Field of the Invention:

The present invention provides novel processes for the preparation of 2-[4-(2-{4-[l-(2- ethoxyethy])-lH-benzimida2ol-2-y]]-l-piperidinyl}ethy])pheny]]-2-methylpropanoic acid represented by the following structural formula-1. The present invention also provides novel intermediate compounds useful for the preparation of compound of formula-1.

Background of the Invention:

2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl}ethyl)phenyl]-2-methylpropanoic acid, commonly known as Bilastine is an antihistamine drug for the treatment of allergic rhinoconjunctivitis and urticaria (hives). It exerts its effect as a selective histamine HI receptor antagonist and has potency similar to cetirizine and is superior to Fexofenadine. US5877187A first discloses the synthesis of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl}ethyl)phenyl]-2-methylpropanoic acid. The process disclosed in the said patent is schematically represented in scheme-A. Scheme-A: The disclosed process involves the preparation of an oxazole intermediate compound followed by cleavage of the said oxazole ring by treating it with 3N hydrochloric acid, which makes the whole process complicated. Further, the synthesis of the said oxazole intermediate involves the reaction of the benzimidazole intermediate with tosylated oxazole intermediate in presence of sodium carbonate as shown in scheme-A. If we observe the structure of the benzimidazole intermediate, there are two active hydrogens present in the compound. Among the two, one is present on one of the nitrogens of the benzimidazole moiety and the other is present on nitrogen atom of the piperidine ring. Whenever the benzimidazole intermediate is reacted with the oxazole intermediate, there is much chance for the formation of the bi-products along with the required compound.

In view of all these disadvantages the disclosed process is inefficient to produce 2-[4-(2-{4-[ 1 -(2-ethoxyethyl)-1 H-benzimidazol-2-yl]-1 -piperidinyl }ethyl)phenyl]-2-methyIpropanoic acid on industrial scale. Hence, there is a significant need in the art to develop a novel process for the preparation of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl}ethyl)phenyl]-2-methyl propanoic acid The present inventors overcome all the disadvantages associated with the prior-art processes by adopting a novel process for the preparation of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]-l -piperidinyl }ethyl)phenyl]-2-methylpropanoic acid.

Brief description of the invention:

The first aspect of the present invention is to provide a novel process for the preparation of 2-[4-(2- {4-[ 1 -(2-ethoxyethyl)-1 H-benzimidazol-2-yl]-1 -piperidinyl }ethyl)phenyl]-2-methyl propanoic acid compound of formula-!. The second aspect of the present invention is to provide a process for the preparation of 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-8. The third aspect of the present invention is to provide a novel process for the preparation of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl}ethyl)phenyl]-2-methyl propanoic acid compound of formula-1. The fourth aspect of the present invention is to provide a novel process for the preparation of 2-[4-(2-{4-[l -(2-ethoxyethyl)- lH-benzimidazol-2-yl]-l-piperidinyl}ethyl) phenyl]-2-methyl propanoic acid compound of formula-1. The fifth aspect of the present invention is to provide a process for the preparation of 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl)piperidin-l-yl)ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-10. The sixth aspect of the present invention is to provide a process for the preparation of 2-(4-(2-(4-( 1 -(2-ethoxyethyl)-l H-benzo[d]imidazol-2-yl)piperidin-1 -yl)ethyl)phenyl)-N-methoxy-N,2-dimethy]propanamide compound of formula-10.

The seventh aspect of the present invention is to provide a process for the preparation of 2-(4-(2-(4-(l -(2-ethoxyethyl)-1 H-benzo[d]imidazol-2-yl)piperidin-1 -yl)-1 -hydroxyethyl)phenyl) -N-methoxy-N,2-dimethylpropanamide compound of formula-12. The eighth aspect of the present invention is to provide a process for the preparation of 2-(4-(2-(4-( 1 -(2-ethoxyethyl)-1 H-benzo[d] imidazol-2-yl)piperidin-1 -yl)ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-10. The ninth aspect of the present invention is to provide a process for the preparation of 2-(4-(2-(4-(lH-benzo[d]imidazol-2-yl)piperidin-l-yl)ethyl)phenyl)-N-methoxy-N]2-dimethyl propanamide compound of formula-14. The tenth aspect of the present invention is to provide a process for the preparation of 2-(4-(2-hydroxyethyl)phenyl)-N-methoxy-N,2-dimethyIpropanamide compound of formula-15. The eleventh aspect of the present invention is to provide novel intermediate compounds ■ which are useful in the synthesis of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl}ethyl)phenyl]-2-methyl propanoic acid compound of formula-1. The twelfth aspect of the present invention is to provide a process for the preparation of 2-(4-(2-(4-( 1 -(2-ethoxyethyl)-1 H-benzo[d]imidazol-2-yl)piperidin-1 -y!)ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-10,

Detailed description of the Invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, petroleum ether (pet ether), benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyi acetate, n-butyl acetate, iso-butyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsuifoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetra chloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, t-butanol, ethane- 1,2-diol, propane-1,2-diol and the like; "polar solvents" such as water; formic acid, acetic acid or their mixtures.

The term "suitable base" refers to inorganic bases selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia, alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tert.butylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyc!o[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), N-methyl morpholine, l,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine, lithium diisopropylamide; organolithium bases like n-butyllithium, organosilicon bases such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide or their mixtures.

The first aspect of the present invention provides a novel process for the preparation of 2-[4-(2-{4-[ 1 -(2-ethoxyethyl)-1 H-benzimidazol-2-yl]-1 -piperidinyl }ethyl)phenyl]-2-methyl propanoic acid compound of formula-1, comprising of;

a) Hydrolyzing the methyl 2-methyl-2-phenylpropanoate compound of formula-2 in presence of suitable base in a suitable solvent to provide 2-methyl-2-phenylpropanoic acid of formula-3,

b) reacting the compound of formula-3 with a suitable chlorinating agent in a suitable solvent to provide 2-methyl-2-phenylpropanoyl chloride compound of formula-4,

c) reacting the compound of formula-4 with N,0-dimethylhydroxylamine hydrochloride in presence of a suitable base in a suitable solvent to provide N-methoxy-N,2-dimethyl-2-phenylpropanamide compound of formula-5,

d) reacting the compound of formula-5 with chloroacetyl chloride in presence of a Lewis acid in a suitable solvent to provide 2-(4-(2-chloroacetyi)phenyl)-N-methoxy-N,2-dimethyl propanamide compound of formula-6,

e) reducing the compound of formula-6 with a suitable reducing agent in presence or absence of a suitable solvent to provide 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethyl propanamide compound of formula-8,

f) reacting the compound of formula-8 with l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole compound of formu!a-9 in presence of a suitable base in a suitable solvent optionally in presence of a suitable catalyst to provide 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo^Jimidazol^-yOpiperidin-l-yOethyOphenyO-N-methoxy-N^-dimethylpropan amide compound of formula-10,

g) hydrolyzing the compound of formula-10 in presence of a suitable acid or a suitable base optionally in presence of a suitable solvent to provide compound of formula-1.

