WO2014188453A2 - Novel process for the preparation of 2-[4-(2-{4-[1-(2-ethoxyethyl)-1h-benzimidazol-2-yl]-1-piperidinyl}ethyl) phenyl]-2-methylpropanoic acid - Google Patents

Novel process for the preparation of 2-[4-(2-{4-[1-(2-ethoxyethyl)-1h-benzimidazol-2-yl]-1-piperidinyl}ethyl) phenyl]-2-methylpropanoic acid Download PDF

Info

Publication number
WO2014188453A2
WO2014188453A2 PCT/IN2014/000353 IN2014000353W WO2014188453A2 WO 2014188453 A2 WO2014188453 A2 WO 2014188453A2 IN 2014000353 W IN2014000353 W IN 2014000353W WO 2014188453 A2 WO2014188453 A2 WO 2014188453A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
solvents
phenyl
acid
Prior art date
Application number
PCT/IN2014/000353
Other languages
French (fr)
Other versions
WO2014188453A3 (en
Inventor
Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Ghojala Venkat Reddy
Original Assignee
Msn Laboratories Private Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Msn Laboratories Private Limited filed Critical Msn Laboratories Private Limited
Priority claimed from IN5394CH2013 external-priority patent/IN2013CH05394A/en
Publication of WO2014188453A2 publication Critical patent/WO2014188453A2/en
Publication of WO2014188453A3 publication Critical patent/WO2014188453A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention provides novel processes for the preparation of 2-[4-(2- ⁇ 4-[l- (2-ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl ⁇ ethyl)phenyl]-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.
  • 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.
  • the disclosed process involves the reaction of the benzimidazole intermediate with tosylated oxazole intermediate in presence of sodium carbonate followed by reaction of obtained intermediate compound with l-chloro-2-ethoxyethane to provide oxazole protected Bilastine. Cleavage of the said oxazole ring by treating it with 3N HC1 provides Bilastine.
  • the above process has several disadvantages in that it involves the preparation of an intermediate compound having oxazole group and then cleavage of oxazole ring by hydrolyzing the compound in presence of acid and this making the whole process complicated.
  • alkali metal hydrides such as sodium hydride as a base. Usage of alkali metal hydrides is not advisable on commercial scale in safety point of view.
  • the present inventors overcome all the disadvantages associated with the prior-art process 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 which is able to produce highly pure Bilastine with better yields.
  • 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 which is able to produce highly pure Bilastine with better yields.
  • the first 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-methylpropanoic acid compound of formula- 1, comprising of;
  • the second 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- 1.
  • the third 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- 1.
  • the fourth 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- 11.
  • the fifth aspect of the present invention is to provide an improved process for the preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2-methylpropanoate compound of formula- 17.
  • the sixth aspect of the present invention is to provide a novel process for the preparation of methyl 2-(4-(2-(4-(l -(2-ethoxyethyl)- lH-benzo[d]imidazol-2-yl)piperidin-l- yl)ethyl)phenyl)-2-methylpropanoate compound of formula- 13.
  • the seventh aspect of the present invention is to provide novel intermediate compounds which are useful for the preparation of 2-[4-(2- ⁇ 4-[l -(2-ethoxyethyl)- 1 H- benzimidazol-2-yl]-l -piperidinyl ⁇ ethyl)phenyl]-2-methyl propanoic acid compound of formula-1.
  • suitable solvent refers to "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petroleum 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, 1,4-dioxane and the like; “ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents” such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidon
  • 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 hyd ride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia, alkali metal and alkaline earth metal salts of
  • 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- methylpropanoic acid compound of formula- 1, comprising of;
  • the suitable base is selected from hydroxides, alkoxides, carbonates and bicarbonates of alkali metals or their mixtures;
  • the suitable chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous trichloride, phosphorous pentachloride;
  • the suitable base is selected from organic bases, inorganic bases or their mixtures;
  • the Lewis acid is selected from but not limited to aluminum chloride, aluminum bromide, boron trifluoride, boron tribromide, tin tetrachloride, tin tetrabromide, stannous chloride (SnCl 2 ), ferric chloride (FeCl 3 ), zinc chloride (ZnCl 2 ), titanium tetrachloride (TiCl 4 ) or mixtures or hydrates thereof;
  • 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 BF 3 -etherate; trichlorosilane, sodium borohydride optionally in combination with BF 3 -etherate, diborane, potassium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminium hydride, diisobutylaluminium hydride (DIBAL), lithium triethylborohydride (LiEt 3 BH), L-selectride (lithium tri-sec-butyl(hydrido)borate(l- )), sodium bis(2-methoxyemoxy)aluminiumhydride (vitride)and the like;
  • trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with a suitable Lewis acid or trifluoroacetic
  • the suitable reducing agent is selected from trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with a suitable Lewis acid or trifluoroacetic acid or BF 3 -etherate, Pd/C, Pt/C and the like;
  • the suitable base is selected from organic bases, inorganic bases or their mixtures;
  • the suitable catalyst is selected from alkali metal halides such as sodium iodide, potassium iodide, sodium bromide, potassium bromide and the like;
  • step-g) is carried out optionally in presence of a suitable phase transfer catalyst such as terra alkyl/aryl ammonium halides/hydroxides;
  • the suitable acid is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and the like;
  • the suitable base is selected from inorganic bases such as hydroxides, alkoxides, carbonates and bicarbonates of alkali metals or their mixtures, preferably alkali metal hydroxides;
  • 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, acetic acid, formic acid or their mixtures.
  • a preferred embodiment of the present invention provides a 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;
  • the hydroxy group of compound of formula-7 can be optionally converted to easily leaving group such as methane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate or the like followed by reduction of the obtained compound with a suitable reducing agent in a suitable solvent provides compound of formula-8.
  • compound of formula-8 can also be prepared by reducing the 2-(4-(2-chloroacetyl)phenyl)-N-methoxy-N,2-dimethyl propanamide compound of formula-6 with a suitable reducing agent in a suitable solvent to directly provide 2-(4-(2-cUoroethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-8.
  • the suitable reducing agent is selected from but not limited to trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with a Lewis acid or trifluoroacetic acid or BF 3 -etherate; sodium borohydride optionally in combination with BF 3 - etherate, hydrazine (Wolff-Kishner reduction), Zn-Hg/HCl (Clemmensen reduction).
  • trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with a Lewis acid or trifluoroacetic acid or BF 3 -etherate
  • sodium borohydride optionally in combination with BF 3 - etherate, hydrazine (Wolff-Kishner reduction), Zn-Hg/HCl (Clemmensen reduction).
  • N-methoxy-N,2-dimethyl-2-phenylpropanamide compound of formula-5 of the present invention can also be prepared by reacting the carboxylic acid compound of formula-3 with N,0-dimethylhydroxylarnine hydrochloride in presence of a suitable coupling agent and a suitable solvent optionally in presence of a suitable base to provide compound of formula-5.
  • the suitable coupling agent is selected from ⁇ , ⁇ '-dicyclohexylcarbodiimide
  • DCC ⁇ , ⁇ '-diisopropylcarbodiimide
  • DIC l-emyl-3-(3-dimemylaminopropyl) carbodiirnide hydrochloride
  • CDI N,N-carbonyldiimidazole
  • alkyl or aryl chloroformates such as ethyl chloroformate, benzylchloroformate, diphenylphosphoroazidate (DPP A), 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), benzotriazol-l-yl-oxy tripyrrolidinophosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride and the like optionally in combination with l-hydroxy-7-azatriazole (HO At), 1-hydroxybenzotriazole
  • the suitable base is selected from organic bases, inorganic bases or their mixtures
  • the suitable solvent is selected from alcohol solvents, ether solvents, ester solvents, chloro solvents, hydrocarbon solvents, nitrile solvents, polar solvents, polar-aprotic solvents, ketone solvents or their mixtures.
  • the second 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;
  • step-a) the suitable Lewis acid and the suitable solvent are same as defined in step-d) of the first aspect of the present invention.
  • step-b) the suitable base, the suitable catalyst and the suitable solvent are same as defined in step-g) of the first aspect of the present invention.
  • the suitable reducing agent is selected from but not limited to trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with a Lewis acid or trifluoroacetic acid or BF 3 -etherate; sodium borohydride optionally in combination with BF 3 - etherate, hydrazine (Wolff-Kishner reduction), Zn-Hg/HCl (Clemmensen reduction) and the suitable solvent is selected from chloro solvents, ketone solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents, polar-aprptic solvents, nitrile solvents, alcohol solvents, acetic acid, formic acid or their mixtures;
  • trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with a Lewis acid or trifluoroacetic acid or BF 3 -etherate
  • sodium borohydride optionally in combination with BF 3 - ether
  • step-d) the suitable base and the suitable solvent are same as defined in step-h) of the 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-emoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl ⁇ ethyl) phenyl]-2-methyl propanoic acid compound of formula- 1, comprising of;
  • compound of formula- 1 can be prepared by hydrolyzing the methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2- yl)piperidin-l-yl)acetyl)phenyl)-2-methyl propanoate compound of formula- 12 in presence of a suitable base followed by reducing the obtained 2r(4-(2-(4-(l-(2-ethoxyethyl)-lH- benzo[d]imidazol-2-yl)piperidin-l-yl)acetyl)phenyl)-2-methylpropanoic acid compound of formula- 14
  • the suitable base is selected from inorganic bases and the suitable reducing agent is same as defined in step-c) of the second aspect of the present invention.
  • the third 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) Reducing the methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl)piperidin- l-yl)acetyl)phenyl)-2 -methyl propanoate compound of formula- 12 with a suitable reducing agent in a suitable solvent to provide methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH- benzo[d]imidazol-2-yl)piperidin- 1 -yl)- 1 -hydroxyethyl)phenyl)-2
  • step-a) the suitable reducing agent and the suitable solvent are same as defined in step-e) of the first aspect of the present invention
  • step-b) the suitable reducing agent and the suitable solvent are same as defined in step-f) of the first aspect of the present invention.
  • step-c) the suitable base and the suitable solvent are same as defined in step-h) of the first aspect of the present invention.
  • the hydroxy group of compound of formula- 16 can be optionally converted to easily leaving group such as methane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate or the like followed by reduction of the obtained compound with a suitable reducing agent in a suitable solvent provides compound of formula- 13.
  • the fourth aspect of the present invention provides a process for the preparation of methyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula-11, 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-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula- 11.
  • the suitable Lewis acid and the suitable solvent are same as defined in step- d) of the first aspect of the present invention.
  • a preferred embodiment of the present invention provides a process for the preparation of methyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula-11, comprising of reacting the methyl 2-methyl-2-phenylpropanoate compound of formula-2 with chloroacetyl chloride in presence of aluminium chloride in dichloromethane to provide compound of formula- 11.
  • the fifth aspect of the present invention provides an improved process for the preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2-methylpropanoate compound of formula- 17,
  • the suitable reducing agent and the suitable solvent are same as defined in step-c) of the second aspect of the present invention.
  • a preferred embodiment of the present invention provides an improved process for the preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2-methylpropanoate compound of formula- 17, comprising of reducing the methyl 2-(4-(2-chloroacetyl)phenyl)-2- methylpropanoate compound of formula-11 with triethylsilane in presence of titanium tetrachloride in dichloromethane to provide compound of formula- 17.
  • the sixth aspect of the present invention provides a novel process for the preparation of methyl 2-(4-(2-(4-( 1 -(2-ethoxyethyl)- 1 H-benzo[d]imidazol-2-yl)piperidin- 1 -yl)ethyl) phenyl)-2-methylpropanoate compound of formula- 13 , comprising of;
  • step-a) the suitable reducing agent and the suitable solvent are same as defined in step-c) of the second aspect of the present invention.
  • step-b) the suitable base, the suitable solvent and the suitable catalyst are same as defined in step-g) of the first aspect of the present invention.
  • a preferred embodiment of the present invention provides a novel process for the preparation of methyl 2-(4-(2-(4-(l -(2-ethoxyethyl)- lH-benzo[d]imidazol-2-yl)piperidin-l- yl)ethyl)phenyl)-2-methylpropanoate compound of formula-13, comprising of;
  • the seventh aspect of the present invention provides novel intermediate compounds which are useful for the preparation of 2-[4-(2- ⁇ 4-[l-(2-emoxyemyl)-lH-benzimidazol-2-yl]- l-piperidinyl ⁇ ethyl)phenyl]-2-methyl propanoic acid compound of formula- 1.
  • the said novel intermediate compounds are represented by. the below mentioned structural formulae;
  • 'Me' represents methyl and 'Et' represents ethyl group.
  • Bilastine obtained by the process of the present invention was analyzed by HPLC under the following conditions;
  • Apparatus A liquid chromatographic system equipped with variable wavelength PDA- detector; Column: Kromasil-5-C18, 250x4.6 mm, 5.0 ⁇ or equivalent; Flow rate: 1.0 mL/min; Wavelength: 220 nm; Column temperature: 45°C; Injection volume: 5 ⁇ .; 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.
  • Bilastine produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball mills, roller and hammer mills and jet mills. Milling or micronization may be performed before drying or after drying of the product.
  • the present invention is schematically represented as follows.
  • 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 rhin at the same temperature. Filtered the solid, washed with water and dried the material to get the title compound.
  • N,0-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 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 ml) 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 with water.
  • BF 3 -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.
  • Example-7 Preparation of 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl) piperidin-l-yI)ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide (Formula-10)
  • Aluminium chloride (112.7 gm) and dichloromethane (500 ml) were added to methyl 2-methyl-2-phenylpropanoate compound of formula-2 (50 gm) at 25-30°C. Cooled the reaction mixture to -10°C to -5°C and chloroacetyl chloride (34 ml) was slowly added. Raised the temperature of the reaction mixture to 25-30°C and stirred for 12 hrs at the same temperature. Quenched the reaction mixture with 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 to get the title compound.
  • Both the organic and aqueous layers were separated and the aqueous layer was neutralized using potassium carbonate. Extracted the aqueous layer with methyl tert-butyl ether. Both the organic and aqueous layers were separated and dried the organic layer over sodium sulfate. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.
  • Titanium tetrachloride (19.3 gm) was slowly added to a pre-cooled mixture of methyl 2-(4-(2-(4-( 1 -(2-ethoxyethyl)- 1 H-benzo[d]imidazol-2-yl)piperidin- 1 -yl)acetyl)phenyl)-2- methylpropanoate compound of formula-12 (10 gm) and dichloromethane (200 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C, triethylsilane (9 gm) was added and stirred the reaction mixture for 4 hrs at the same temperature. Quenched the reaction mixture with water at below 10°C. 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.
  • Example-12 Preparation of methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazoI- 2-yl)piperidin-l-yl)-l-hydroxyethyl)phenyl)-2-methyIpropanoate (Formula-16)
  • Example-13 Preparation of methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol- 2-yl)piperidin-l-yl)ethyl)phenyl)-2-methylpropanoate (Formula-13)
  • Methane sulfonyl chloride (1.4 gm) was slowly added to a mixture of methyl 2-(4-(2- (4-( 1 -(2-ethoxyethyl)- 1 H-benzo[d]imidazol-2-yl)piperidin- 1 -yl)- 1 -hydroxyethyl)phenyl)-2- methylpropanoate compound of formula- 16 (5 gm), dichloromethane (35 ml) and triethylamine (1.25 gm) at 25-30°C and stirred for 3 hrs at the same temperature. Water and dichloromethane were added to the reaction mixture.
  • Titanium tetrachloride (37.2 gm) was slowly added to a pre-cooled mixture of methyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula- 11 (10 gm) and dichloromethane (200 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25- 30°C, triethylsilane (17.3 gm) was added and stirred the reaction mixture for 4 hrs at the same temperature. Quenched the reaction mixture with water at below 10°C. 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.
  • Example-15 Preparation of methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzold]imidazol- 2-yl)piperidin-l-yl)ethyl)phenyl)-2-methylpropanoate (Formula-13)
  • a mixture of benzene- 1,2-diamine compound of formula-29 (100 gm), piperidine-4- carboxylic acid compound of formula-30 (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 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 solid, washed with water.
  • Example-17 Preparation of tert-butyl 4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl) piperidine-l-carboxylate (Formula-32)
  • 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 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 to get the title compound.
  • D(0.1) is 2.88 ⁇
  • D(0.5) is 12.48 ⁇
  • D(0.9) is 34.09 ⁇ .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to novel process for the preparation of 2-[4-(2-{4-[l-(2- ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl}ethyl)phenyl]-2-methylpropanoic acid represented by the following structural formula- 1. Formula- 1 The present invention also provides novel intermediate compounds useful for the preparation of compound of formula- 1.

