Field of the invention:

The present invention relates to novel polymorphic forms of 2-ethoxy-l-{[2'-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2, its derivatives and their pharmaceutically acceptable salts thereof.

Background of the invention:

(5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate is developed by Takeda pharmaceuticals and is marketed under the trade name Edarbi. It was approved by U.S. Food and Drug Administration on 25th February 2011 for the treatment of high blood pressure in adults.

US5243054A patent disclosed the benzimidazole derivatives which are used as angiotensin-II receptor antagonists and process for their preparation. US7157584B2 specifically disclosed the (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} -1 H-benzimidazole-7-carboxylate, its pharmaceutically acceptable salts and processes for their preparation.

Polymorphs are distinct solids having the same molecular formula yet having distinct advantageous physical properties compared to other polymorphic forms of the same compound. The difference in the physical properties of different polymorphic forms results from the orientation and intermolecular interactions of adjacent molecules in the bulk solid.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphic forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption and solid state NMR spectrum. One polymorphic form may give rise to thermal behavior different from that of another polymorphic form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) as well as content of solvent in the polymorphic form, which have been used to distinguish polymorphic forms.

Till date there are no polymorphic forms reported for 2-ethoxy-l-{[2'-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2, its derivatives and salts. Hence there is a need in the art to provide novel polymorphic forms for the same, which shows advantageous properties in the formulation process such as flowability, solubility, chemical purity, stability such as storage stability, polymorph stability, low hygroscopicity and low content of residual solvents.

Brief description of the invention:

The first aspect of the present invention is to provide a novel crystalline form of 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid compound of formula-2.

The second aspect of the present invention is to provide a novel crystalline form of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-- yl)biphenyl-4-yl]methyl} -1H-benzimidazole-7-carboxylate compound of formula-1.

The third aspect of the present invention is to provide amorphous form of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1.

The fourth aspect of the present invention is to provide a novel crystalline form of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt of formula-la.

The fifth aspect of the present invention is to provide a process for the preparation of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula-la.

The sixth aspect of the present invention is to provide a process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula-la, comprising of treating the (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate compound of formula-1 with potassium tert butoxide in a suitable solvent.

The seventh aspect of the present invention is to provide a process for the preparation of amorphous form of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3 -yl)biphenyl-4-yl]methyl} -1 H-benzimidazole-7-carboxylate compound of formula-1.

The eighth aspect of the present invention is to provide a process for the purification of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate potassium salt compound of formula-la.

The ninth aspect of the present invention is to provide a process for the preparation of methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula-10, comprising of deprotecting the methyl 2-(tert-butoxycarbonyl((2'-cyanobiphenyl-4-yl)methyl)amino)-3-nitrobenzoate compound of formula-9 by treating with a suitable deprotecting agent in a suitable solvent.

The tenth aspect of the present invention is to provide a process for the preparation of methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino) benzoate compound of formula-11, comprising of reducing the methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula-10 with a suitable reducing agent in a suitable solvent.

The eleventh aspect of the present invention is to provide a process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7-carboxylate compound of formula-1.

Brief description of the drawings:

Figure-1: Illustrates the X-Ray powder diffraction pattern of crystalline form-M of 2-ethoxy-1- {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7- carboxylic acid compound of formula-2.

Figure-2: Illustrates the X-Ray powder diffraction pattern of crystalline form-S of (5-methyl-2- oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl- 4-yl]methyl} -1 H-benzimidazole-7-carboxylate compound of formula-1.

Figure-3: Illustrates the DSC thermogram of crystalline form-S of (5-methyl-2-oxo-l,3-dioxol- 4-yl)methyl 2-ethoxy-1 -{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}- 1H- benzimidazole-7-carboxylate compound of formula-1.

Figure-4: Illustrates the X-Ray powder diffraction pattern of amorphous form of (5-methyl-2- oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl- 4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1.

Figure-5: Illustrates the X-Ray powder diffraction pattern of crystalline form-N of (5-methyl-2- oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl- 4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula-la.

Detailed description of the invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethylether, diethylether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, dioxane, acetonitrile and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform and the like; "ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, t-butanol and the like; "polar solvents" such as water; and/or their mixtures thereof.

As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as sodium carbonate, potassium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium 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 tert.butoxide and the like; alkali metal phosphates such as disodium hydrogen phosphate, dipotassium hydrogen phosphate and organic bases like diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine and the like.

The first aspect of the present invention provides a novel crystalline form of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} -1 H-benzimidazole-7-carboxylic acid compound of formula-2 characterized by its X-Ray powder diffraction pattern having peaks at about 9.1, 12.7, 14.9, 15.4, 16.2, 17.9, 18.3, 18.6, 19.3, 19.9, 20.4, 21.4, 21.8, 23.5, 23.9, 25.2, 25.6, 26.7, 28.7 ± 0.2 degrees of 2-theta values. This novel crystalline form is herein designated as crystalline form-M and is further characterized by the PXRD pattern as depicted in figure-1.

