparation of Bilastine Form-III directly from methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazole-2yl)piperidin-1-yl)ethyl)phenyl)-2-methyl propanoate having the following structure of Formula B.

Formula B

In yet another aspect, the present invention provides novel process for the preparation of Bilastine crystalline form-III comprising the steps of
a) hydrolyzing the compound of Formula B using a base in a solvent and obtaining the solution of compound of Formula-A in a suitable solvent or mixture of solvents,
b) optionally slurring the reaction mas of step (a) in a suitable second solvent or mixture of solvents,
c) adjusting the pH of the reaction mass initially to 4.0-6.0 using an acid followed by raising the pH to 7.5 – 8.5 using a base ,
d) distilling off the solvent completely from the solution under reduced pressure,
and
e) drying the compound to provide crystalline Form-III of compound of Formula-A.

In a specific embodiment, the present invention provides novel process for the preparation of Bilastine crystalline form-III comprising the steps of:
a) hydrolyzing the compound of Formula B using a base in a solvent and obtaining the solution of compound of Formula-A in methanol,
b) distilling off the solvent completely from the solution under reduced pressure,
c) optionally slurring the reaction mas of step (a) in mixture of water and toluene / water and MTBE,
d) adjusting the pH of the reaction mass initially to 4.0-6.0 using an acid followed by raising the pH to 7.5 – 8.5 using a base ,
e) distilling off the solvent completely from the solution under reduced pressure, and
f) drying the compound to provide crystalline Form-III of compound of Formula-A.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides novel process for the preparation of intermediate compound of Formula (I).

In the process of the invention, the compound of Formula (II) is reacted with compound of Formula (III) to give compound of Formula (IV). The obtained compound of Formula (IV) is hydrolyzed to compound of Formula (I).

The compound of Formula (I) wherein R represents hydrogen is further converted to its ester having C1-C4 alkyl groups.

In a specific embodiment, the compound of Formula (II) is reacted with compound of Formula (III) in suitable organic solvent and in presence of lewis acid. The compound of Formula (II) i.e. N,N, 2-trimethyl-2-phenylpropanamide is reacted with chloroacetylchloride in a suitable solvent. After completion of the reaction, the compound of Formula (IV) is extracted with an appropriate solvent or mixture of solvents.

The obtained intermediate compound of Formula (IV) is hydrolyzed to compound of Formula (I). The hydrolysis is carried out by a suitable hydrolyzing agent as used herein is an acid.

The obtained intermediate compound of Formula (I) wherein R represents hydrogen is esterified to give the compound of Formula (I) having C1-C4 alkyl groups. The esterification reaction is achieved by using alcoholic hydrochloride solution or using thionyl chloride in appropriate alcohols.
In yet another embodiment, the lewis acid used in the present invention is selected from BF3, BCl3, BBr3, Bl3, SbF5, AlCl3, AlBr3, TiBr4, TiCl4, TiCl3, ZrCl4, PF5, FeCl3, FeBr3, ZnCl2, Titanium tetraisopropoxide, and a halide or a trifluoromethanesulfonate of a transition metal of the lanthanide series.

The leaving group (Lg) employed in the present invention include groups such as -OMs, -OTs, -OTf, -ONs, and the like. Here, “Ms” refers to a methanesulfonyl group, “Ts” refers to a para-toluenesulfonyl group, “Tf” refers to a trifluoromethanesulfonyl group, and “Ns” refers to an ortho-nitrobenzenesulfonyl group and halogens like Cl, Br, F and Iodine.

In yet another embodiment, the acid used in the present invention are not limited to acids inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid and perchloric acid, polyphosphoric acid; organic acid selected from formic acid, acetic acid, propionic acid, citric acid and oxalic acid, TsOH or mixture thereof.

In yet another embodiment, the base used in the present invention is selected from either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or Silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, Lithium hexamethyldisilazide, Sodium hexamethyldisilazide and potassium hexamethyldisilazide or organic bases such as LDA (lithium diisopropylamide), triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and the like.

