DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR PREPARATION OF BILASTINE INTERMEDIATES AND USE THEREOF

We, VIRUPAKSHA ORGANICS LIMITED
a company incorporated under the companies act, 1956 having address at
B-4, IDA, Gandhinagar, Hyderabad- 500037, Telangana State, India.

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Bilastine Intermediate compounds.

The present invention also relates to novel intermediate compounds and process for the preparation of novel intermediate compounds.

The present invention particularly relates to use of intermediate compounds in the preparation of Antihistamine agents.

The present invention more particularly relates to use of intermediate compounds in the preparation of Bilastine of Formula (I)

Formula (I)
or its pharmaceutically acceptable salts.

The present invention also relates to novel crystalline forms of Bilastine and process for the preparation of crystalline forms of Bilastine.

BACKGROUND OF THE INVENTION
Bilastine is a second generation antihistamine compound for the treatment of allergic rhinoconjunctivitis and urticaria (hives). The product is approved in the European Union under the tradename Bilaxten for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. 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 2276/CHE/2013 discloses a process for the preparation of Bilastine which is 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 as follows:

WO 2018/042305 discloses a process for the preparation of Bilastine as shown below:

Synthetic Communications 2011, Vol. 41, Issue 9, page 1394-1402 describes the synthesis of Bilastine as shown below:

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 5,877,187 confers the rights to bilastine, a preparation with antihistaminic properties without sedative or cardiovascular effects. This patent also concerns a procedure to prepare bilastine. The procedure described in US 5,877,187 generates a mixture of crystalline forms 2 and 3.

US 7,612,095 B2 describes that bilastine can exist in three clearly different polymorphic forms called crystalline form 1, crystalline form 2 and crystalline form 3. The crystalline form 1 of pure bilastine is prepared according to the procedures of this invention. The crystalline forms 1 and 2 are stable. Crystalline form 3 is not very stable and is difficult to obtain in the pure form. Both crystalline form 2 and crystalline form 3 are converted into crystalline form 1 by the procedures of this invention.

WO 2017/017301 A1 describes crystalline forms Alpha and beta of Bilastine. This patent describes the above apha and beta forms are stable under the conditions of manufacture and storage of the pharmaceutical composition, which ensures the reproducibility of manufacture and the quality of the composition.

WO 2017/191651 A1 describes amorphous form of Bilastine and also presents details for the preparation of the pure amorphous form.

Polymorphism is the ability of a solid material to exist in more than one form or crystal structure. An important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered pharmaceutical compound may reach the patient's bloodstream. The rate of dissolution is a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.

Although therapeutic or clinical efficacy is the primary concern for a drug (or an active pharmaceutical ingredient), the salt and solid-state form (i.e., the crystalline or amorphous form) of a drug candidate can be critical to its pharmacological properties and to its development as a viable drug. Crystalline forms of drugs have been used to alter the physicochemical properties of a particular drug. Each crystalline form of a drug candidate can have different solid-state (physical and chemical) properties which may be relevant for drug delivery. Crystalline forms often have better chemical and physical properties than corresponding non-crystalline forms such as the amorphous form. The differences in physical properties exhibited by a novel solid form of a drug (such as a cocrystal or polymorph of the original drug) affect pharmaceutical parameters such as storage stability, compressibility and density (relevant for formulation and product manufacturing), and dissolution rates and solubility (relevant factors in achieving suitable bioavailability).

Dissolution rates of an active ingredient in-vivo (e.g., gastric or intestinal fluid) may have therapeutic consequences since it affects the rate at which an orally administered active ingredient may reach the patient's bloodstream. In addition, solubility, a thermodynamic quantity, is a relevant property in evaluating drug delivery because a poorly soluble crystalline form of a drug will deliver less drug than a more soluble one in the same formulation.
Because these practical physical properties are influenced by the solid-state properties of the crystalline form of the drug, they can significantly impact the selection of a compound as a drug, the ultimate pharmaceutical dosage form, the optimization of manufacturing processes, and absorption in the body. Moreover, finding the most adequate solid state form for further drug development can reduce the time and the cost of that development.

Obtaining suitable crystalline forms of a drug is a necessary stage for many orally available drugs. Suitable crystalline forms possess the desired properties of a particular drug. Such suitable crystalline forms may be obtained by forming a cocrystal between the drug and a coformer. Cocrystals often possess more favorable pharmaceutical and pharmacological properties or may be easier to process than known forms of the drug itself. For example, a cocrystal may have different dissolution and solubility properties than the drug. Further, cocrystals may be used as a convenient vehicle for drug delivery, and new drug formulations comprising cocrystals of a given drug may have superior properties, such as solubility, dissolution, hygroscopicity, and storage stability over existing formulations of the drug.

To the best of the inventor’s knowledge, the present polymorphic forms of Bilastine have not been reported in the prior-art. The prior-art does not even provide a clear procedure for the crystallization of Bilastine.

In view of the importance of Antihistaminic agents such as Bilastine, 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 invented novel compounds which can be used as intermediates in the preparation of Bilastine. Bilastine prepared according to the present invention is of high yield and purity.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of Bilastine Intermediates.

Another objective of the present invention is to provide novel intermediate compounds and process for the preparation of intermediate compounds.

Another preferred objective present invention particularly relates to use of intermediate compounds in the preparation of Antihistamine agents.

Another more preferred objective of the present invention is to provide use of intermediate compounds in the preparation of Bilastine of Formula (I)

Formula (I)
or its pharmaceutically acceptable salts which are commercially feasible / industrially scalable.

In yet another objective of the present invention is to provide novel crystalline forms of Bilastine and process for preparation of crystalline forms of Bilastine.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of compound of Formula (VI)

Formula (VI)
wherein Lg represents leaving group; and R is H or C1-C3 alkyl; the process comprising the steps of:
a) reacting intermediate compound of formula (II)

Formula (II)
with in presence of base and a suitable solvent to obtain an intermediate compound of Formula (III),

Formula (III)

wherein R1 and R2 together to form a cyclic heterocyclic ring
b) converting intermediate compound of Formula (III) to produce the intermediate compound of Formula (IV),
Formula (IV)
wherein Lg represents leaving group; and R1 and R2 are as defined above
c) reducing compound of Formula (IV) optionally in presence of lewis acid to produce compound of Formula (V), and
Formula (V)
wherein Lg represents leaving group; and R1 and R2 are as defined above
d) hydrolyzing compound of Formula (V) in presence of organic or inorganic acid or mixture to produce compound of Formula (VI) and optionally converting to compound of Formula (VI), wherein R is alkyl.