Description

Novel process for the preparation of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH- benzimidazol-2-yll-l-piperidinv ethyl)phenyll-2-methylpropanoic acid
Related Applications:
This application claims the benefit of priority of our Indian patent applications 2276/CHE/2013 filed on 24th May 2013 and 5394/CHE/2013 filed on 22nd Nov 2013 which are incorporated herein by reference.
Field of the Invention:
The present invention provides novel processes for the preparation of 2-[4-(2-{4-[l- (2-ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl}ethyl)phenyl]-2 -methylpropanoic acid represented by the following structural formula- 1.
Figure imgf000002_0001
Formula-!
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-[ 1 -(2-ethoxyethyl)- 1 H-benzimidazol-2-yl]- 1 -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 2-[4-(2-{4-[l -(2-ethoxyethyl)- 1 H-benzimidazol-2-yl]- 1- piperidinyl}ethyl)phenyl]-2-methylpropanoic acid and its synthesis. The process disclosed in the said patent is schematically represented in scheme- A. Scheme-A:
Figure imgf000003_0001
The disclosed process involves the reaction of the benzimidazole intermediate with tosylated oxazole intermediate in presence of sodium carbonate followed by reaction of obtained intermediate compound with l-chloro-2-ethoxyethane to provide oxazole protected Bilastine. Cleavage of the said oxazole ring by treating it with 3N HC1 provides Bilastine.
The above process has several disadvantages in that it involves the preparation of an intermediate compound having oxazole group and then cleavage of oxazole ring by hydrolyzing the compound in presence of acid and this making the whole process complicated.
The above process involves the usage of alkali metal hydrides such as sodium hydride as a base. Usage of alkali metal hydrides is not advisable on commercial scale in safety point of view.
Further, the above process produces Bilastine in very low yields with number of by-products. In view of all these disadvantages, 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 process 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 which is able to produce highly pure Bilastine with better yields. 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-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl} ethyl) phenyl]-2-methylpropanoic acid compound of formula- 1, comprising of;
a) Hydrolyzing the methyl 2-methyl-2-phenylpropanoate compound of formula-2 in presence of a suitable base in a suitable solvent to provide 2-methyl-2-phenylpropanoic acid compound 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 Ν,Ο-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 suitable 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- 1 -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 presence of a suitable solvent to provide 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2- dimethylpropanamide compound of formula-8,
g) 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 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-berizo[d]imidazol-2-yl)piperidin- 1 -yl)ethyl)phenyl)-N-methoxy-N,2- dimethylpropanamide compound of formula- 10,
h) hydrolyzing the compound of formula- 10 in presence of a suitable acid or a suitable base in a suitable solvent to provide 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)- 1 H-benzimidazol-2-yl]- 1 -piperidinyl} ethyl) phenyl] -2-methyl propanoic acid compound of formula- 1. The third 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- 1.
The fourth 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- 11.
" The fifth aspect of the present invention is to provide an improved process for the preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2-methylpropanoate compound of formula- 17.
The sixth aspect of the present invention is to provide a novel process for the preparation of methyl 2-(4-(2-(4-(l -(2-ethoxyethyl)- lH-benzo[d]imidazol-2-yl)piperidin-l- yl)ethyl)phenyl)-2-methylpropanoate compound of formula- 13. The seventh aspect of the present invention is to provide novel intermediate compounds which are useful for the preparation of 2-[4-(2- {4-[l -(2-ethoxyethyl)- 1 H- benzimidazol-2-yl]-l -piperidinyl} ethyl)phenyl]-2-methyl propanoic 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, petroleum 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, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride 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, tert-butanol, ethane- 1,2-diol, propane- 1,2-diol and the like; "polar solvents" such as water; acetic acid, formic acid or their mixtures.
The term "suitable base" used in the present invention 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 hyd ride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia, alkali metal and alkaline earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; "organic bases" like dimemylamine, diethylamine, diisopropyl amine, diisopropylemylamine, di n-butylamine, diisobutylamine, triethylamine, tributylamine, tert- butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), N-methylmorpholine (NMM), l,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine, lithium diisopropylamide; "organolithium bases" such as n-butyl lithium, "organosilicon bases" such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) 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- methylpropanoic acid compound of formula- 1, comprising of;
a) Hydrolyzing the methyl 2-methyl-2-phenylpropanoate compound of formula-2
Figure imgf000007_0001
Formula-2
in presence of a suitable base in a suitable solvent to provide 2-methyl-2-phenylpropanoic acid compound of formula-3,
Figure imgf000007_0002
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,
Figure imgf000007_0003
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,
Figure imgf000007_0004
Formula-5
d) reacting the compound of formula-5 with chloroacetyl chloride in presence of a suitable Lewis acid in a suitable solvent to provide 2-(4-(2-chloroacetyl)phenyl)-N-methoxy-N,2- dimethylpropanamide co
Figure imgf000007_0005
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,
Figure imgf000008_0001
Formula-7
f) reducing the compound of formula-7 with a suitable reducing agent optionally in presence of a suitable solvent to provide 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2- dimethylpropanamide comp
Figure imgf000008_0002
Formula-8
g) reacting the compound of formula-8 with l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH- benzo[d]imidazole compound of
Figure imgf000008_0003
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)ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula- 10,
Figure imgf000008_0004
Formula- 10
h) hydrolyzing the compound of formula- 10 in presence of a suitable acid or a suitable base in 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 or their mixtures;
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 organic bases, inorganic bases or their mixtures;
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 (SnCl2), ferric chloride (FeCl3), zinc chloride (ZnCl2), titanium tetrachloride (TiCl4) 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, diborane, potassium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminium hydride, diisobutylaluminium hydride (DIBAL), lithium triethylborohydride (LiEt3BH), L-selectride (lithium tri-sec-butyl(hydrido)borate(l- )), sodium bis(2-methoxyemoxy)aluminiumhydride (vitride)and the like;
In step-f) the suitable reducing agent is selected from trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with a suitable Lewis acid or trifluoroacetic acid or BF3-etherate, Pd/C, Pt/C and the like;
In step-g) the suitable base is selected from organic bases, inorganic bases or their mixtures; the suitable catalyst is selected from alkali metal halides such as sodium iodide, potassium iodide, sodium bromide, potassium bromide and the like; step-g) is carried out optionally in presence of a suitable phase transfer catalyst such as terra alkyl/aryl ammonium halides/hydroxides;
In step-h) the suitable acid is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and the like; the suitable base is selected from inorganic bases such as hydroxides, alkoxides, carbonates and bicarbonates of alkali metals or their mixtures, preferably alkali metal hydroxides;
In step-a) to step-h) 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, acetic acid, formic acid or their mixtures. A preferred embodiment of the present invention provides a 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) Hydrolyzing the methyl 2-methyl-2-phenylpropanoate compound of formula-2 in presence of sodium hydroxide in aqueous methanol to provide 2-methyl-2- phenylpropanoic acid compound of formula-3,
b) reacting the compound of formula-3 with thionyl chloride in dichloromethane and optionally amount of 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 compound of formula-7,
f) reducing the compound of formula-7 with triethylsilane in combination with BF3- etherate to provide 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-8,
g) 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 sodium carbonate, potassium iodide and tetrabutylammonium bromide in toluene to provide 2-(4-(2-(4-(l-(2- ethoxyethyl)- 1 H-berizo[d]imidazol-2-yl)piperidin- 1 -yl)ethyl)phenyl)-N-methoxy-N,2- dimethylpropanamide compound of formula- 10,
h) hydrolyzing the compound of formula- 10 in presence of hydrochloric acid in water to provide compound of formula- 1. In the above process, the hydroxy group of compound of formula-7 can be optionally converted to easily leaving group such as methane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate or the like followed by reduction of the obtained compound with a suitable reducing agent in a suitable solvent provides compound of formula-8.
The present inventors earnestly tried different processes for the preparation of compound of formula- 1 and found the above process as very advantageous over the prior known processes in terms of yield and quality of the product. In the other embodiment of the present invention, compound of formula-8 can also be prepared by reducing the 2-(4-(2-chloroacetyl)phenyl)-N-methoxy-N,2-dimethyl propanamide compound of formula-6 with a suitable reducing agent in a suitable solvent to directly provide 2-(4-(2-cUoroethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-8.
Wherein, the suitable reducing agent is selected from but not limited to trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with a Lewis acid or trifluoroacetic acid or BF3-etherate; sodium borohydride optionally in combination with BF3- etherate, hydrazine (Wolff-Kishner reduction), Zn-Hg/HCl (Clemmensen reduction). The N-methoxy-N,2-dimethyl-2-phenylpropanamide compound of formula-5 of the present invention can also be prepared by reacting the carboxylic acid compound of formula-3 with N,0-dimethylhydroxylarnine hydrochloride in presence of a suitable coupling agent and a suitable solvent optionally in presence of a suitable base to provide compound of formula-5.