Wherein, in step-a) the suitable base is selected from hydroxides, alkoxides, carbonates and bicarbonates of alkali metals; In step-b) the suitable chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous trichloride, phosphorous pentachloride; In step-c) the suitable base is selected from but not limited to organic bases, inorganic bases such as carbonates, bicarbonates, hydroxides, alkoxides, hydrides, acetates and amides of alkali and alkali earth metals; In step-d) the Lewis acid is selected from but not limited to aluminum chloride, aluminum bromide, boron trifluoride, boron tribromide, tin tetrachloride, tin tetrabromide, stannous chloride (SnCb), ferric chloride (FeCb), zinc chloride (ZnCb), titanium tetrachloride (TiCLi) or mixtures or hydrates thereof; In step-e) the suitable reducing agent is selected from but not limited to trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with a suitable Lewis acid or trifluoroacetic acid or BF3-etherate; trichlorosilane, sodium borohydride optionally in combination with BF3-etherate or Lewis acid or trifluoroacetic acid, diborane, potassium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminium hydride, diisobutylaluminium hydride (DIBAL), lithium triethylborohydride (LiEt3BH), L-selectride (lithium tri-sec-butyl(hydrido)borate( 1 -)), sodium bis(2-methoxyethoxy)aluminiumhydride (vitride)and the like;

In the present invention the reduction of ketone compound of formula-6 to compound of formula-8 can also be done by using diphenylsilane, tetramethyl disiloxane (TMDS), Clemmensen reduction or Wolff-Kishner reduction. In step-f) the suitable base is selected from but not limited to organic bases, inorganic bases such as carbonates, bicarbonates, hydroxides, alkoxides, hydrides, acetates and amides of alkali and alkali earth metals; the suitable catalyst is selected from alkali metal halides such as sodium bromide, sodium iodide, potassium bromide, potassium iodide and the like; In step-g) the suitable acid is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; the suitable base is selected form hydroxides, alkoxides, carbonates and bicarbonates of alkali metals; In step-a) to step-g) the suitable solvent is selected from chloro solvents, ketone solvents, ether solvents, ester solvents, hydrocarbon solvents, alcohol solvents, polar solvents, polar-aprotic solvents, nitriie solvents or their mixtures. The l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazo!e compound of formula-9 utilized in step-f) of the first aspect of the present invention can be synthesized by any of the processes known in the art such as Drugs of the future, 2010, 35(2), 98-105, US20110009636A1, Synthetic Communications, 2011, 41, 1394-1402. The compound of formula-9 can also be prepared by the process as mentioned in the below provided examples of the present application.

The second aspect of the present invention provides a process for the preparation of 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide of formula-8, comprising of;

a) Hydrolyzing the methyl 2-methyl-2-phenylpropanoate compound of formula-2 in presence of suitable base in a suitable solvent to provide 2-methyl-2-phenylpropanoic acid of formula-3,

b) reacting the compound of formula-3 with a suitable chlorinating agent in a suitable solvent to provide 2-methyl-2-phenylpropanoyl chloride compound of formula-4,

c) reacting the compound of formula-4 with N,0-dimethylhydroxylamine hydrochloride in presence of a suitable base in a suitable solvent to provide N-methoxy-N,2-dimethyl-2-phenylpropanamide compound of formula-5,

d) reacting the compound of formula-5 with chloroacetyt chloride in presence of a Lewis acid in a suitable solvent to provide 2-(4-(2-chloroacetyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-6,

e) reducing the compound of formula-6 with a suitable reducing agent in a suitable solvent to provide 2-(4-(2-chloro-l-hydroxyethyl)phenyl)-N-methoxy-N)2-dimethylpropanamide compound of formula-7, f) reducing the compound of formula-7 with a suitable reducing agent optionally in a suitable solvent to provide compound of formula-8. Wherein, the suitable solvent, suitable base, suitable chlorinating agent, suitable Lewis acid and suitable reducing agent used in step-a) to step-e) are same as defined in step-a) to step-e) of first aspect of the present invention. In step-f) the suitable reducing agent is selected from trialkyl silanes such as trimethylsilane, triethyisilane optionally in combination with a suitable Lewis acid or trifluoroacetic acid or BF3-etherate, sodium borohydride optionally in combination with BF3-etherate or Lewis acid or trifluoroacetic acid; and the suitable solvent is selected from ketone solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents, alcohol solvents, chloro solvents, polar-aprotic solvents, nitrile solvents or their mixtures.

A preferred embodiment of the present invention provides a process for the preparation of 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide of formula-8, comprising;

a) Hydrolyzing the methyl 2-methyl-2-phenylpropanoate compound of formula-2 in presence of aqueous sodium hydroxide in methanol to provide 2-methy!-2-phenylpropanoic acid compound of formula-3,

b) reacting the compound of formula-3 with thionyl chloride in dichloromethane and in presence of catalytic amounts of N,N-dimethylformamide to provide 2-methyl-2-phenylpropanoyl chloride compound of formula-4,

c) reacting the compound of formula-4 with N,0-dimethylhydroxylamine hydrochloride in presence of potassium carbonate in a mixture of dichloromethane and water to provide N-methoxy-N,2-dimethyl-2-phenylpropanamide compound of formula-5,

d) reacting the compound of formula-5 with chloroacetyl chloride in presence of aluminium chloride in dichloromethane to provide 2-(4-(2-chloroacetyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-6,

e) reducing the compound of formula-6 with sodium borohydride in tetrahydrofuran to provide 2-(4-(2-chloro-1 -hydroxyethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide of formula-7,

f) reducing the compound of formula-7 with triethyisilane in presence of BF3-etherate to provide compound of formula-8. The third aspect of the present invention provides a novel process for the preparation of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl}ethyl)phenyl]-2-meth'ylpropanoic acid compound of formula-1, comprising of;

a) Reacting the 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-8 with l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole compound of formula-9 in presence of a suitable base in a suitable solvent optionally in presence of a catalyst to provide 2-(4-(2-(4-(l -(2-ethoxyethyl)-l H-benzo[d]imidazol-2-yl)piperidin-l -yl)ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-10,

b) hydrolyzing the compound of formula-10 in presence of a suitable acid or a suitable base optionally in presence of a suitable solvent to provide compound of formula-1.