The second aspect of the present invention provides a novel crystalline form of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1- {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1 herein designated as crystalline form-S characterized by its X-Ray powder diffraction pattern having peaks at about 8.6, 9.8, 13.0, 16.1, 16.8, 17.2, 17.4, 18.5, 19.3, 19.9, 20.6, 21.9, 22.4, 22.9, 23.5, 25.8, 26.3±0.2 degrees of 2-theta values and DSC pattern having one endotherm at 130°C and another endotherm at 171 °C. The novel crystalline form-S is further characterized by the PXRD pattern as depicted in figure-2 and DSC thermogram as depicted in figure-3.

The third aspect of the present invention provides amorphous form of (5-methyl-2-oxo- 1,3-dioxol-4-yl)methyl 2-ethoxy-1- {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl}-lH-benzimidazole-7-carboxylate compound of formula-1 characterized by its PXRD pattern as depicted in figure-4.

The fourth aspect of the present invention provides a novel crystalline form of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl -4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula-la characterized by its X-Ray powder diffraction pattern having peaks at about 6.2, 6.7, 13.4, 14.1, 14.5, 14.8, 16.0, 18.7, 20.3, 21.4, 22.8, 23.8, 27.6 ± 0.2 degrees of 2-theta values. This novel crystalline form is herein designated as crystalline form-N and is further characterized by the PXRD pattern as depicted in figure-5.

The fifth aspect of the present invention provides a process for the preparation of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1, comprising;

a) Esterification of 3-nitro phthalic acid compound of formula-3 with methanol in presence of thionyl chloride to provide 2-(methoxycarbonyl)-6-nitro benzoic acid of formula-4,
b) converting the compound of formula-4 into methyl 2-(chlorocarbonyl)-3-nitrobenzoate compound of formula-5 by treating with thionyl chloride in dichloromethane,

c) treating the compound of formula-5 in-situ with sodium azide in dimethyl formamide to provide methyl 2-(azidocarbonyl)-3-nitrobenzoate compound of formula-6,

d) treating the compound of formula-6 in-situ with tert.butanol to provide methyl 2-(tert-butoxycarbonylamino)-3-nitrobenzoate compound of formula-7,

e) condensing the compound of formula-7 with 4'-(bromomethyl)biphenyl-2-carbonitrile compound of formula-8 in presence of potassium carbonate and acetonitrile optionally in presence of tetra butyl ammonium bromide to provide methyl 2-(tert-butoxycarbonyl((2'-cyanobiphenyl-4-yl)methyl) amino)-3-nitrobenzoate compound of formula-9,

f) deprotecting the compound of formula-9 by treating with trifluoro acetic acid in dichloromethane to provide methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula-10,

g) reducing the compound of formula-10 with Raney Ni in ethyl acetate to provide methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino) benzoate compound of formula-11,

h) cyclization of compound of formula-11 by treating in-situ with tetraethyl north carbonate in acetic acid to provide methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-1H-benzimidazole -7-carboxylate compound of formula-12, i) treating the compound of formula-12 with hydroxylamine hydrochloride in presence of triethyl amine in dimethyl sulfoxide to provide (Z)-methyl 2-ethoxy-1-((2'-(N' hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-1 H-benzimidazole-7-carboxylate compoundof formula-13, j) cyclization of compound of formual-13 by treating with ethyl chloroformate in presence of triethyl amine in tetrahydrofuran to provide methyl 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)biphenyl-4-yl)methyl)-1 H-benzimidazole-7-carboxylate compound of formula-14, k) hydrolyzing the compound of formula-14 in presence of lithium hydroxide in methanol to provide 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} -1H- benzimidazole-7-carboxylic acid compound of formula-2, 1) condensing the compound of formula-2 with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one in acetone to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1, m) converting the compound of formula-1 into its potassium salt compound of formula-la by treating with a suitable potassium source selected from potassium 2-ethyl hexanoate and potassium tert.butoxide in acetone.

The 3-nitro phthalic acid compound of formula-3 used in step-a) of the fifth aspect can be synthesized by any of the processes known in the art such as Journal of the American Chemical Society, 1925, 47 (7), 1980-1981; Journal of the chemical society, 1914, 105, 2476; Organic Syntheses, Coll. Vol. 1, p.408 (1941); Vol. 7, p.70 (1927) etc.

All the prior reported processes for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula-la involves the usage of potassium 2-ethyl hexanoate as a potassium source.

