Z WIPO wont DOCUMENT MADE AVAILABLE UNDER THE PATENT COOPERATION TREATY (PCT) International application number: PCT/IN2014/000353, International filing date: 26 May 2014 (26.05.2014) Document type: Certified copy of priority document Document details: CountrylOfiee. © IN Number 2276/CHE/2013 Fling date: 24 May 2013 (24.05.2013) Date of receipt at the International Bureau: 02 September 2014 (02.09.2014) Remark: Priority document submitted or transmitted to the International Bureau in compliance with Rule 17.1(a),(b) or (b-bis) 211 Geneva 20, www.wipo.intpetln2014/oco 353 a INTELLECTUAL PROPERTY INDIA GOVERNMENT OF INDIA PATENT OFFICE Ministry of Commerce and Industry Department of Industrial Policy and Promotion It is hereby certified that annexed here to is a true copy of Provisional Specification and Abstract of the patent application as filed and detailed below :- Date of application : 24/05/2013 ApplicationNo. :_ 2276/CHE/2013 Applicant : M/s, MSN Laboratories Private Limited, Factory Sy. No. 317 & 323, Rudraram (Vil), Patancheru (Mal), Medak @ist.) - 502 329, Andhra Pradesh, India. In witness there of Thave here unto set my hand Dated this the 24" day of July 2014 2" day of Shravana, 1936 (Saka) By Authority of THE CONTROLLER GENERAL OF PATENTS, DESIGNS AND TRADE MARKS. ptt (O. PRASAD RAO) ASSISTANT CONTROLLER OF PATENTS & DESIGNS PATENT OFFICE INTELLECTUAL PROPERTY RIGHTS BUILDING GS.T. ROAD, GUINDY, CHENNAI ~ 600 032.€ FORM? ° | . ‘THE PATENT ACT 1970 G9 of 1970) & ‘The Patents Rules, 2003 PROVISIONAL SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION | Novel process for the preparation of 2-[4-(2-{4-[1-(2-ethoxyethyl)-1H- | berizimidazol-2-yl]-1-piperidiny!}ethy!)phenyl}-2-methylpropanoic acid 2. APPLICANT(S) - (@) NAME: MSN LABORATORIES PRIVATE LIMITED (by NATIONALITY: Indian. (©) ADDRESS MSN Laboratories Private Limited, Factory: Sy.No:317 & 323, Rudratamn (Vil), Patanicheru (Mal), Medak (Dist), Andhra Pradesh India ~ 502 329. . PREAMBLE TO THE DESCRIPTION PROVISIONAL ORIGINAL | The following specification particularly describes the invention, coe 6 seu {OWS 227Field of the Invention: ‘The present invention provides novel processes: for the prepatation of 2[4.(2-(4-[1-2- ‘thoxyethyl)-1H-beiwzitnidazol-2-yl}-1-piperidiny!} ethyDphenyl}-2-methylpropanote acid reptesented by the following struceufal formuta-t CHOY O yon a é Formula-1 The present invention also provides novel intermediate compounds uséful for the repatation of compound of formula-1 Background of the Invention: 2-{44(2-{4-[1-(2ethoxyethyl)-1H-benzimidazol-2-yl]-I-piperidinyl}ethyl)phenyl}-2- ‘imethyIpropanoie’ acid, commonly known as Bilastine is an antihistamine drug for the treatment of allergic rhinotonjunctivitis and urticaria (hives). It exerts itS effect as a: selective histamine Hi receptor antagonist and his a potency similar to cetirizine and is superior tofexofenatine. US5877187A fitst discloses the synthesis of 2-[44(2-4-[1-@-ethoxyethyl)-IH- bbenwzimidacol-2-y1}-1-piperidinyt} ethy!)phenyl]-2-methylpropanoie acid. ‘The process disclosed in the said patent is schematically represented in scheime-A.x CHO 2 Oe oO Oe OOOH as Oy BOY The disclosed process involves the reaction of the benzimidazole intermediate with tosylated oxazole intermediate in presence of sodium carbonate as shown in scheme-A to provide an oxazole intermediate compound followed by cleavage of the said oxazole ring by treating it with 3N hydrocori acd, wich makes the whole process complicated, 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} ethy!)phenyl]-2-methylpropanoic acid on industrial scale Hence, there is a significant need in the art to develop a riovel process for the preparation of 2f4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-I-piperidiny!