Wherein in step-a) the suitable base, the suitable solvent and the suitable catalyst are same as defined in step-f) of first aspect of the present invention; In step b) the suitable acid, the suitable base and the suitable solvent are same as defined in step-g) of first aspect of the present invention. A preferred embodiment of the present invention provides a novel process for the preparation of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl}ethyl) phenyl]-2-methylpropanoic acid compound of formula-1, comprising of;

a) Reacting the 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-8 with l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole compound of formula-9 in presence of potassium carbonate and potassium iodide in N,N-dimethylformamide to provide 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl) piperidin-1 -yl)ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide of formula-10,

b) hydrolyzing the compound of formula-10 in presence of hydrochloric acid to provide compound of formula-1.

By adopting the above said novel process, the present inventors were able to get compound of formula-1 with excellent yield and purity with all the impurities within the levels as defined by ICH. The fourth aspect of the present invention provides a novel process for the preparation of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl}ethyl)phenyl]-2-methyl propanoic acid compound of formula-1, comprising of hydrolyzing the 2-(4-(2-(4-(I-(2-ethoxyethyl)-1 H-benzo[d]imidazol-2-y l)piperidin-1 -yl)ethyl)phenyl)-N-methoxy-N,2-dimethyl propanamide compound of formula-10 in presence of a suitable acid or a suitable base optionally in presence of a suitable solvent to provide compound of formula-1. Wherein the suitable acid, the suitable base and the suitable solvent are same as defined in step-g) of first aspect of the present invention. A preferred embodiment of the present invention provides a novel process for the preparation of 2-[4-(2- {4-[l -(2-ethoxyethyl)-1 H-benzimidazol-2-yI]-1 -piperidinyl }ethyl) phenyl]-2-methylpropanoic acid compound of formula-1, comprising of hydrolyzing the 2-(4-(2-(4-( 1 -(2-ethoxyethyl)-1 H-benzo[d]imidazol-2-yl)piperidin-1 -yl)ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-10 in presence of hydrochloric acid to provide compound of formula-1.

The fifth aspect of the present invention provides a process for the preparation of 2-(4-(2-(4-( ] -(2-ethoxyethyl)-1 H-benzo[d]imidazol-2-yl)piperidin-1 -yl)ethyl)phenyl)-N-methoxy-N,2-di methyl propanamide compound of formula-10, comprising of reacting the 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-8 with l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole compound of formula-9 in presence of a suitable base in a suitable solvent and optionally in presence of a suitable catalyst to provide compound of formula-10. Wherein the suitable base, the suitable solvent and the suitable catalyst are same as defined in step-f) of first aspect of the present invention. A preferred embodiment of the present invention provides a novel process for the preparation of 2-(4-(2-(4-( 1 -(2-ethoxyethyl)-1 H-benzo[d]imidazol-2-yl)piperidin-1 -yl)ethyl) phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-10, comprising of reacting the 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-8 with l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole compound of formula-9 in presence of potassium carbonate and potassium iodide in NjN-dimethylformamide to provide compound of formula-10.

The sixth aspect of the present invention provides a process for the preparation of 2-(4-(2-(4-(l -(2-ethoxyethyl)-1 H-benzo[d]imidazol-2-yl)piperidin-1 -yl)ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-10, comprising of;

a) reacting the 2-(4-(2-chloroacetyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-6 with l-(2-ethoxyethyl)-2-(piperidin-4-yi)-lH-benzo[d]imidazole compound of formula-9 in presence of a suitable base in a suitable solvent optionally in presence of a suitable catalyst to provide 2-(4-(2-(4-( 1 -(2-ethoxyethyl)-1 H-benzo[d]imidazol-2- |t> -yl)piperidin-l-yl)acetyl)phenyl)-N-methoxy-N,2-dimethyl,propanarnideofformula-ll,

b) reducing the compound of formula-11 with a suitable reducing agent in a suitable solvent to provide 2-(4-(2-(4-( 1 -(2-ethoxyethyl)-1 H-benzo[d]imidazol-2-yl)piperidin-1 -yl)-1 -hydroxy ethyl)phenyl)-N-methoxy-Ns2-dimethylpropanamide compound of formula-12,

c) reducing the compound of formula-12 with a suitable reducing agent in a suitable solvent to provide compound of formula-10.

Wherein in step-a) the suitable base, the suitable catalyst and the suitable solvent are same as defined in step f) of first aspect of the present invention; In step-b) and step-c) the suitable reducing agent and the suitable solvent are same as defined in step-e) & step-f) respectively of the first aspect of the present invention. The seventh aspect of the present invention provides a process for the preparation of 2-(4-(2-(4-(l -(2-ethoxyethyl)-1 H-benzo[d]imidazol-2-yl)piperidin-1 -yl)-1 -hydroxyethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-12, comprising of reacting the 2-(4-(2-chloro-1 -hydroxyethyl)phenyl)-N-methoxy-N32-dimethylpropanamide compound of formula-7 with 1 -(2-ethoxyethyl)-2-(piperidin-4-yl)-l H-benzo[d]imidazole compound of formula-9 in presence of a suitable base in a suitable solvent optionally in presence of a suitable catalyst to provide compound of formula-12. Wherein the suitable base, the suitable catalyst and the suitable solvent are same as defined in step-f) of the first aspect of the present invention.