The present inventors earnestly tried different potassium sources such as potassium hydroxide, potassium carbonate, potassium HMDS and potassium tert.butoxide. We found potassium tert.butoxide as an advantageous source of potassium for this step, which is a simple, commercially available and cost-effective reagent when compared to the conventional potassium 2-ethyl hexanoate.

The sixth aspect of the present invention provides a process for the preparation of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula-la, comprising of treating the (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1 with potassium tert.butoxide in a suitable solvent selected from ketone solvents, ester solvents, polar-aprotic solvents, hydrocarbon solvents, ether solvents and/or their mixtures thereof.

The amount of potassium tert.butoxide used in this process is in an amount ranging from 0.8-1.7 moles, preferably 0.9 to 1.5 moles per one mole of compound of formula-1 and the reaction can be carried out at a temperature of-10°C to 60°C, preferably -5°C to 35°C.

In this process, potassium bis(trimethylsilyl)amide (KHMDS) can also be used as a potassium source in place of potassium tert.butoxide.

A preferred embodiment of the present invention provides a process for the preparation of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7-carboxylate potassium salt compound of formula-la, comprising of treating the (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1 with potassium tert.butoxide in a mixture of acetone and ethyl acetate.

The seventh aspect of the present invention provides a process for the preparation of amorphous form of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} -1 H-benzimidazole-7-carboxylate compound of formula-1, comprising of; a) Condensing the 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4- yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2 or its disodium salt compound of formula-2a with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one in a suitable solvent to provide (5-methyl- 2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl} - lH-benzimidazole-7-carboxylate compound of formula-1,

b) treating the compound of formula-1 in-situ with a suitable potassium source in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt of formula-la,

c) treating the potassium salt obtained in step-b) in-situ with a suitable acid in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7-carboxylate of formula-1,

d) isolating the compound of formula-1 from a suitable solvent to provide amorphous form of compound of formula-1.

Wherein, in step-a) the suitable solvent is selected from polar-aprotic solvents, ketone solvents, hydrocarbon solvents, chloro solvents and/or their mixtures thereof;

In step-b) the suitable potassium source is selected from potassium 2-ethyl hexanoate, potassium tert.butoxide and potassium bis(trimethylsilyl)amide (KHMDS); the suitable solvent is selected from ketone solvents, ether solvents, ester solvents and/or their mixtures thereof;

In step-c) the suitable acid is selected from acetic acid and hydrochloric acid; and the suitable solvent is selected form water, hydrocarbon solvents, alcoholic solvents and/or their mixtures thereof; in step-d) the suitable solvent is preferably selected from hydrocarbon solvents.

A preferred embodiment of the present invention provides a process for the preparation of amorphous form of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3 -yl)biphenyl-4-yl]methyl} -1 H-benzimidazole-7-carboxylate compound of formula-1, comprising of;

a) Condensing the 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2 or its disodium salt compound of formula-2a with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one in N,N-dimethyl formamide to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1,

b) treating the compound of formula-1 in-situ with potassium 2-ethyl hexanoate in acetone to provide (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt of formula-la,

c) neutralizing the potassium salt obtained in step-b) with acetic acid in water to provide (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7-carboxylate compound of formula-1,

d) isolating the compound of formula-1 from cyclohexane to provide amorphous form of compound of formula-1.

The eighth aspect of the present invention provides a process for the purification of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula-la, comprising of; a) Adding a suitable solvent to (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} -1 H-benzimidazole-7-carboxylate potassium salt compound of formula-la,

b) heating the reaction mixture,

c) stirring the reaction mixture,

d) cooling the reaction mixture,

e) stirring the reaction mixture,

f) filtering the compound followed by washing with a suitable solvent to provide pure (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula-la.

Wherein, the suitable solvent used in step-a) and step-f) can be selected from ester solvents, ketone solvents, ether solvents and/or their mixtures thereof; preferably ethyl acetate.

The ninth aspect of the present invention provides a process for the preparation of methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula-10 comprising of deprotecting the methyl 2-(tert-butoxycarbonyl((2'-cyanobiphenyl-4-yl)methyl) amino)-3-nitrobenzoate compound of formula-9 by treating with a suitable deprotecting agent selected from trifluoro acetic acid, methane sulfonic acid and hydrochloric acid in a suitable solvent selected from chloro solvents, ether solvents, alcoholic solvents, hydrocarbon solvents and/or their mixtures thereof.

A preferred embodiment of the present invention provides a process for the preparation of methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula-10 comprising of deprotecting the methyl 2-(tert-butoxycarbonyl((2'-cyanobiphenyl-4-yl)methyl)amino)-3-nitrobenzoate compound of formula-9 by treating with trifluoro acetic acid in dichloromethane.