} ethyl)phenyl]-2-methyl propanoie 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-{1-2-ethoxyethyl)-IH- benzimidazol-2-yl}-1-piperidinyl}ethy!)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)-1H-benzimidazol-2-yl]-|-piperidinyl} ethy!)phenyl]-2-methyl propanoic acid compound of formula-1, comprising of; 8) Reacting the methyl 2-methyl-2-phenylpropanoate compound of formula-2 with chloroacetyl chloride in presence of a Lewis acid in a suitable solvent to provide methyl 2-(4-(2- chloroacetyl)phenyl)-2-methylpropanoate compound of formmula-3, 3b) reacting the compound of formula-3 with 1-Q-ethoxyethyl)-2-(piperidin-4-yl)-1H- benzo[illienidazole compound of formula-< in presence of a suitable base in a suitable solvent to provide methyl. 2-(4-(-(4-(1-(2-ethonyethyl)-1H-benzo{d]imidazol-2-yl)piperidin-1-y1) acetyl)phenyl)-2-methylptopanoate compound of formula-5, ©) hydrolyzing the compound of formula-S in presence of a suitable base in a suitable solvent to provide 2-(4-(2-(4-(1-(2-ethoxyethyl)-IH-benzo[d]imidazol-2-yl)piperidin-I-yDacetyl) phenyl)-2-methylpropanoie acid compound of formula-6, 4) reducing the compound of formula-6 with a suitable reducing agent in a suitable’ solvent to provide 2-[4(2- (4-{1-(2-ethoxyethy!)-H-benzimidazol-2-yl}-L-piperidinyl}ethyl) phenyl)- 2-methylpropanoie acid compound of formula-1. The second aspect of the present invention is to provide a novel process for the preparation of 2-[4-(2-(4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl} |-piperidinyl} ethyl) phionyl]-2-methylpropanoic acid compound of formula-1, comprising 2) Reacting the methyl 2-methy-2-phenylpropanoate compound of forinule2 with chloroacety! chloride in presence of a Lewis acid in a suitable solvent to provide methyl 2-(4(2- chloroacetyl)pheny)-2-methylpropancate compound of formul-3, tb) reacting the compound of formula-3 with 1-(2-ethoxyéthyl}-24piperiin-4-yl)-1H- ‘benzo[djimidazole conipound of formula-4 in presence of a suitable base in a suitable solvent to provide methyl 2-(4(2-4-(1-(-ethoxyethy)-1H-benzo{djimidazol-2-y)piperidin-1-y) acctyl)pheay)-2-methslpropanoate compound of formula, ©) reducing the compound of formula-5 with a suitable reducing agent in a suitable solvent to provide methyl 2-(4-(2-(4-(I-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yljethyl) phenyl)-2-methylpropanoate compound of formula-7, ©) hydrolyzing the compound of formula-7 in presence of a suitable base in a suitable solvent to provide 2-[4-(2-(4-[1-(-ethoxyethyl)-1H-benzimidazol-2-yl]-I-piperidinyl}ethyl) phenyl]- 2-methylpropanoie acid compound of formula-t. The third aspect of the present invention is to provide & process for the preparation of ‘methyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula-3, comprising of reacting the methyl 2-methyl-2-phenylpropanoate compound of formula-2 with chloroacetylchloride in presence of a Lewis acid in a suitable solvent 10 provide methyl 2-(4-(2- chloroacety!)pheny!)-2-methiylpropanoate compound of formula-3. The fourth aspect ofthe present invention is to provide a process for the preparation of 2- [4-(2-(4-(1-@-ethoxyethy!)-H-benzimidazol-2-yi}-I-piperidinyl} ethy!)phenyl}-2- methylpropanoic acid compound of formmula-1, comprising of; a) Reducing the methyl 2-(4-(2-(4-(1-(2-cthoxyethyl)-1H-benzofd]imidazol-2-yl)piperidin-1-yl) acetyl)phenyl)-2-methylpropanoate compound of formula-S with a suitable reducing agent in 4 suitable solvent to provide methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-bertzo[limidazol-2-yl) piperidin- b) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent to yl)+I-hydroxyethy!)phenyl)-2-methylpropanoate compound of formula-8, provide methyl 