In another aspect, the present invention provides an improved process for the preparation of compound of Formula (V)

Formula (V)
wherein Lg represents leaving group; and R1 and R2 are as defined above; the process comprises the steps of:
a) reacting intermediate compound of formula (II)

Formula (II)

wherein Lg represents leaving group;

with using base and a suitable solvent to obtain an intermediate compound of Formula (III),

Formula (III)
wherein R1 and R2 are as defined above
b) converting intermediate compound of Formula (III) to produce the intermediate compound of Formula (IV), and

Formula (IV)

wherein Lg represents leaving group; wherein R1 and R2 are as defined above
c) reducing compound of Formula (IV) optionally in presence of lewis acid to produce compound of Formula (V).

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

Formula (IV)
wherein the process comprises the steps of:
a) reacting intermediate compound of formula (II)

Formula (II)
wherein Lg represents leaving group;
with in presence of base and a suitable solvent to obtain an intermediate compound of Formula (III), and

Formula (III)
wherein R1 and R2 are as defined above
b) converting intermediate compound of Formula (III) to produce the intermediate compound of Formula (IV).

In yet another aspect, the present invention provides novel intermediate compounds of Formulae (IV) and (V).

Formula (IV)

Formula (V)
wherein Lg represents leaving group; wherein R1 and R2 are as as defined above.

In yet another preferred aspect, the present invention provides use of novel intermediate compounds of Formula (IV) and (V) in the preparation of Bilastine of Formula (I) or its salts.

In yet another preferred aspect, the present invention provides use of intermediate compounds of Formula (III) and (VI) in the preparation of Bilastine of Formula (I) or its salts.

In another aspect of the present invention provides an improved process for the preparation of compound of Formula (I).

Formula (I)
wherein the process comprises the steps of:
a) coupling intermediate compound of Formula (IV)

Formula (IV)
wherein Lg represents leaving group; and R1 and R2 are as defined above with compound of Formula (VII)

Formula (VII)
to obtain an intermediate compound of Formula (VIII),
Formula (VIII)
wherein R1 and R2 are as defined above
b) reducing the intermediate compound of Formula (VIII) to produce the intermediate compound of Formula (IX),
Formula (IX)
wherein R1 and R2 are as defined above
c) hydrolyzing the compound of Formula (IX) to produce compound of Formula (I).

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

Formula (I)
wherein the process comprises the steps of:
a) condensing the obtained compound of Formula (V)
Formula (V)
wherein R1 and R2 together to form a cyclic heterocyclic ring
b) with the compound of Formula (VII)
Formula (VII)
to produce compound of Formula (IX), and
Formula (IX)
c) hydrolyzing compound of Formula (IX) to produce compound of Formula (I).

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

Formula (I)
wherein the process comprises the steps of:
a) reacting intermediate compound of Formula (II)

Formula (II)
wherein Lg represents leaving group; with in presence of base and a suitable solvent to obtain an intermediate compound of Formula (III),

Formula (III)
wherein R1 and R2 are as defined above
b) converting intermediate compound of Formula (III) to produce the intermediate compound of Formula (IV),
Formula (IV)

wherein Lg represents leaving group; wherein R1 and R2 are as defined above
c) reducing compound of Formula (IV) optionally in presence of lewis acid to produce compound of Formula (V)
Formula (V)
wherein Lg represents leaving group; wherein R1 and R2 represents as defined above
d) condensing the obtained compound of Formula (V) with the compound of Formula (VII)
Formula (VII)
e) to produce compound of Formula (IX), and
Formula (IX)
f) hydrolyzing compound of Formula (IX) to produce compound of Formula (I).

In yet another preferred aspect, the present invention provides novel crystalline Form A of Bilastine which is characterized by X-ray powder diffraction pattern having peaks at 11.2, 12.3, 14.9, 16.17, 17.03, 18.8, 19.5, 19.6 and 21.03 ± 0.2º 2? values.

In yet another preferred aspect, the present invention provides novel crystalline Form A of Bilastine which is further characterized by X-ray powder diffraction pattern having peaks at 3.68, 7.4, 10.4, 11.2, 12.3, 14, 14.6, 14.9, 15.3, 16.17, 17.03, 17.9, 18.3, 18.8, 19.5, 19.6, 20.09, 21.03, 22.1, 22.5, 22.6, 22.9, 23.1, 24, 24.4, 24.7, 25.6 and 26.3 ± 0.2º 2? values .

In yet another preferred aspect, the present invention provides a process for preparation of novel crystalline Form A of Bilastine, wherein the process comprises:
a) dissolving Bilastine crude into an alcohol solvent or mixture of solvents,
b) heating the reaction mass to 60-65 ºC and maintaining the temperature for 1.30 hr –2 hrs,
c) cooling the reaction mass to 25-35ºC and maintain for 22-24 hrs at 25-35ºC,
d) filtering the reaction mass followed washing the wet compound with alcohol solvent, and
e) drying the material at 65-70ºC for 10-12 to obtained Bilastine Form-A.

In yet another preferred aspect, the present invention provides novel crystalline Form B of Bilastine which is characterized by X-ray powder diffraction pattern having peaks at 9.2, 12.7, 15.6, 17.6, 18.3 and 19.9 ± 0.2º 2? values.

In yet another preferred embodiment, the novel crystalline Form B of Bilastine which is further characterized by X-ray powder diffraction pattern having peaks at 6.42, 9.2, 9.5, 10.8, 12.7, 13.48, 14.8, 15.6, 16.03, 16.9, 17.6, 18.3, 18.8, 19.9, 21.2, 21.9, 22.3, 24, 25.3 and 26.2 ± 0.2º 2? values.

In yet another preferred aspect, the present invention provides a process for preparation of novel crystalline Form B of Bilastine, wherein the process comprises:

a) dissolving Bilastine crude into an alcohol solvent or mixture of solvents,
b) heating the reaction mass to 105-115ºC and maintained for 30-45 min at 105-115ºC,
c) cooling the reaction mass to 85-95ºC and maintained the reaction mass for 1-2 hrs at 85-95ºC,
d) further cooling the reaction mass to 25-35ºC and maintain for 30-45 min at 25-35ºC,
e) filtering the reaction mass followed, and
f) drying the material at 65-70ºC for 10-12 to obtained Bilastine Form-B.

We have also discovered that the new crystalline form A and form B of bilastine are very stable and is not transformed into any of the other polymorphs.