In yet another embodiment, solvents used in the present invention are selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine and/or mixtures thereof.

The term “salts” as used herein refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, nitrate, oxalate, phthalate, phosphate, monohydro genphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propionate, phenylpropionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like.

In yet another preferred embodiment, the present invention provides use of intermediates in the process for preparing Bilastine or its salts. The intermediates formed in the present invention may or may not be isolated. Any of the above reactions may be carried out in-situ reactions to obtain intermediate compound of Formula (I).

In another preferred embodiment, a process for the preparation of compound of Formula (I) which yields the compounds with high chemical purity.

In yet another preferred embodiment, the present invention provides use of intermediate compounds of Formula (I) in the preparation of Bilastine.

In yet another preferred embodiment, the present invention provides novel process for the preparation of compound of Formula (IA)

Formula (IA)
wherein the process comprising the steps of:
a) reacting intermediate compound of Formula (II)

Formula (II)
with the compound of Formula (IIIA)

Formula (IIIA)
in presence of a lewis acid in suitable solvent to obtain an intermediate compound of Formula (IVA),

Formula (IVA)
b) hydrolyzing the intermediate compound of Formula (IVA) using hydrochloric acid in the presence of suitable solvent to produce the intermediate compound of Formula (IB),

Formula (IB)
c) optionally esterifying the compound of Formula (IB) using thionyl chloride in the presence of suitable solvent or mixture of solvents to produce compound of Formula (IA).

In yet another preferred embodiment, the present invention provides for the conversion of compound of Formula (B) directly to compound of Bilastine Form-III.

The conversion of compound of Formula (B) to Bilastine Form-III is achieved by first hydrolyzing the compound of Formula (B) with sodium hydroxide dissolved in methanol. After completion of hydrolysis, methanol was completely distilled off and the crude reaction mass was heated in toluene and water to affect complete dissolution. Aqueous layer and organic layers were separated. The aqueous layer was washed with toluene and methyl tert butyl ether was added. After addition of methyl tert butyl ether, pH of the reaction mass was adjusted first to 5.0 to 5.5 with dilute HCl and then pH was raised to 7.5 to 8 with liquor ammonia. The obtained material was filtered and washed with methanol and water followed by methyl tert butyl ether. The obtained wet cake was stirred in methanol and methanol was again removed and again dissolved in a mixture of methanol and dichloromethane until a clear solution is obtained. The solvent is again distilled off completely and the obtained crude was dissolved in a mixture of DMSO and methanol and heated to 65-70oC and cooled to 25-30oC. The reaction mass was filtered and washed with methanol again. The obtained wet cake was dissolved in a mixture of methanol and toluene and heated to 65-70oC until clear solution is obtained followed by cooling the solvent mixture to 0-5oC. The precipitated material was filtered and washed chilled mixture of toluene and methanol. The obtained wet cake was dried to get the Form-III.

The hydrolysis of compound of Formula B is carried out in presence of bases like sodium hydroxide, potassium hydroxide and the like.