2-(4-(2-(4-(I-(2-ethoxyethyl)-IH-benzo{d}imidazol-2-yDpiperidin-1-yl)ethyl) phenyl)-2-methylpropanoate compound of formula-7, : ©) hydrolyzing the compound of formuls-7 in presence of a suitable base in a suitable solvent to Provide 2-[4-(2-(4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-I-piperidinyl} ethyl) phényl]- 2-methylptopanoic 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-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl}-1-piperidinyl}ethyl)phenyl]-2- methylpropanoic acid compound of formula-1, comprising of, a) Reducing the methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo{d]imidazol-2-y))piperidin-1-yl) acety!)phenyl)-2-methylpropanoate compound of formula-S with a suitable reducing agent in «a suitable solvent to provide methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-F-benzofd}i piperidin-1-yl)-1-hydroxyethyl)phenyl)-2-methylpropanoate compound of formula-8, wzol-2-yl) ') hydrolyzing the compound of formula-8 in presence of a suitable base in a suitable solvent to provide 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo{djimidazol-2-yl)piperidin-1-yl)-I-hydroxy cethy!)pheny!)-2-methyipropanoie acid compound of formula-9, | ©) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent to provide 2-[4-(2-{4-(1-(2-cthoxyethyl)-1H-benzimidazol-2-yl)-I-piperidinyl} ethyl) phenyl]- ‘2-methylpropanoic acid compound of formula-L.‘The sixth aspect of the present invention is to provide a novel process for the preparation of 2{4+(2-{4-[1-2-ethoxyethyl)-1H-benzimidazol-2-yl}-1-piperidiny!} ethylphenyl)-2-methyl propanoie acid compound of forimula-1, comprising of; a) Hydrolyzing the methyl 2-(4-(2-(4-(1-(2-ethoxyethy!)-1H-benz0|dJimidazol-2-y))piperidin- 1-yDacetyl)pheny!)-2-methylpropanoate compound of formula-5 in presence of a suitable base in a suitable solvent to provide 2-(4-(2-(4-(1-(2-ethoxyethyl)-IH-benzo[d]imidazol-2- y0piperidin-1-yl)acetyl) phenyl)-2-methylpropanoie acid compound of formula-6, ) teducing the compound of formula-6 with a suitable reducing agent in a suitable solvent to provide 2-(4-(2-(4-(1-(2-ethoxyethyl)-IH-benzof d}imidazol-2-yl)piperidin-1-yl)-1-hydroxy ethy!)phenyl)-2-methylpropanoic acid compound of formula-9, ©) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent to provide 2-[4-(2-(4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl}-1-piperidiny!} ethyl) phenyl)- 2-methylpropanoic acid compound of formula-1. ‘The seventh aspect of the present invention is to provide a process for the preparation of methyl 2-(4-(2-chloroethyl)pheny!)-2-methylpropanoate compound of formula-1Q, which is an intermediate useful in the synthesis of compound of formula-1, comprising of reducing the methyl 2-(4-(2-chlotoacetyl)pheny!)-2-methylpropancate compound pf formula-3 with a suitable reducing agent in a suitable solvent to provide methyl 2-(4-(2-chlorocthyl)phenyl)-2- methylpropanvate compound of formula-10. ‘The eighth aspect of the present invention is to provide a novel process for the preparation of methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d}imidazol-2-yl)piperidin-1-yl) éthyl)phenyl)-2-methyiproparioate compound of formula-7, comprising of; a) Reducing the micthyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula-3 with a suitable reducing agent ina suitable solvent to provide methyl 2-(4-(2- chloroethyl)phenyl)-2-methylpropanoste compound of formula-10, b) reacting the compound of ‘formula-10 with 1-(2-cthoxyethyl)-2-(piperidin-4-)l)-1H- ‘benzo[dJimidazole compound of formula-4 in presence of a suitable base in a suitable solvent to provide methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d}imidazol-2-yl)piperidin-1-y!) cthyl)phenyl)-2-methylpropanoate compound of formula-7,‘The ninth aspect of the present invention is to provide novel intermediate compounds useful for the preparation of —2-[4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-1- pipetidinyl} ethy!)phenyl}-2-methylpropanoic acid compound of formula-1. 