The eighth aspect of the present invention provides a process for the preparation of 2-(4-(2-(4-( 1 -(2-ethoxyethyl)-1 H-benzo[d]imidazol-2-yl)piperidin-1 -yl)ethyl)phenyl)-N-methoxy-N,2 dimethylpropanamide compound of formula-10, comprising of;

a) reacting the 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N)2-dimethylpropanamide compound of formula-8 with 2-(piperidin-4-yl)-1 H-benzo[d]imidazole compound of formula-13 in presence of a suitable base in a suitable solvent optionally in presence of a catalyst to provide 2-(4-(2-(4-(lH-benzo[d]imidazol-2-yl)piperidin-l-yl)ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-14,

b) reacting the compound of formula-]4 with l-chloro-2-ethoxyethane or l-bromo-2-ethoxyethane in presence of a base in a suitable solvent to provide compound of formula-10.

Wherein in step-a) & step-b) the suitable base, the suitable catalyst and the suitable solvent are same as defined in step-f) of the first aspect of the present invention. The compound of formula-13 utilized in the present invention can be prepared by any of the conventional methods known in the art. The ninth aspect of the present invention provides a process for the preparation of 2-(4-(2-(4-( 1 H-benzo[d]imidazol-2-yl)piperidin-1 -yl)ethyl)phenyl)-N-methoxy-N,2-dimethyl propanamide compound of formula-14, comprising of reacting the compound of general formula-16, with 2-(piperidin-4-yl)-lH-benzo[d]imidazole compound of formula-13 in presence of a suitable base in a suitable solvent optionally in presence of a suitable catalyst to provide compound of formula-14. Wherein in the suitable base, the suitable catalyst and the suitable solvent are same as defined in step-f) of the first aspect of the present invention. The compound of general formula-16 used in the present invention can be synthesized by reacting the 2-(4-(2-hydroxyethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-15 with a suitable alkyl or aryl sulfonyl halides or anhydrides in presence of a suitable base in a suitable solvent. The suitable base and the suitable solvent are same as defined above.

The tenth aspect of the present invention provides a process for the preparation of 2-(4-(2-hydroxyethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide of formula-15, comprising of;

a) reacting the methyl 2-(4-bromophenyl)acetate compound of formula-17 with a suitable methylating agent in presence of a suitable base in a suitable solvent to provide methyl 2-(4-bromophenyl)-2-methylpropanoate compound of formula-18,

b) hydrolyzing the compound of formula-18 in presence of a suitable base in a suitable solvent to provide 2-(4-bromophenyl)-2-methylpropanoic acid compound of formula-19,

c) reacting the compound of formula-19 with a suitable chlorinating agent in a suitable solvent to provide 2-(4-bromophenyl)-2-methylpropanoyl chloride compound of formula-20,

d) reacting the compound of formula-20 with N,0-dimethylhydroxylamine hydrochloride in presence of a suitable base in a suitable solvent to provide 2-(4-bromophenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-21,

e) reacting the compound of formula-21 with oxirane in presence of magnesium (or) n-butyl lithium in a suitable solvent to provide compound of formula-15.

Wherein in step-a) the suitable methylating agent is selected from methyl iodide, dimethyl sulfate, dimethyl carbonate, trimethyloxonium tetrafluoroborate (MesO.BF,}), methyl methane sulfonate (MeOMs), methyl trifluoromethanesulfonate (MeOTf), methyl toluene sulfonate (MeOTs) and the like; the suitable base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal amides, organolithium bases or mixtures thereof; the suitable solvent is selected from ether solvents, ester ■solvents, polar solvents, chloro solvents, ketone solvents, hydrocarbon solvents, polar-aprotic solvents, alcohol solvents, nitrile solvents or their mixtures; In step-b) the suitable base and the suitable solvent are same as defined in step-a) of first aspect of the present invention; In step-c) the suitable chlorinating agent and the suitable solvent are same as defined in step-b) of first aspect of the present invention; In step-d) the suitable base and the suitable solvent are same as defined in step-c) of first aspect of the present invention; In step-e) the suitable solvent is selected from ether solvents, ester solvents, chloro solvents, ketone solvents, hydrocarbon solvents, polar-aprotic solvents, alcohol solvents, nitrile solvents, polar solvents or their mixtures.

The amide compounds of formula-5 and formula-21 of the present invention can also be prepared by reacting the corresponding carboxylic acid compounds of formula-3 and formula-19 respectively with N,0-dimethylhydroxylamine hydrochloride in presence of a suitable coupling agent and a suitable solvent optionally in presence of a suitable base. Wherein the suitable coupling agent is selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1 -ethyl-3-(3-dimethylaminopropyi)carbodiimide hydrochloride (EDC.HC1), N,N-carbonyldiimidazole (CDI), alkyl or aryl chloroformates such as ethyl chloro formate, benzylchloroformate, diphenylphosphoroazidate (DPPA), thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride and the like optionally in combination with l-hydroxy-7- azatriazole (HOAt), 1 -hydroxybenzotriazole (HOBt), 1 -hydroxy-1H-1,2,3-triazole-4- carboxylate (HOCt), 0-(benzotriazol-l-yl)-N,N,N\N^etramethyluronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS), 4-dimethylaminopyridine (DMAP); the suitable base is selected from organic or inorganic bases; the suitable solvent is selected from alcohol solvents, ether solvents, ester solvents, chloro solvents, hydrocarbon solvents, nitrile solvents, polar solvents, polar-aprotic sovlents, ketone solvents or their mixtures.

The eleventh aspect of the present invention provides novel intermediate compounds which are useful in the synthesis of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl}ethyl)phenyl]-2-methyl propanoic acid compound of formula-1. The novel intermediate compounds are represented by the structural formulae given below; The twelfth aspect of the present invention provides a process for the preparation of 2-(4-(2-(4-( 1 -(2-ethoxyethyl)-1 H-benzo[d]imidazol-2-yl)piperidin-1 -yl)ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-10, comprising of;

a) reacting the 2-(4-(2-chloroacetyl)phenyl)-N-methoxy-N)2-dimethylpropanamide compound of formula-6 with l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole compound-of formula-9 in presence of a suitable base in a suitable solvent optionally in presence of a suitable catalyst to provide 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl) piperidin-l-yl)acetyl)phenyl)-N-methoxy-N,2-dimethyl propanamide of formula-11,

b) reducing the compound of formula-11 with a suitable reducing agent in presence or absence of a solvent to provide compound of formula-10. ■

Wherein in step-a) the suitable base, the suitable catalyst and the suitable solvent are same as defined in step-f) of the first aspect of the present invention;

In step-b) the suitable reducing agent and the suitable solvent are same as defined in step-e) of first aspect of the present invention.