The tenth aspect of the present invention provides a process for the preparation of methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino) benzoate compound of formula-11,

comprising of reducing the methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula-10 with a suitable reducing agent selected from Raney Ni, NaBHVC and Pd/C in a suitable solvent selected from ester solvents, alcoholic solvents, ether solvents, chloro solvents, hydrocarbon solvents and/or their mixtures thereof.

A preferred embodiment of the present invention provides a process for the preparation of methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino) benzoate compound of formula-11, comprising of reducing the methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula-10 with Raney Ni in ethyl acetate.

The eleventh aspect of the present invention provides a process for the preparation of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1, comprising of reacting the 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2 with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one in presence of a suitable alkali metal bicarbonate and optionally in presence of a suitable phase transfer catalyst such as tetra butyl ammonium bromide in a suitable solvent selected from ketone solvents, polar-aprotic solvents, ester solvents and ether solvents.

A preferred embodiment of the present invention provides a process for the preparation of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1, comprising of reacting the 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2 with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one in presence of sodium bicarbonate and tetra butyl ammonium bromide in acetone.

The PXRD analysis of the crystalline and amorphous compounds of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10° per minute.

2-Ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1H-benzimidazole-7-carboxylic acid compound of formula-2, (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} -1H-benzimidazole-7-carboxylate compound of formula-1 and its potassium salt compound of formula-la of the present invention were analyzed by HPLC under the following conditions; Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector and integrator; Column: Inertsustain CI8, 150x4.6 mm, 5.0 um or equivalent; Flow rate: 1.5 mL/min; Wavelength: 220 nm; Column temperature: 40°C; Injection volume: 10 uL; Run time: 33 min; Diluent: acetonitrile:buffer (90:10 v/v); Elution: gradient; Buffer: Weigh accurately 1.36 gm of potassium dihydrogen orthophosphate into 1000 ml of milli-Q-water. Adjust the pH to 2.8 with diluted ortho phosphoric acid and filtered the solution through 0.22 um Nylon membrane filter paper; Mobile phase-A: Buffer; Mobile phase-B: acetonitrile:water (90:10 v/v); Auto sampler temperature: 5°C.

(5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl} -1 H-benzimidazole-7-carboxylate potassium salt compound of formula-la 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 the completion of drying of the product. The present invention is schematically represented as follows. Scheme-I:

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention. Examples: Example-1: Preparation of 2-(methoxycarbonyl)-6-nitro benzoic acid

(Formula-4)

Slowly added thionyl chloride (340 gm) to a pre-cooled solution of 3-nitro phthalic acid (Formula-3) (400 gm) in methanol (600 ml) at 10-15°C and stirred the reaction mixture for 15 min at the same temperature. Heated the reaction mixture to reflux temperature and stirred for 5 hrs at the same temperature. After the completion of the reaction, cooled the reaction mixture to 0-5°C. 900 ml of water was slowly added to the reaction mixture at 0-5°C and stirred for 60 min at the same temperature. Filtered the compound, washed with water and then dried to get the title compound. Yield: 410.0 gm.

Example-2: Preparation of methyl 2-(chlorocarbonyI)-3-nitrobenzoate

(FormuIa-5)

Thionyl chloride (98 gm) was slowly added to a pre-cooled mixture of dichloromethane (500 ml), 2-(methoxycarbonyl)-6-nitro benzoic acid (Formula-4) (100 gm) and N,N-dimefhyl formamide (10 ml) at 15-20°C and stirred for 30 min at the same temperature. Heated the reaction mixture to reflux temperature and stirred for 4 hrs at the same temperature. After the completion of the reaction, cooled the reaction mixture to 0-5°C and adjusted the pH of the reaction mixture to 9 with 20% sodium carbonate solution at the same temperature. The temperature of the reaction mixture was raised to 15-20°C. Both the organic layer and aqueous layers were separated and extracted the aqueous layer with dichloromethane. The combined organic layer was washed with water and dried over sodium sulfate. The resulting organic layer containing methyl 2-(chlorocarbonyl)-3-nitrobenzoate was utilized in the next step without isolating the compound from the reaction mixture.

Example-3: Preparation of methyl 2-(azidocarbonyl)-3-nitrobenzoate

(Formula-6)

The organic layer containing methyl 2-(chlorocarbonyl)-3-nitrobenzoate obtained in example-2 was added to a pre-cooled mixture of sodium azide (40 gm) in N,N-dimethyl formamide (160 ml) at 0-5°C and stirred for 60 min at the same temperature. After the completion of the reaction, 500 ml of water was added to the reaction mixture at 0-5°C. Both the organic and aqueous layers were separated, the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water and dried over sodium sulfate. The resulting organic layer containing methyl 2-(azidocarbonyl)-3-nitrobenzoate was utilized in the next step without isolating the compound from the reaction mixture.