EXAMPLES
Example 1: Preparation of 2-(4-(2-chloroacetyl)phenyl)–N,N-2-trimethyl propanamide:
Thionylchloride (145g) was added to the mixture of 2-methyl-2-phenylpropanoic acid (100g) and MDC (300 ml) at room temperature and heated to reflux. The reaction mixture was maintained for 6-8 hrs, and after completion of the reaction, the solvent was distilled off completely under vacuum and co-distilled with 100 ml of MDC. The crude was dissolved in 500 ml of MDC, and cooled to 0-10°C followed by addition of 342.7g of aqueous dimethyl amine solution at below 10oC. The reaction mixture was maintained for 8-10hrs at 25-30°C. After completion of the reaction as monitored by TLC, the reaction mass was diluted with 200 ml of water. The organic layer was separated. Aqueous layer was extracted with 100 ml of MDC. The combined organic layers were washed with 300.0ml of water, then added 300 ml of water to organic layer. The pH adjusted to 6.0-6.5 with dilute HCl solution. Both organic layer and aqueous layers were separated. Organic layer was washed with 300 ml of water and organic layer was dried over with sodium sulphate and cool to 10-15oC. To the organic layer, 186.7g of AlCl3, was then slowly added a mixture of 65.3g of chloroacetylchloride and 50 ml of MDC at 10-15oC. The reaction mass temperature was raised to 25-35oC and stirred for 4-5hrs at 25-35oC. After completion of the reaction as monitored by TLC, the reaction mass was quenched into 1000 ml of water and 300 ml of conc. HCl and cooled to 5-10oC. The organic is separated and aqueous layer was extracted with 200 ml of MDC. Combined organic layers were washed with 300 ml of water followed by pH adjustment of organic layer to 7.0-7.5 with saturated sodium bicarbonate solution followed by washing with 300 ml of water. Organic layer was dried over sodium sulphate. Organic layer was distilled off completely at below 45oC. To the obtained crude, 15 ml of methanol and 300 ml of di-isopropylether was added and heated to 50-55oC. The organic layer was cooled to 0-5oC, stir for 60-90 min, and the obtained material was filtered and washed with 50 ml of chilled di-isopropyl ether. Dry the wet cake at 50-55oC.
Yield: 110.0g (67.5%), Purity by HPLC:>99.0%, Meta isomer impurity: <1.0% at 1.03RRT by HPLC.

Example-2: Preparation of methyl-2-(4-(2-chloroacetyl)phenyl)-2-methyl propanoate:
100 g of 2-(4-(2-chloroacetyl)phenyl)-N,N,2-trimethylpropanamide and 500 ml of conc. HCl was charged into RB flask and the reaction mass was heated to 90-95°C and stir for 55-60 hrs at 90-95oC. After completion of the reaction as monitored by TLC, reaction mass was cooled to 45-50°C. 300.0ml of water and 400 ml of toluene was added. Organic layer was separated. Aqueous layer was extracted with 200 ml of toluene. The combined organic layers were washed with 300 ml of water and then organic layer dried over with sodium sulphate. The organic layer was then distilled off completely under vacuum followed by co-distillation with 100 ml of methanol to yield 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoic acid. 500 ml of methanol was added to the crude, and the reaction mass was cooled to 0-10°C. 53.4g of thionyl chloride was added slowly at 0-10°C under nitrogen atmosphere. The temperature was raised to 60-64°C and stirred for 4-5 hrs at 60-65°C. After reaction is complete as monitored by TLC, methanol was distilled off completely, then 400 ml of water and 300 ml of MDC was added. The organic layer was separated. Aqueous layer was extracted with 200 ml of MDC. Combined organic layers were washed with 400 ml of water followed by neutralization with sodium bicarbonate solution. Organic layer was dried over with sodium sulphate, then MDC was distilled off completely under vacuum to yield methyl2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate.
Yield: 83.4g (87.7%); purity by HPLC>95.0%.

Example-3: Preparation of methyl 2-(4-(2-chloroethyl) phenyl)-methylpropanoate:
1000 ml of MDC and 100g of methyl-2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate were dissolved in an RB flask, cooled to 0-10oC and slowly 409 g of titanium tetrachloride was added at 0-10oC under nitrogen atmosphere. After the addition is complete 137g of triethylsilane was added slowly into reaction mass at 0-30oC. The reaction mass was maintained for 2-3 hrs at 25-30°C. After reaction is completed as monitored by TLC, the reaction mass was cooled to 0-10°C. Take 1000 ml of water into another RB flask, cool to 5-10oC, slowly quench above chilled reaction mass at below 10oC. After quenching reaction mass temperature was raised to 25-30oC and organic layer is separated. Aqueous layer was extracted with 2×200 ml of MDC. The combined organic layers were washed with 200 ml of water, again washed with 8.0% of sodium chloride solution. pH of the reaction mass was adjusted to 7.5-8.0 with 8% of sodium bicarbonate solution and stirred for 30-60min at 25-30oC. Both organic layer and aqueous layers were separated. The Organic layer was washed with 200 ml of water and dried over with sodium sulphate. The organic is then distilled off completely under vacuum at below 40oC followed by co distillation with 100 ml of toluene at below 90oC. The obtained crude subjected to high vacuum distillation to get pure product.
Yield: 62.5g (66.2%), Purity by HPLC about 90.0%.