The another embodiment of the present invention provides a process for the preparation of 2-(4-(2-(4-( 1 -(2-ethoxyethyl)-1 H-benzo[d]imidazol-2-yl)piperidin-1 -yl)ethyl)phenyl)-N- methoxy-N,2-dimethylpropanamide compound of formula-10, comprising of reacting the l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole compound of formula-9 with compound of general formula-16 in presence of a suitable base in a suitable solvent to provide compound of formula-10. Wherein the suitable base and the suitable solvent are same as defined in step-f) of the first aspect of the present invention. Bilastine obtained by present invention was analyzed by HPLC under the following conditions; Apparatus: A liquid chromatographic system equipped with variable wavelength PDA-detector; Column: Kromasil-5-Cl8, 250*4.6 mm, 5.0 jam or equivalent; Flow rate: 1.0 mL/min; Wavelength: 220 nm; Column temperature: 45°C; Injection volume: 5 jiL; Run time: 42 min; Diluent: acetonitrile:water (50:50, v/v); Elution: gradient; Buffer: Weigh accurately 1.72 gm of dipotassium hydrogen phosphate into 1000 ml of milli-Q-water. Adjust the pH to 6.5 with diluted ortho phosphoric acid and filtered the solution through 0.22 u.m Nylon membrane filter paper and degas the solution in a sonicator; Mobile phase-A: Buffer:acetonitrile (95:05 v/v); Mobile phase-B: acetonitrile:water (90:10 v/v).

Bilastine obtained by present invention was also analyzed by UPLC under following conditions; Apparatus: A liquid chromatographic system equipped with variable wavelength PDA-detector; Column: ACQUITY UPLC CSH CI8 1.7u 2.1x100 mm; Wavelength: 210 nm; Column temperature: 50°C; Injection volume: 1.5 uL; Diluent: acetonitrile:water (20:80, v/v); Elution: gradient; Sample concentration: 1.0 mg/mL; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Buffer (70:30 v/v); Buffer: Take 1 mL of orthophosphoric acid and 3 gm of 1-octane sulfonic acid sodium salt anhydrous in 1000 mL of Milli-Q-water and filter this solution through 0.22 um Nylon membrane filter paper. The present invention is schematically represented as follows. The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

Examples:

Example-1: Preparation of 2-methyl-2-phenylpropanoic acid (Formula-3) To 100 gm of 2-methyl-2-phenylpropanoate (Formula-2) in 500 ml of methanol added aqueous sodium hydroxide solution (45 gm of NaOH dissolved in 500 ml of water) at 25-30°C. Heated the reaction mixture to 60-65°C and stirred the reaction mixture for 3 hours at a same temperature. Cooled the reaction mixture to 25-30°C and acidified the reaction mixture using aqueous hydrochloric acid. Extracted the compound from the reaction mixture using dichloromethane and washed the organic layer using 10% aqueous sodium chloride solution. Distilled off the solvent completely from organic layer to get the title compound. Yield: 87.0 gm.

Example-2: Preparation of N-methoxy-N,2-dimethyI-2-phenylpropanamide (Formula-5) To 85 gm of 2-methyl-2-phenylpropanoic acid (Formula-3) in 850 ml of dichloromethane and 8 ml of dimethylformamide added 154 gm of thionyl chloride at 25-30°C. Heated the reaction mixture to reflux temperature and stirred the reaction mixture for 15 hours at the same temperature. Distilled off the solvent completely from the reaction mixture. Dichloromethane (250 ml) was added to the obtained compound and added this reaction mixture to a 10-15°C pre-cooled solution of potassium carbonate (179 gm) & N,0-dimethylhydroxylamine hydrochloride (56.5 gm) dissolved in 425 ml of water at 10-15°C. Raised the temperature of the reaction mixture to 25°C and stirred the reaction mixture for 10 hours at the same temperature. Separated the both aqueous and organic layers and extracted the aqueous layer with dichloromethane. Washed the organic layer with 10% sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 107.3 gm.

Example-3: Preparation of 2-(4-(2-chloroacetyl)phenyl)-N-methoxy-N,2-dimethyl propanamide (FormuIa-6) To 206.5 gm of aluminium trichloride added 1000 ml of dichloromethane and cooled the reaction mixture to 0-5°C. A solution of 86.7 gm of chloroacetyl chloride in 100 ml of dichloromethane was added to the above reaction mixture at 0-5°C and stirred for 15 minutes. To this reaction mixture added a solution of N-methoxy-N,2-dimethyl-2-phenylpropanamide compound of formula-5 (107 gm) in dichloromethane (100 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hours at a same temperature. Quenched the reaction mixture with water and separated the both aqueous and organic layers. Extracted the aqueous layer with dichloromethane and combined the total organic layer. Washed the organic layer with 10% sodium bicarbonate solution followed by washing with 10% sodium chloride solution. Distilled off the solvent completely under reduced pressure and co-distilled with cyclohexane (50 ml). Ethyl acetate (50 ml) was added to the obtained compound and heated the reaction mixture to reflux temperature. Cooled the reaction mixture to 25-30°C and added 500 ml of petroleum ether to it. Cooled the reaction mixture to 10-15°C and stirred for 40 minutes at the same temperature. Filtered the precipitated solid to get the title compound. Yield: 146.5 gm; M.R: 80-81°C.

Example-4: Preparation of 2-(4-(2-chloroethyI)phenyl)-N-methoxy-N,2-dimethyl propanamide (Formula-8) To a solution of 2-(4-(2-chloroacetyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-6 (10 gm) in dichloromethane (100 ml) added triethyl silane (41 gm) and BF3-etherate (25 gm) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and further heated the reaction mixture to reflux temperature and stirred for 10 hours at the same temperature. Cooled the reaction mixture to 25-30°C and quenched the reaction mixture with 200 ml of water. Dichloromethane (100 ml) was added to the reaction mixture and stirred for 15 minutes. Separated the both aqueous and organic layers and extract the aqueous layer with dichloromethane. Combined the total organic layers and washed with 10% aqueous sodium hydroxide solution. Distilled off the solvent completely under reduced pressure to get the title compound. Yield: 8.8 gm.