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, pet ether, benzene, toluene, xylene and the like; “ether solvents” such as dimethyl ether, diethyl ether, methyl tert-butyl ether, 1,2- dimethoxy ethane, tetrahydrofuran, dioxane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate and the like; “polar-aprotic solvents sich as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl Ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile and the like; “alcoholic 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; and/or their mixtures thereof. ‘The term “suitable base” used in the present invention refers to inorganic bases selected fiom “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 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 tertbutoxide, potassium tertbutoxide, lithivin tertbutoxide; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; atimonia, alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetaté, magnesium acetate, calcium acetate and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tertbutylamine, pytidine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[S.4.0}undec-7-ene (DBU), 1,5- Diazabicyclo[4.3.0}non-S-cne (DBN), N-methyl morpholine (NMM), 1,4-diazabieyclo(2.2.2] 7octane (DABCO), 2,6-lutidine, lithium diisopropylamide; organolithium bases such as. n- butyllithium, orgenosilicon bases such as lithium hexamethyldisilazide (LIHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or their mixtures thereof. The first aspect of the present invention provides & novel process for the preparation of 2- [4-2- (4-{1-2-ethoxyethyl)-1H-benzimidazol-2-yl]-1-piperidiny!} ethy!)phenyl]-2- methylpropanoic acid compound of formula-1, comprising of, a) Reacting the methyl 2-methy!-2-phenylpropanoate compound of formula-2 : oye : Formula-2 with chloroacetyl chloride in presence of a Lewis acid in a suitable solvent to provide methyl 2-(4-(2-chloroacety!)phenyl)-2-methylpropanoate compound of formula-3, Hy cr 6 ° Formula-3 ») rescting the compound of formula-3 with * 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H- benzo[d]imidazole compound of formula-4 x a COO Et Formula-4 ‘wherein, ‘Et’ represents ethyl group; in presence of a suitable base in a suitable solvent to provide methyl 2-(4-(2-(4-(1-4(2- ‘ethioxyethyl)-1H-benzo(d]imidazol-2-yl)piperidin- L-yl)acety!)phenyl)-2-methylpropanoate ‘compound of formula-5, 4 . CHOP OF cox, Et Formula-S 8©) hydrolyzing the compound of formula-5 in presence of a suitable base in a suitable solvent to provide 2-(4-(2-(4-(I-(2-ethoxyethy!)-LH-benzo{d]imidazol-2-yl)piperidin-1-yDacetyl) phenyl)-2-methylpfopanoic acid compound of formula-6, CFO TO Son bee Formula-6 4) reducing the compound of formula-6 with a suitable reducing agent in a suitable solvent to provide 2-[4-(2-{4[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl}-1-piperidiny!} ethyl) pheny!]- 2methylpropanoic acid compound of formula-1. Wherein, in step-a) the suitable Lewis acid is selected from but not limited to aluminum chloride, aluminum bromide, boron trifluoride, boron tribromide, boron tribromide, tin tetrachloride, tin tetrabromide, stannous chloride (SnCk), ferric chloride (FeCl), zine chloride (ZnCl), titanium tetrachloride (TiCly) or mixture or hydrates thereof; and the suitable solvent can be selected from chiloro solvents, ketone solvents, ether solvents, estet solvents, hydrocarbon solvents, polar solvents, polar-aprotic solvents, nitrile solvents, alcoholic solvents or mixtures thereof, In step-b) the suitable base