Example-4: Preparation of methyl 2-(tert-butoxycarbonyIamino)-3-nitrobenzoate
(Formula-7)

Tert.butanol (200 ml) was added to the organic layer containing methyl 2-(azidocarbonyl)-3-nitrobenzoate obtained in example-3 at 25-3 5°C and stirred for 15 min at the same temperature. Distilled off the solvent completely under atmospheric pressure at 90-95°C and stirred for 30 min at the same temperature. After the completion of the reaction, water (750 ml) was added at 90-95°C. Cooled the reaction mixture to 25-35°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 110.0 gm.

Example-5: Preparation of methyl 2-(tert-butoxycarbonyl ((2'-cyanobiphenyl-4-yl)methyl) amino)-3-nitrobenzoate

(Formula-9)

A mixture of acetonitrile (500 ml), methyl 2-(tert-butoxycarbonylamino)-3-nitrobenzoate (Formula-7) (100 gm), potassium carbonate (56 gm) and tetra butyl ammonium bromide (10.8 gm) was stirred for 45 min at 25-35°C and 4'-(bromomethyl)biphenyl-2-carbonitrile (Formula-8) (91.9 gm) was added to it. Heated the reaction mixture to reflux temperature and stirred for 4 hrs at the same temperature. After the completion of the reaction, cooled the reaction mixture to 40-45°C. Filtered the unwanted compound, washed with acetonitrile at 40-45°C. Distilled off the solvent completely from the filtrate under reduced pressure. Isopropyl alcohol (100 ml) was added to the obtained compound and distilled off the solvent completely under reduced pressure. Isopropyl alcohol (500 ml) was added to the reaction mixture at 25-35°C. Heated the reaction mixture to reflux temperature and stirred for 45 min at the same temperature. Cooled the reaction mixture to 40-45°C and stirred for 40 min at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried to get the title compound.; Yield: 120.0 gm.

Example-6: Preparation of methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate (Formula-10)

Trifluoro acetic acid (292.6 ml) was slowly added to a mixture of dichloromethane (200 ml) and methyl 2-(tert-butoxycarbonyl((2'-cyanobiphenyl-4-yl)methyl)amino)-3-nitrobenzoate (Formula-9) (100.0 gm) at 25-30°C and stirred for 60 min at the same temperature. After the completion of the reaction, distilled off the solvent completely under reduced pressure at below 50°C. Cooled the reaction mixture to 25-35°C, ethyl acetate (400 ml) was added and stirred for 30 min at the same temperature. Filtered the precipitated solid and washed with ethyl acetate. To the wet compound, ethyl acetate (400 ml) was added at 25-35°C and stirred for 30 min at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 75.0 gm.

Example-7: Preparation of methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino) benzoate

(Formula-11)

Ethyl acetate (450 ml), methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate (Formula-10) (50 gm) followed by Raney-Ni (22.62 gm) were charged into an autoclave vessel at 25-30°C. 2.0-3.0 Kg/cm of hydrogen gas pressure was applied to the reaction mixture at 25-30°C and stirred for 2 hrs under the same reaction conditions. After completion of the reaction, filtered the reaction mixture and washed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure and the resulting reaction mixture containing methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino)benzoate was utilized in the next step without isolating the compound from the reaction mixture.

Example-8: Preparation of methyl l-((2'-cyanobiphenyl-4-yI)methyl)-2-ethoxy-lH-benzimidazole-7-carboxylate
(Formula-12)

Acetic acid (28.7 gm) followed by tetraethyl ortho carbonate (30.4 gm) were slowly added to the reaction mixture obtained in example-7 at 25-35°C and stirred for 2 hrs at the same temperature. After the completion of the reaction, water (250 ml) was added to the reaction mixture at 25-35°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 50.0 gm.

Example-9: Purification of methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-lH-benzimidazole-7-carboxylate

(Formula-12)

A mixture of ethyl acetate (350 ml) and methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-lH-benzimidazole-7-carboxylate (100 gm) was heated to reflux and stirred for 30 min at the same temperature. Cooled the reaction mixture to 25-35°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and then dried to get the pure title compound. Yield: 85.0 gm.

Example-10: Preparation of (Z)-methyl 2-ethoxy-l-((2,-(N'-hydroxycarbamimidoyl) biphenyl-4-yl)methyl)-lH-benzimidazole-7-carboxyIate

(Formula-13)
A mixture of dimethyl sulfoxide (750 ml) and hydroxyl amine hydrochloride (216 gm) was stirred for 15 min at 25-35°C. A solution of triethyl amine (314 gm) in tetrahydrofuran (900 ml) was slowly added to the reaction mixture at 35-40°C and stirred for 60 min at the same temperature. Filtered the precipitated unwanted solid and washed with tetrahydrofuran. Distilled off the solvent from the filtrate under reduced pressure. To the obtained reaction mixture, methyl 1 -((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-1 H-benzimidazole-7-carboxylate (Formual-12) (100 gm) followed by triethylamine (62 gm) were added at 40-45°C. Heated the reaction mixture to 65-70°C and stirred for 18 hrs at the same temperature. After completion of the reaction, reduced the temperature of the reaction mixture to 25-35°C. The resulting reaction mixture was slowly added to water (3000 ml) at 25-30°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 95.0 gm.

Example-11: Preparation of methyl 2-ethoxy-l-((2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yI)methyI)-lH-benzimidazole-7-carboxylate
(Fromula-14)

A mixture of tetrahydrofuran (380 ml), (Z)-methyl 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-1 H-benzimidazole-7-carboxylate (Formula-13) (100 gm) and triethyl amine (24 gm) was stirred for 15 min at 25-30°C. Cooled the reaction mixture to 0-5°C. Slowly added ethyl chloroformate (21.5 gm) to the reaction mixture at 0-5°C and stirred for 60 min at the same temperature. After completion of the reaction, filtered the precipitated unwanted solid and washed with tetrahydrofuran. Distilled off the solvent from the filtrate under reduced pressure. Toluene (300 ml) was added to the obtained residue at 25-35°C and heated the reaction mixture to reflux temperature and stirred for 12 hrs at the same temperature. Reduced the temperature of the reaction mixture to 25-35°C and stirred for 90 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with toluene and dried to get the title compound. Yield: 65.0gm; Purity by HPLC: 91.60%

Example-12: Purification of methyl 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH-benzimidazole-7-carboxylate
(Formula-14)

A mixture of methanol (900 ml) and methyl 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH-benzimidazole-7-carboxylate (60 gm) was heated to reflux temperature and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-35°C and stirred for 45 min at the same temperature. Further cooled the obtained reaction mixture to 0-5°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the pure title compound. Yield: 45.0 gm; Purity by HPLC: 98.60%

Example-13: Preparation of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid

(Formula-2)

A solution of lithium hydroxide (16.5 gm) in water (330 ml) was slowly added to a mixture of methanol (1650 ml) and methyl 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH-benzimidazole-7-carboxylate (Formula-14) (55 gm) at below 35°C. Heated the reaction mixture to reflux temperature and stirred for 4 hrs at the same temperature. After completion of the reaction, the solvent was completely distilled off from the reaction mixture under reduced pressure. Carbon (5 gm) was added to the obtained compound at 25-30°C and stirred for 15 min at the same temperature. Filtered the reaction mixture through high-low bed and washed with water. Adjusted the pH of the filtrate to 3.0 with dil HCl at 25-30°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with water and then dried to get the title compound. The PXRD of the obtained compound is shown in figure-1. Yield: 52.0 gm.

Example-14: Preparation of disodium salt of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl}-lH-benzimidazole-7-carboxylic acid (Formula-2a)

Ethanol (285 ml) and 28% sodium methoxide solution in methanol (25 gm) were charged into a clean and dry RBF at 25-35°C. Distilled off the solvent completely under reduced pressure at below 60°C and cooled the reaction mixture to 25-30°C. Ethanol (285 ml) and 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7-carboxylic acid (30 gm) were added to the reaction mixture at 40°C and stirred for 15 min at the same temperature. Distilled off the solvent completely under reduced pressure. Ethanol (142 ml) was added to the reaction mixture at 40-45°C and stirred for 15 min at the same temperature. Distilled off the solvent completely under reduced pressure and the resulting reaction mixture containing disodium salt of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid was utilized in the next step without isolating the compound from the reaction mixture.

Example-15: Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate

(Formula-1)

A mixture of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid (Formula-2) (50 gm), acetone (1000 ml), sodium bicarbonate (10 gm) and tetra butyl ammonium bromide (2.0 gm) was heated to 40-45°C and stirred for 60 min at the same temperature. 4-(Chloromethyl)-5-methyl-l,3-dioxol-2-one (16.5 gm) was added to the reaction mixture at 40-45°C and stirred for 24 hrs at the same temperature. Sodium bicarbonate (5.0 gm) and 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one (8.0 gm) were added to the reaction mixture at 40-45 °C and stirred for 24 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C and filtered. The filtrate was added to a pre-cooled mixture of water (1400 ml) and sodium carbonate (10 gm) at 0-5°C. Ethyl acetate (250 ml) and vacuum salt (50 gm) were added to the reaction mixture at 0-5°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated, extracted the aqueous layer with ethyl acetate. The combined organic layer was washed with brine solution followed by 1% HC1 solution. The organic layer was dried over vacuum salt followed by sodium sulfate. Carbon (5 gm) was added to the reaction mixture and stirred for 15 min. Filtered the reaction mixture through high-low bed and washed with ethyl acetate. Distilled off the solvent completely under reduced pressure at below 50°C and cooled the residue to 25-30°C. Ethyl acetate (60 ml) was added to the obtained residue at 25-30°C and stirred for 20 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. The PXRD of the obtained compound is shown in figure-2. Yield: 18.0 gm; M.R: 167-171°C.

Example-16: Preparation of amorphous form of (5-methyl-2-oxo-l,3-dioxol-4-yI)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate

(Formula-1)

4-(Chloromethyl)-5-methyl-l,3-dioxol-2-one (16 gm) was slowly added to a pre-cooled solution of disodium salt of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid (Formula-2a) (32 gm) in N,N-dimethyl formamide (320 ml) at 0-5°C under N2 atmosphere and stirred for 60 hrs at the same temperature. After the completion of the reaction, water (960 ml), ethyl acetate (250 ml) followed by vacuum salt (150 gm) were slowly added at 0-10°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. The combined organic layer was washed with brine solution followed by 1% HC1 solution. Dried the organic layer over vacuum salt followed by sodium sulfate and distilled off the solvent completely under reduced pressure. Acetone (100 ml) was added to the obtained residue at 25-3 0°C and stirred for 15 min at the same temperature. Carbon (1.0 gm) was added to the reaction mixture at 25-3 0°C and stirred for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with acetone. Cooled the filtrate to 0-5°C, a solution of potassium 2-ethyl hexanoate (10 gm) in acetone (50 ml) was slowly added and stirred for 10 min at the same temperature. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Heated the reaction mixture to 40-45°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 60 min at the same temperature. Filtered the precipitated solid and washed with acetone. The obtained compound was slowly added to a pre-cooled mixture of water (80 ml) and acetic acid (0.9 gm) at 0-5°C and stirred for 2 hrs at the same temperature. Filtered the solid and washed with water. The obtained wet compound was added to acetone (40 ml) at 25-30°C and cooled the reaction mixture to 0-5°C. Water (40 ml), ethyl acetate (40 ml) followed by vacuum salt (40 gm) were slowly added to the reaction mixture and stirred for 15 min. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. The combined organic layer was dried over sodium sulfate and distilled off the solvent completely under reduced pressure at below 50°C. Cooled the reaction mixture to 25-30°C, cyclohexane (25 ml) was added and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with cyclohexane and then dried to get the title compound. The PXRD of the obtained compound is shown in figure-4. Yield: 5.5 gm. M.R: 68-77°C.

Example-17: Preparation of potassium salt of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate
(Formula-la)
A mixture of 10 gm of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} -1 H-benzimidazole-7-carboxylate (Formula-1) obtained in example-15 or example-16 and acetone (125 ml) was heated to 40-45°C and stirred for 15 min at the same temperature. Carbon (1.0 gm) was added to the reaction mixture at 40-45 °C and stirred for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with acetone. Cooled the filtrate to 0-5°C and a solution of potassium 2-ethyl hexanoate (3.2 gm) in ethyl acetate (35 ml) was slowly added and stirred for 90 min at the same temperature. Filtered the precipitated solid and washed with ethyl acetate to get the title compound. Yield: 7.5 gm; Purity by HPLC: 97.9%.

Example-18: Preparation of potassium salt of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate

(Formula-1a)

Acetone (12.5 ml) and (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} -1 H-benzimidazole-7-carboxylate (Formula-1) (1.0 gm) were charged into a clean and dry RBF at 25-30°C. Cooled the reaction mixture to 0-5 °C and a pre-cooled solution of potassium tert butoxide (0.2 gm) in ethyl acetate (3.5 ml) was slowly added to it at the same temperature. Stirred the reaction mixture for 90 min at 0-5°C. The precipitated solid was filtered, washed with ethyl acetate and then dried to get the title compound. The PXRD of the obtained compound is shown in figure-5. Yield: 0.6 gm.

Example-19: Preparation of potassium salt of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate
(Formula-la)

Acetone (18 ml) and (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3 -yl)biphenyl-4-yl]methyl} -1 H-benzimidazole-7-carboxylate (Formula-1) (1.0 gm) were charged into a clean and dry RBF at 25-30°C. Cooled the reaction mixture to 0-5°C and a pre-cooled solution of potassium tert.butoxide (0.2 gm) in acetone (4 ml) was slowly added at the same temperature. Stirred the reaction mixture for 90 min at 0-5 °C. The precipitated solid was filtered, washed with ethyl acetate and then dried to get the title compound. Yield: 0.62 gm.

Example-20: Purification of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt
(Formula-la)

A mixture of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1 H-benzimidazole-7-carboxylate potassium salt (8.0 gm) and ethyl acetate (40 ml) was heated to 40-45°C and stirred for 20 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 min at the same temperature. Filtered the compound, washed with ethyl acetate and then dried to get the title compound. The PXRD of the obtained compound is shown in figure-5.

Yield: 7.0 gm; M.R: 209-213°C; Purity by HPLC: 99.85%.

Example-21: Purification of (5-methyl-2-oxo-l,3-dioxoI-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt
(Formula-la)

A mixture of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt (8.0 gm) and methyl isobutyl ketone (43 ml) was heated to 40-45°C and stirred for 20 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 min at the same temperature. Filtered the compound, washed with methyl isobutyl ketone and dried to get the title compound. The PXRD of the obtained compound is shown in figure-5. Yield: 6.9 gm. Purity by HPLC: 99.80%.

We Claim:

1. Crystalline form-M of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2, characterized by its X-Ray powder diffraction pattern having peaks at about 9.1, 12.7, 14.9, 15.4, 16.2, 17.9, 18.3, 18.6, 19.3, 19.9, 20.4, 21.4, 21.8, 23.5, 23.9, 25.2, 25.6, 26.7, 28.7 ± 0.2 degrees of 2-theta values.

2. Crystalline form-S of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} -1 H-benzimidazole-7-carboxylate compound of formula-1, characterized by;

a) its X-Ray powder diffraction pattern having peaks at about 8.6, 9.8, 13.0, 16.1, 16.8, 17.2, 17.4, 18.5, 19.3, 19.9, 20.6, 21.9, 22.4, 22.9, 23.5, 25.8, 26.3 ± 0.2 degrees of 2-theta values,

b) DSC pattern having one endotherm at 130°C and another endotherm at 171°C.

3. Amorphous form of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1, characterized by its X-Ray powder diffraction pattern substantially as depicted in figure-4.

4. Crystalline form-N of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula-la, characterized by its X-Ray powder diffraction pattern having peaks at about 6.2, 6.7, 13.4, 14.1, 14.5, 14.8, 16.0, 18.7, 20.3, 21.4, 22.8, 23.8, 27.6 ± 0.2 degrees of 2-theta values.

5. A process for the preparation of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula-la, comprising of treating the (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1 with potassium tert butoxide in a suitable solvent or mixture of solvents.

6. A process according to claim 6, wherein potassium tert butoxide is used in an amount ranging from 0.8-1.7 moles, preferably 0.9 to 1.5 moles per one mole of compound of formula-1 at a temperature of -10°C to 60°C, preferably -5°C to 35°C and the suitable solvent is selected from ketone solvents, ester solvents, polar aprotic solvents, hydrocarbon solvents and/or their mixtures thereof; preferably mixture of acetone and ethyl acetate.

7. A process for the preparation of amorphous form of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-1 - {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} -1H-benzimidazole-7-carboxylate compound of formula-1, comprising of;

a) Condensing the 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2 or its disodium salt compound of formula-2a with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one in N,N-dimethyl formamide to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} -1 H-benzimidazole-7-carboxylate compound of formula-1,

b) treating the compound of formula-1 in-situ with potassium 2-ethyl hexanoate in acetone to provide its potassium salt of formula-la,

c) neutralizing the potassium salt obtained in step-b) by treating in-situ with acetic acid in water to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylateof formula-1,

d) isolating the compound of formula-1 from cyclohexane to provide amorphous form of compound of formula-1.

8. A process for the preparation of methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3- nitrobenzoate compound of formula-10 comprising of deprotecting the methyl 2-(tert-butoxycarbonyl((2'-cyanobiphenyl-4-yl)methyl)amino)-3-nitrobenzoate compound of formula-9 by treating with trifluoro acetic acid in a suitable solvent selected from chloro solvents, ether solvents, alcoholic solvents, hydrocarbon solvents and/or their mixtures thereof.

9. A process for the preparation of methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino) benzoate compound of formula-11, comprising of reducing the methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula-10 with Raney Ni in a suitable solvent selected from ester solvents, alcoholic solvents, ether solvents, chloro solvents, hydrocarbon solvents and/or their mixtures thereof.

10. A process for the purification of (5-methyl-2-oxo-l,3-dioxol-4-yi)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate otassium salt compound of formula-la, comprising of;

a) Adding a suitable ester solvent, preferably ethyl acetate to (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula-la,

b) heating the reaction mixture,

c) stirring the reaction mixture,

d) cooling the reaction mixture,

e) stirring the reaction mixture,

f) filtering the compound followed by washing with ethyl acetate to provide pure (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1- {[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula-la.

11. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1, comprising of reacting the 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7-carboxylic acid compound of formula-2 with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one in presence of a suitable alkali metal bicarbonate and optionally in presence of a suitable phase transfer catalyst such as tetra butyl ammonium bromide in a suitable solvent selected from ketone solvents, polar-aprotic solvents, ester solvents and ether solvents.