Example-5: Preparation of 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethyl propanamide (Formula-8) To 10 gm of 2-(4-(2-chloroacetyl)phenyl)-N-rnethoxy-N,2-dimethylpropanamide (Formula-6) added triethylsilane (41 gm) and BF3-etherate (25 gm) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and quenched the reaction mixture with 200 ml of water. Dichloromethane (100 ml) was added to the reaction mixture and stirred for 15 minutes. Separated the both aqueous and organic layers and extract the aqueous layer with dichloromethane. Combined the total organic layers and washed with 10% aq.NaOH solution. Distilled off the solvent completely under reduced pressure to get the title compound. Yield: 9.0 gm.

Example-6: Preparation of 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl) piperidin-l-yl)ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide (Formula-10) 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-8 (1.5 gm), l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole compound of formula-9 (1.5 gm), sodium carbonate (1.2 gm) potassium iodide (0.) gm) and toluene (15 ml) were charged into a clean and dry RBF at 25-30°C. Heated the reaction mixture to 110-115°C and stirred for 20 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and water was added. Both the organic and aqueous layers were separated and IN HC1 solution was added to the organic layer. Both the organic and aqueous layers were separated and adjusted the pH of the aqueous layer to 7.0-7.5 using 20% sodium carbonate solution. Sodium chloride was added to the reaction mixture and the product is extracted with ethyl acetate. Distilled off the solvent completely form the reaction mixture under reduced pressure to get the title compound. Yield: 1.0 gm.

Example-7: Preparation of 2-|4-(2-{4-|l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl}ethyl)phenyl]-2-methylpropanoic acid (Formula-1 Conc.HCl (10 ml) and water (10 ml) were added to 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl)piperidin-l-yl)ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-10 (1.0 gm) at 25-30°C. Heated the reaction mixture to 105-110°C and stirred for 8 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and washed with methyl tert.butyl ether. Adjusted the pH of the reaction mixture to 6.5-7.0 using 20% potassium carbonate solution. Sodium chloride was added to the reaction mixture and the product is extracted with ethyl acetate. Distilled off the solvent completely form the reaction mixture under reduced pressure to get the title compound. Yield: 0.7 gm. Example-8: Preparation of 2-methyl-2-phenylpropanoic acid (Formula-3) Methyl 2-methyl-2-phenylpropanoate compound of formula-2 (100 gm) and methanol (500 ml) were added to a pre-cooled mixture of sodium hydroxide (45 gm) and water (500 ml) at 10-15°C. Heated the reaction mixture to reflux temperature and stirred for 3 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure and cooled the reaction mixture to 25-30°C. Water was added to the reaction mixture and cooled to 5-10°C. Acidified the reaction mixture using dil.HCl solution at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 30 min at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 89.0 gm.

Example-9: Preparation of 2-methyl-2-phenylpropanoyl chloride (Formula-4) Thionyl chloride (217.2 gm) was slowly added to a mixture of 2-methyl-2-phenylpropanoic acid compound of formula-3 (100 gm), dichloromethane (500 ml) and N,N-dimethylformamide (8.9 gm) at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 12 hrs at the same temperature. Distilled off the solvent completely form the reaction mixture under reduced pressure and the obtained compound is directly utilized in the next step.

Example-10: Preparation of N-methoxy-N,2-dimethyl-2-phenylpropanamide (Formula-5) N.O-dimethylhydroxylamine hydrochloride (66.8 gm) was added to a pre-cooled mixture of potassium carbonate (210.4 gm) and water (500 ml) at 0-5°C. A solution of 2-methyl-2-phenylpropanoyl chloride compound of formula-4 obtained in example-9 in dichloromethane (500 ml) was added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous NaCl solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 84.0 gm.

Example-ll: Preparation of 2-(4-(2-chIoroacetyI)phenyl)-N-methoxy-N,2-dimethyI propanamide (Formula-6) A mixture of aluminium chloride (206.3 gm) and dichloromethane (1000 ml) was cooled to 0-5°C. A solution of chloroacetyl chloride (86.7 gm) in dichloromethane (100 m!) was slowly added to the reaction mixture at 0-5°C under nitrogen atmosphere and stirred for 15 min at the same temperature. A solution of N-methoxy-N,2-dimethyl-2-phenylpropanamide compound of formula-5 (107 gm) in dichloromethane (100 ml) was added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Quenched the reaction mixture into water. Both the organic and aqueous layers were separated and the organic layer was washed with aqueous sodium bicarbonate solution followed by with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with cyclohexane. Ethyl acetate (50 ml) was added to the obtained compound and heated the reaction mixture to reflux temperature. Cooled the reaction mixture to 25-30°C and petroleum ether (500 ml) was added to it. Further cooled the reaction mixture to 10-I5°C and stirred for 40 min at the same temperature. Filtered the precipitated solid; washed with petroleum ether and dried the material to get the title compound. Yield: 90.0 gm.

Example-12: Preparation of 2-(4-(2-chloro-l-hydroxyethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide (Formula-7) . Sodium borohydride (1.3 gm) was slowly added to a pre-cooled solution of 2-(4-(2-chloroacetyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-6 (10 gm) in tetrahydrofuran (100 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 10 min at the same temperature. Quenched the reaction mixture with aqueous acetic acid solution. Ethyl acetate was added to the reaction mixture and stirred for 5 min. Both the organic and aqueous layers were separated and the organic layer was washed with water. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 10.0 gm.

Example-13: Preparation of 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethyl propanamide (Formula-8) BF3-etherate (6.25 gm) was added to a pre-cooled mixture of 2-(4-(2-chloro-l-hydroxyethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-7 (5 gm) and triethylsilane (20.3 gm) at 0-5°C. Heated the reaction mixture to 40-45°C and stirred for 14 hrs at the same temperature. Further heated the reaction mixture to 60-65°C and stirred for 44 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and quenched with water. Ethyl acetate was added to the reaction mixture and stirred for 15 min. Both the organic and aqueous layers were separated and the organic layer was washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 3.4 gm.

Example-14: One-pot process for the preparation of 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethyl propanamide (Formula-8) A solution of chloroacetyl chloride (86.7 gm) in dichloromethane (100 ml) was added to a pre-cooled mixture of aluminium chloride (206 gm) and dichloromethane (1000 ml) at 0-5°C and stirred the reaction mixture for 15 min at the same temperature. A solution of N-methoxy-N,2-dimethyl-2-phenylpropanamide compound of formula-5 (107 gm) in dichloromethane (100 ml) was added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for. 2 hrs at the same temperature. Cooled the reaction mixture to 0-5°C. Sodium borohydride (95 gm) was slowly added to the reaction mixture at 0-5°C and stirred for 4 hrs at the same temperature. Triethylsilane (60 gm) was slowly added to the reaction mixture at 0-5°C and stirred the reaction mixture for 2 hrs 15 min at the same temperature. Water was slowly added to the reaction mixture at 0-5°C, raised the temperature of the reaction mixture to 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 130.0 gm.