Wherein the suitable coupling agent is selected from Ν,Ν'-dicyclohexylcarbodiimide
(DCC), Ν,Ν'-diisopropylcarbodiimide (DIC), l-emyl-3-(3-dimemylaminopropyl) carbodiirnide hydrochloride (EDC.HC1), N,N-carbonyldiimidazole (CDI), alkyl or aryl chloroformates such as ethyl chloroformate, benzylchloroformate, diphenylphosphoroazidate (DPP A), 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), benzotriazol-l-yl-oxy tripyrrolidinophosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride and the like optionally in combination with l-hydroxy-7-azatriazole (HO At), 1-hydroxybenzotriazole
(HOBt), l-hydroxy-lH-l,2,3-triazole-4-carboxylate (HOCt), O-(benzotriazol-l-yl)-
Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS); the suitable base is selected from organic bases, inorganic bases or their mixtures; the suitable solvent is selected from alcohol solvents, ether solvents, ester solvents, chloro solvents, hydrocarbon solvents, nitrile solvents, polar solvents, polar-aprotic solvents, ketone solvents or their mixtures.
The second 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) Reacting the methyl 2-methyl-2-phenylpropanoate compound of formula-2
Figure imgf000012_0001
Formula-2
with chloroacetyl chloride in presence of a Lewis acid in a suitable solvent to provide methyl 2-(4-(2-chloroacetyl)p compound of formula-11,
Figure imgf000012_0002
Formula- 1 1
b) reacting the compound of formula-11 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 methyl 2-(4-(2-(4-(l-(2- ethoxyemyl)-lH-benzo[d]imidazol-2-yl)piperidin-l-yl)acetyl)phenyl)-2 -methyl propanoate compound of formula- 12,
Figure imgf000012_0003
Formula- 12 c) reducing the compound of formula- 12 with a suitable reducing agent in a suitable solvent to provide methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl)piperidin-l- yl)ethyl)phenyl)-2-methylpropanoate compound of formula- 13,
Figure imgf000013_0001
Formula- 13
d) hydrolyzing the compound of formula- 13 in presence of a suitable base in a suitable solvent to provide compound of formula- 1.
Wherein, in step-a) the suitable Lewis acid and the suitable solvent are same as defined in step-d) of the first aspect of the present invention;
In step-b) the suitable base, the suitable catalyst and the suitable solvent are same as defined in step-g) of the first aspect of the present invention;
In step-c) the suitable reducing agent is selected from but not limited to trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with a Lewis acid or trifluoroacetic acid or BF3-etherate; sodium borohydride optionally in combination with BF3- etherate, hydrazine (Wolff-Kishner reduction), Zn-Hg/HCl (Clemmensen reduction) and the suitable solvent is selected from chloro solvents, ketone solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents, polar-aprptic solvents, nitrile solvents, alcohol solvents, acetic acid, formic acid or their mixtures;
In step-d) the suitable base and the suitable solvent are same as defined in step-h) of the 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-emoxyethyl)-lH-benzimidazol-2-yl]-l-piperidinyl} ethyl) phenyl]-2-methyl propanoic 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 aluminium chloride in dichloromethane to provide methyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula-11, b) reacting the compound of formula- 11 with l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH- benzo[d]imidazole compound of formula-9 in presence of potassium carbonate in acetone to provide methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl)piperidin-l- yl)acetyl)phenyl)-2 -methyl propanoate compound of formula- 12,
c) reducing the compound of formula- 12 with triethylsilane in dichloromethane in presence of titanium tetrachloride to provide methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH- benzo[d]imidazol-2-yl)piperidin- 1 -yl)ethyl)phenyl)-2-methylpropanoate compound of formula- 13,
d) hydrolyzing the compound of formula- 13 in presence of sodium hydroxide in ethanol to provide compound of formula- 1.
In the other embodiment of the present invention, compound of formula- 1 can be prepared by hydrolyzing the methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2- yl)piperidin-l-yl)acetyl)phenyl)-2-methyl propanoate compound of formula- 12 in presence of a suitable base followed by reducing the obtained 2r(4-(2-(4-(l-(2-ethoxyethyl)-lH- benzo[d]imidazol-2-yl)piperidin-l-yl)acetyl)phenyl)-2-methylpropanoic acid compound of formula- 14
Figure imgf000014_0001
Formula- 14
with a suitable reducing agent in a suitable solvent.
Wherein, the suitable base is selected from inorganic bases and the suitable reducing agent is same as defined in step-c) of the second aspect of the present invention.
The third 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) Reducing the methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl)piperidin- l-yl)acetyl)phenyl)-2 -methyl propanoate compound of formula- 12 with a suitable reducing agent in a suitable solvent to provide methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH- benzo[d]imidazol-2-yl)piperidin- 1 -yl)- 1 -hydroxyethyl)phenyl)-2-methylpropanoate compound of formula- 16,
Figure imgf000015_0001
Formula- 16
b) reducing the compound of formula- 16 with a suitable reducing agent in a suitable solvent to provide methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl)piperidin-l- yl)ethyl)phenyl)-2-methylpropanoate compound of formula- 13,
c) hydrolyzing the compound of formula- 13 in presence of a suitable base in a suitable solvent to provide compound of formula- 1.
Wherein, in step-a) the suitable reducing agent and the suitable solvent are same as defined in step-e) 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-f) of the first aspect of the present invention;
In step-c) the suitable base and the suitable solvent are same as defined in step-h) of the first aspect of the present invention.
In the above process, the hydroxy group of compound of formula- 16 can be optionally converted to easily leaving group such as methane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate or the like followed by reduction of the obtained compound with a suitable reducing agent in a suitable solvent provides compound of formula- 13. The fourth aspect of the present invention provides a process for the preparation of methyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula-11, 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-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula- 11.
Wherein, the suitable Lewis acid and the suitable solvent are same as defined in step- d) of the first aspect of the present invention.
A preferred embodiment of the present invention provides a process for the preparation of methyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula-11, comprising of reacting the methyl 2-methyl-2-phenylpropanoate compound of formula-2 with chloroacetyl chloride in presence of aluminium chloride in dichloromethane to provide compound of formula- 11. The fifth aspect of the present invention provides an improved process for the preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2-methylpropanoate compound of formula- 17,
Figure imgf000016_0001
Formula- 17
comprising of reducing the methyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula-11 with a suitable reducing agent in a suitable solvent to provide compound of formula- 17.
Wherein, the suitable reducing agent and the suitable solvent are same as defined in step-c) of the second aspect of the present invention.
A preferred embodiment of the present invention provides an improved process for the preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2-methylpropanoate compound of formula- 17, comprising of reducing the methyl 2-(4-(2-chloroacetyl)phenyl)-2- methylpropanoate compound of formula-11 with triethylsilane in presence of titanium tetrachloride in dichloromethane to provide compound of formula- 17. The sixth aspect of the present invention provides a novel process for the preparation of methyl 2-(4-(2-(4-( 1 -(2-ethoxyethyl)- 1 H-benzo[d]imidazol-2-yl)piperidin- 1 -yl)ethyl) phenyl)-2-methylpropanoate compound of formula- 13 , comprising of;
a) Reducing the methyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula- 11 with a suitable reducing agent in a suitable solvent to provide methyl 2-(4-(2- chloroethyl)phenyl)-2-methylpropanoate compound of formula- 17,
b) reacting the compound of formula- 17 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-13.
Wherein, in step-a) the suitable reducing agent and the suitable solvent are same as defined in step-c) of the second aspect of the present invention;
In step-b) the suitable base, the suitable solvent and the suitable catalyst are same as defined in step-g) of the first aspect of the present invention.
A preferred embodiment of the present invention provides a novel process for the preparation of methyl 2-(4-(2-(4-(l -(2-ethoxyethyl)- lH-benzo[d]imidazol-2-yl)piperidin-l- yl)ethyl)phenyl)-2-methylpropanoate compound of formula-13, comprising of;
a) Reducing the methyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula- 11 with triethylsilane in presence of titanium tetrachloride in dichloromethane to provide methyl 2-(4-(2-chloroethyl)phenyl)-2-methylpropanoate compound of formula- 17,
b) reacting the compound of formula- 17 with l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH- benzo[d]imidazole compound of formula-9 in presence of sodium carbonate in toluene to provide compound of formula- 13.
The seventh aspect of the present invention provides novel intermediate compounds which are useful for the preparation of 2-[4-(2-{4-[l-(2-emoxyemyl)-lH-benzimidazol-2-yl]- l-piperidinyl}ethyl)phenyl]-2-methyl propanoic acid compound of formula- 1. The said novel intermediate compounds are represented by. the below mentioned structural formulae;
Figure imgf000018_0001
Wherein, 'Me' represents methyl and 'Et' represents ethyl group.
Bilastine obtained by the process of the present invention was analyzed by HPLC under the following conditions;
Apparatus: A liquid chromatographic system equipped with variable wavelength PDA- detector; Column: Kromasil-5-C18, 250x4.6 mm, 5.0 μηι or equivalent; Flow rate: 1.0 mL/min; Wavelength: 220 nm; Column temperature: 45°C; Injection volume: 5 μΐ.; 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 μπι 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 produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball mills, roller and hammer mills and jet mills. Milling or micronization may be performed before drying or after drying of the product. The present invention is schematically represented as follows.
Figure imgf000019_0001
Scheme-II:
Figure imgf000020_0001