BRIEF DESCRIPTION OF DRAWINGS
Figure 1: Represents X-ray powder diffraction pattern of novel crystalline Form A of Bilastine.
Figure 2: Represents X-ray powder diffraction pattern of novel crystalline Form B of Bilastine.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of intermediate compound of Formula (VI) starting from compounds of Formula (II).

In yet another preferred embodiment, the compound of Formula (VI) is prepared by reacting intermediate compound of Formula (II) with in presence of base and a suitable solvent to obtain intermediate compound of Formula (III) followed by converting the obtained intermediate compound of Formula (III) to get intermediate compound of Formula (IV). The intermediate compound of Formula (IV) is reduced optionally in presence of lewis acid to give intermediate compound of Formula (V) which is finally hydrolysed in presence of organic or inorganic acid or mixture to give intermediate compound of Formula (VI).

In yet another preferred embodiment, the compound of Formula (V) is prepared by reacting intermediate compound of Formula (II) with in presence of base and a suitable solvent to obtain intermediate compound of Formula (III) followed by converting the obtained intermediate compound of Formula (III) to get intermediate compound of Formula (IV). The intermediate compound of Formula (IV) is reduced optionally in presence of lewis acid to give intermediate compound of Formula (V).

In yet another preferred embodiment, the compound of Formula (IV) is prepared by reacting intermediate compound of Formula (II) with in presence of base and a suitable solvent to obtain intermediate compound of Formula (III) followed by converting the obtained intermediate compound of Formula (III) to get intermediate compound of Formula (IV).

In yet another preferred embodiment, the compound of Formula (IV) is prepared by reacting intermediate compound of Formula (II) with in presence of base and a suitable solvent to obtain intermediate compound of Formula (III).

In yet another preferred embodiment, the compound of Formula (V) is prepared by converting intermediate compound of Formula (IV).

In yet another preferred embodiment, the compound of Formula (IV) is prepared by converting intermediate compound of Formula (III).

In yet another aspect of the present invention provides an improved process for the preparation of compound of Formula (I) which comprises reacting the compound of Formula (II) with in presence of base and a suitable solvent to obtain an intermediate compound of Formula (III) and then subsequent conversion of compound of Formula (III) to produce the intermediate compound of Formula (IV). The compound of Formula (IV) is reduced optionally in the presence of lewis acid to produce compound of Formula (V). The compound of Formula (V) is condensed with compound of Formula (VII) to produce compound of Formula (IX) and followed by hydrolyzing the compound of Formula (IX) to produce compound of Formula (I).
In yet another aspect of the present invention provides, the group wherein R1 and R2 together to form a cyclic heterocyclic ring represent piperidine or morpholine or pyrrolidine,

In yet another embodiment, the reducing agent as used herein is and not limited to silanes such as trimethylsilane, triethylsilane; siloxane such as tetramethyldisiloxane optionally in combination with a suitable Lewis acid or trifluoroacetic acid or BF3-etherate; trichlorosilane, sodium borohydride optionally in combination with BF3-etherate, diborane, potassium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminium hydride, diisobutylaluminium hydride (DIBAL), lithium triethylborohydride (LiEt3BH), L-selectride (lithium tri-sec-butyl(hydrido)borate(l-)), sodium bis(2-methoxyemoxy)aluminiumhydride (vitride) and the like.

In yet another embodiment, the lewis acid used in the present invention is selected from hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, 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.

In yet another embodiment of the present invention Lg represents a suitable leaving group which is selected from chlorine, bromine, iodine, fluorine, amino acid, substituted or unsubstitutedaryloxy, alkoxyalkyloxy, aryloxyalkyloxy, C1 to C4 alkoxy, sulfonate esters, mono, di, or triphosphate ester, trityl, monomethoxy-trityl, trialkylsilyl, isopropyldialkylsilyl, alkyldiisopropylsilyl, triisopropylsilyltetraisopropyldisilyl, t-butyldialkylsilyl or t-butyldiphenylsilyl or trifluoroacetate or alkylsulfonyloxy group such as methanesulfonyloxy and the like or trifluoroalkylsulfonyloxy such as a trifluoromethanesulfonyloxy and the like or arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, o-nitrobenzenesulfonyloxy, fluorosulfonyl, camphorsulfonyl and the like or phenoxides such as pentafluorophenoxide, p-NO2-phenoxide and the like or thio phenyls and the like or 2,2-dimethyl-3-(3-(trifluoromethyl)phenyl)propanoyl chloride and the like; bicyclic compounds such as indole, benzotriazoles or tricyclic compounds.

In yet another embodiment of the present invention, the alkyl group represents C1-C3 alkyl selected from methyl, ethyl, propyl, isopropyl.

In yet another embodiment, hydrolyzing agent as used herein and 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 or mixture thereof.

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, methyl isobutyl 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.

In yet another preferred embodiment 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.

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 novel intermediate compounds of Formula (IV) and (V) in the preparation of Bilastine of Formula (I) or its salts and process for their preparation.

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 (VI) or its derivative. The above compounds may be isolated as salts or free bases, if the above compounds are isolated as salts they are converted to their free bases first and used for further reactions.

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

In yet another preferred embodiment, the present invention provides use of novel intermediate compounds of Formula (V) and (VI) in the preparation of Bilastine of Formula (I) or its salts.

In yet another preferred embodiment, the present invention provides use of intermediate compounds of Formula (III) and (VI) in the preparation of Bilastine of Formula (I) or its salts.

In yet another preferred embodiment, the present invention provides novel crystalline Form A of Bilastine is which characterized by X-ray powder diffraction pattern having peaks at 11.2, 12.3, 14.9, 16.17, 17.03, 18.8, 19.5, 19.6 and 21.03 ± 0.2º 2? values .

In yet another preferred embodiment, the present invention provides novel crystalline Form A of Bilastine which is further characterized by X-ray powder diffraction pattern having peaks at 3.68, 7.4, 10.4, 11.2, 12.3, 14, 14.6, 14.9, 15.3, 16.17, 17.03, 17.9, 18.3, 18.8, 19.5, 19.6, 20.09, 21.03, 22.1, 22.5, 22.6, 22.9, 23.1, 24, 24.4, 24.7, 25.6 and 26.3 ± 0.2º 2? values.

In yet another preferred embodiment, the present invention provides novel crystalline Form B of Bilastine which is characterized by X-ray powder diffraction pattern having peaks at 9.2, 12.7, 15.6, 17.6, 18.3 and 19.9 ± 0.2º 2? values.

In yet another preferred embodiment, the novel crystalline Form Bof Bilastine which is further characterized further by X-ray powder diffraction pattern having peaks at 6.42, 9.2, 9.5, 10.8, 12.7, 13.48, 14.8, 15.6, 16.03, 16.9, 17.6, 18.3, 18.8, 19.9, 21.2, 21.9, 22.3, 24, 25.3 and 26.2 ± 0.2º 2? values.

EXAMPLES:

Example 1: Preparation of 2-(4-(2-chloroacetyl)phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one:
Dichloromethane and 2-methyl-2-phenyl propionic acid were charged into the round bottom flask at room temperature. The reaction mixture was stirred for 10-15 minutes. Then slowly DMF was added followed by thionyl chloride into the reaction mass at 25-35 °C under nitrogen atmosphere. The reaction mass was maintained at 25-35 °C for 1-2 hrs. The solvent was completely distilled under atmospheric pressure & co-distilled with MDC. In another round bottomed flask sodium carbonate solution was added and cooled to 0-5 °C followed by drop wise addition of piperidine at 0-5 °C. Then acid chloride was added to the reaction mass at -5 to 5 °C. The reaction mass was maintained at -5 to 5 °C for 15–30 minutes. The temperature was allowed to raised up to 25-35 °C. The reaction mass was maintained for 6-8 hrs and allowed to settle. The organic and aqueous layer was separate. The aqueous layer was extracted with MDC. The combined organic layers were washed with water. The organic layer was dried over with sodium sulphate. The organic layer was cooled to 0-5°C and slowly AlCl3 was added portion wise at 0-5 °C. The reaction mass was maintained at 0-5 °C for 30 minutes. Chloro acetyl chloride was added into the reaction mass at 0-5 °C. The temperature was raised to 25-30 °C. The reaction mass was maintained for 4-5 hrs at 25-30 °C. The reaction mass was quenched in ice cold water below 10 °C. The organic and aqueous layer was separated. The aqueous layer was extracted with MDC. Both organic layers were combined and distilled out completely to obtain crude compound. Ethyl acetate and heptane were charged into the crude and the reaction mass was cooled to -20 to -30 °C. The reaction mass was maintained for 2 hrs at -20 to -30 °C and the obtained solid was filtered and washed with heptane. The compound was purified in ethyl acetate and heptane to obtain 2-(4-(2-chloroacetyl)phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one.
Example-2: Preparation of 2-(4-(2-chloroacetyl)phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one:
Dichloromethane (3.0 L) and 2-methyl-2-phenyl propionic acid (600.0 g) was charged into the RBF at room temperature. The reaction mixture was stirred for 10-15 minutes. Then slowly DMF (30.0 mL) was added followed by thionyl chloride (652.0 g) into the reaction mass at 25-35°C under nitrogen atmosphere. The reaction mass was maintained for 1-2 hrs at 25-35°C. The solvent was completely distilled under the atmospheric pressure and co-distil with MDC (600.0 mL). MDC (3.0 L) was charged to the residue. In another RBF, sodium carbonate solution (465.0 g in 3.0 L DM water) was prepared and cooled to 0-5oC. Piperidine (374.0 g) was charged slowly at 0-5oC. Acid chloride was added to reaction mass at -5 to 5oC. The reaction mass was maintained for 15–30 minutes at -5 to 5oC. The temperature was raised to 25-35oC and maintained for 6-8 hrs. The reaction mass was settled for 10-15 minutes. Organic and aqueous layers were separated. Aqueous layer was extracted with MDC (1.4 L). The combined organic layer was washed with water. Organic layer was dried over sodium sulphate (300.0 g) and cooled to 0-5oC. AlCl3 (1.56 kg) was added slowly portion wise at 0-5oC. The reaction mass was maintained at 0-5 oC for 30 minutes. Chloro acetyl chloride (1.14 kg) was added slowly into the reaction mass at 0-5oC. The temperature was raised to 25-30oC. The reaction mass was maintained for 4-5 hrs at 25-30oC. Quenched the reaction mass in ice cold water at below 10 oC. Organic and aqueous layers were separated. The aqueous layer was Extract with MDC (1.5L). Both organic layers were combined and distilled out completely. Crude was obtained. Charged ethyl acetate (540.0 mL) and heptanes (900.0 mL) into the crude and cooled the reaction mass to -20 to -30oC. Maintained the reaction mass for 2 hrs at -20 to -30oC. Filtered the solid and washed with heptane. Purified the compound in ethyl acetate and heptane then filtered to obtain 2-(4-(2-chloroacetyl)phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one.
Yield: 672.0 g

Example 3: Preparation of 2-(4-(2-chloroethyl) phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one:
2-(4-(2-chloroacetyl)phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one was dissolved in dichloromethane in a round bottom flask at room temperature at 0-5 °C. AlCl3 was added portion wise at 0-5°C. The reaction mass was maintained at 0-5 °C for 30 minutes. 1,1,3,3-tetramethyldisiloxane was added slowly in 30–60 minutes and the reaction mass was maintained for 4-5 hrs at 0-5°C. The reaction mass was quenched in ice cold water below 10 °C. The organic and aqueous layer were Separated and the aqueous layer was extracted with MDC. The Combined organic layers were washed with sodium carbonate solution followed by NaCl solution. The organic layer was distilled out completely under vacuum at 50 °C. The reaction mass was cooled to 25-35°C. The reaction was charged with cyclohexane and stirred for 10-15 minutes. The cyclohexane layer was passed through silica bed and the bed was washed with mixture of cyclohexane and ethyl acetate. The solvent was completely distilled out under vacuum to obtain 2-(4-(2-chloroethyl) phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one.

Example 4: Preparation of 2-(4-(2-chloroethyl) phenyl)-2-methyl-1-(piperidin-1-yl) propan-1-one:
Dichloromethane (6.6L) and 2-(4-(2-chloroacetyl)phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one (660.0 g) were charged into the RBF at room temperature. The reaction mixture was cooled to 0-5oC. AlCl3 (844.0 g) was added portion wise at 0-5oC and maintained the reaction mass at 0-5 oC for 30 minutes. 1,1,3,3-tetramethyl disiloxane (TMDS) (396.0 g) was added in 30–60 minutes. The reaction mass was maintained for 4 - 5 hrs at 0-5oC. Quenched the reaction mass in ice cold water (6.6 L) at below 10 oC. The Organic and aqueous layers were seperated. The aqueous layer was extracted with MDC (660.0 mL). Both organic layers combined and washed with sodium bicarbonate solution (660g in 6.6 L Dm water) followed by NaCl solution (660.0 g in 6.6 L DM water). The organic layer was distilled completely under the reduced pressure at 50oC. The reaction mass was cooled to 25-35oC. Cyclohexane (660.0 mL) was charged and stirred for 10-15 minutes. Filtered the cyclohexane layer through silica bed (3.3 Kg). Washed the bed with mixture of cyclohexane (12.0 L), ethyl acetate (1.3 L) and cyclohexane (3.3 L). The solvent was distilled out completely under vacuum to obtain 2-(4-(2-chloroethyl) phenyl)-2-methyl-1-(piperidin-1-yl) propan-1-one.
Yield: 566.0 g (89.6%)

Example 5: Preparation of 2-(4-(2-bromoethyl) phenyl)-2-methylpropanoic acid:
To 2-(4-(2-chloroethyl)phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one was added mixture of 33 % HBr in acetic acid and Aq HBr in a round bottomed flask. The temperature was raised to 95-100°C and the reaction mass was maintained at 95-100°C for 24-28 hrs. The reaction mass was cooled to 25-30 °C followed by addition of DM water into the reaction mass. The reaction mass was extracted with MDC. The organic and aqueous layers were separated. The aqueous layer was extracted with MDC. The combined organic layers were washed with water and the organic layer was dried with sodium sulphate. The organic layer was distilled out completely under vacuum. The obtained crude compound was purified in ethyl acetate and cyclohexane to obtain 2-(4-(2-bromoethyl) phenyl)-2-methylpropanoic acid.

Example 6: Preparation of 2-(4-(2-bromoethyl) phenyl)-2-methylpropanoic acid:
2-(4-(2-chloroethyl)phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one (270.0 g) and mixture of 33% HBr in acetic acid (1.35 L) and aqueous HBr (0.4 L) was charged into the RBF. The temperature was raised to 95-100oC and maintained the reaction mass at 95-100oC for 24-28 hrs. The reaction mass was cooled to 25-30oC. DM water (2.7 L) was charged into the reaction mass. The reaction mixture was extracted with MDC (2.0 L). Organic and aqueous layers were separated. Extracted the aqueous layer with MDC (540mL). Both organic layers were combined and wash with water. The organic layer was dried with sodium sulphate (100.0 g). Activated carbon (54.0 g) was charged to the organic layer and stirred for 30 minutes at 25-30oC. Filtered the organic layer through Hyflow bed. The organic layer was distilled out completely under vacuum. The compound was purified in ethyl acetate (80.0 mL) and cyclohexane(445.0 mL) to obtain 2-(4-(2-bromoethyl) phenyl)-2-methylpropanoic acid.
Yield:147.0 g (59%)

Example 7: Preparation of 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole:
Dimethyl sulfoxide, Sodium hydroxide and tert-butyl 4-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (BLS Int-I) was charged into the RBF at 25-35°C. Charge Sodium iodide into the reaction mass at 25-35 °C. 2-ethoxyethyl methane sulfonate (BLS Int-II) was added in to the reaction mass at 25-35 °C. The temperature in the reaction mass was raised to 65-75°C. The reaction mass was maintained for 12-14 hrs at 65-75°C. The reaction mass was then cooled to 10-20°C. DM Water Lot-I was charged in to the reaction mass at 10-20°C. Slowly, Hydrochloric acid was charged into the reaction mass and maintained at below 25°C. The temperature was raised to 25-35°C and the reaction mass was stirred for 4-6 hrs at 25-35°C. C. The reaction mass was washed with Dichloromethane and cooled to 10-15°C. The pH was adjusted to 7.0–8.5 with sodium hydroxide at below 35°C and the reaction mass was maintained at 25-35°C for 1-2 hrs. Dichloromethane was charged in to the reaction mass at 25-35°C and stirred for 20-30 min at 25-35°C. The reaction mass was allowed to settle for 1-2 hrs at 25-35°C and both the organic & aqueous layer were separated. Sodium chloride was charged to aqueous layer into the RBF at 25-35°C. Dichloromethane was again added into the reaction mass at 25-35°C and stirred for 45-60 min at 25-35°C. The reaction mass was allowed to settle for 1-2 hrs at 25-35°C. The reaction mass was filtered through Hyflow bed and washed the Hyflow bed with Dichloromethane. The reaction mass was stirred for 45-60 min at 25-35°C and the reaction mass was allowed to settle for 1-2 hrs at 25-35°C. Both the organic & aqueous layers were separated and the aqueous layer was extracted with Dichloromethane and the organic layer were dried over sodium sulphate. The organic layer was distilled at 35-40 °C under vacuum and the remaining solvent was distilled at 50°C. Co-distil with acetone and heat the reaction mass at 55-60°C. The reaction mass was maintained for 30-45 min at 55-60°C. The reaction mass was cooled at 30±5°C and the reaction mass was maintained for 30-45 min at 25-35°C. The reaction mass was filtered and washed with acetone to obtain 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole.

Example 8: Preparation of 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole:
Dimethyl sulfoxide (1.2 L), sodium hydroxide (180.0 g) and tert-butyl 4-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (1.2 Kg) were charged into the RBF at 25-35 °C. Sodium iodide (0.12 Kg) and 2-ethoxyethyl methane sulfonate (940.0 g) were charged into the reaction mass at 25-35 °C. The temperature of the reaction mass was raised to 65-75°C and maintained the reaction mass for 12-14 hrs at 65-75°C. The reaction mass was cooled to 10-20°C. DM water (3.6 L) was charged into the reaction mass at 10-20°C. Hydrochloric acid (2.4 L) was charged slowly into the reaction mass at below 25°C. The temperature was raised to 25-35°C and maintained the reaction mass for 4-6 hrs at 25-35°C. The reaction mass was washed with dichloromethane (2.4 L). The reaction mass was cooled tp 10-15°C. The pH was adjusted to 7.0 – 8.5 slowly with sodium hydroxide (780.0 g) at below 35°C. Maintained the reaction mass at 25-35°C for 1-2 hrs. Dichloromethane (2.4 L) was charged into the reaction mass at 25-35°C. The reaction mass was stirred for 20-30 min at 25-35°C and settled for 1-2 hrs at 25-35°C. The organic and aqueous layers were separated. The organic layer was distilled out at 35-40 °C under reduced pressure and co-distilled with acetone (1.2 L). The reaction mass was cooled to 25-35°C. Filtered the reaction mass and washed with Acetone (1.2 L) to obtain 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole.
Yield: 640.0 g (59 %)

Example 9: Preparation of 2-(4-(2-(4-(1-(2-ethoxyethyl)-1Hbenzo[d]imidazol-2-yl)piperidin-1-yl)ethyl) phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one:
Sodium carbonate, MIBK and DM water was charged into the RBF and stirred for 10-15 minutes. Then 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1 H-benzo[d]imidazole, 2-(4-(2-chloroethyl) phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one and TBAB were charged into the RBF. The temperature was raised to 95-100 oC. The reaction mass was maintained at 95-100 oC for 24 hrs. The reaction mass was cooled to 25-30 oC. DM water was charged into the reaction mass and stirred for 30-60 minutes. The organic and aqueous layers were separated and the organic layer was extracted with aqueous HCl. The aqueous layer was washed with MIBK. The pH of the aqueous was adjusted to 7.0-9.0 with aqueous sodium carbonate solution. The aqueous layer was extracted with MDC. Organic layers were washed with water. The organic layer was distilled out completely at below 50 oC under vacuum to obtain crude compound 2-(4-(2-(4-(1-(2-ethoxyethyl)-1Hbenzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one.

Example 10: Preparation of 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methyl -1-morpholinopropan-1-one:
Sodium carbonate (10.0 g), DM water (8.0 mL) and MIBK (90.0 mL) were charged into the RBF. Stired the reaction mixture for 10 minutes. 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole (15.0 g) and 2-(4-(2-chloroethyl)phenyl)-2-methyl-1-morpholinopropan-1-one (17.0 g) were added slowly at 25 -30 oC. The reaction mass was heated to to 95-100 oC and maintained for 28 hrs. DM water (75.0 mL) was added slowly and stirred for 10 mins. The aqueous and organic layers were separated and washed the organic layer with water. The organic layer was washed with dilute HCl (15mL in 45 mL DM water). Washed the aqueous layer with MIBK (50.0 mL). The aqueous layer and organic layer were separated. Washed the organic layer with MDC (75.0 mL) then separated the aqueous layer and organic layer. The pH to 7-9 of the aqueous layer was adjusted with sodium carbonate solution(15g in 30 mL Dm water). Extracted the compound with MDC (5.0 mL). The aqueous and organic layers were separated. Washed the organic layer with brine solution (15g in 150mL DM water). The aqueous and organic layers were separated. Distilled out the organic layer under vacuum at 50-55 oC to obtain 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methyl -1-morpholinopropan-1-one.
Yield: 11.0 g (41%)

Example 11: Preparation of 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one:
Sodium carbonate (15.0 g), DM water (10.0 mL) and MIBK (100.0 mL) were added into the RBF. Stirred the reaction mixture for 10 min. 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole (19.0 g), 2-(4-(2-chloroethyl)phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one (20.0 g) and TBAB (1.1 g) were added at 25 -30 °C. The reaction mass was heated to 100-110 oC and maintained for 36 hrs. Dilute HCl (19mL in 30mL DM water) was charged and stirred for 10 min. The aqueous layer and organic layer were separated. Adjusted aqueous layer pH to 7-9 with sodium carbonate solution (17.0 g in 54.0 mL DM water). Extracted the compound with MDC (75.0 mL). The aqueous layer and organic layer were separated. The organic layer was washed with water (100mL). The aqueous layer and organic layer were separated. Distilled out the organic layer under vacuum at 50-55 oC to obtain2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one.
Yield: 15.0 g

Example 12: Preparation of 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl) phenyl) -2-methylpropanoic acid (Bilastine Crude):
2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methyl-1-morpholinopropan-1-one (1.0 g) and dilute HCl (10.0 mL) were charged into the RBF. The reaction mass was stirred for 15 minutes. The reaction mass was heated to 110-115 °C and maintained the temperature for 36 hrs. The reaction mass was cooled to 25 -30 oC slowly. Washed the reaction mass with MDC (5.0 mL) and separated the aqueous layer and organic layer. Adjusted the aqueous layer pH to 6-7 with potassium carbonate solution and stirred for 10 min. The compound was extracted with MDC (5.0 mL). The aqueous layer and organic layer were separated. The organic layer was washed with water (10.0 mL). The aqueous layer and organic layer were separated. The organic layer was distilled out under vacuum at 50-55 oC to obtain Bilastine crude compound [Formula (I)].
Yield: 165.0 mg

Example 13: Preparation of 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methyl propanoic acid (Bilastine Crude):
2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one (1.0 g) and HCl (5.0 mL) were charged into the RBF The reaction mass was heated to 100 °C and maintained for 48 hrs. TLC was checked and adjusted the reaction mass pH to 5-7 with sodium hydroxide solution. Stirred the reaction mass for 30 mins. Filtered the solid to obtain Bilastine crude compound [Formula (I)].
Yield: 100.0 mg

Example 14: Preparation of 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl) phenyl)-2-methylpropanoic acid (Formula I):
2-(4-(2-(4-(1-(2-ethoxyethyl)-1Hbenzo[d]imidazol-2-yl)piperidin-1-yl)ethyl) phenyl)-2-methyl-1-(piperidin-1-yl)propan-1-one was charged into the RBF. Added Aq HCl solution slowly into the RBF. Raised the temperature to 95-100oC. Maintained the reaction mass at 95-100oC for 24-28 hrs. Cooled the reaction mass to 25-30 oC. Charged DM water into the reaction mass. Adjusted the pH to 5.0-7.0 with NaOH solution. Stirred for 1hrs. Filtered the solid. An off white solid is formed 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoic acid (Formula I).

Example 15: Preparation of methyl 2-(4-(2-bromoethyl)phenyl)-2-methylpropanoate:
2-(4-(2-bromoethyl)phenyl)-2-methylpropanoic acid and methanol was charged into the RBF. Stirred the reaction mixture for 10-15 minutes. Added sulphuric acid slowly. Raised the reaction mass temperature to 50-60oC. Maintained the reaction mass at 50-60oC for 8- 10 hrs distilled out the methanol completely. Charged DM water and ethyl acetate into the reaction mass. Separated organic and aqueous layer. Distilled out organic layer completely under vacuum to obtain methyl 2-(4-(2-bromoethyl)phenyl)-2-methylpropanoate.

Example 16: Preparation of methyl 2-(4-(2-bromoethyl)phenyl)-2-methylpropanoate:
2-(4-(2-bromoethyl)phenyl)-2-methylpropanoic acid (140.0 g) and methanol (1.4 L) were charged into the RBF. Stirred the reaction mass for 10-15 minutes. Sulphuric acid (29.0 mL) was added slowly. The reaction mass temperature was raised to 50-60oC and maintained at 50-60oC for 8- 10 hrs. The methanol was distil out completely. DM water (1.4 L) and ethyl acetate (560.0 mL) was charged into the reaction mass. Organic and aqueous layers were separated. The organic layer was distil out completely under vacuum to obtain methyl 2-(4-(2-bromoethyl)phenyl)-2-methylpropanoate.
Yield:138.0 g (93.5%)

Example 17: Preparation of Bilastine API (Form A):
Method-I:
To the compound of 2-(4-(2-(4-(1-(2-Ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methyl propanoic acid (Bilastine Crude) (50.0 g), was charged methanol (1250.0 mL) under nitrogen. The reaction mass was heated to 60-65 ºC and maintain for 1.30 hr –2 hrs. Cooled the reaction mass slowly to 25-35ºC and maintained for 10 h at 25-35ºC. Filtered the reaction mass and washed the wet compound with methanol (50 mL). The material was dried at 65-70ºC for 10-12 hrs to obtained Bilastine Form-A characterised by X-ray powder diffraction pattern having peaks at 3.63, 10.42, 11.15, 12.36, 13.94, 14.14, 14.95, 15.33, 16.15, 17.04, 17.98, 18.31, 18.77, 19.58, 20.96, 22.02, 22.60, 24.72 and 42.29 ± 0.2 2? values.
Yield: 35.0 g (70%)

Method-II:
To the compound of 2-(4-(2-(4-(1-(2-Ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methyl propanoic acid (Bilastine Crude) (45.0 g), was charged isopropyl alcohol/methanol (10:20 vol). The reaction mass was heated to 60-65 °C and maintained for 1.30 h – 2 h. Cooled the reaction mass to 25-35ºC and maintain for 22-24 h at 25-35ºC. Filtered the reaction mass and washed the wet compound with methanol (45mL). The material was dried at 65-70ºC for 10-12 hrs to obtained Bilastine Form-A characterised by X-ray powder diffraction pattern having peaks at 3.63, 10.42, 11.15, 12.36, 13.94, 14.14, 14.95, 15.33, 16.15, 17.04, 17.98, 18.31, 18.77, 19.58, 20.96, 22.02, 22.60, 24.72 and 42.29 ± 0.2 2? values. Yield: 40.0 g (88%)

Example 18: Preparation of Bilastine API (Form B):
Method-I:
To the compound of 2-(4-(2-(4-(1-(2-Ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)-2-methyl propanoic acid (Bilastine Crude) (50.0 g), was charged n-Butanol (400.0 mL) to the reaction mass under nitrogen. The reaction mass was heated to 105-115ºC and maintained for 30-45 min at 105-115ºC. The reaction mass was cooled to 85-95ºC and maintained the reaction mass for 1-2 hr at 85-95ºC. Cooled the reaction mass to 25-35ºC and maintain for 30-45 min at 25-35ºC. Filtered the reaction mass. The material was dried at 65-70ºC for 10-12 hrs to obtained Bilastine Form-B, characterized by X-ray powder diffraction pattern having peaks at 3.76, 10.60, 11.2, 12.44, 14.07, 14.25, 15.10, 16.28, 17.14, 17.41, 18.44, 18.94, 19.72, 21.14, 22.19, 22.78, 24.91, and 29.16 ± 0.2 2? values.
Yield: 36.0 g

,CLAIMS:We Claim:
1. Novel intermediate compounds of Formula (IV)

Formula (IV)
wherein Lg represents leaving group; wherein R1 and R2 together to form a cyclic heterocyclic ring.
2. Novel intermediate compounds of Formula (V)

Formula (V)
wherein Lg represents leaving group; wherein R1 and R2 together to form a cyclic heterocyclic ring.
3. A process for the preparation of novel intermediate compound of Formula (IV) as claimed in claim 1,

Formula (IV)
wherein Lg represents leaving group; wherein R1 and R2 together to form a cyclic heterocyclic ring, wherein the process comprises the steps of:
a) reacting intermediate compound of formula (II)

Formula (II)
wherein Lg represents leaving group;
with in presence of base and a suitable solvent to obtain an intermediate compound of Formula (III), and

Formula (III)
wherein R1 and R2 are as defined above
b) converting intermediate compound of Formula (III) to produce the intermediate compound of Formula (IV).
4. A process for preparation of novel intermediate compound of Formula (V) as claimed in claim 2,

Formula (V)
wherein Lg represents leaving group; wherein R1 and R2 together to form a cyclic heterocyclic ring; wherein the process comprises the steps of:
a) reacting intermediate compound of formula (II)

Formula (II)

wherein Lg represents leaving group;

with using base and a suitable solvent to obtain an intermediate compound of Formula (III),

Formula (III)
wherein R1 and R2 are as defined above
b) converting intermediate compound of Formula (III) to produce the intermediate compound of Formula (IV), and

Formula (IV)

wherein Lg represents leaving group; wherein R1 and R2 are as defined above
c) reducing compound of Formula (IV) optionally in presence of lewis acid to produce compound of Formula (V).
5. An improved process for the preparation of compound of Formula (VI)

Formula (VI)
wherein Lg represents leaving group; and R is H or C1-C3 alkyl; the process comprising the steps of:
a) reacting intermediate compound of Formula (II)

Formula (II)
with in presence of base and a suitable solvent to obtain an intermediate compound of Formula (III),

Formula (III)
wherein R1 and R2 together to form a cyclic heterocyclic ring
b) converting intermediate compound of Formula (III) to produce the intermediate compound of Formula (IV),
Formula (IV)
wherein Lg represents leaving group; and R1 and R2 are as defined above
c) reducing compound of Formula (IV) optionally in presence of lewis acid to produce compound of Formula (V), and
Formula (V)
wherein Lg represents leaving group; and R1 and R2 are as defined above
d) hydrolyzing compound of Formula (V) in presence of organic or inorganic acid or mixture to produce compound of Formula (VI) and optionally converting to compound of Formula (VI), wherein R is alkyl.
6. An improved process for the preparation of compound of Formula (I),

Formula (I)
wherein, the process comprises the steps of:
a) coupling intermediate compound of Formula (IV)

Formula (IV)
wherein Lg represents leaving group; and R1 and R2 together to form a cyclic heterocyclic ring;
with compound of Formula (VII)

Formula (VII)
to obtain an intermediate compound of Formula (VIII),
Formula VIII
wherein R1 and R2 together to form a cyclic heterocyclic ring
b) reducing the intermediate compound of Formula (VIII) to produce the intermediate compound of Formula (IX),

Formula (IX)
wherein R1 and R2 together to form a cyclic heterocyclic ring
c) hydrolyzing the compound of Formula (IX) to produce compound of Formula (I).
7. An improved process for preparation of compound of Formula (I),

Formula (I)
wherein the process comprises the steps of:
a) condensing the obtained compound of Formula (V)
Formula (V)
wherein Lg represents leaving group; wherein R1 and R2 together to form a cyclic heterocyclic ring,
with the compound of Formula (VII)
Formula (VII)
to produce compound of Formula (IX), and

b) hydrolyzing compound of Formula (IX) to produce compound of Formula (I).
8. An improved process for preparation of compound of Formula (I),

Formula (I)
wherein the process comprises the steps of:
a) reacting intermediate compound of Formula (II)

Formula (II)
wherein Lg represents leaving group; with in presence of base and a suitable solvent to obtain an intermediate compound of Formula (III),

Formula (III)
wherein R1 and R2 together to form a cyclic heterocyclic ring
b) converting intermediate compound of Formula (III) to produce the intermediate compound of Formula (IV),
Formula (IV)
wherein Lg represents leaving group; wherein R1 and R2 together to form a cyclic heterocyclic ring
c) reducing compound of Formula (IV) optionally in presence of lewis acid to produce compound of Formula (V),
Formula (V)
wherein Lg represents leaving group; wherein R1 and R2 as defined above
d) condensing the obtained compound of Formula (V) with the compound of Formula (VII),
Formula VII
to produce compound of Formula (IX), and

wherein R1 and R2 as defined above
e) hydrolyzing compound of Formula (IX) to produce compound of Formula (I).
9. Novel crystalline Form A of Bilastine which is characterized by X-ray powder diffraction pattern having peaks at 11.2, 12.3, 14.9, 16.17, 17.03, 18.8, 19.5, 19.6 and 21.03 ± 0.2º 2? values.
10. The novel crystalline Form A of Bilastine as claimed in claim 9 further characterized by X-ray powder diffraction pattern having peaks at 3.68, 7.4, 10.4, 11.2, 12.3, 14, 14.6, 14.9, 15.3, 16.17, 17.03, 17.9, 18.3, 18.8, 19.5, 19.6, 20.09, 21.03, 22.1, 22.5, 22.6, 22.9, 23.1, 24, 24.4, 24.7, 25.6 and 26.3 ± 0.2º 2? values.
11. A process for preparation of novel crystalline Form A of Bilastine as claimed in claim 9, wherein the process comprises:
a) dissolving Bilastine crude into an alcohol solvent or mixture of solvents,
b) heating the reaction mass to 60-65 ºC and maintaining the temperature for 1.30 hr –2 hrs,
c) cooling the reaction mass to 25-35ºC and maintain for 22-24 hrs at 25-35ºC,
d) filtering the reaction mass followed washing the wet compound with alcohol solvent, and
e) drying the material at 65-70ºC for 10-12 to obtained Bilastine Form-A.
12. Novel crystalline Form B of Bilastine which is characterized by X-ray powder diffraction pattern having peaks at 9.2, 12.7, 15.6, 17.6, 18.3 and 19.9 ± 0.2º 2? values.
13. The novel crystalline Form B of Bilastine as claimed in claim 12 further characterized by X-ray powder diffraction pattern having peaks at 6.42, 9.2, 9.5, 10.8, 12.7, 13.48, 14.8, 15.6, 16.03, 16.9, 17.6, 18.3, 18.8, 19.9, 21.2, 21.9, 22.3, 24, 25.3 and 26.2 ± 0.2º 2? values.
14. A process for preparation of novel crystalline Form B of Bilastine as claimed in claim 12, wherein the process comprises:
a) dissolving Bilastine crude into an alcohol solvent or mixture of solvents,
b) heating the reaction mass to 105-115ºC and maintained for 30-45 min at 105-115ºC,
c) cooling the reaction mass to 85-95ºC and maintained the reaction mass for 1-2 hrs at 85-95ºC,
d) further cooling the reaction mass to 25-35ºC and maintain for 30-45 min at 25-35ºC,
e) filtering the reaction mass followed, and
f) drying the material at 65-70ºC for 10-12 to obtained Bilastine Form-B.
15. The reducing agent used as herein in claims 4, 5, 6 and 8 is selected from but not limited to silanes such as trimethylsilane, triethylsilane; siloxane such as tetramethyldisiloxane optionally in combination with a suitable Lewis acid or trifluoroacetic acid or BF3-etherate; trichlorosilane, sodium borohydride optionally in combination with BF3-etherate, diborane, potassium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminium hydride, diisobutylaluminium hydride (DIBAL), lithium triethylborohydride (LiEt3BH), L-selectride (lithium tri-sec-butyl(hydrido)borate(l-)), sodium bis(2-methoxyemoxy)aluminiumhydride (vitride) and the like.
16. The lewis acid used as claimed in claims 4, 5, 8 and 15 is selected from hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, 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.
17. The Lg represents a suitable leaving group used as herein in claims 1-8 is selected from chlorine, bromine, iodine, fluorine, amino acid, substituted or unsubstitutedaryloxy, alkoxyalkyloxy, aryloxyalkyloxy, C1 to C4 alkoxy, sulfonate esters, mono, di, or triphosphate ester, trityl, monomethoxy-trityl, trialkylsilyl, isopropyldialkylsilyl, alkyldiisopropylsilyl, triisopropylsilyltetraisopropyldisilyl, t-butyldialkylsilyl or t-butyldiphenylsilyl or trifluoroacetate or alkylsulfonyloxy group such as methanesulfonyloxy and the like or trifluoroalkylsulfonyloxy such as a trifluoromethanesulfonyloxy and the like or arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, o-nitrobenzenesulfonyloxy, fluorosulfonyl, camphorsulfonyl and the like or phenoxides such as pentafluorophenoxide, p-NO2-phenoxide and the like or thio phenyls and the like or 2,2-dimethyl-3-(3-(trifluoromethyl)phenyl)propanoyl chloride and the like; bicyclic compounds such as indole, benzotriazoles or tricyclic compounds.
18. The alkyl group represents C1-C3 alkyl used as herein in claim 5 is selected from methyl, ethyl, propyl or isopropyl.
19. The hydrolyzing agent used as herein in claims 5, 6, 7 and 8 is selected from 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 or mixture thereof.
20. The solvent used as herein in claims 3, 4, 5, 8, 11 and 14 is 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, methyl isobutyl 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.
21. The base used as herein in claims 3, 4, 5 and 8 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.

Dated this Tenth (10th) day of June, 2020

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