Example-4: Preparation of 2-(piperidin-4-yl)-1h-benzo[d] imidazole hydrate:
200 ml of water was taken into RB flask, 250 ml of ~85% w/w of ortho phosphoric acid was added at below 40oC. Then added 100g of Benzene-1,2-diamine was added slowly at below 40oC. After addition of diamine 155g of Piperidine-4-carboxylic acid was added slowly at below 40oC. The reaction mass was heated to 100-105oC and maintained for 20-24 hrs at 100-110°C. After completion of the reaction as monitored by TLC and the reaction mass was cooled to 25-30°C. The pH of the reaction mass was adjusted to 7.5-8.5 with sodium hydroxide solution at 25-30°C and the reaction mass was stirred for 1.5-2 hrs at 40-45oC. The material was filtered and washed with 100 ml of water. 500 ml water was charged and above wet cake into RB flask. Then pH of the reaction mass was adjusted to 1.0-2.0 with conc. HCl at 25-30°C. The filtrate was washed with 2×200 ml of ethyl acetate. The aqueous layer pH was adjusted to 7.5-8.5 with mixture of 200g of sodium hydroxide and 400 ml of water solution at 25-30°C. The reaction mass was stirred for 2.0-3.0 hrs at 25-30oC. Filter the material and wash with 100 ml of water, wet cake dry at 85-90°C until M.C between 6.0-9.0%.
Yield: 160.0g (79.2%), Purity by HPLC:>98.0%.

Example-5: Preparation of tert-butyl 4-(1h-benzo[d] imidazol-2-yl) piperidine-1-carboxylate:
400 ml of water and 38.3g of sodium bicarbonate was taken into RB flask and stirred till solution becomes clear. Then added 200 ml of THF and 100 g of 2-(piperidin-4-yl)-1H-benzo[d]imidazole hydrate was added and cooled to 0-5oC. Mixture of 120 g of di-tert-butyldicarbonate and 100 ml of THF solution was added into reaction mass at 0-5oC. The reaction mass was maintained for 60-90 min at 0-5oC. After completion of the reaction as monitored by TLC, pH of the reaction mass was slowly adjusted to 6.0-6.5 with 35 ml of acetic acid at 0-5°C.The reaction mass was stirred for 50-60 min at 0-5°C and the material was filtered and washed with 100 ml of chilled water. Then 300 ml of cyclohexane was added to the above wet cake and stirred for 45-60 min at 25-30°C. The material was filtered and washed with 100 ml of cyclohexane. The wet material was dried at 55-60°C until LOD not more than 1.0%.
Yield: 110.0g (80.3%), Purity by HPLC >99.0%.

Example-6: Preparation of tert-butyl 4-(1-(2-ethoxyethyl)-1H-benzo [d]imidazol-2-yl)piperidine-1-carboxylate:
Take 300 ml of DMSO, 47g of potassium hydroxide powder and 100g of tert-butyl 4-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate were stirred in an RB flask. Mixture of 90g of 2-ethoxyethyl 4-methyl benzenesulfonate and 100 ml of DMSO solution were added slowly at 25-30oC. The reaction mass was heated to 40-45oC, and maintain for 2-3 hrs at 40-45oC. After completion of the reaction as monitored by TLC, the reaction mass was cooled to 25-30°C, 500 ml of water and 500 ml of MDC was added. The reaction mass was stirred for 20-30 min at 25-30°C and the organic layer was separated. Aqueous layer was extracted with 300 ml of MDC. Combined organic layer were washed with 200 ml of 5% of sodium hydroxide solution, 2×200 ml of 10% of sodium chloride solution followed by 200 ml of water. Organic layer was dried over sodium sulphate, and MDC was distilled off completely under vacuum at below 40°C to yield crude of tert-butyl 4-(1-(2-ethoxyethyl)-1h-benzo[d]imidazol-2-yl)piperidine-1-carboxylate.
Yield: 113 g (91.3%), Purity by HPLC >95.0%.

Example-7: Preparation of 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1h-benzo[d] imidazole hydrochloride:
Take 700 ml of ethyl acetate and 100g of tert-butyl 4-(1-(2-ethoxy ethyl)-1H-benzo[d] imidazol-2-yl) piperidine-1-carboxylate were taken in an RB flask and 256g of IPA. HCl was added slowly at 25-30oC. The reaction mixture was maintained for 9-10 hrs at 25-30oC. After completion of the reaction as monitored by TLC, the material was filtered and washed with100 ml of ethyl acetate. The obtained wet material was dried for at 70-75°C until LOD NMT 1.0% to yield 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole hydrochloride.
Yield: 70.0g (85.3%), Purity by HPLC ~95.0%.

Example-8: Preparation of methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1h-benzo [d] imidazol-2-yl) piperidin-1-yl) ethyl) phenyl)-2-methylpropanoate:
1 lit of toluene, 100 g of 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d] imidazole hydrochloride, 86 g of methyl 2-(4-(2-chloroethyl)phenyl)-methylpropanoate, 102.4g of sodium carbonate, 10 g of TBAB and 5g of potassium iodide were dissolved in an RB flask and heated to 85-90oC. The water was removed by azeotrope at 85-110oC. The reaction mass was maintained for 20-22 hrs at 105-110°C. After completion of the reaction as monitored by TLC, reaction mass was cooled to 25-30°C. The salts were filtered and washed with 100 ml of toluene followed by 700 ml of water. The obtained reaction mass was cooled to 10-15°C and conc. HCl was added slowly until reaction mass pH attained 1-2 at 10-15°C. After the pH adjustment the temperature was raised to 25-30oC. Both the bottom aqueous layer and upper organic layer were separated. Aqueous layer was washed with 200 ml of toluene. Take aqueous layer and 500 ml of toluene into RB flask and the reaction mass was cooled to 10-15oC. The pH of the reaction mas was slowly adjusted to10-11with mixture of 100 g of sodium hydroxide and 200 ml of water solution at 10-15°C. The reaction mass temperature was raised to 25-30oC and both aqueous layer and organic layers were separated. Aqueous layer was extracted with 200 ml of toluene and combined organic layers were washed with 200 ml of water. Organic layer was distilled off completely under vacuum at below 60 °C and the reaction mass was cooled to 40oC and added 400 ml of di isopropyl ether, cool the reaction mass to 0-5oC, stir for 30-60 min at 0-5oC. The crude the material was filtered and washed with 50 ml of chilled di isopropyl ether, Dry the wet material at 55-60°C until LOD less than 1.0%.
Yield: 96.0g (67.7%), Purity by HPLC ~93.0%.

Example-9: Preparation of 2-(4-(2-(4-(1h-benzo [d] imidazol-2-yl) piperidin-1-yl) ethyl) phenyl)-2-methylpropanoic acid (Bilastine Form-III):
500 ml of methanol and 50.5g of sodium hydroxide flakes into RB flask were dissolved and stirred until clear solution is obtained. Then 100g of methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-l)ethyl)phenyl)-2-methyl propanoate was added and the reaction mass was heated to 60-65oC. The reaction mass was maintain for 10-12 hrs at 60-65oC. After completion of the reaction as monitored by TLC, methanol was distilled off completely under vacuum at below 55oC. To the reaction mass, 1.0 lit of water was added and 200 ml of toluene and heated to 65-70oC. The reaction mass was stirred for 15-20 min at 65-70°C. Aqueous layer and organic layers were separated. Aqueous layer was washed with 200.0ml of toluene. The aqueous layer was cooled to 25-30oC, added 200 ml of MTBE was added. Slowly adjust reaction mass pH to 5.0-5.5 with dilute HCl at 10-15°C and raise the pH to 7.5-8 with liquor ammonia at 10-15°C. The reaction mass temperature was raised to 25-30°C and stirred for 2-3 hrs at 25-30°C. The obtained material was filtered and washed with 100 ml of water followed by 100 ml of MTBE. To the wet cake, added 200 ml of methanol and distill off methanol under vacuum at below 50oC. After completion of distillation, added 350 ml of methanol and 150 ml of MDC was added and stirred until clear solution is obtained. The filtrate was distilled off completely under vacuum at below 55oC. To the crude, was added 150 ml of DMSO and 150 ml of methanol and heated to 65-70°C. The reaction mass was stirred for 30-45 min at 65-70°C and the reaction mass was cooled to 25-30°C. The obtained reaction mass was maintained for 45-60 min at 25-30°C. Filter the material and wash with 50 ml of methanol. To the wet cake, added 300 ml of methanol, stir for 30-45 min at 25-30°C. Filter the material and wash with 50 ml of methanol. To the wet cake, added 1120 ml of toluene and 100 ml of methanol and heated to 65-70oC. The reaction mass was stirred until clear solution is obtained. The reaction mass was filtered through micron filter and washed with mixture of 22 ml of toluene and 1.5 ml of methanol. The reaction mass was cooled to 0-5oC and stirred for 60-90 min at 0-5oC. Filter the material and wash with mixture of chilled (0-5oC) 45 ml of toluene and 6 ml of methanol. The wet cake was dried for 1-2 hrs at 25-30°C for 16-18 hrs at 100-105 °C, until LOD Not more than 0.5%w/w.
Yield: 57.5g (59.2%), purity by HPLC >99.8%, Meta Isomer: <0.05%.

,CLAIMS:We Claim:
1. Novel process for the preparation of compound of Formula (I)

Formula (I)
wherein Lg represents leaving group and R is H, C1-C4 alkyl; wherein the process comprising the steps of:
a) reacting intermediate compound of Formula (II)

Formula (II)
with the compound of Formula (III)

Formula (III)
wherein Lg represents leaving group in presence of a lewis acid in suitable solvent to obtain an intermediate compound of Formula (IV),

Formula (IV)
b) hydrolyzing the intermediate compound of Formula (IV) using an acid in suitable solvent to produce the intermediate compound of Formula (I),

Formula (I)
wherein Lg is as defined above and R represents hydrogen,
c) optionally esterifying the compound of Formula (I)

Formula (I)
where R is hydrogen to produce compound of Formula (I)

Formula (I)
where R is C1-C4 alkyl ; wherein Lg is as defined as above.

2. A process for the preparation of compound of Formula (IV)

Formula (IV)
wherein Lg represents leaving group, which comprises reacting intermediate compound of Formula (II)

Formula (II)
with compound of Formula (III),

Formula (III)
wherein Lg is as defined above, in presence of a lewis acid in suitable solvent to obtain an intermediate compound of Formula (IV).

3. A process for the preparation of compound of Formula (I)

Formula (I)
wherein Lg represents leaving group and R represents hydrogen; which comprises hydrolyzing the intermediate compound of Formula (IV),

Formula (IV)
wherein Lg is as defined above, using an acid in suitable solvent to obtain compound of Formula (I).

4. The process for the preparation of Bilastine compound of Formula (A)

Formula A
or its pharmaceutically acceptable salts comprising the process for the preparation of compound of Formula (I) and (IV) as claimed in any of claims 1-3.

5. Novel process for the preparation of Bilastine Form-III directly from methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazole-2yl)piperidin-1-yl)ethyl)phenyl)-2-methyl proponoate having the following structure of Formula B,

Formula B
wherein the process comprising the steps of:
a) hydrolyzing the compound of Formula B using a base in a solvent and obtaining the solution of compound of Formula-A

Formula A
in a suitable solvent or mixture of solvents,
b) optionally slurring the reaction mas of step (a) in a suitable second solvent or mixture of solvents,
c) adjusting the pH of the reaction mass initially to 4.0-6.0 using an acid followed by raising the pH to 7.5 – 8.5 using a base ,
d) distilling off the solvent completely from the solution under reduced pressure, and
e) drying the compound to provide crystalline Form-III of compound of Formula-A.

6. The process as claimed in claim 5, wherein the process comprising the steps of:
a) hydrolyzing the compound of Formula B

Formula B
using a base in a solvent and obtaining the solution of compound of Formula-A

Formula A
in methanol ,
b) distilling off the solvent completely from the solution under reduced pressure,
c) optionally slurring the reaction mas of step (a) in mixture of water and toluene / water and MTBE,
d) adjusting the pH of the reaction mass initially to 4.0-6.0 using an acid followed by raising the pH to 7.5 – 8.5 using a base,
e) distilling off the solvent completely from the solution under reduced pressure, and
f) drying the compound to provide crystalline Form-III of compound of Formula-A.

7. The process as claimed in claim 1 for the preparation of compound of Formula (IA)

Formula (IA)
comprising the steps of:
a) reacting intermediate compound of Formula (II)

Formula (II)
with the compound of Formula (IIIA)

Formula (IIIA)
in presence of a lewis acid in suitable solvent to obtain an intermediate compound of Formula (IVA),

Formula (IVA)
b) hydrolyzing the intermediate compound of Formula (IVA) using hydrochloric acid in the presence of suitable solvent to produce the intermediate compound of Formula (IB),

Formula (IB)
c) optionally esterifying the compound of Formula (IB) using thionyl chloride in the presence of suitable solvent or mixture of solvents to produce compound of Formula (IA).

8. The process as claimed in claims 1-3 and 7, wherein the lewis acid used in the present invention is selected from BF3, BCl3, BBr3, Bl3, SbF5, AlCl3, AlBr3, TiBr4, TiCl4, TiCl3, ZrCl4, PF5, FeCl3, FeBr3, ZnCl2, Titanium tetraisopropoxide, and a halide or a trifluoromethanesulfonate of a transition metal of the lanthanide series.

9. The process as claimed in claims 1-3 and 7, wherein the leaving group (Lg) employed in the present invention include groups such as -OMs, -OTs, -OTf, -ONs, and the like; here, “Ms” refers to a methanesulfonyl group, “Ts” refers to a para-toluenesulfonyl group, “Tf” refers to a trifluoromethanesulfonyl group, and “Ns” refers to an ortho-nitrobenzenesulfonyl group and halogens like Cl, Br, F and Iodine.

10. The process as claimed in any of the claims 1-7, wherein the acid used in the present invention are not limited to acids inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid and perchloric acid, polyphosphoric acid; organic acid selected from formic acid, acetic acid, propionic acid, citric acid and oxalic acid, TsOH or mixture thereof.

11. The process as claimed in any of the claims 5 and 6, wherein the base used in the present invention is selected from either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or Silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, Lithium hexamethyldisilazide, Sodium hexamethyldisilazide and potassium hexamethyldisilazide or organic bases such as LDA (lithium diisopropylamide), triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and the like.

12. The process as claimed in any of the claims 1-7 solvents used in the present invention are selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine and/or mixtures thereof.

Dated this Fifth (05th) day of November, 2020

_________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883