Scheme-Ill:
Figure imgf000020_0002
Scheme-IV:
Figure imgf000021_0001
Scheme-V:
Figure imgf000021_0002
Wherein ¾' represents alkyl or aryl sulfonyl group. Scheme- VI:
Figure imgf000022_0001
Scheme- VII:
Formula-29
Figure imgf000022_0002
Formula-9 Formula-32
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-l: Preparation of 2-methyl-2-phenylpropanoic acid (FormuIa-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 rhin at the same temperature. Filtered the solid, washed with water and dried the material to get the title compound.
Yield: 89.0 gm.
Example-2: Preparation of 2-methyl-2-phenylpropanoyl chloride (FormuIa-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 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 utilized in the next step. Example-3: Preparation of N-methoxy-N,2-dimethyl-2-phenylpropanamide (FormuIa-5)
N,0-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-2 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 arid washed the organic layer with sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.
Yield: 84.0 gm. Example-4: Preparation of 2-(4-(2-chloroacetyl)phenyl)-N-methoxy-N,2-dimethyl propanamide (FormuIa-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 ml) 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 with 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 reaction mixture 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 10-15°C and stirred for 45 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-5: Preparation of 2-(4-(2-chloro-l-hydroxyethyl)phenyl)-N-methoxy-N,2- dimethylpropanamide (FormuIa-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 (dilute 30 ml of acetic acid with 70 ml of water). 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-6: 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-7: Preparation of 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl) piperidin-l-yI)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 sodium bicarbonate. 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 to get the title compound.
Yield: 8.0 gm. Example-8: Preparation of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazol-2-yl]-l- piperidinyl}ethyl)phenyl]-2-methylpropanoic acid (Formula-1)
A mixture 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 (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. Water and dichloromethane were added to the reaction mixture 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 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 solid, washed with acetone and dried the material to get the title compound.
Yield: 9.5 gm.
ExampIe-9: Preparation of methyl 2-(4-(2-chloroacetyl)phenyl)-2-methyIpropanoate (Formula-11)
Aluminium chloride (112.7 gm) and dichloromethane (500 ml) were added to methyl 2-methyl-2-phenylpropanoate compound of formula-2 (50 gm) at 25-30°C. Cooled the reaction mixture to -10°C to -5°C and chloroacetyl chloride (34 ml) was slowly added. Raised the temperature of the reaction mixture to 25-30°C and stirred for 12 hrs at the same temperature. Quenched the reaction mixture with 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 to get the title compound.
Yield: 70.5 gm.
ExampIe-10: Preparation of methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol- 2-yl)piperidin-l-yl)acetyl)phenyl)-2-methylpropanoate (Formula-12)
A mixture of methyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula- 11 (14 pi), l-(2-emoxyemyl)-2-^iperidm-4-yl)-lH-benzo[d]mudazole compound of formula-9 (15 gm), acetone (150 ml) and potassium carbonate (15 gm) was stirred for 6 hrs at 25-30°C. Water and methyl tert-butyl ether were added to the reaction mixture and stirred for 10 min. Both the organic and aqueous layers were separated. 2N HCl solution was added to the organic layer and stirred for 5 min. Both the organic and aqueous layers were separated and the aqueous layer was neutralized using potassium carbonate. Extracted the aqueous layer with methyl tert-butyl ether. Both the organic and aqueous layers were separated and dried the organic layer over sodium sulfate. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.
Yield: 21.5 gm.
Example-11: Preparation of methyl 2-(4-(2-(4-(l-(2-ethoxyethyI)-lH-benzo[d]imidazol- 2-yl)piperidin-l-yl)ethyl)phenyl)-2-methylpropanoate (FormuIa-13)
Titanium tetrachloride (19.3 gm) was slowly added to a pre-cooled mixture of methyl 2-(4-(2-(4-( 1 -(2-ethoxyethyl)- 1 H-benzo[d]imidazol-2-yl)piperidin- 1 -yl)acetyl)phenyl)-2- methylpropanoate compound of formula-12 (10 gm) and dichloromethane (200 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C, triethylsilane (9 gm) was added and stirred the reaction mixture for 4 hrs at the same temperature. Quenched the reaction mixture with water at below 10°C. 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: 9.0 gm.
Example-12: Preparation of methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazoI- 2-yl)piperidin-l-yl)-l-hydroxyethyl)phenyl)-2-methyIpropanoate (Formula-16)
Sodium borohydride (1.54 gm) was slowly added to a pre-cooled mixture of methyl
2-(4-(2-(4-( 1 -(2-ethoxyethyl)- 1 H-benzo[d]imidazol-2-yl)piperidin- 1 -yl)acetyl)phenyl)-2- methylpropanoate compound of formula-12 (10 gm) and methanol (50 ml) under nitrogen atmosphere at -10°C to -15°C and stirred the reaction mixture for 2 hrs at the same temperature. 12% aqueous sodium bicarbonate solution and dichloromethane were slowly added to the reaction mixture at -10°C to -15°C. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with 12% aqueous sodium bicarbonate solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.
Yield: 9.5 gm.
Example-13: Preparation of methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol- 2-yl)piperidin-l-yl)ethyl)phenyl)-2-methylpropanoate (Formula-13)
Methane sulfonyl chloride (1.4 gm) was slowly added to a mixture of methyl 2-(4-(2- (4-( 1 -(2-ethoxyethyl)- 1 H-benzo[d]imidazol-2-yl)piperidin- 1 -yl)- 1 -hydroxyethyl)phenyl)-2- methylpropanoate compound of formula- 16 (5 gm), dichloromethane (35 ml) and triethylamine (1.25 gm) at 25-30°C and stirred for 3 hrs at the same temperature. Water and dichloromethane were added to the reaction mixture. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with 10% aqueous sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely under reduced pressure. Dissolved the obtained compound in methanol (100 ml) at 25-30°C and 5% Pd/C (5 gm) was added. Transferred the obtained reaction mixture into an autoclave vessel and 4Kg/Cm2 hydrogen gas pressure was applied. Heated the reaction mixture to 40-45 °C and stirred for 14 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and released the hydrogen gas pressure. Filtered the reaction mixture through hyflow bed and washed with methanol. Distilled off the solvent completely from the filtrate and dried the obtained material to get the title compound.
Yield: 3.9 gm.
Example-14: Preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2-methylpropanoate (Formula-17)
Titanium tetrachloride (37.2 gm) was slowly added to a pre-cooled mixture of methyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula- 11 (10 gm) and dichloromethane (200 ml) at 0-5°C. Raised the temperature of the reaction mixture to 25- 30°C, triethylsilane (17.3 gm) was added and stirred the reaction mixture for 4 hrs at the same temperature. Quenched the reaction mixture with water at below 10°C. 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: 9.5 gm.
Example-15: Preparation of methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzold]imidazol- 2-yl)piperidin-l-yl)ethyl)phenyl)-2-methylpropanoate (Formula-13)
Sodium carbonate (2.7 gm) was added to a mixture of methyl 2-(4-(2- chloroethyl)phenyl)-2-methylpropanoate compound of formula- 17 (3.4 gm), l-(2- ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole compound of formula-9 (3.5 gm) and toluene (35 ml) at 25-30°C. Heated the reaction mixture to 105-110°C and stirred for 12 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Water was added to the reaction mixture and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated. IN HC1 solution was added to the organic layer and stirred for 5 min. Both the organic and aqueous layers were separated and the aqueous layer was neutralized using aqueous sodium carbonate solution. Extracted the aqueous layer with methyl tert-butyl ether. The organic layer was washed with sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.
Yield: 3.0 gm.
Example-16: Preparation of tert-butyl 4-(lH-benzo[d]imidazol-2-yl)piperidine-l- carboxylate (Frormula-31)
A mixture of benzene- 1,2-diamine compound of formula-29 (100 gm), piperidine-4- carboxylic acid compound of formula-30 (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 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 solid, 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 gm.
Example-17: Preparation of tert-butyl 4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl) piperidine-l-carboxylate (Formula-32)
Tert-butyl 4-(lH-benzo[d]imidazol-2-yl)piperidine-l-carboxylate compound of formula-31 (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. 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 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 to get the title compound.
Yield: 93.0 gm.
Example-18: Preparation of l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH-benzo[d]imidazole (Formula-9)
A mixture of tert-butyl 4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl)piperidine-l- carboxylate compound of formula-32 (50 gm), hydrochloric acid (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-butanol completely. Dichloromethane (500 ml) was added to the obtained compound at 25-30°C and stirred for 10 min at the same j 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-19: Preparation of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazoI-2-yl]-l- piperidinyl}ethyl)phenyl]-2-methylpropanoic acid (Formula-1)
A mixture of methyl 2-(4-(2-(4-(l-(2-eth0xyethyl)-lH-benzo[d]imidazol-2-yl) piperidin-l-yl)ethyl)phenyl)-2-methylpropanoate compound of formula- 13 (3 gm), sodium hydroxide (0.5 gm) and ethanol (21 ml) was heated to 65-70°C and stirred for 4 hrs at the same temperature. Water and dichloromethane were added to the reaction mixture and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was neutralized using acetic acid. Extracted the aqueous layer with dichloromethane. Both the organic and aqueous layers were separated and the organic layer was washed with sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.
Yield: 1.3 gm. Example-20: Purification of 2-[4-(2-{4-[l-(2-ethoxyethyl)-lH-benzimidazoI-2-yl]-l- piperidinyl}ethyl)phenyI]-2-methylpropanoic acid (Formula-1)
A mixture of 2-[4-(2-{4-[l-(2-ethoxyemyl)-lH-berizimidazol-2-yl]-l-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 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 μπι; D(0.5) is 12.48 μπι; D(0.9) is 34.09 μπι.