Example-15: Preparation of tert-butyl 4-(lH-benzo[d]imidazol-2-yl)piperidine-l-carboxylate (Formula-23) A mixture of benzene- 1,2-diamine (100 gm), piperidine-4-carboxylic acid (131.2 gm) and polyphosphoric acid (600 gm) was heated to 115-120°C and stirred for 20 hrs at the same temperature. Reduced the temperature of the reaction mixture to 80-85°C and quenched the reaction mixture with water. Cooled the reaction mixture to 10-15°C and basified using aqueous sodium hydroxide solution. Di.tert-butyl dicarbonate (222 gm) was slowly added to the reaction mixture at 10-15°C and stirred for 6 hrs at the same temperature. Filtered the precipitated solid and washed with water. Cyclohexane (1000 ml) was added to the obtained compound at 25- 30°C. Heated the reaction mixture to 80-85°C and stirred for 40 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 40 min at the same temperature. Filtered the solid, washed with cyclohexane and dried the material to get the title compound. Yield: 230.0 gm.

Example-16: Preparation of tert-butyl 4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl) piperidine-1-carboxylate (Formula-24) Tert-butyl 4-(lH-benzo[d]imidazol-2-yl)piperidine-l-carboxylate compound of formula-23 (100 gm), sodium iodide (10 gm) and l-chloro-2-ethoxyethane (54 gm) were slowly added to a pre-heated mixture of dimethylsulfoxide (200 ml) and sodium hydroxide (39.8 gm) at 40-45°C. Heated the reaction mixture to 95-100°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 10-15°C and water was slowly added to the reaction mixture at below 30°C. Neutralized the reaction mixture using aqueous hydrochloric acid. Ethyl acetate was added to the reaction mixture and stirred for 20 min. Both the organic and aqueous layers were separated and the organic layer was washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate (50 ml) was added to the obtained compound. Heated the reaction mixture to 60-65°C and stirred for 15 min at the same temperature. Reduced the temperature of the reaction mixture to 40-45°C and petroleum ether (650 ml) was slowly added. Cooled the reaction mixture to 0-5°C and stirred for 10 min at the same temperature. Filtered the precipitated solid, washed with petroleum ether and dried the material to get the title compound. Yield: 93.0 gm. '

Example-17: Preparation of l-(2-ethoxyethyl)-2-(piperidin-4-yI)-lH-benzo[d]imidazole (Formula-9) A mixture of tert-butyl 4-(l-(2-ethoxyethyl)-1 H-benzo[d]imidazol-2-yl)piperidine-1 -carboxylate compound of formula-24 (50 gm), HC1 (70 ml) and water (700 ml) was stirred for 6 hrs at 25-30°C. Neutralized the reaction mixture using ammonia solution. Sodium chloride was added to the reaction mixture and stirred for 10 min. Extracted the reaction mixture with n-butanol and distilled off n-butano! completely. Dichloromethane (500 ml) was added to the obtained compound at 25-30°C and stirred for 10 min at the same temperature. Filtered the reaction mixture and distilled off the solvent completely from the filtrate. Petroleum ether (250 ml) was added to the obtained compound at 25-30°C and stirred for 5 min at the same temperature. Filtered the solid, washed with petroleum ether and dried to get the title compound. Yield: 34.0 gm.

Example-18: Preparation of 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl) piperidin-l-yl)ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide (Formula-10) Sodium carbonate (3.9 gm), potassium iodide (0.6 gm) followed by tetrabutyl ammonium bromide (1.2 gm) were added to a mixture of l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole compound of formula-9 (5 gm), 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethyl propanamide compound of formula-8 (5 gm) and toluene (50 ml) at 25-30°C. Heated the reaction mixture to 105-110°C and stirred for 24 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, water was added and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Combined the organic layers and IN HC1 solution was added and stirred for 15 min. Both the organic and aqueous layers were separated and the aqueous layer was basified using aqueous sodium bicarbonate solution. Extracted the aqueous layer with dichloromethane and washed the dichloromethane layer with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 8.0 gm.

Example-19: Preparation of 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl) piperidin-l-yl)ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide (Formula-10) Potassium carbonate (10 gm) and potassium iodide (1.6 gm) were added to a mixture of l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole compound of formula-9 (9.2 gm), 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethy! propanamide compound of formula-8 (13 gm) and N,N-dimethylformamide (65 ml) at 25-30°C. Heated the reaction mixture to 65-70°C and stirred for 16 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, water was added to it. Extracted the reaction mixture with ethyl acetate, IN HC1 was added to ethyl acetate layer and stirred the reaction mixture for 10 min. Both the organic and aqueous layers were separated and the aqueous layer was washed with dichloromethane. Basified the aqueous layer using aqueous sodium carbonate solution and stirred the reaction mixture for 10 min. Extracted the aqueous layer with dichloromethane and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with ethyl acetate. To the obtained compound, ethyl acetate (52 ml) was added. Heated the reaction mixture to 55-60°C and stirred for 20 min at the same temperature. Cooled the reaction mixture to 25-3Q°C, further cooled to 0-5°C and stirred for 45 min at the same temperature. Filtered the solid, washed with ethyl acetate and dried the material to get the title compound. Yield: 10.0 gm; MR: 156-159°C.

Example-20: Preparation of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]-l piperidinyI}ethyl)phenyl]-2-methylpropanoic acid (Formula-1) A ' mixture of 2-(4-(2-(4-(l-(2-ethoxyethyl)-1 H-benzo[d]imidazol-2-yl)piperidin-1 -yl) ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-10 (14 gm), conc.HCl (45 ml) and water (45 ml) was heated to 90-95°C and stirred for 4 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, water and dichloromethane were added and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was neutralized using aqueous potassium carbonate solution. Extracted the aqueous layer with dichloromethane and washed the combined organic layer with aqueous sodium chloride solution. Distilled off the solvent completely form the organic layer under reduced pressure. Acetone (70 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for '20 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 5 hrs at the same temperature. Filtered the precipitated solid, washed with acetone and dried the material to get the title compound. Yield: 9.5 gm.