can be selected from but not limited to organic bases, inorganic bases such as carbonates, bicarbonates, hydroxides, alkoxides, hydrides, acetates and atnides of alkali and alkali earth metals; and the suitable solvent can be selected from chloro solverits, ketone solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents, polar-aprotic solvents, nitrile solvents, alcoholic solvents or mixtures thereof, In step-c) the suitable base can be selected from hydroxides, alkoxides, carbongtes and bicarbonates of alkali metals; and the suitable solvent can be selected from chloro solvents, ketone solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents, polar-aprotic solvents, nitrile solvents alcoholic solvents or mixtures thereof; In step-d) the suitable reducing agent can be selected from but not limited to trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with a suitable Lewis acid as defined in step-a) oF trifluoroacetic acid or BFy-ctherate; sodium borohydride optionally 9in combination with BF;-etherate, hydrazine (Wolff-Kishner reduction), Zn-Hg/HCl (Clemmensen reduction), Pd/C, PUC, Pd(OH)., polymethylhydrosiloxane (PMHS) in presence of FeCl; anid the like; the suitable solvent can be selected from ketone solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents, alcoholic solvents or mixtures thereof; ‘The 1-(2-ethoxyethyl)-2-(piperidin-4-y!)-1H-benzo[d]imidazole compound of formula-4 utilized in step-b) of the first aspect of the present invention can be synthesized by any of the processes known in thé art such as Drugs of the future, 2010, 35(2), 98-105, US20110009636A1, Synthetic Communications, 41, 1394-1402, 2011 The second aspect ofthe present invention provides a novel process for the preparation of 2-{4-(2-{4-{1-(2-ethonyethy!)-IH-benzimidazol-2-yl}--piperidinyl}ethy)phenyl]-2- methylpropanoic acid compound of formula-1, comprising of, a) Reacting the methyl 2-methyl-2-phenylpropanoate compound of formula-2 with chloroacetyl chloride in presence of a Lewis acid in a suitable solvent to provide methyl 2-(4-(2- chloroacetyl)phenyl)-2-methylpropanoate compound of formula-3, b) reacting the compound of formula-3 with 1-(2-ethoxyethyl)-2(piperidin-4-y1)-IH- bbenz0{dJimidazale compound of formule-4 in presence of a suitable base in a suitable solvent to provide methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[dJimidazol-2-ylpiperidin-1-yl) acetyl)phenyl)-2-methylpropanoate compound of formula-5, * ©) reducing the compound of formula-5 with a suitable reducing agent in a suitable solvent to provide methyl 2-(4-(2-(4-(1-(2-cthoxyethy!)-1H-benzold}imidazol-2-yl)piperidin-1-yl) cehyphensl).2-mcthypropanoste compound of formula, : NOD OFO Soc, bee . Fomule-7 4) hydrolyzing the compound of formula-7 in presence of a suitable base in a suitable solvent to provide 2-{4-(2-{4-[1-(2-cthoxyethyl)-1H-benzimidazol-2-yl]-I-piperidinyl}ethyl) phenyl]- 2-methylpropanoic acid compound of formuls-In step-a) and step-b) the suitable Lewis acid, the suitable base and the suitable solvent are satme as defied for step-a) and step-b) respectively of the first aspect of the present invention; In step-c) the suitable reducing agent and the suitable Solverit are same as defined for step-d) of the first aspect of the present invention; In step-d) the suitable base and the suitable solvent are same as defined for step-c) of the first aspect of the present invention ‘The third aspect of the present invention is to provide a process for the preparation of methyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula-3, comprising of reacting the methyl 2-methyl-2-phenylpropanoate compound of formula-2 with chloroacetyl chloride in presence of a Lewis acid in a suitable solvent to provide methyl 2.(4-(- chloroacety!}phenyl)-2-methylpropanoate compound of formula-3, wherein the suitable Lewis acid and the suitable Solvent are same as defined for step-a) of the first aspect of the present invention. ‘The fourth aspect of the present invention provides a process for the preparation of 2-[4- (2: {4-{1-(2-ethoxyethyl)-1#-benzimidazol-2-yl}-1-piperidinyl} ethylphenyl]-2-methylpropanoic acid compound of formuls-1, comprising of, a) Reducing the methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo{d}imidazol-2-yl)piperidin-1-y1) acetyl)phenyl)-2-methylpropanoate compound of formula-S with a suitable reducing agent in thoxyethyl)- H-benzofd]imidazol-2-yl) a suitable solvent to provide methyl 2-(4-(2-(4-(L-@. piperidin-1-yl)-1-hydroxyethyl)phenyl)-2;methylpropanoate compound of formula-8, Oo *, Oyo poets Fone 'b) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent to provide methyl 2-(4-(2-(4-(1-(2-cthoxyethyl)-1 H-benzo{d]imidazol-2-yl)piperidin-I-yl) ethy!)ptienyl)-2-methylpropanoate compound of formula-7, ul©) hydrolyzing the compound of formula-7 in presence of a suitable base in a suitable solvent to provide 2-[4-(2-f4-[1-(2-ethoxyethy!)-IH-benzimidazol-2-yl]-I-piperidinyl) ethy!)phenyl]- 2-methylpropanoic acid compound of formula Wherein in step-a) the suitable reducing agent can be selected from but not limited to ‘tialkyl silanes such as trimethylsilane, triethyisilane optionally in combination with a suitable Lewis acid or trifluoroacetic acid or BF;-etherate; trichlorosilane, sodium borohydride optionally in combination with BFs-etherate, diborane, potassium borohydrite, sodium eyanoborohyiride, lithium borohydride, ditsobutylaluminium hydride (DIBAL), lithium triethylborohydride (LiEtBH), L-selectride (lithium tr-sec-butyl(hydrido)borate(1-)) and the fi In step-b) the suitable reducing agent can be selected from tralkyl silanes such as trimethylsilane, triethylsilane optionally in combination with a suitable Lewis acid or trifluoroacetic acid or BF;-etherate; The suitable solvent used in step-a) and step-b) can be selected from ketqne solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents, alcoholic solvents or mixtures thereof; . «In step-c) the suitable base and the suitable solvent are same as defined for step-c) of the first aspect of the present invention. In the above process, the hydroxy group of compound of formula-8 can be optionally converted to easily leaving groups such as methane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate or the like followed by reducing the obtained compound with a suitable reducing agent in a suitable solvent to provide compound of formula-7. ° ‘The fifth aspect of the present invention provides a process for the preparation of 2-[4-(2- {4-{1-(2-cthoxyethyl)-1H-benzimidazol-2-yl}-1-piperidinyl} ethyl)phenyl]-2-methylpropanoic acid compound of férmula-1, comprising of, a) Reducing the methyl 2-(44(2+(4-(1-(2-ethoxyethyl)-lH-benzo{d]imidazol-2-yl)piperidin-1-y!) acetyl)phenyl)-2-methylpropanoate compound of formula-S with a suitable reducing agent in 128 suitable solvent to provide methyl 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzofd]imidazol-2-yl) iperidin-1-yl)-1-hydroxyethy!)phenyl)-2-methylpropanoate compound of formula-8, ) hydrolyzing the compound of formula:8 in presence of a suitable base in a suitable solverit to provide 2-(4-(2-(4-(I-(2-ethoxyethyl)-Li-benzo[d]imidazol-2-yl)piperidin-I-yl)-I-hydroxy ethy!)phenyl)-2-methylpropanoie acid compound of formula-9, CHO Fon Et Formula-9 ©) reducing the compound of formula-9 with a suitable reducing agent in 4 suitable solvent to provide 2-[4-(2- (4-{-(2-ethoxyethyl)-1H-benzimidazol-2-yl]-I-piperidinyl} ethyl)phenyl}-2- rmethylpropanoic acid compound of formula-1 In step-a) the suitable reducing agent and the suitable solvent are Same as defined for sttp-a) of the fourth aspect of the present invention; In step-b) the suitable base and the suitable solvent are sain as defined for step-c) of the fitst aspect of the present invention; In step) the suitable reducing agent and the suitable solvent are same as defined for step-b) of the fourth aspect of the present invention, ‘The sixth aspect of the present invention provides a novel process for the preparation of 2-{4-(2-{4-[1-(2-ethoxyethyl)-LH-benzimidazol-2-yl]-1-piperidinyl}ethylpheny!]-2- ‘methylpropanoic acid Compound of formuls-1, comprising of, a) Hydrolyzing the methyl 2-(4-(2-(44(1-(2-cthoxyethyl)-IH{-benzo[d}imidazol-2-yl)piperidin- 1-yDacetyl)phenyl)-2-methylpropanoate compound of formula-5 in presence of a suitable base ina suitable solvent to provide 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2- -ypiperidin-1-yDacetyl) phenyl)-2-methylpropanoic acid compound of formula-6; ') reducing the compound of formula-6 with a suitable reducing agent in a suitable solvent to provide 2-(4-(-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-|-yl)-I-hydroxy ethyl)phenyl)-2-methylpropanoic acid compound of formula-9, 3«) teducing the compound of formula) with a suitable reducing agent in a suitable solvent provide 2-[4-(2-(4-[1-(-ethoxyethyl}-H-benzimidazol-2-yl]-1-piperidinyl}ethyl) phenyl} 2-methylpropanoic acid compound of formula-1 In step-a) the suitable base and the suitable solvent are samme as defined for step-c) of the first aspect ofthe present invention; In step-b) the suitable reducing agent and the suitable solvent are same as defined for step-a) of the fourth aspect of the present invention; In step-c) the suitable reducing agent and the suitable solvent are same as defined for step-b) of the fourth aspect of the present invention. ‘The hydroxy group of compound of formula-9 obtained in step-b) of the fifth and sixth aspects of the present invention can be optionally converted to easily leaving groups such as methane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate or the like followed by reducing the obtained compound with a suitable reducing agent in a suitable solvent to provide compound of formula-1. The seventh aspect of the present invention provides a process for the preparation of methyl 2-(4-(2-chloroethy! pheny!)-2-methylpropanoate compound of formula-10, Formula-10 which is an intermedite useful in the synthesis of compound of formula-1, comprising of reducing the methyl 2-(4-(2-chloroacety!)phenyl)-2-methylpropanoate compound of formula-3 with a suitable reducing agent in a suitable solvent to provide methyl 2-(4-(2-chloroethy!) phenyl)-2-methylpropanoate compound of formula-10. Wherein, the suitable reducing agent and the suitable solvent are same as defined for step-d) of the frst aspect of the present invention. 4‘The eighth aspect of the present invention provides a novel process for the preparation of methyl 2-(4-Q-(4(I-(-ethoxyethyl)- H-benzo{d}imidazol-2-y)pipetidin-1-yl) ethyl)phenyl)-2- rmethylpropanoste compound of formula-7, comprising of; 4) Reducing the methyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate ‘compound of formula-3 with a suitable reducing agent in a suitable solvent to provide methyl 2-(4-2- chlordethyl)phenyl)-2-methylpropanoate compound of formula-10, b) reacting the compound of formula-10 with 1-(2-cthoxyethyl)-2-(piperidin-4-yl)-1H- benzo[d]imidazole compound of formule in presence of a suitable base in a suitable solvent to provide methyl 2-(4-(2-(4-(1-(2-cthoxyethyl)-1H-benzof dJimidazol-2-y)piperidin-1-yl) ethy))phenyl)-2-methylpropanoate compound of formula-7, Wherein, in step-a) the suitable reducing agent and the suitable solvent are same as defined for step-d) of the first aspect of the present invention; In step-b) the suitable base and the suitable solvent are same as defined for step-b) of the first aspect of the present invention The ninth aspect of the present invention provides novel intermediate compounds useful for the preparation of 2-(4-(2-{4-[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl}-1-piperidinyl} ethyl) phenyl]-2-methylprdpanoic acid compound of formula-1. The novel intermediate compounds are represented by the structural formulae given below; CEOS OK ec, OF O7 OF oe bet COOP OS ca, OOO fon 6 Se och, cr 6 Wherein, ‘Et’ represents ethyl group. . 15‘The present invention is schematically represented as follows. Schem ore Coe wl ¢, Formula-2 oe + Formula-4 = OCH AL. or 6 cr 7 ay © Formula-3 > Ease 3 CHO OS cn, Reston OLSON vO’. oct Formula-7 : CO Formutas OBL 1 a lee |r ‘ ° COO Fen Reduction COOP OF en Bilastine Gey Formula-t ba Formula-6 16SchemestI: OOF OF, (Formula. be Reduction, Hydroiysis Mt 9 WOK OPO OS en 2. Formutus © gO Forinalas ° OF XG, Ob: F Redtion aN | Resuetioin or O Fons CEOP OF an OF Formula-7 yy Formulad ore Hydrolysis ob + [soviten N, OOF Bilastine 8 Formula-1 Scheme-IML aR a Reduction, nog Oy yt Forthula:3 Formala-10 “be A Base : ; COOK ce, ¢— Formuta-7 OFt [Hvar BilastineExamples: , Example-1: (Formula-3) Aluminium chloride (78.4 gm) was slowly added to a pre-cooled solution of methyl Preparation of methyl 2-(4-(2-chiloroacetyl)phenyl)-2-methylpropanoate 2-methyl-2-phenylpropanoate compound of formula-2 (50 gm) in dichloromethane (1500 ml) at 0-5°C. Chloroacetyl chloride (38 gm) was slowly added to the reaction mixture at O-5°C and stirred for 15 min at the same temperature. Raised the temperature of the reaction mixture to 25- 30°C and stirred for 10 hrs at the same temperature. After completion of the reaction, the reaction mixture was slowly added to pre-cooled 2N hydrochloric acid solution at 0-5°C and stiered for 10 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane, The combined organic layer was “washed with 10% sodium bicarbonate solution followed by sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely under reduced pressure to get the ttle compound, Yield: $5.0 gm. Example-2: Preparation of methyl 2-(4-(2-(4-(J-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl) piperidin-1-yl)acety!)phenyl)-2-methylpropanoate (Formula-5) A mixture of 1-@-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzofd]imidazole compound of formula-4 (2 gm), acetone (30 ml) and potassium carbonate (1.51 gm) was stired for 2 hrs at 25- compound of 30°C, A solution of methyl 2-(4(2-chloroacey!)pheny)-#-methylpropanoa formal (1.86 gm) in acetone (10 ml) was slowly added to the reaction mixture at 25-20°C and stirred for 10 hrs atthe same temperature. After completion ofthe reaction, water and cthyt acetate were’ added to the reaction mixture. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate, The combined organie layers were washed with 10% sodium bicarbonate sofution followed by sodium chloride solution, Dried the organic layer over sodium sulfate and distilled off the solvent completely under reduced pressure to get the ttle compound, Yield: 3.2 gm. 18i vd Dated this day_2.2°° _ of May 2013. Authorized Signatory (Srinivasan Thirumalai Rajan) MSN Laboratories Private Limited 19Abstract ‘The pfesent invention relates to novel process for the preparation of 2:[4-2-(4-[1-2- ethoxyethyl)-1H-benzintidazol-2-yl}-1-piperidinyl} ethy)phenyl}-2-methylpropanoie acid reptesented by the following structural formula-1 COW O Fm e The present invention also provides novel intermediate compounds useful for the Formula-1 preparation of éompound of formulae1