Claims

We Claim:
1. A 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;
a) Hydrolyzing the methyl 2-meth -2-phenylpropanoate compound of formula-2
Figure imgf000032_0001
Formula-2
in presence of a suitable base in a suitable solvent to provide 2-methyl-2- phenylpropanoic acid compo
Figure imgf000032_0002
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,
Figure imgf000032_0003
Formula-4
c) reacting the compound of formula-4 with Ν,Ο-dimethymydroxylamine hydrochloride in presence of a suitable base in a suitable solvent to provide N-methoxy-N,2- dimethyl-2-phenylpropanamide compound of formula-5,
Figure imgf000032_0004
Formula-5
d) reacting the compound of formula-5 with chloroacetyl chloride in presence of a suitable Lewis acid in a suitable solvent to provide 2-(4-(2-chloroacetyl)phenyl)-N- methoxy-N,2-dim a-6,
Figure imgf000032_0005
Forrhula-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-dimethyl propanamide compound of formula-7,
Figure imgf000033_0001
Formula-7
f) reducing the compound of formula-7 with a suitable reducing agent optionally in presence of a suitable solvent to provide 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2- dimethylpropanamide compound of formula-8,
Figure imgf000033_0002
Formula-8
g) reacting the compound of formula-8 with l-(2-ethoxyethyl)-2-(piperidin-4-yl)-lH- benzo[d]imidazole compound of formula-9
Figure imgf000033_0003
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-emoxyemyl)-lH-ber^o[d]imidazol-2-yl) piperidin- 1 -yl)ethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula- 10,
Figure imgf000033_0004
Formula- 10
h) hydrolyzing the compound of formula- 10 in presence of a suitable acid or a suitable base in a suitable solvent to provide compound of formula- 1.
2. A process according to claim 1, wherein,
in step-a) the suitable base is selected from hydroxides, alkoxides, carbonates and bicarbonates of alkali metals or their mixtures;
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 organic bases, inorganic bases or their mixtures;
in step-d) the Lewis acid is selected from aluminum chloride, aluminum bromide, boron trifluoride, boron tribromide, tin tetrachloride, tin tetrabromide, stannous chloride (SnCl2), ferric chloride (FeCl3), zinc chloride (ZnCl2), titanium tetrachloride (TiCl4) or mixtures or hydrates thereof;
in step-e) 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; trichlorosilane, sodium borohydride optionally in combination with BF3-etherate, diborane, potassium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminium hydride, DIBAL, LiEt3BH, L-selectride, vitride;
in step-f) the suitable reducing agent is selected from trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with a suitable Lewis acid or trifluoroacetic acid or BF3-etherate, Pd/C, Pt/C;
in step-g) the suitable base is selected from organic bases, inorganic bases or their mixtures; the suitable catalyst is selected from alkali metal halides such as sodium iodide, potassium iodide, sodium bromide, potassium bromide; and step-g) is carried out optionally in presence of a suitable phase transfer catalyst;
in step-h) the suitable acid is selected from inorganic acids such as HC1, HBr, H2S04, HN03, the suitable base is selected from inorganic bases such as hydroxides, alkoxides, carbonates, bicarbonates of alkali metals, preferably alkali metal hydroxides; in step-a) to step-h) 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, acetic acid, formic acid or their mixtures.
A 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) Hydrolyzing the methyl 2-methyl-2-phenylpropanoate compound of formula-2 in presence of sodium hydroxide in aqueous methanol to provide 2-methyl-2- phenylpropanoic acid compound of formula-3,
b) reacting the compound of formula-3 with thionyl chloride in dichloromethane and optionally amount of 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-dimethyl propanamide compound of formula-7,
f) reducing the compound of formula-7 with triethylsilane in combination with BF3- etherate to provide 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2-dimethyl propanamide compound of formula-8,
g) 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 sodium carbonate, potassium iodide and tetrabutylammonium bromide in toluene to provide 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,
h) hydrolyzing the compound of formula- 10 in presence of hydrochloric acid in water to provide compound of formula- 1.
A process for the preparation of 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2- dimethylpropanamide compound of formula-8, comprising of reducing the 2-(4-(2- chloro- 1 -hydroxyethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-7 with a suitable reducing agent optionally in presence of a suitable solvent to provide compound of formula-8.
A process according to claim 4, wherein,
the suitable reducing agent is selected from trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with a suitable Lewis acid or trifluoroacetic acid or BF3-etherate, Pd/C, Pt/C;
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, acetic acid, formic acid or their mixtures.
A process for the preparation of 2-(4-(2-chloroethyl)phenyl)-N-methoxy-N,2- dimethylpropanamide compound of formula-8, comprising of reducing the 2-(4-(2- chloro- 1 -hydroxyethyl)phenyl)-N-methoxy-N,2-dimethylpropanamide compound of formula-7 with triethylsilane in combination with BF3-etherate to provide compound of formula-8.
A 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; a) Reacting the 2-(4-(2-cUoroemyl)phenyl)-N-memoxy-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 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-dimethylpropanamide compound of formula- 10,
b) hydrolyzing the compound of formula- 10 in presence of a suitable acid or a suitable base in a suitable solvent to provide compound of formula- 1.
A process according to claim 7, wherein,
in step-a) the suitable base is selected from organic bases, inorganic bases or their mixtures; the suitable catalyst is selected from alkali metal halides such as sodium iodide, potassium iodide, sodium bromide, potassium bromide;
in step-b) the suitable acid is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid; the suitable base is selected from inorganic bases such as hydroxides, alkoxides, carbonates and bicarbonates of alkali metals, preferably alkali metal hydroxides;
in step-a) & step-b) 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, , acetic acid, formic acid or their mixtures.
9. A process for the preparation of 2-[4-(2- {4-[ 1 -(2-ethoxyethyl)- 1 H-benzimidazol-2-yl]- 1 - piperidinyl}ethyl)phenyl]-2-methylpropanoic acid compound of formula- 1, comprising of;
a) 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 sodium carbonate, potassium iodide and tetrabutylammonium bromide in toluene to provide 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,
b) hydrolyzing the compound of formula- 10 in presence of hydrochloric acid in water to provide compound of formula- 1.
10. Process for the preparation of 2-(4-(2-(4-(l-(2-emoxyemyl)-lH-benzo[d]imidazol-2-yl) piperidin-l-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 a suitable base in a suitable solvent optionally in presence of a suitable catalyst to provide compound of formula- 10,
11. A process according to claim 10, wherein
the suitable base is selected from organic bases, inorganic bases or their mixtures; the suitable catalyst is selected from alkali metal halides such as sodium iodide, potassium iodide, sodium bromide, potassium bromide; and the reaction is carried out optionally in presence of a suitable phase transfer catalyst such as tetra alkyl/aryl ammonium halides/hydroxides;
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.
12. A 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 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 a suitable acid or a suitable base optionally in presence of a solvent to provide compound of formula- 1.
13. A 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 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 in water to provide compound of formula- 1.
14. Compound having the following structural formula;
Figure imgf000038_0001
15. Compound having the following structural formula;
Figure imgf000038_0002
16. A process for the preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2-methylpropanoate compound of formula- 17,
Figure imgf000039_0001
Formula- 17
comprising of reducing the methyl 2-(4-(2-chloroacetyl)phenyl)-2-methylpropanoate compound of formula- 11
Figure imgf000039_0002
Formula- 11
with a suitable reducing agent in presence of a Lewis acid or BF3-etherate in a suitable solvent to provide compound of formula- 17.
17. A process according to claim 16, wherein,
the suitable reducing agent is selected from trialkyl silanes such as trimethylsilane, triethylsilane and sodium borohydride;
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, acetic acid, formic acid or their mixtures.
18. A process for the preparation of methyl 2-(4-(2-chloroethyl)phenyl)-2-methylpropanoate compound of formula- 17, comprising of reducing the methyl 2-(4-(2- chloroacetyl)phenyl)-2-methylpropanoate compound of formula- 11 with triethylsilane in dichloromethane in presence of titanium tetrachloride to provide compound of formula- 17.
19. A 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; 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- 11, b) reacting the compound of formula- 11 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 to provide methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2- yl)piperidin-l-yl)acet l)phenyl)-2-methyl propanoate compound of formula- 12,
Figure imgf000040_0001
Formula- 12
c) reducing the compound of formula- 12 with a suitable reducing agent in a suitable solvent to provide methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl) piperidin-l-yl)ethyl of formula- 13,
Figure imgf000040_0002
Formula- 13
d) hydrolyzing the compound of formula- 13 in presence of a suitable base in a suitable solvent to provide compound of formula- 1.
20. A process according to claim 19, wherein,
in step-a) the suitable Lewis acid is selected from aluminum chloride, aluminum bromide, boron trifluoride, boron tribromide, tin tetrachloride, tin tetrabromide, stannous chloride (SnCl2), ferric chloride (FeCl3), zinc chloride (ZnCl2), titanium tetrachloride (TiCLt) or mixture or hydrates thereof;
in step-b) the suitable base is selected from organic bases, inorganic bases or their mixtures;
in - step-c) the suitable reducing agent is selected from trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with a Lewis acid or trifluoroacetic acid or BF3-etherate; sodium borohydride optionally in combination with BF3-etherate, hydrazine, Zn-Hg/HCl;
in step-d) the suitable base is selected from hydroxides, alkoxides, carbonates and bicarbonates of alkali metals;
in step-a) to step-d) 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, acetic acid, formic acid or their mixtures.
21. A 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) Reducing the methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH-benzo[d]imidazol-2-yl) piperidin-l-yl)acetyl)phenyl)-2-methylpropanoate compound of formula- 12 with a suitable reducing agent in a suitable solvent to provide methyl 2-(4-(2-(4-(l -(2- ethoxyethyl)- 1 H-benzo[d]imidazol-2-yl)piperidin- 1 -yl)- 1 -hydroxyethyl)phenyl)-2- methylpropanoate com ound of formula- 16,
Figure imgf000041_0001
Formula- 16
b) optionally converting the hydroxy group of compound of formula- 16 to a suitable leaving group,
c) reducing the compound of formula- 16 or the compound obtained in step-b) with a suitable reducing agent in a suitable solvent to provide methyl 2-(4-(2-(4-(l-(2- ethoxyethyl)- 1 H-benzo[d]imidazol-2-yl)piperidin- 1 -yl)ethyl)phenyl)-2 -methyl propanoate compound of formula- 13,
d) hydrolyzing the compound of formula- 13 in presence of a suitable base in a suitable solvent to provide compound of formula- 1.
22. A process according to claim 21, wherein,
in step-a) the suitable reducing agent is selected from trialkyl silanes optionally in combination with a suitable Lewis acid or trifluoroacetic acid or BF3-etherate; trichlorosilane, sodium borohydride optionally in combination with BF3-etherate, potassium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminium hydride, DIBAL, lithium triethylborohydride, L-selectride, vitride;
in step-c) the suitable reducing agent is selected from trialkyl silanes such as trimethylsilane, triethylsilane optionally in combination with a suitable Lewis acid or trifluoroacetic acid or BF3-etherate, Pd/C, Pt/C;
in step-d) the suitable acid is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid; the suitable base is selected from inorganic bases such as hydroxides, alkoxides, carbonates and bicarbonates of alkali metals, preferably alkali metal hydroxides.
in step-a), step-c) and step-d) 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, acetic acid, formic acid or their mixtures.
23. A process for the preparation of methyl 2-(4-(2-(4-(l-(2-ethoxyethyl)-lH- benzo[d]imidazol-2-yl)piperidin- 1 -yl)- 1 -hydroxyethyl)phenyl)-2-methylpropanoate compound of formula- 16, comprising of reducing the methyl 2-(4-(2-(4-(l-(2- ethoxyethyl)- 1 H-benzo[d]imidazol-2-yl)piperidin- 1 -yl)acetyl)phenyl)-2-methyl propanoate compound of formula- 12 with a suitable reducing agent in a suitable solvent to provide compound of formula- 16.
24. A process according to claim 23, wherein,
the suitable reducing agent is selected from 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, diborane, potassium borohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminium hydride, diisobutylaluniinium hydride (DIBAL), lithium triethylborohydride (LiEt3BH), L-selectride (lithium tri-sec- butyl(hydrido)borate(l-)), sodium bis(2-methoxyethoxy)aluminium hydride (vitride); 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, acetic acid, formic acid or their mixtures.
25. Compound having the followin structural formula;
Figure imgf000043_0001
26. Compound having the followin structural formula;
Figure imgf000043_0002
27. 2-[4-(2- {4-[ 1 -(2-ethoxyethyl)- 1 H-benzimidazol-2-yl]- 1 -piperidinyl} ethyl)phenyl]-2- methylpropanoic acid having particle size distribution of D 0 less than 150 μηι.
28. 2-[4-(2- {4-[l-(2-ethoxyethyl)-lH-berizirmdazol-2-yl]-l-piperidinyl}ethyl)phenyl]-2- methylpropanoic acid having particle size distribution of D90 less than 100 μηι.
29. 2-[4-(2- {4-[ 1 -(2-ethoxyethyl)- 1 H-benzimidazol-2-yl]- 1 -piperidinyl} ethyl)phenyl]-2- methylpropanoic acid having particle size distribution of D90 less than 50 μηι.
Dated this day 12^^ of May 2014.
PCT/IN2014/000353 2013-05-24 2014-05-26 Novel process for the preparation of 2-[4-(2-{4-[1-(2-ethoxyethyl)-1h-benzimidazol-2-yl]-1-piperidinyl}ethyl) phenyl]-2-methylpropanoic acid WO2014188453A2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN2276/CHE/2013 2013-05-24
IN2276CH2013 2013-05-24
IN5394/CHE/2013 2013-11-22
IN5394CH2013 IN2013CH05394A (en) 2013-11-22 2014-05-26

Publications (2)

Publication Number Publication Date
WO2014188453A2 true WO2014188453A2 (en) 2014-11-27
WO2014188453A3 WO2014188453A3 (en) 2015-02-26

Family

ID=51934282

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2014/000353 WO2014188453A2 (en) 2013-05-24 2014-05-26 Novel process for the preparation of 2-[4-(2-{4-[1-(2-ethoxyethyl)-1h-benzimidazol-2-yl]-1-piperidinyl}ethyl) phenyl]-2-methylpropanoic acid

Country Status (1)

Country Link
WO (1) WO2014188453A2 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105254579A (en) * 2015-09-19 2016-01-20 万全万特制药江苏有限公司 Method for preparing bilastine intermediate through one-kettle process
CN106631687A (en) * 2016-12-21 2017-05-10 山东新和成药业有限公司 Method for synthesizing leaf alcohol under silane-Lewis acid catalysis system
CN106699728A (en) * 2015-07-13 2017-05-24 南京长澳医药科技有限公司 Bilastine intermediate impurity and preparation method thereof
CN107365298A (en) * 2017-03-14 2017-11-21 罗欣生物科技（上海）有限公司 A kind of preparation method of the benzyl propionate derivant of 2 methyl 2 '
WO2018042305A1 (en) * 2016-08-29 2018-03-08 Symed Labs Limited Improved processes for preparation of bilastine using novel intermediates
CN109810093A (en) * 2017-11-20 2019-05-28 重庆华邦胜凯制药有限公司 A kind of preparation method of bilastine intermediate
EP3599235A1 (en) * 2018-07-24 2020-01-29 Faes Farma, S.A. Process and intermediates for the preparation of bilastine
CN110950837A (en) * 2018-09-27 2020-04-03 上海天慈中商药业有限公司 Preparation method of bilastine
CN111039784A (en) * 2019-12-18 2020-04-21 厦门云凡医药科技有限公司 Preparation method of bilastine intermediate
CN111039922A (en) * 2019-12-27 2020-04-21 山东罗欣药业集团恒欣药业有限公司 Preparation process of bilastine

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2124167B1 (en) * 1996-06-04 1999-09-16 Espanola Prod Quimicos NEW DERIVATIVES OF BENZMIDAZOLE WITH ANTIHISTAMINE ACTIVITY.
DE60216641T2 (en) * 2002-04-19 2007-09-27 Faes Farma S.A. POLYMORPH OF 4-Ä2-Ä4-Ä1- (2-ETHOXYETHYL) -1H-BENZIMIDAZOLE-2-YLÜ-1-PIPERIDINYLÜETHYLÜ-ALPHA, ALPHA-DIMETHYLBENZOLIC ACIDIC ACID

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106699728A (en) * 2015-07-13 2017-05-24 南京长澳医药科技有限公司 Bilastine intermediate impurity and preparation method thereof
CN105254579A (en) * 2015-09-19 2016-01-20 万全万特制药江苏有限公司 Method for preparing bilastine intermediate through one-kettle process
WO2018042305A1 (en) * 2016-08-29 2018-03-08 Symed Labs Limited Improved processes for preparation of bilastine using novel intermediates
CN106631687B (en) * 2016-12-21 2019-08-30 山东新和成药业有限公司 A method of with synthesizing leaf alcohol under silane-Lewis acid catalytic systems
CN106631687A (en) * 2016-12-21 2017-05-10 山东新和成药业有限公司 Method for synthesizing leaf alcohol under silane-Lewis acid catalysis system
CN107365298A (en) * 2017-03-14 2017-11-21 罗欣生物科技（上海）有限公司 A kind of preparation method of the benzyl propionate derivant of 2 methyl 2 '
CN109810093A (en) * 2017-11-20 2019-05-28 重庆华邦胜凯制药有限公司 A kind of preparation method of bilastine intermediate
EP3599235A1 (en) * 2018-07-24 2020-01-29 Faes Farma, S.A. Process and intermediates for the preparation of bilastine
WO2020020873A1 (en) * 2018-07-24 2020-01-30 Faes Farma, S.A. Process and intermediates for the preparation of bilastine
US11370742B2 (en) 2018-07-24 2022-06-28 Faes Farma, S.A. Process and intermediates for the preparation of bilastine
CN110950837A (en) * 2018-09-27 2020-04-03 上海天慈中商药业有限公司 Preparation method of bilastine
CN111039784A (en) * 2019-12-18 2020-04-21 厦门云凡医药科技有限公司 Preparation method of bilastine intermediate
CN111039922A (en) * 2019-12-27 2020-04-21 山东罗欣药业集团恒欣药业有限公司 Preparation process of bilastine

Also Published As

Publication number Publication date
WO2014188453A3 (en) 2015-02-26

Similar Documents

Publication Publication Date Title
WO2014188453A2 (en) Novel process for the preparation of 2-[4-(2-{4-[1-(2-ethoxyethyl)-1h-benzimidazol-2-yl]-1-piperidinyl}ethyl) phenyl]-2-methylpropanoic acid
US20160237066A1 (en) Improved process for the preparation of ((3s,5r)-5-((1h-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl-4-methylbenzenesulfonate
US20140343285A1 (en) Process for the Preparation of Triazole Antifungal Drug, Its Intermediates and Polymorphs Thereof
US20170029398A1 (en) Process for the preparation of (1s)-1,5-anhydro-1-c-{4-chloro-3-4[(4-ethoxyphenyl)methyl]phenyl]-glucitol and its solvate thereof
WO2013186792A2 (en) Process for the preparation of (5-methyl-2-oxo-l,3-dioxoi-4-vl)methvl 2- ethoxv-l-{[2'-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vl)biphenyi-4-vl]methyl}- lh-benzimidazole-7-carboxyiate and its salts
US20160122354A1 (en) PROCESS FOR THE PREPARATION OF (3R,4R)-4-METHYL-3-(METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL-AMINO)-ß-OXO-1-PIPERIDINEPROPANENITRILE AND ITS SALTS
US11261160B2 (en) Process for the preparation of N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide, (2S)-hydroxybutanedioate and its polymorphs thereof
US10633372B2 (en) Process for the preparation of amorphous (1S)-1,5-anhydro-1-[3-[[5-(4 fluorophenyl)-2-thienyl]-4-methylphenyl]-D-glucitol and its polymorphs thereof
ES2357362T3 (en) DERIVATIVES OF BENCIMIDAZOLONA AS LIGANDOS OF THE RECEIVER CB2.
CA2743558C (en) Carbamate derivatives of alkyl-heterocycles, preparation thereof and therapeutic use thereof
WO2018104953A1 (en) Improved process for the preparation of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]butoxy}-2oxo-3,4-dihydro-2h-quinolin-1-yl)methyl dodecanoate
KR20120014202A (en) 5-membered heterocyclic compound cyclopenta[c]pyrrolylalkylcarbamate derivatives, preparation thereof, and therapeutic use thereof
US9388168B2 (en) Process for the preparation of 1-([1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine
US11279696B2 (en) Processes for the preparation of 7-{4-[4-(1-benzothiophen-4-yl) piperazin-1-yl]butoxy}quinolin-2(1H)-one
US20210163410A1 (en) An improved process for the preparation of (2s)-2-[(4r)-2-oxo-4-propyltetrahydro-1h-pyrrol-1-yl] butanamide and its intermediates thereof
US11236050B2 (en) Polymorphs of 4-[3-chloro-4-(n′-cyclopropyl ureido)phenoxy] -7-methoxyquinoline-6-carboxamide, its salts and process for the preparation thereof
WO2006101245A1 (en) N-substituted-n-(4-piperidinyl) amide derivative
JP5102038B2 (en) Aryl-substituted nitrogen-containing heterocyclic compounds
WO2014188445A1 (en) PROCESS FOR THE PREPARATION OF (3β)-17-(3-PYRIDINYL)ANDROSTA-5,16-DIEN-3-YL ACETATE AND POLYMORPH THEREOF
US20100076197A1 (en) Process for rimonabant
WO2016193997A2 (en) Process for the preparation of 6-(3-chloro-2-fluorobenzyl)-1-[(2s)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and pharmaceutically acceptable salts thereof
WO2018096550A1 (en) Process for the preparation of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate and its polymorphs thereof
WO2006030931A1 (en) N-substituted n-(4-piperidinyl)amide derivative
US11434256B2 (en) Process for the preparation of 3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oic acid
TW200403222A (en) Process for the preparation of amino-pyrrolidine derivatives

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14801659

Country of ref document: EP

Kind code of ref document: A2

122 Ep: pct application non-entry in european phase

Ref document number: 14801659

Country of ref document: EP

Kind code of ref document: A2