Example-21: Purification of compound of formula-1 A mixture of 2-[4-(2- {4-[ 1 -(2-ethoxyethyl)-1 H-benzimidazol-2-yl]-1 -piperidinyl} ethyl)phenyl]-2-methylpropanoic acid compound of formula-1 (8 gm) and n-butanol (75 ml) was heated to 110-115°C and stirred for 10 min at the same temperature. Carbon (0.8 gm) was added to the reaction mixture and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with n-butanol. Cooled the reaction mixture to 5-10°C and stirred for 30 min at the same temperature. Filtered the precipitated solid, washed with n-butanol and dried the material to get pure title compound. Yield: 7.0 gm; Purity by HPLC: 99.6%. Particle size distribution: D(0.1) is 2.88 urn; D(0.5) is 12.48 u.m; D(0.9) is 34.09 jam.

We Claim:

1. A process for the preparation of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperid'myl}ethyl)phcnyl]-2-melhyl propanoic acid compound of formula-1, comprising of;

a) Reacting the N-methoxy-N,2-dimethyl-2-phenylpropanamide compound of formula-5 with chloroacetyl chloride in presence of Lewis acid in a suitable solvent to provide 2-(4-(2-chloroacetyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-6,

b) reducing the compound of formula-6 with a suitable reducing agent in presence or absence of a suitable solvent to provide 2-(4-(2-chloro-l-hydroxyethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of forrnula-7,

c) further reducing the compound of formua-7 with a suitable reducing agent optionally in presence of a suitable solvent to provide 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethyl propanamide compound of formu!a-8,

d) reacting the compound of formula-8 with l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-ben^o[d]imidazole compound of formula-9 in presence of a suitable base in a suitable solvent optionally in presence of a suitable catalyst to provide 2-(4-(2-(4-(l-(2-ethoxyethyl)-1 H-benzo[d]imidazol-2-yl)piperidin-1 -yl)ethyl)phenyl)-N-methoxy-N,2-dimethy lpropanamide compound of formula-10,

e) hydrolyzing the compound of formula-10 in presence of a suitable acid or a suitable base optionally in presence of a suitable solvent to provide compound of formula-1.

2. A process according to claim 1, wherein;

in step-a) the Lewis acid is selected from aluminum chloride, aluminum bromide, boron trifluoride, boron tribromide, tin tetrachloride, tin tetrabromide, stannous chloride (SnCb), ferric chloride (FeCl3), zinc chloride (ZnCl2), titanium tetrachloride (TiCl4) or their mixtures;

in step-b) the suitable reducing agent is selected from trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with suitable Lewis acid or trifluoroacetic acid or BF3-etherate; trich/orosi/ane, sodium borohydride optionally in combination with BF3-etherate or Lewis acid or trifluoroacetic acid, diborane, KBH4, NaCNBH4, lithium borohydride, LiAlH4, DIBAL, LiEt3BH, L-selectride, vitride;

in step-c) the suitable reducing agent is selected from trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with Lewis acid or trifluoroacetic acid or BF3-etherate, NaBH4 optionally in combination with BF3-etherate or Lewis acid;

in step-d) the suitable base is selected from organic bases, inorganic bases; the suitable catalyst is selected from alkali metal halides such as sodium bromide, sodium iodide, potassium bromide, potassium iodide;

in step-e) the suitable acid is selected from inorganic acids, the suitable base is selected from inorganic bases;

in step-a) to step-e) the suitable solvent is selected from chloro solvents, ketone solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents, polar-aprotic solvents, nitrile solvents; alcohol solvents or their mixtures. A process for the preparation of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl}ethyl)pheny(]-2-methyi propanoic acid compound of formula-1, comprising of;

a) Reacting the compound of formula-5 with chloroacetyl chloride in presence of aluminium chloride in dichloromethane to provide 2-(4-(2-chloroacetyl)phenyl)-N- methoxy-N,2-dimethylpropanamide compound of formula-6,

b) ■ reducing the compound of formula-6 with sodium borohydride in tetrahydrofuran to provide 2-(4-(2-chloro-1 -hydroxyethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formuIa-7,

c) further reducing the 2-(4-(2-chloro-1 -hydroxyethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-7 with triethylsilane-BF3.etherate to provide 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethyl propanamide of formula-8,

d) reacting the compound of formula-8 with l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole compound of formula-9 in presence of potassium carbonate and potassium iodide in N,N-dimethylformamide to provide 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl)piperidin-l-yl)ethyl)phenyl)-N-methoxy-N,2-dimethyl propanamide compound of formula-10,

e) hydrolyzing the compound of formula-10 in presence of hydrochloric acid to provide compound of formula-1. A process for the preparation of 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethyl propanamide compound of formula-8, comprising of reducing the 2-(4-(2-chloro-l-hydroxyethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-7 with a suitable reducing agent optionaJly in presence of a suitable solvent to provide compound of formula-8.

5. A process for the preparation of 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethyl propanamide compound of formula-8, comprising of reducing the 2-(4-(2-chloroacetyl) phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-6 with a suitable reducing agent optionally in presence of suitable solvent to provide compound of formula-8.

6. A process for the preparation of 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl) piperidin-l-yl)ethyi)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-10, comprising of reacting the 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethyl propanamide compound of formula-8 with l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole compound of formula-9 in presence of a suitable base in a suitable solvent optionally in presence of a suitable catalyst to provide compound of formula-10.

7. Novel process for the preparation of 2-[4-(2- (4-[ 1 -(2-ethoxyethyl)-1 H-benzimidazol-2-yl]-1 -piperidinyl}ethyl)phenyl]-2-methyl propanoic acid compound of formula-1, comprising of hydrolyzing the 2-(4-(2-(4-(l -(2-ethoxyethyl)-1 H-benzo[d]imidazol-2-yl)piperidin-1 -yl) ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-10 in presence of suitable acid or a suitable base to provide compound of formula-1.

8. A process according to claim 7, wherein the preparation of compound of formula-1, comprises hydrolyzing the compound of formula-10 in presence of hydrochloric acid.

9. Compounds having the following structural formulae;

10. Solid state form of 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl)piperidin-l-yl) ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide.