WO2017163258A1

WO2017163258A1 - Process for the preparation of n-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifiuoromethoxy) [1,1' -biphenyi]-3-carboxamide and its polymorphs thereof

Info

Publication number: WO2017163258A1
Application number: PCT/IN2017/000062
Authority: WO
Inventors: Srinivasan Thirumalai Rajan
Original assignee: Msn Laboratories Private Limited; Eswaraiah, Sajja; Venkata Panakala Rao, Gogulapati; RAJESHWAR REDDY, Sagyam; RAJESHAM, Boge; PURNA CHNDRASEKHAR REDDY, Thippireddy
Priority date: 2016-03-22
Filing date: 2017-03-20
Publication date: 2017-09-28

Abstract

The present invention relates to process for the preparation of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4' -(trifluoromethoxy) [1,1'-biphenyl]-3-carboxamide compound of formula-1, it's salts and their polymorphs thereof.

Description

Process for the preparation of N-[6-(cis-2,6-dimethylmorphoIin-4-yl)pyridine-3-yl]-2- methyl-ΐ' -(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide and its polymorphs thereof

Related Applications:

This application claims the benefit of priority of our Indian patent application numbers 201641009952 filed on 22^nd March 2016, 201641017584 filed on 23^rd May 2016, 201641024486 filed on 18^th July 2016 and 201641035869 filed on 20^th October 2016 which are incorporated herein by reference.

Field of the Invention:

The present invention relates to process for the preparation of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide diphosphate compound of formula- 1 a.

Formula- la

The present invention also relates to acid addition salts of N-[6-(cis-2,6-dimethyl mo holin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide compound of formula- 1.

Further, the present invention relates to amorphous form of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl] -2 -methyl-4' -(trifluoromethoxy) [1 ,1 '-biphenyl]-3-carboxamide diphosphate compound of formula- la and its solid dispersions.

Further, the present invention also relates to novel crystalline form of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 ,1 '-biphenyl]- 3- carboxamide phosphate salt and process for its preparation thereof.

Background of the Invention: Sonidegib (INN), also known as LDE225 and marketed as Odomzo, is a Hedgehog signaling pathway inhibitor (via smoothened antagonism) being developed as an anticancer agent by Novartis.

Sonidegib was approved by U.S Food and Drug Administration in 24 July 2015 for the treatment of patients with locally advanced basal cell carcinoma.

ODOMZO has also been approved by the European Commission for the Treatment of pediatric and adult patients with hedgehog pathway-activated medulloblastoma.

Sonidegib, chemically known as N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]- 2-methyl-4'-(trifluoromethoxy) [l,r-biphenyl]-3-carboxamide compound of formula-1.

International (PCT) publication No. WO2007/131201 Al first disclosed Sonidegib and process for its preparation.

International (PCT) publication No. WO2010/033481 Al discloses various salts of Sonidegib and process for its preparation.

International (PCT) publication No. WO2011/009852 Al discloses the various crystalline forms of Sonidegib free base, Form- A, Form-B and Amorphous form.

International (PCT) publication No. WO2015/092720 Al discloses the various metabolites of Sonidegib.

Brief description of the Invention:

The first aspect of the present invention relates to acid addition salts of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide compound of formula-1 and process for its preparation.

The second aspect of the present invention relates to novel crystalline acid addition salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [ 1 , 1 ' rbiphenyl] -3 -carboxamide compound of formula- 1.

The third aspect of the present invention is to provide a process for the preparation of novel crystalline acid addition salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide compound of formula-1.

The fourth aspect of the present invention is to provide a process for the preparation of crystalline form-A of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [l, -biphenyl]-3-carboxamide compound of formula- 1.

The fifth aspect of the present invention is to provide amorphous form of N-[6-(cis- 2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide diphosphate compound of formula- la and process for its preparation.

The sixth aspect of the present invention is to provide amorphous solid dispersions of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 , 1 '- biphenyl] -3 -carboxamide diphosphate compound of formula- la in combination with one or more pharmaceutical acceptable carriers.

The seventh aspect of the present invention is to provide process for the preparation of amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl- 4 '-(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide diphosphate compound of formula-la in combination with one or more pharmaceutical acceptable carrier.

The eighth aspect of the present invention is to provide novel crystalline form of N-[6- (cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [1,1 '- biphenyl]-3-carboxamide diphosphate compound of formula- la, herein after designated as form-M and process for its preparation.

The ninth aspect of the present invention is to provide novel crystalline form of N-[6- (cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1'- biphenyl] -3 -carboxamide monophosphate compound of formula- lb, herein after designated as form-S and process for its preparation.

The tenth aspect of the present invention is to provide a process for the preparation of crystalline form-S of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide monophosphate compound of formula-lb.

The eleventh aspect of the present invention relates to N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 ,1 '-biphenyl]-3 -carboxamide monophosphate compound of formula- lb. The twelfth aspect of the present invention is to provide crystalline form of N-[6-(cis- 2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl]-3- carboxamide hydrochloride salt compound of formula- lc, herein after designated as form-M and process for its preparation.

The thirteenth aspect of the present invention is to provide an improved process for the preparation of N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoro methoxy)[l,l '-biphenyl]-3-carboxamide diphosphate compound of formula-la.

The fourteenth aspect of the present invention is to provide an improved process for the preparation of 2-methyl-4'-(trifluoromethoxy)-[l, -biphenyl]-3-carboxylic acid compound of formula-8.

The fifteenth aspect of the present invention is to provide a process for the preparation of amorphous N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoro methoxy) [l,l '-biphenyl]-3-carboxamide compound of formula- 1.

Brief description of the Drawings:

Figure 1: Illustrates the PXRD pattern of crystalline form-M of hydro bromide salt of N-[6- (cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l , 1 '- biphenyl]-3-carboxamide compound of formula-Id.

Figure 2: Illustrates the PXRD pattern of crystalline form-M of paratoluene sulfonate salt of N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl]-2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' - biphenyl]-3-carboxamide compound of formula- le.

Figure 3: Illustrates the PXRD pattern of crystalline form-S of paratoluene sulfonate salt of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' - biphenyl]-3-carboxamide compound of formula-le.

Figure 4: Illustrates the PXRD pattern of crystalline form-M of oxalate salt of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l, -biphenyl]-3- carboxamide compound of formula- If. Figure 5: Illustrates the PXRD pattern of crystalline form-S of oxalate salt of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl]-3 - carboxamide compound of formula- If.

Figure 6: Illustrates the PXRD pattern of crystalline form-M of maleate salt of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3-yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide compound of formula- lg.

Figure 7: Illustrates the PXRD pattern of crystalline form-S of maleate salt of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide compound of formula- lg.

Figure 8: Illustrates the PXRD pattern of crystalline form-M of methane sulfonate salt of N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , - biphenyl] -3 -carboxamide compound of formula- lh.

Figure 9: Illustrates the PXRD pattern of crystalline form-S of methane sulfonate salt of N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4' - (trifluoromethoxy) [ 1 , - biphenyl] -3 -carboxamide compound of formula-lh.

Figure 10: Illustrates the PXRD pattern of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3- yl]-2-methyl-4'-(trifluoromethoxy)[l, -biphenyl]-3-carboxamide compound of formula-1, obtained according to example- 11.

Figure 11: Illustrates the PXRD pattern of amorphous form of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide diphosphate compound of formula- 1 a.

Figure 12: Illustrates the PXRD pattern of amorphous solid dispersion of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide diphosphate in combination with HPMC.

Figure 13: Illustrates the PXRD pattern of amorphous solid dispersion of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide diphosphate in combination with PVP K-30.

Figure 14: Illustrates the PXRD pattern of amorphous solid dispersion of N-[6-(cis-2,6- dimethylmo holin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 , -biphenyl] -3- carboxamide diphosphate in combination with HPMC AS. Figure 15: Illustrates the PXRD pattern of amorphous solid dispersion of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl] -3- carboxamide diphosphate in combination with HPC.

Figure 16: Illustrates the PXRD pattern of crystalline form-M of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl]-3 -carboxamide diphosphate compound of formula- la.

Figure 17: Illustrates the PXRD pattern of crystalline form-S of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4' -(trifluoromethoxy) [1 ,1 '-biphenyl] -3- carboxamide monophosphate compound of formula- lb.

Figure 18: Illustrates the PXRD pattern of crystalline form-M of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl]-2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide hydrochloride salt compound of formula- lc.

Figure 19: Illustrates the PXRD pattern of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3- yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide compound of formula-1. Figure 20: Illustrates the PXRD pattern of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3- yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , Γ -biphenyl] -3 -carboxamide compound of formula- 1.

Detailed description of the Invention:

Different salts and solid state forms of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

Discovering new salts and solid state forms of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New salts and solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, or improved shelf-life. For at least these reasons, there is a need for additional salts and solid state forms of Sonidegib; in particular there is a need for salts and solid state forms that have improved solubility.

As used herein the term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; "ether solvents" such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), 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, methylisobutylketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2- fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethylether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.

As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium 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 ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropylamine, diisopropyl ethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylamino pyridine (DMAP), N-methylmorpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.

The first aspect of the present invention relates to acid addition salts of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide compound of formula- 1 and process for its preparation, which comprises of reacting the compound of formula- 1 with a suitable acid in a suitable solvent to provide acid addition salts of compound of formula- 1.

Wherein, the acid addition salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3- yl]-2-methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl]-3 -carboxamide compound of formula-1 are selected from salts of inorganic acids, such as hydro bromic acid, hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; and salt of organic acids, such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, 2-chloromandelate, p-toluene sulfonic acid, ethane- 1,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid.

The suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents, polar solvents like water or mixture thereof.

In an embodiment of the present invention the above said acid addition salts of Sonidegib are useful in the preparation of pure Sonidegib compound of formula- 1.

Further, the acid addition salts of Sonidegib can be converted into highly pure Sonidegib free base compound of formula- 1, by treating the acid addition salts of Sonidegib with a suitable base.

The second aspect of the present invention provides novel crystalline acid addition salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide compound of formula- 1, which include:

a) Crystalline hydrobromide salt compound of formula- Id herein after designated as form-M and is characterized by its P-XRD pattern which is depicted in figure- 1. b) Crystalline paratoluene sulfonate salt compound of formula- le herein after designated as form-M and is characterized by its P-XRD pattern which is depicted in figure-2.

c) Crystalline paratoluene sulfonate salt compound of formula- le herein after designated as form-S and is characterized by its P-XRD pattern which is depicted in figure-3.

d) Crystalline oxalate salt compound of formula- If herein after designated as form-M and is characterized by its P-XRD pattern which is depicted in figure-4.

e) Crystalline oxalate salt compound of formula- If herein after designated as form-S and is characterized by its P-XRD pattern which is depicted in figure-5.

f) Crystalline maleate salt compound of formula- lg herein after designated as form-M and is characterized by its P-XRD pattern which is depicted in figure-6.

g) Crystalline maleate salt compound of formula- lg herein after designated as form-S and is characterized by its P-XRD pattern which is depicted in figure-7.

h) Crystalline methane sulfonate salt compound of formula- lh herein after designated as form-M and is characterized by its P-XRD pattern which is depicted in figure-8. i) Crystalline methane sulfonate salt compound of formula- lh herein after designated as form-S and is characterized by the P-XRD pattern which is depicted in figure-9.

The third aspect of the present invention provides a process for the preparation of crystalline acid addition salts of N-[6-(cis-2,6-dimethylmoφholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide compound of formula-1, comprising of the following steps:

a) Adding a suitable solvent to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide compound of formula-

^■ 1,

b) adding a suitable acid to the reaction mixture,

c) heating the reaction mixture to a suitable temperature and stirring the reaction mixture,

d) cooling the reaction mixture to a suitable temperature and stirring the reaction mixture,

e) filtering the precipitated solid to provide corresponding crystalline acid addition salts of N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoro methoxy) [l,l '-biphenyl]-3-carboxamide compound of formula-1.

Wherein, in step-a) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, chloro solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, nitrile solvents, and polar solvents like water or mixture thereof;

in step-b) the suitable acid used is same as defined in the first aspect of the present invention; in step-c) the suitable temperature is ranging from ambient temperature to the reflux temperature of solvent used in the reaction;

in step-d) the suitable temperature is ranging from 0°C to 35°C.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide hydrobromide salt compound of formula- Id, comprising of the following steps:

a) Adding acetone to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide compound of formula-1, b) adding hydro bromic acid to the reaction mixture,

c) heating the reaction mixture to 55-60°C and stirring the reaction mixture,

d) cooling the reaction mixture to 25-30°C and stirring the reaction mixture, e) further cooling the reaction mixture to 0-5°C and stirring the reaction mixture, f) filtering the precipitated solid to provide crystalline form-M of N'[6-(cis-2,6- dimethylmoφholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '- biphenyl]-3-carboxamide hydrobromide salt compound of formula-1 d.

In another preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide paratoluene sulfonate salt compound of formula-1 e, comprising of the following steps:

a) Adding acetone to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide compound of formula- 1 , b) adding paratoluene sulfonic acid to the reaction mixture,

c) heating the reaction mixture to 55-60°C and stirring the reaction mixture,

d) cooling the reaction mixture to 25-30°C and stirring the reaction mixture,

e) further cooling the reaction mixture to 0-5°C and stirring the reaction mixture, f) filtering the precipitated solid to provide crystalline form-M of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' - biphenyl] -3 -carboxamide paratoluene sulfonate salt compound of formula-1 e.

In another preferred embodiment of the present invention, using the same procedure as described above the following crystalline forms can be prepared as illustrated below:

05 Sonidegib free Acetone -do- Crystalline form-S of base compound of Sonidegib maleate salt formula- 1 compound of formula- lg

06 Sonidegib free Acetone Methane Crystalline form-M of

base compound of sulfonic acid Sonidegib methane formula- 1 sulfonate salt compound of formula- lh

07 Sonidegib free Acetone -do- Crystalline form-S of

base compound of Sonidegib methane formula- 1 sulfonate salt compound of formula- lh

The fourth aspect of the present invention provides a process for the preparation of crystalline form-A of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide compound of formula-1 , comprising of: a) Adding a suitable solvent to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide compound of formula- 1,

b) heating the reaction mixture to a suitable temperature and stirring the reaction mixture,

c) optionally, treating the reaction mixture with activated carbon and filtering the reaction mixture through hyflow bed,

d) cooling the filtrate obtained in step-c) and stirring at a suitable temperature, e) filtering the precipitated solid to provide crystalline form-A of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [1,1 '- biphenyl]-3-carboxamide compound of formula-1.

in step-b) the suitable temperature is ranging from ambient temperature to the reflux temperature of solvent used in the reaction;

in step-d) the suitable temperature is ranging from 0°C to 45°C.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-A of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l, -biphenyl]-3-carboxamide compound of formula- 1, comprising of:

a) Adding acetone to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide compound of formula- 1, b) heating the reaction mixture to 55-60°C and stirring the reaction mixture,

c) cooling the reaction mixture to 25-30°C and stirring the reaction mixture,

d) further cooling the reaction mixture to 0-5°C and stirring at the same temperature, e) filtering the precipitated solid to provide crystalline form-A of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 ,1 '-biphenyl]-3- carboxamide compound of formula- 1.

The preferred embodiment of the present invention provides a process for the preparation, of crystalline form-A of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide compound of formula-1, comprising of:

a) Adding acetonitrile to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl -4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide compound of formula-1, b) heating the reaction mixture to 80-85°C and stirring the reaction mixture,

c) treating the reaction mixture with carbon and filtering the reaction mixture through hyflow bed,

d) cooling the filtrate obtained in step-c) to 25-30°C and stirring at 25-30°C,

e) further cooling the reaction mixture to 0-5 °C and stirring at the same temperature, f) filtering the precipitated solid to provide crystalline form-A of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl]-3- carboxamide compound of formula-1.

In another preferred embodiment of the present invention provides a process for the preparation of crystalline form-A of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide compound of formula-1 , comprising of: a) Adding isopropanol to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl -4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide compound of formula-1, b) heating the reaction mixture to 80-85°C and stirring the reaction mixture,

d) cooling the filtrate obtained in step-c) to 25-30°C and stirring at the same temperature,

e) further cooling the reaction mixture to 0-5 °C and stirring at the same temperature, f) filtering the precipitated solid to provide crystalline form-A of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide compound of formula-1.

WO2011/009852 Al discloses process for the preparation of crystalline form-A of N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [1,1 '- biphenyl] -3 -carboxamide compound of formula-1 using preparative HPLC column. However the said process is tedious, time consuming and not suitable for commercial scale.

In order to overcome the problem associated with the prior art, the present inventors has developed a recrystallization process which is simpler, less time consuming and which is well applicable for industrial scale. Hence the present invention is more advantageous when compared over the prior art process.

The fifth aspect of the present invention provides amorphous form of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide diphosphate compound of formula- la and process for its preparation.

The amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl -4' -(trifluoromethoxy). [1,1 '-biphenyl] -3 -carboxamide diphosphate of the present invention is characterized by its P-XRD diffractogram which is depicted in figure- 11.

In an embodiment of the present invention provides a process for the preparation of amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate compound of formula- la, comprising of:

a) Dissolving N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' - (trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate in a suitable solvent, b) stirring the reaction mixture,

c) isolating the amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]- 2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide diphosphate compound of formula- 1 a.

Wherein, in step-a) the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixtures thereof.

The preferred embodiment of the present invention provides a process for the preparation of amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide diphosphate compound of formula- la, comprising of:

a) Dissolving N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' - (trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide diphosphate in a mixture of methanol and dichloromethane,

b) stirring the reaction mixture,

c) isolating the amorphous form of N-[6-(cis-2,6-dimethylmoφholin-4-yl)pyridine-3-yl]- 2-methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl]-3 -carboxamide diphosphate compound of formula- la.

In an embodiment of the present invention provides a process for the preparation of amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide diphosphate compound of formula- la, comprising of: _^

a) Adding a suitable solvent to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide compound of formula- 1, b) stirring the reaction mixture, c) adding phosphoric acid to the reaction mixture,

d) stirring the reaction mixture and isolating the amorphous form of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '- biphenyl]-3-carboxamide diphosphate compound of formula-la.

The preferred embodiment of the present invention provides a process for the preparation of amorphous form of N-[6-(cis-2,6-dimethylmo holin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate compound of formula- la, comprising of:

a) Adding methanol to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl- 4 '-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide compound of formula-1, b) stirring the reaction mixture,

c) adding phosphoric acid to the reaction mixture,

d) stirring the reaction mixture and isolating the amorphous form of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '- biphenyl]-3-carboxamide diphosphate compound of formula- la.

Amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl- 4 '-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula- la prepared according to the present invention is substantially free of any of the crystalline forms of compound of formula- la.

Amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl- 4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate compound of formula-la prepared according to the present invention is stable.

Amorphous N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -

(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula- la obtained according to the present invention is having particle size distribution D90 < 100 μηι. The sixth aspect of the present invention provides amorphous solid dispersion of N-[6- (cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 , 1 '- biphenyl]-3-carboxamide diphosphate compound of formula- la in combination with one or more pharmaceutical acceptable carriers.

Wherein, the term pharmaceutical acceptable carrier refers to a polymeric carrier, and more preferably at least one from the group consisting of starches, modified starches, cellulose, methyl cellulose (MC), Microcrystalline cellulose (MCC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC AS), polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives, polymethacrylates, polyvinyl pyrrolidone (PVP), PVP K-30, polyvinyl acetate (PVAc), PVP vinylacetate-copolymer (PVP-VA), Kollidon VA 64 (a vinylpyrrolidone-vinyl acetate copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, isomalt, cyclodextrins such as cc-cyclodextrins, β-cyclodextrins, γ-cyclodextrins, hydroxyl-propyl-cyclodextrins, hydroxyl propyl-cyclodextrin, sodiumcarboxymethylcellulose cross-linked polyacrylic acid (carbipol), or a mixture thereof.

In an embodiment of the present invention provides amorphous solid dispersion of N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [1 ,1 '- biphenyl]-3-carboxamide diphosphate compound of formula-la in combination with HPMC and the P-XRD pattern is depicted in figure- 12.

The another embodiment of the present invention provides amorphous solid dispersion of N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' - biphenyl]-3-carboxamide diphosphate compound of formula- la in combination with PVP K- 30 and the P-XRD pattern is depicted in figure-13.

The another embodiment of the present invention provides amorphous solid dispersion of N-[6-(cis 2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' - biphenyl]-3-carboxamide diphosphate compound of formula- la in combination with HPMC AS and the P-XRD pattern is depicted in figure- 14. The another embodiment of the present invention provides amorphous solid dispersion of N-[6-(cis-2j6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [ 1 , 1 '- biphenyl]-3-carboxamide diphosphate compound of formula- la in combination with HPC and the P-XRD pattern is depicted in figure-15.

In general, the term "solid dispersion" refers to a system in a solid state comprising at least two components, wherein one component is dispersed throughout the other component or components.

The term "amorphous solid dispersion" as used herein, refers to solid dispersion which is substantially amorphous, that is, at least 80%, preferably at least 90%, most preferably at least 95%, is in amorphous form as determined by powder x-ray diffraction pattern.

The seventh aspect of the present invention provides a process for the preparation of amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl- 4'-(trifluoromethoxy) [l,l '-biphenyl]-3^carboxamide diphosphate compound of formula-la in combination with one or more pharmaceutical acceptable carrier, comprising of:

a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmo holin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate and one or more pharmaceutical acceptable carrier in a suitable solvent,

b) stirring the reaction mixture,

c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide diphosphate compound of formula- la with one or more pharmaceutical acceptable carrier.

Wherein, in step-a) the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixture thereof and suitable pharmaceutical acceptable carrier is same as defined in the sixth aspect of the present invention.

The preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine- 3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula- la in combination with HPMC, comprising of:

a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate and HPMC in a mixture of methanol and dichloromethane,

b) stirring the reaction mixture,

c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate compound of formula- la in combination with HPMC.

The preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine- 3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate compound of formula- la in combination with PVP K-30, comprising of:

a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate and PVP K-30 in a mixture of methanol and dichloromethane,

b) stirring the reaction mixture,

c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 ,1 '-biphenyl]-3-carboxamide diphosphate compound of formula- la in combination with PVP K-30.

The preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine- 3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula-l a in combination with HPMC AS, comprising of:

a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate and HPMC AS in a mixture of methanol and dichloromethane,

b) stirring the reaction mixture, c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 ,1 '-biphenyl]-3-carboxamide diphosphate compound of formula- la in combination with HPMC AS.

The preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of N-[6-(cis-2,6-dimethylmo holin-4-yl)pyridine- 3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula- 1 a in combination with HPC, comprising of:

a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate and HPC in a mixture of methanol and dichloromethane,

b) stirring the reaction mixture,

c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl]-3-carboxamide diphosphate compound of formula- la in combination with HPC.

The amorphous form and amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide diphosphate obtained according to the present invention can be isolated using a rotational distillation device such as a Buchi Rotavapor, vacuum drying, spray drying, spray granulating, freeze drying and spray-freeze drying, agitated thin film drying (ATFD) or melt extrusion or freeze drying (lyophilization), anti-solvent or by any other suitable techniques.

In the present invention, the composition of the solid dispersion containing mole ratio of the amount of the N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide diphosphate compound of formula- 1 to the amount of the pharmaceutical acceptable carrier is ranging from about 1 :0.5 to 1 : 10 by weight.

The eighth aspect of the present invention provides novel crystalline form-M of N-[6- (cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' - biphenyl] -3 -carboxamide diphosphate compound of formula- la characterized by its X-ray powder diffractogram having peaks at 4.9, 10.0, 12.7, 13.7, 15.1, 16.1, 17.3, 17.9, 18.7, 20.3, 21.8, 24.0 and 26.3 ± 0.2 degrees two-theta as illustrated in figure-16.

In an embodiment of the present invention provides a process for the preparation of crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate compound of formula- la, comprising of the following steps:

a) Adding suitable solvent to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide,

b) heating the reaction mixture to suitable temperature,

c) adding phosphoric acid to the reaction mixture,

d) stirring the reaction mixture,

e) cooling the reaction mixture to suitable temperature,

f) stirring the reaction mixture and filtering the precipitated solid to provide crystalline form-M of N- [6-(cis-2,6-dimethylmo holin-4-yl)pyridine-3 -yl] -2-methyl-4 ' - (trifluoromethoxy) [l ,l '-biphenyl]-3-carboxamide diphosphate compound of formula- la.

Wherein, in step-a) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, chloro solvents, ether solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents and polar solvents like water or mixture thereof;

in step-b) the suitable temperature is ranging from 25°C to the reflux temperature of solvent used in the reaction;

in step-e) the suitable temperature is ranging from -10°C to 15°C.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate compound of formula- la, comprising of the following steps:

a) Adding methanol to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl- 4' -(trifluoromethoxy) [1 , 1 '-biphenyl]-3-carboxamide,

b) heating the reaction mixture to 40-45°C, c) adding phosphoric acid to the reaction mixture,

d) stirring the reaction mixture,

e) cooling the reaction mixture to 0-5°C,

f) stirring the reaction mixture and filtering the precipitated solid to get crystalline form- M of N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4' -(trifluoro methoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula- la.

The ninth aspect of the present invention provides crystalline form-S of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide monophosphate compound of formula- lb characterized by its X-ray powder diffractogram having peaks at 5.0, 9.7, 10.1, 11.8, 12.6, 14.7, 15.4, 16.0, 16.4, 17.2, 18.4, 18.9, 19.3, 19.6, 20.3, 21.2, 21.8, 22.4, 24.2, 25.0, 25.6, 26.3, 26.5 and 29.6 ± 0.2 degrees two-theta as illustrated in figure- 17.

In an embodiment of the present invention provides a process for the preparation of crystalline form-S of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide monophosphate compound of formula- lb, comprising of the following steps:

a) Adding a suitable solvent to N-[6-(cis-2,6-dimethylmo holin-4-yl)pyridine-3-yl]-2- methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide,

b) heating the reaction mixture to a suitable temperature,

c) stirring the reaction mixture,

d) optionally, filtering the reaction mixture through hyflow bed,

e) adding phosphoric acid to the filtrate obtained in step-c) or step-d),

f) cooling the reaction mixture to a suitable temperature,

g) stirring the reaction mixture and filtering the precipitated solid to provide crystalline form-S of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoro methoxy) [1,1 '-biphenyl] -3 -carboxamide monophosphate compound of formula-lb.

Wherein, in step-a) the suitable solvent is selected from alcohol solvents, hydrocarbon solvents, ketone solvents, ester solvents, chloro solvents, ether solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixture thereof; in step-b) the suitable temperature is ranging from 25°C to the reflux temperature of solvent used in the reaction;

in step-f) the suitable temperature is -10°C to 30°C.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide monophosphate compound of formula- lb, comprising of the following steps:

a) Adding acetonitrile to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl- 4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide,

b) heating the reaction mixture to 55-60°C and stirring the reaction mixture,

c) filtering the reaction mixture through hyflow bed,

d) adding phosphoric acid to the filtrate obtained in step-d),

e) cooling the reaction mixture to 0-5°C,

f) stirring the reaction mixture and filtering the precipitated solid to provide crystalline form-S of N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoro methoxy) [l,l '-biphenyl]-3-carboxamide monophosphate compound of formula-lb.

In another preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide monophosphate compound of formula- lb, comprising of the following steps:

a) Adding a mixture of isopropanol and methanol to N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , Γ -biphenyl] -3 -carboxamide, b) heating the reaction mixture to 55-60°C and stirring the reaction mixture,

c) adding phosphoric acid to the reaction mixture,

d) cooling the reaction mixture to 0-5°C,

e) stirring the reaction mixture and filtering the precipitated solid to provide crystalline form-S of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyndine-3-yl]-2-methyl-4'-(trifluoro methoxy) [l,V -biphenyl] -3 -carboxamide monophosphate compound of formula-lb. The tenth aspect of the present invention provides a process for the preparation of crystalline form-S of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide monophosphate compound of formula-lb, comprising of the following steps: ^~

a) Adding a suitable solvent to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl]-3-carboxamide diphosphate,

b) heating the reaction mixture to a suitable temperature,

c) stirring the reaction mixture,

d) cooling the reaction mixture to a suitable temperature,

e) filtering the precipitated solid to provide crystalline form-S of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl]-3- carboxamide monophosphate compound of formula- lb.

Wherein, in step-a) the suitable solvent is selected from alcohol solvents; ketone solvents; ester solvents, chloro solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixture thereof;

in step-d) the suitable temperature is 0-30°C.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [l ,l '-biphenyl]-3-carboxamide monophosphate compound of formula- lb, comprising of the following steps:

a) Adding methanol to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl- 4 '-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate,

b) heating the reaction mixture to 55-60°C,

c) stirring the reaction mixture,

d) cooling the reaction mixture to 25-30°C, e) filtering the precipitated solid to provide crystalline form-S of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 ,1 '-biphenyl]-3- carboxamide monophosphate compound of formula- lb.

The eleventh aspect of the present invention relates to N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl]-2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide monophosphate compound of formula- lb.

N- [6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [1,1 ' -biphenyl] -3 -carboxamide monophosphate compound of formula- lb produces according to the present invention is useful in the preparation of pharmaceutical formulation.

N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide monophosphate compound of formula- lb obtained according to the present invention is having particle size distribution Ds>o less than 150 μηι, preferably less than 100 μπι, more preferably less than 50 μηι.

The twelfth aspect of the present invention provides crystalline form-M of N-[6-(cis- 2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4' -(trifluoromethoxy) [1 ,1 '-biphenyl]-3- carboxamide hydrochloride salt compound of formula- lc characterized by its X-ray powder diffractogram having peaks at 3.43, 4.81, 9.95, 10.81, 11.42, 13.55, 14.46, 16.69, 17.01, 17.48, 18.34, 19.10, 20.35, 21.96, 23.08, 23.48, 24.17, 24.44, 24.53, 25.24, 27.61, 29.90, 30.94, 31.44, 34.94, 38.25, 40.64 and 41.40 ± 0.2 degrees two-theta as illustrated in figure-18.

The crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide hydrochloride salt compound of formula- 1 c is useful in the preparation of pure compound of formula- 1 a.

Another embodiment of the present invention provides a process for the preparation of crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide hydrochloric acid salt compound of formula- lc, comprising of the following steps :

a) Dissolving N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridihe-3 -yl] -2-methyl-4 ' - (trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide compound of formula-1 in a suitable first solvent,

b) optionally, treating the reaction mixture with activated carbon,

c) adding a suitable hydrochloric acid source to the reaction mixture obtained in step-a) or step-b),

d) stirring the reaction mixture,

e) filtering the precipitated solid,

f) dissolving the obtained solid in step-e) in a suitable second solvent,

g) adding a suitable third solvent to the reaction mixture,

h) stirring the reaction mixture,

i) filtering the precipitated solid to provide crystalline form-M of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide hydrochloric acid salt compound of formula- lc.

Wherein, in step-a), f) and g) the suitable solvent is selected from alcohol solvents, ether solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixture thereof;

in step-c) the suitable hydrochloric acid source is selected from HCl gas, hydrochloric acid, aqueous hydrochloric acid, ethyl acetate-HCl, methanolic-HCl, ethanolic-HCl and IPA-HC1.

The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide hydrochloric acid salt compound of formula- lc, comprising of the following steps:

a) Dissolving N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' - (trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide compound of formula-1 in acetone, b) treating the reaction mixture with activated carbon,

c) filtering the reaction mixture through hyflow bed,

d) adding hydrochloric acid to the obtained filtrate,

e) stirring the reaction mixture,

f) filtering the precipitated solid, g) dissolving the obtained solid in step-f) in methanol,

h) adding water to the reaction mixture,

i) stirring the reaction mixture,

j) filtering the precipitated solid to get crystalline form-M of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 ,1 '- biphenyl] -3-carboxamide hydrochloric acid salt compound of formula- lc.

Prior reported process for the purification of N-[6-(cis-2,6-dimethyl morpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 ,1 '-biphenyl] -3-carboxamide compound of formula-1 involves the usage of preparative column chromatography, which is expensive, tedious, time consuming and provides compound of formula-1 with low yield and purity.

In order to overcome the aforementioned problems, inventors of the present invention have found that the conversion of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide compound of formula-1 into its acid addition salts using a suitable acid and then converting the acid addition salts into free base by treating it with a suitable base provided pure N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [ 1,1 ' -biphenyl] -3-carboxamide compound of formula-1 with high purity.

The crude compound of formula-1 was treated with a suitable acid selected from inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; and organic acid such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, 2-chloromandelate, p-toluene sulfonic acid, ethane- 1 ,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid to provide its corresponding acid addition salts of compound of formula-1 and further neutralizing the acid addition salts of compound of formula-1 with a suitable base selected from a group consisting of alkali metal carbonates like sodium carbonate, lithium carbonate, potassium carbonate; or an alkali metal hydroxide like sodium hydroxide, potassium hydroxide, lithium hydroxide; or alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate; or an organic base like triethylamine, tributylamine, diisopropylethlyamine to provide pure compound of formula- 1.

Efforts are made to prepare pharmaceutical products of a high grade and with a minimum amount of impurities present. The control of impurities requires a study of various options to decide upon the reaction conditions and testing protocols necessary to insure that drugs which are administered to the public are substantially pure. Accordingly, there remains a need for an improved process for preparing Sonidegib that eliminates or substantially reduces the impurities in a convenient and cost efficient manner to provide highly purified Sonidegib.

The thirteenth aspect of the present invention provides an improved process for the preparation of N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoro methoxy)[l,l '-biphenyl]-3-carboxamide diphosphate compound of formula-la,

a) Reacting 2-chloro-5-nitropyridine compound of formula-2 with cis-2,6-dimethyl morpholine compound of formula-3 in presence of a suitable base in a suitable solvent to provide cis-2,6-dimethyl-4-(5-nitropyridin-2-yl)mo holine compound of formula- 4,

b) reducing the compound of formula-4 with a suitable reducing agent in a suitable solvent to provide 6-((cis)-2,6-dimethylmo holino)pyridin-3-amine compound of formula-5,

c) optionally, purifying the compound of formula-5 with a suitable solvent to provide pure compound of formula-5,

d) reacting the compound of formula-5 obtained in step-(b) or step-(c), with 2-methyl-4'- (trifluoromethoxy)-[l, -biphenyl]-3-carboxylic acid compound of formula-8 in presence of suitable coupling agent and a suitable base in a suitable solvent to provide N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [1,1 '-biphenyl]-3-carboxamide compound of formula-1,

e) treating the compound of formula-1 with a suitable acid in a suitable solvent to provide its corresponding acid addition salt of compound of formula-1 ,

f) optionally, purifying the acid addition salt of compound of formula-1 using a suitable solvent,

g) treating the acid addition salts compound of formula- 1 with a suitable base in a suitable solvent to provide pure N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]- 2-methyl-4'-(trifluoromethoxy)[l, -biphenyl]-3-carboxamide compound of formula- 1,

h) treating the compound of formula- 1 with phosphoric acid in a suitable solvent to provide N- [6-(cis-2,6-dimethylmo holin-4- l)pyridine-3 -yl] -2-methyl-4 ' -(trifluoro methoxy) [l,l '-biphenyl]-3-carboxamide diphosphate compound of formula- la.

Wherein, in step-a), d) and g) the suitable base is selected from organic or inorganic base; in step-b) the suitable reducing agents is selected from Sn in acidic media like HCl, Zn dust, Zn in acidic media like HCl or NH4CI, ammonium acetate or acetic acid, stannous chloride (SnCh), NaBH4, L1AIH4, L1BH4, diborane, borane-THF complex, hydrazine hydrate, hydrogenation catalysts such as Rhodium, sulfides, alkali metal dithionite, alkali metal dithionate and sodium amalgam;

in step-d) the suitable coupling agent is selected from thionyl chloride, (DCC) N,N- dicyclohexylcarbodimide, Ν,Ν'-diisopropylcarbodiimide, N-di-tert-butylcarbodiimide, 1 ,3-di- p-tolylcarbodiimide, bis(3-chloro-2-methylphenyl)carbodiimide, bis(otolylcarbodiimide), 1- tert-butyl-3-ethylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethyl carbodiimide, bis(2,6- diisopropylphenyl)carbodiimide, bis(2,6-diethylphenyl)carbodiimide, N-cyclohexyl-N'-iso propylcarbodiimide, N-methyl-N'-phenylcarbocliimide, 1 -cyclohexyl-3-(2-(4-morpholinyl) ethyl)carbodiimide, Ν,Ν'-dicyclohexyl-N-methylcarbodiimidium iodide, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC-HC1), ((O-benzotriazol-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluroniumtetrafluoroborate) (TBTU), 2-chloro-4,6-dimethoxy-l ,3,5- triazine (CDMT), 2-chloro-l,3-dimethylimidazolium chloride (DMC), alkyl chloroformate compounds (e.g. ethyl chloroformate, isobutyl chloroformate (IBCf), or the like) and optionally, in addition to the coupling agent, a catalytic auxiliary nucleophile may be used to activate the carboxyl group.

Suitable catalytic auxiliary nucleophiles which can be used to promote the reaction include, but are not limited to 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimede 5 (HOSu) and N-hydroxy-5-norbene-endo-2,3-dicarboxamide (HONB); in step-e) the suitable acid is selected from inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; and organic acid such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, 2-chloromandelate, p-toluene sulfonic acid, ethane- 1,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid and aspartic acid;

in step-a) to step-h) the suitable solvent is selected from alcohol solvents, chloro solvents, nitrile solvents, ester solvents, hydrocarbon solvents, chloro solvents, ketone solvents, ether solvents, polar parotic solvents, polar solvents like water or mixture thereof.

The preferred embodiment of the present invention provides an improved process for the preparation of N-[6-(cis-2,6-dimethylmo holin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoro methoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide diphosphate compound of formula- 1 a,

a) Reacting 2-chloro-5-nitropyridine compound of formula-2 with cis-2,6-dimethyl morpholine compound of formula-3 in presence of sodium carbonate in dimethyl formamide to provide cis-2,6-dimethyl-4-(5-nitropyridin-2-yl)morpholine compound of formula-4,

b) reducing the compound of formula-4 with palladium carbon in ethyl acetate to provide 6-((cis)-2,6-dimethylmorpholino)pyridin-3 -amine compound of formula-5,

c) purifying the compound of formula-5 with n-heptane to provide pure compound of formula-5,

d) reacting the compound of formula-5 with 2-methyl-4'-(trifluoromethoxy)-[l,r-bi phenyl] -3 -carboxylic acid compound of formula-8 in presence of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole in diisopropylethylamine and dimethylformamide to provide N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4' -(trifluoromethoxy)[ 1 , 1 ' -biphenyl] -3 - carboxamide compound of formula- 1,

e) treating the compound of formula-1 with hydrochloric acid in acetone to provide N-[6- (cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' - biphenyl] -3 -carboxamide hydrochloric acid salt compound of formula- lc, f) purifying the compound of formula- lc using a mixture of methanol and water, g) treating the compound of formula- lc of step-(e) or (f) with sodium hydroxide in water to provide pure N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy)[l,l'-biphenyl]-3-carboxamide compound of formula- 1,

h) treating the compound of formula- 1 with phosphoric acid in acetonitrile to provide N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula- la.

Earlier reported process for the reduction of cis-2,6-dimethyl-4-(5-nitropyridin-2-yl) morpholine compound of formula-4 involves the usage of palladium in alcohol solvents such as methanol (or) isopropanol to provide 6-((cis)-2,6-dimethylmorpholino)pyridin-3-amine compound of formula-5 as an oil. Inventors of the present invention, when carried out the same reaction, it is observed that the reaction was incomplete, required longer time and obtained the compound of formula-5 as an oil with low yield and purity.

When the reduction of compound of formula-4 was carried out in Raney nickel in the presence of methanol; Fe/NH₄C1 in the presence of methanol and Fe/HCl in the presence of ethanol, it is observed that the reaction was not initiated.

Reduction of compound of formula-4 in the presence of palladium in methyl tertiary butyl ether, the reaction was incomplete and further needed cumbersome workups to provide compound of formula-5 with low yield.

Inventors of the present invention when carried out the reduction reaction in presence of ester solvents such as ethyl acetate, it is surprisingly noticed that the reaction was completed in short period of time and provided the compound of formula-5 with high yield and purity. Hence, when compared over the prior art process, the present invention is simple, less time consuming, eco-friendly and more advantageous.

N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide diphosphate compound of formula- la, obtained according to the present invention having the following impurities less than 0.05% as measured by HPLC:

N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate compound of formula- la produced according to the present invention is useful in the preparation of pharmaceutical formulation. The fourteenth aspect of the present invention provides an improved process for the preparation of 2-methyl-4'-(trifluoromethoxy)-[l, -biphenyl]-3-carboxylic acid compound of formula-8, comprising of reacting 3-bromo-2-methyl benzoic acid compound of formula-6 with (4-(trifluoromethoxy)phenyl)boronic acid compound of formula-7 in the presence of palladium catalyst in a suitable base in a suitable solvent to provide 2-methyl-4'- (trifiuoromethoxy)-[l, -biphenyl]-3-carboxylic acid compound of formula-8.

Wherein, the suitable base is selected from inorganic or organic base and suitable solvent is selected from ketone solvents, ester solvents, hydrocarbon solvents, chloro solvents and polar solvents like water or mixture thereof.

The preferred embodiment of the present invention provides an improved process for the preparation of 2-methyl-4'-(trifluoromethoxy)-[l ,l'-biphenyl]-3-carboxylic acid compound of formula-8, comprising of reacting 3-bromo-2-methyl benzoic acid compound of formula-6 with (4-(trifluoromethoxy)phenyl)boronic acid compound of formula-7 in the presence of palladium catalyst in potassium carbonate in water to provide 2-methyl-4'- (trifluoromethoxy)-[l,r-biphenyl]-3-carboxylic acid compound of formula-8.

WO2015/092720 Al and medicinal chemistry letters-2010, vol-1 , pages-130-134 involves process for the preparation of 2-methyl-4'-(trifluoromethoxy)-[l, -biphenyl]-3- carboxylic acid compound of formula-8 by reacting compound of formula-6 with compound of formula-7 in the presence of Pd(PPh)₄, in the presence of 1 ,4-dioxane in a sealed tube at 130°C for longer reaction time period to provide compound of formula-8 with low yield and purity, which is further purified by using preparative HPLC to provide compound of formula- 8 with low yield.

As the above mentioned prior process involves the usage of expensive reagents like Pd(PPh)₄, high boiling and toxic solvents like 1 ,4-Dioxane which is classified by the National Toxicology Program and IARC as possibly carcinogenic to humans. The said process also involves sealed tube reaction with longer reaction time period and tedious preparative HPLC purification provides compound of formula-8 with low yield and purity and not suitable for commercial scale. In order to overcome the problems associated with the prior process, inventors of the present invention has developed simple process, which involves the reaction of compound of formula-6 with compound of formula-7 in the presence of Pd/c and potassium carbonate in water to provide compound of formula-8 with increased yield and purity.

The present invention involves the usage of cheaper reagents, avoids toxic solvents and tedious purifications. Hence, the present invention is advantageous, less time consuming, economical and suitable for commercial scale.

The fifteenth aspect of the present invention provides a process for the preparation of amorphous N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoro methoxy) [l,l'-biphenyl]-3-carboxamide compound of formula-1, comprising of:

a) Dissolving N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' - (trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide in a suitable solvent,

b) stirring the reaction mixture,

c) isolating the amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]- 2-methyl-4' -(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide compound of formula- 1.

in step-c) the isolation of compound of formula-1 can be carried out by filtration, solvent dry distillation, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique or by adding suitable anti-solvent.

The preferred embodiment of the present invention provides a process for the preparation of amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide compound of formula-1, comprising of:

a) Dissolving N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' - (trifluoromethoxy) [ 1 , Γ -biphenyl] -3 -carboxamide in methanol,

b) stirring the reaction mixture, c) isolating the amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]- 2-methyl-4'-(trifluoromethoxy) [l ,l '-biphenyl]-3-carboxamide compound of formula- 1.

Amorphous form of compound of formula- la, crystalline forms and acid addition salts of N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl]-2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' - biphenyl]-3-carboxamide compound of formula-1 produced by the present invention can be further micronized or milled in a conventional techniques 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, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.

N-[6-(eis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l, -biphenyl]-3-carboxamide compound of formula-1 used in the present invention can be prepared according to the present invention or any of the process known in the art.

N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate compound of formula-la obtained according to the present invention is having particle size distribution Ds>o less than 150 μηι, preferably less than 100 μηι, more preferably less than 50 μιη

The invention also encompasses pharmaceutical compositions comprising compound of formula- la or salts thereof of the present invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

P-XRD Method of Analysis:

PXRD analysis of compounds produced by the present invention were carried out using BRUKER D8 ADVANCE/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

The process of the present invention can be represented schematically as follows:

Scheme-A:

Formula-1

Scheme-B:

F

Formula-la Formula-lh Methane sulfonic acid PSD method of Analysis:

Particle size distribution (PSD) analysis of compound of formula- la produced by the present invention was carried out using 15 Malvern Mastersizer 2000 instrument

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples

Example-l: Preparation of crystalline form-A of N-[6-(cis-2,6-dimethyl morphoIin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide: (Formula- 1)

A mixture of acetone (10 ml) and N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3- yl]-2-methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide (1.0 gm) were heated to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 0.8 gm.

The P-XRD pattern of the obtained compound is matching with the P-XRD pattern of figure- 3 of US8722672 B2.

Example-2: Preparation of crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l,l'-biphenyl]-3-carboxamide

hydrobromide salt: (Formula-Id)

Aqueous hydro bromic acid (0.70 ml) was added to a mixture of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide (1.0 gm) and acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 1.0 gm.

The P-XRD pattern of the obtained compound is depicted in figure- 1. Example-3: Preparation of crystalline form-M of N-[6-(cis-2,6-dimethyImorpholin-4-yl) pyridine-3-yl]-2-methyI-4'-(trifluoromethoxy)[l,l'-biphenyl]-3-carboxamide

paratoluene sulfonate salt: (Formula-le)

Paratoluene sulfonic acid (0.38 gm) was added to a mixture of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' _^biphenyl] -3 - carboxamide (1.0 gm) and acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 0.7 gm.

The P-XRD pattern of the obtained compound is depicted in figure-2.

Example-4: Preparation of crystalline form-S of N-[6-(cis-2,6-dimethylmorphoIin-4-yl) pyridine-3-yl] -2-methyl-4' -(trifluoromethoxy) [1,1' -biphenyl] -3-carboxamide

paratoluene sulfonate salt: (Formula-le)

Paratoluene sulfonic acid (0.74 gm) was added to a mixture of N-[6-(cis-2,6- dimethylmo holin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl] -3- carboxamide (1 gm) and acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 0.7 gms.

The P-XRD pattern of the obtained compound is depicted in figure-3.

ExampIe-5: Preparation of crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yI]-2-methyl-4'-(trifluoromethoxy)[l,l'-biphenyl]-3-carboxamide oxalate salt: (Formula-lf)

Oxalic acid (0.27 gms) was added to a mixture of N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l ,l '-biphenyl]-3-carboxamide (1.0 gm) and acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound.

Yield: 0.5 gms; The P-XRD pattern of the obtained compound is depicted in figure-4.

Example-6: Preparation of crystalline form-S of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l,l'-biphenyl]-3-carboxamide oxalate salt: (Formula-lf)

Oxalic acid (0.54 gms) was added to a mixture of N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide (1.0 gm) and acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 60 minutes at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound.

Yield: 0.9 gms; The P-XRD pattern of the obtained compound is depicted in figure-5.

Example-7: Preparation of crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l,l'-biphenyl]-3-carboxamide maleate salt: (Formula-lg)

Maleic acid (0.26 gms) was added to a mixture of N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide (1.0 gm) and acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 0.8 gm. The P-XRD pattern of the obtained compound is depicted in figure-6.

Example-8: Preparation of crystalline form-S of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl] -2-methy 1-4 '-(trifluoromethoxy) [1,1 '-biphenyl] -3-carboxamide maleate salt: (Formula-lg) Maleic acid (0.50 gms) was added to a mixture of N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide (1.0 gm) and acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound.

Yield: 0.8 gms; The P-XRD pattern of the obtained compound is depicted in figure-7.

Example-9: Preparation of crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l,l'-biphenyl]-3-carboxamide methane sulfonate salt: (Formula-lh)

Methane sulfonic acid (0.21 gms) was added to a mixture of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl]-2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide (1.0 gm) and acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 0.9 gm.

The P-XRD pattern of the obtained compound is depicted in figure-8.

Example-10: Preparation of crystalline form-S of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l,l'-biphenyl]-3-carboxamide methane sulfonate salt: (Formula-lh)

Methane sulfonic acid (0.41 gm) was added to a mixture of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [ 1,1 ' -biphenyl] -3- carboxamide (1.0 gm) and acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 1.0 gm.

The P-XRD pattern of the obtained compound is depicted in figure-9.

Example-11: Preparation of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy)[l,l'-biphenyl]-3-carboxamide: (Formula-l)

Dimethoxy ethane (200 ml) was added to 3-bromo-N-(6-((2S,6R)-2,6-dimethyl morpholine)pyridine-3-yl)-2-methylbenzamide (20 gms) compound of formula-9 at 25-30°C. (4-(trifluoromethoxy)phenyl)boronic acid (20.38 gms) compound of formula- 10, aqueous sodium carbonate solution (1.0 gms of sodium carbonate in 5.0 ml of water) and tetrakis(triphenylphosphine)palladium(0) (0.13 gms) were added to the reaction mixture at 25- 30°C. Heated the reaction mixture to 80-85°C and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-30°C. Water and ethyl acetate was added to the reaction mixture at 25-30°C and stirred form 10 minutes at the same temperature. Both the organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with 10% sodium chloride solution. Dried the organic layer with sodium sulphate. Distilled off the solvent completely under reduced pressure and co- distilled with methanol. Water (50 ml) was added to the obtained compound. Adjusted the pH of the reaction mixture to 8-9 using and aqueous sodium carbonate solution at 25-30°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.

Yield: 20 gms; The P-XRD pattern of the obtained compound is depicted in figure- 10.

Example-12: Preparation of crystalline form-A of N-[6-(cis-2,6-dimethyl morpholin-4-yI) pyridine-3-yl]-2-methyl-4' -(trifluoromethoxy) [ 1 ,1 ' -biphenyl] -3-carboxamide:

(Formula-l)

A mixture of acetonitrile (50 ml) and N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine- 3 -yl]-2-methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl] -3-carboxamide (5.0 gms) were heated to 80-85°C and stirred for 15 minutes at the same temperature. Activated carbon was added to the reaction mixture at 80-85°C. Filtered the reaction mixture through hyflow bed. Cooled the obtained filtrate to 25-30°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hour at the same temperature. Filtered the precipitated solid, washed with acetonitrile and dried to get the title compound. Yield: 2.5 gms.

The P-XRD pattern of the obtained compound is matching with the P-XRD pattern of figure-3 of US8722672 B2.

Example-13: Preparation of crystalline form-A of N-[6-(cis-2,6-dimethyl morpholin-4-yI) pyridine-3-yI]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide:

(Formula-1)

A mixture of isopropanol (50 ml) and N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine- 3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide (5.0 gms) were heated to 80-85°C and stirred for 15 minutes at the same temperature. Activated carbon (0.5 gms) was added to the reaction mixture at 80-85°C. Filtered the reaction mixture through hyflow bed. Cooled the obtained filtrate to 25-30°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hour at the same temperature. Filtered the precipitated solid, washed with isopropanol and dried to get the title compound.

Yield: 2.0 gms.

Exampie-14: Preparation of Amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yI) pyridine-3-yl]-2-methyI-4'-(trifluoromethoxy) [l,l'-biphenyI]-3-carboxamide diphosphate (Formula-la)

A mixture of dichloromethane (100 ml) and methanol (100 ml) was added to N-[6- (cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifiuoromethoxy) [1,1 '- biphenyl]-3-carboxamide diphosphate (5.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. The reaction mixture was spray dried at below mentioned parameters to obtain amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate:

Operation parameters:

Labultima Instrument

Inlet temperature: 40°C

Feed rate: lO ml/min

Aspirator flow rate: 70% Gas flow N₂ pressure: 5.0 kg/ cm

Yield: 2.5 gms; The P-XRD pattern of the obtained compound was depicted in figure-11. Particle size distribution: (PSD): D(0.9) is 30.5 μηι; D[4.3] is 15.4 μηι.

Example-15: Preparation of Amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3- carboxamide diphosphate in combination with HPMC: (1:1)

A mixture of dichloromethane (150 ml) and methanol (150 ml) was added to N-[6- (cis-2,6-dimethylmo holin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 ,1 '- biphenyl]-3-carboxamide diphosphate (5.0 gms) and HPMC (5.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. The reaction mixture was spray dried at below mentioned parameters to obtain amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide diphosphate with HPMC:

Operation parameters:

Labultima Instrument

Inlet temperature: 55°C

Feed rate: 10 ml/min

Aspirator flow rate: 70%

Gas flow N₂ pressure: 5.0 kg/ cm

Yield: 5.0 gms; The P-XRD pattern of the obtained compound was depicted in figure- 12. Example-16: Preparation of Amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yI]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3- carboxamide diphosphate in combination with PVP K-30: (1:1)

A mixture of dichloromethane (150 ml) and methanol (150 ml) was added to N-[6- (cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [1,1 '- biphenyl] -3 -carboxamide diphosphate (5.0 gms) and PVP K-30 (5.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. The reaction mixture was spray dried at below mentioned parameters to obtain amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 , -biphenyl] -3 -carboxamide diphosphate with PVP K-30: Operation parameters:

Labultima Instrument

Inlet temperature: 55°C

Feed rate: 10 ml/min

Aspirator flow rate: 70%

Gas flow N₂ pressure: 5.0 kg/ cm

Yield: 6.0 gms; The P-XRD pattern of the obtained compound was depicted in figure-13. Example-17: Preparation of Amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholin-4-yI)pyridine-3-yI]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3- carboxamide diphosphate in combination with HPMC AS: (1:1)

A mixture of dichloromethane (150 ml) and methanol (150 ml) was added to N-[6- (cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' - biphenyl]-3-carboxamide diphosphate (5.0 gms) and HPMC AS (5.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. The reaction mixture was spray dried at below mentioned parameters to obtain amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide diphosphate with HPMC AS:

Operation parameters:

Labultima Instrument

Inlet temperature: 55°C

Feed rate: 10 ml/min

Aspirator flow rate: 70%

Gas flow N₂ pressure: 5.0 kg/ cm

Yield: 5.0 gms; The P-XRD pattern of the obtained compound was depicted in figure-14. Example-18: Preparation of Amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholine-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3- carboxamide diphosphate in combination with HPC: (1:1)

A mixture of dichloromethane (150 ml) and methanol (150 ml) was added to N-[6- (cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl] -2-methyl-4' -(trifluoromethoxy) [1,1 '- biphenyl]-3-carboxamide diphosphate (5.0 gms) and HPC (5.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. The reaction mixture was spray dried at below mentioned parameters to obtain amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl]-2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide diphosphate with HPC:

Operation parameters:

Labultima Instrument

Inlet temperature: 55°C

Feed rate: 10 ml/min

Aspirator flow rate: 70%

Gas flow N₂ pressure: 5.0 kg/ cm

Yield: 5.0 gms. The P-XRD pattern of the obtained compound was depicted in figure-15. Example-19: Preparation of Crystalline form-M of N-(6-(cis-2,6-dimethylmorpholino) pyridin-3-yl)-2-methyl-4-(trifluoromethoxy)-[l,l'-biphenyl]-3-carboxamide

diphosphate: (Formula-la)

Methanol (40 ml) was added to N-(6-(cis-2,6-dimethylmorpholino)pyridin-3-yl)-2- methyl-4-(trifluoro methoxy)-[l ,l'-biphenyl]-3-carboxamide (2.0 gms) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 40-45°C. Phosphoric acid (8.5 gms) was added to the reaction mixture at 40-45°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture slowly to 0-5°C and stirred for 4 hours at the same temperature. Filtered the solid and dried to get the title compound.

Yield: 1.8 gms; Phosphate content: 27.66%.

The P-XRD pattern of the obtained compound was depicted in figure- 16.

ExampIe-20: Preparation of crystalline form-S of N-(6-(cis-2,6-dimethylmorpholino) pyridin-3-yl)-2-methyl-4-(trifluoromethoxy)-[l,l'-biphenyl]-3-carboxamide

monophosphate: (Formula-lb)

Acetonitrile (140 ml) was added to N-(6-(cis-2,6-dimethylmorpholino)pyridin-3-yl)-2- methyl-4-(trifluoro methoxy)-[l,l'-biphenyl] -3 -carboxamide (10 gms) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through hyflow bed. Phosphoric acid (2.37 gms) was slowly added obtained filtrate at 55-60°C. Cooled the reaction mixture to 25-30°C and stirred for 45 minutes at the same temperature. Further cooled the reaction mixture to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with acetonitrile and dried to get the title compound.

Yield: 10.6 gms; Phosphate content: 16.08%.

The P-XRD pattern of the obtained compound was depicted in figure- 17.

Example-21: Preparation of crystalline form-S of N-(6-(cis-2,6-dimethylmorpholino) pyridin-3-yl)-2-methyl-4-(trifluoromethoxy)-[l,l'-biphenyl]-3-carboxamide

monophosphate: (Formula-lb)

A mixture of methanol (10 ml) and isopropanol (20 ml) were added to N-(6-(cis-2,6- dimethylmo holino)pyridin-3-yl)-2-methyl-4-(trifluoromethoxy)-[ 1 , 1 '-biphenyl]-3- carboxamide (1.0 gms) at 25-30°C. Heated the reaction mixture slowly to 60°C and stirred for 20 minutes at the same temperature. Phosphoric acid (0.95 gms) was slowly added to the reaction mixture at 55-60°C. Cooled the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid and dried to get the title compound.

Yield: 1.5 gms; Phosphate content: 17.89%.

The P-XRD pattern of the obtained compound was depicted in figure- 17.

Example-21: Preparation of crystalline form-S of N-(6-(cis-2,6-dimethylmorpholino) pyridin-3-yl)-2-methyI-4-(trifluoromethoxy)-[l,l'-biphenyl]-3-carboxamide

monophosphate: (Formula-lb)

Methanol (15 ml) was added to N-(6-(cis-2,6-dimethylmorpholino)pyridin-3-yl)-2- methyl-4-(trifluoro methoxy)-[l ,l'-biphenyl]-3-carboxamide diphosphate (1.0 gms) at 25- 30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 40°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid and dried to get the title compound. Yield: 0.8 gms; Phosphate content: 16.10%.

The P-XRD pattern of the obtained compound was depicted in figure- 17.

Example-22: Preparation of cis-2,6-dimethyl-4-(5-nitropyridin-2-yl)morpholine:

(Formula-4)

A mixture of dimethylformamide (400 ml), 2-chloro-5-nitropyridine (100 gms) and sodium carbonate (66.86 gms) was stirred for 10 minutes at 25-30°C. Cis-2,6-dimethyl morpholine (87.06 gms) was slowly added to the reaction mixture at 25-30°C and stirred for 3 hours at the same temperature. Water was slowly added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 140 gms; M.R: 125-130°C.

Example-23: Preparation of 6-((cis)-2,6-dimethyImorpholino)pyridin-3-amine:

(Formula-5)

Ethyl acetate (700 ml) was added to cis-2,6-dimethyl-4-(5-nitropyridin-2-yl) morpholine (100 gms) in an autoclave at 25-30°C and stirred for 10 minutes at the same temperature. 5% Pd/C (15 gms) was added into the reaction mixture in an autoclave. The reaction mixture was hydrogenated at 60-65°C by applying 5.0 kg/cm² hydrogen gas pressure for 4 hours. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture through hyflow bed and washed the bed with ethyl acetate. Distilled off the solvent completely from the obtained filtrate under reduced pressure and co-distilled with n-heptane. To the obtained solid, n-heptane (300 ml) was added at 25-30°C and stirred for 15 minutes at the same temperature. 6-((cis)-2,6-dimethylmorpholino)pyridin-3-amine seed crystals were added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with chilled n-heptane and dried to get the title compound.

Yield: 80 gms; M.R: 56-60°C.

Example-24:

Preparation of 6-((cis)-2,6-dimethylmorpholino)pyridin-3-amine: (Formula-5)

Ethyl acetate (700 ml) was added to cis-2,6-dimethyl-4-(5-nitropyridin-2-yl) morpholine (100 gms) in an autoclave at 25-30°C and stirred for 10 minutes at the same temperature. 5% Pd/C (15 gms) was added into the reaction mixture in an autoclave. The reaction mixture was hydrogenated at 60-65°C by applying 5.0 kg/cm² hydrogen gas pressure for 4 hours. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture through hyflow bed and washed the bed with ethyl acetate. Distilled off the solvent completely from the obtained filtrate under reduced pressure and co-distilled with n-heptane. To the obtained solid, n-heptane (300 ml) was added at 25-30°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with chilled n-heptane and dried to get the title compound. Yield: 78 gms; M.R: 56-60°C.

ExampIe-25: Preparation of 2-methyl-4'-(trifluoromethoxy)-[l,l'-biphenyl]-3-carboxyIic acid: (Formula-8)

A mixture of 1,4-dioxane (800 ml), 3-bromo-2-methylbenzoic acid (100 gms), 4- (trifluoromethoxy)phenyl)boronic acid (120 gms) and tetrakis(triphenylphosphine)palladium (2 gms) was stirred for 10 minutes at 25-30°C. Aqueous sodium carbonate solution was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 10 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Activated carbon (10 gms) was added to the reaction mixture at 25-30°C and stirred for 10 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed and washed the bed with water. To the obtained filtrate, water was added at 25-30°C and washed twice with toluene. Cooled the aqueous layer to 15-20°C. Adjusted the pH of the aqueous layer using aqueous hydrochloric acid solution at 15-20°C. Raised the temperature of reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 120 gms; M.R: 112-116°C.

Example-26: Preparation of 2-methyl-4'-(trifluoromethoxy)-[l,l'-biphenyl]-3-carboxylic acid: (Formula-8)

Potassium carbonate solution (128.5 gms potassium carbonate in 500 ml of water) was added to a mixture of water (800 ml), 3-bromo-2-methylbenzoic acid (100 gms), 4-(trifluoro methoxy)phenyl)boronic acid (105.4 gms) and Pd/C (2.0 gms) at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 5 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture through hyflow bed and washed the bed with water. Water and toluene was added to the obtained filtrate at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. Aqueous layer was cooled to 10-15°C. Acidifying the aqueous layer using aqueous hydrochloric acid solution at 10-15°C. Raised the temperature of the reaction mixture to 25- 30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid and washed with water. To the obtained solid, water (1300 ml) was added at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 132.0 gms; M.R: 117°C-120°C.

ExampIe-27: Preparation of N-(6-(cis-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyI- 4'-(trifluoromethoxy)-[l,l'-biphenyl]-3-carboxamide: (Formula-1)

A mixture of dimethylformamide (250 ml), 6-(cis-2,6-dimethylmorpholino)pyridin-3- amine (35 gms), 2-methyl-4'-(trifluoromethoxy)-[l,r-biphenyl]-3-carboxylic acid (50 gms), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (40.2 gms) and 1 -hydroxy benzotriazole (2.25 gms) was stirred for 10 minutes at 25-30°C. Diisopropylethylamine (27.1 gms) was added to the reaction mixture at 25-30°C and stirred for 4 hours at the same temperature. Water was slowly added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 80 gms; Purity by HPLC: 91.79%; Bromo amide impurity: 3.28 %; Desbromo amide impurity: 0.04%; Regio isomer impurity I: 0.1%; Trans isomer impurity: 0.14%; Regio isomer impurity: 0.08%; Unknown impurities: 4.41%.

Example-28: Preparation of crystalline form-M of N-(6-(cis-2,6-dimethylmorpholino) pyridin-3-yl)-2-methyl-4^,-(trifluoromethoxy)-[l,l'-biphenyl]-3-carboxamide

hydrochloride salt: (Formula-lc)

To the compound of formula-1 obtained according to example-27, acetone (800 ml) was added at 25-30°C and stirred for 15 minutes at the same temperature. Activated carbon (2.5) was added to the reaction mixture at 25-30°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed the bed with acetone. To the obtained filtrate, hydrochloric acid (25 ml) was added at 25-30°C and stirred the reaction mixture for 12 hours at the same temperature. Filtered the precipitated solid and washed with acetone. To the obtained compound, methanol (325 ml) was added at 25-30°C and stirred for 20 minutes at the same temperature. Water (650 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.

Yield: 58 gms; chloride content: 6.8% w/w; Purity by HPLC: 99.92%; Bromo amide impurity: 0.01%; Desbromo amide impurity: Not detected; Regio isomer impurity I: Not detected; Trans isomer impurity: 0.03%; Regio isomer impurity; 0.02%. Unknown impurities: 0.02%; The P-XRD pattern of the obtained compound was depicted in figure-18. Example-29: Preparation of N-(6-(cis-2,6-dimethyImorpholino)pyridin-3-yl)-2-methyl- 4'-(trifluoromethoxy)-[l,l'-biphenyl]-3-carboxamide hydrochloride: (Formula-lc)

Thionyl chloride (80.3 gms) was slowly added to the mixture of 2-methyl-4'- (trifluoromethoxy)-[l, -biphenyl]-3-carboxylic acid (100 gms) and N-methylpyrrolidone (500 ml) at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for 40 minutes at the same temperature. 6-(cis-2,6-dimethylmorpholino)pyridin-3 -amine (70 gms) was added to the reaction mixture at 45-50°C and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 25-30°C. Acetone (1 Its) was added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid and washed with acetone. To the obtained compound, methanol (600 ml) was added at 25-30°C and stirred for 10 minutes at the same temperature. Activated carbon was added to the reaction mixture at 25-30°C. Filtered the reaction mixture through hy-flow bed and washed with methanol. Water was slowly added to the obtained filtrate at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with water and dried to get the title compound.

Yield: 120 gms; Purity by HPLC: 99.74%.

Example-30: Preparation of N-(6-(cis-2,6-dimethylmorphoIino)pyridin-3-yI)-2-methyl- 4'-(trifluoro methoxy)-[l,l'-biphenyl]-3-carboxamide diphosphate: (Formula-la)

Aqueous sodium hydroxide solution was added to a mixture of N-(6-(cis-2,6-dimethyl moφholino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)-[l, -biphenyl]-3-carboxamide hydrochloride (100 gms) and water (900 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Dichloromethane (700 ml) was added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure. Acetonitrile (1400 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 20 minutes at the same temperature. Activated carbon (5.0 gms) was added to the reaction mixture at 55- 60°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed the bed with acetonitrile. To the obtained filtrate, phosphoric acid (47.49 gms) was slowly added at 50-55°C. Cooled the reaction mixture slowly to 25-30°C and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with acetonitrile and dried to get the title compound. Yield: 120 gms; M.R: 213-217°C; Phosphoric acid content: 28.82 %; Purity by HPLC: 99.96%. Particle size distribution: (PSD): D(0.1) is 10.7 μιη; D(0.5) is 19.6 μm; D(0.9) is 37.9 μm; D[4.3] is 22.5 μπι.

Example-31: Preparation of N-(6-(cis-2,6-dimethyImorpholino)pyridin-3-yl)-2-methyI- 4'-(trifluoromethoxy)-[l,l'-biphenyl]-3-carboxamide: (Formula-l)

Aqueous sodium hydroxide solution was added to a mixture of N-(6-(cis-2,6-dimethyl mo holino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)-[l , -biphenyl]-3-carboxamide hydrochloride (100 gms) and water (900 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Dichloromethane (700 ml) was added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure. Yield: 90.0 gms.

The P-XRD pattern of the obtained compound was depicted in figure- 19.

ExampIe-32: Preparation of Amorphous N-(6-(cis-2,6-dimethyImorpholino)pyridin-3-yl) -2-methyl-4'-(trifluoromethoxy)-[l,r-biphenyI]-3-carboxamide: (Formula-l)

Methanol (150 ml) was added to N-(6-(cis-2,6-dimethylmo holino)pyridin-3-yl) -2- methyl-4^,-(trifluoromethoxy)-[l,r-biphenyl]-3-carboxamide (5.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. The reaction mixture was spray dried at below mentioned parameters to obtain amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl]-3-carboxamide.

Operation parameters:

Labultima Instrument

Inlet temperature: 60°C

Feed rate: 10 ml/min

Aspirator flow rate: 65%

Gas flow N₂ pressure: 5.0 kg/ cm²

Yield: 2.5 gms; The P-XRD pattern of the obtained compound was depicted in figure-20.

ExampIe-33: Preparation of cis-2,6-dimethyl-4-(5-nitropyridin-2-yl)morphoIine:

(Formula-4)

A mixture of dimethylformamide (16 Its) and 2-chloro-5-nitropyridine (4.0 kgs) was stirred for 10 minutes at 25-30°C. Sodium carbonate (2.68 kgs) was added to the reaction mixture at 25-30°C and stirred for 10 minutes at the same temperature. Cis-2,6- dimethylmorpholine (3.48 kgs) was slowly added to the reaction mixture at 25-30°C and stirred for 3 hours at the same temperature. Water was slowly added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.

Yield: 5.80 kgs; Purity by HPLC: 99.87%; Hydroxy nitro pyridine impurity: Not detected; Chloro nitro pyridine impurity: Not detected; Trans isomer impurity: 0.05%; HIUI: 0.07%. Example-34: Preparation of 6-((cis)-2,6-dimethylmorpholino)pyridin-3-amine:

(Formula-5)

Ethyl acetate (20 Its) was added to a mixture of cis-2,6-dimethyl-4-(5-nitropyridin-2- yl) morpholine (5.50 kgs) and ethyl acetate (10 Its) in a pressure reactor at 25-30°C and stirred for 15 minutes at the same temperature. Pd/C (0.83 kgs) and ethyl acetate (8.5 Its) was added to the reaction mixture. The reaction mixture was hydrogenated at 60-65°C by applying 3.0 kg/cm² hydrogen gas pressure for 4 hours. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture through hyflow bed and washed the bed with ethyl acetate. Distilled off the solvent completely from the obtained filtrate under reduced pressure and co- distilled with n-heptane. To the obtained solid, n-heptane (16.5 Its) was added at 25-30°C and stirred for 15 minutes at the same temperature. 6-((cis)-2,6-dimethylmorpholino)pyridin-3- amine seed crystals were added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with chilled n-heptane and dried to get the title compound.

Yield: 4.40 kgs; Purity by HPLC: 99.72%; Nitro impurity: Not detected; Chloro nitro pyridine impurity: 0.02%; Trans isomer impurity: 0.05%; HIUI: 0.06%.

Example-35: Preparation of 2-methyl-4'-(trifIuoromethoxy)-[l,l^,-biphenyl]-3-carboxylic acid: (Formula-8)

Water (40 Its) was added to a mixture of 3-bromo-2-methylbenzoic acid (5.0 kgs), 4- (trifluoromethoxy)phenyl)boronic acid (5.30 kgs) and Pd/C (0.10 kgs) at 25-30°C and stirred for 10 minutes at the same temperature. Potassium carbonate solution (6.40 kgs of potassium carbonate in 25 Its of water) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture through hyflow bed and washed the bed with water. Water and toluene was added to the obtained filtrate at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. Aqueous layer was cooled to 10-15°C. Acidifying the aqueous layer using aqueous hydrochloric acid solution at 10-15°C. Raised the temperature of the reaction mixture to 25- 30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid and washed with water. To the obtained solid, water (65 Its) was added at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with water and dried to get the title compound.

Yield: 6.89 kgs; Purity by HPLC: 99.98%; Amino methyl benzoic acid impurity: Not detected; Ortho toluic acid impurity: Not detected; Bromomethyl benzoic acid impurity: 0.01%; Regio isomer impurity: Not detected; Meta isomer impurity: Not detected; HIUI: 0.01%.,

Example-36: Preparation of N-(6-(cis-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyI- 4'-(trifluoromethoxy)-[l,l'-biphenyl]-3-carboxaiiiide hydrochloride salt: (Formula-lc)

Dimethyl formamide (28 Its) was added to 6-(cis-2,6-dimethylmorpholino)pyridin-3-amine (3.85 kgs) and 2-methyl-4'-(trifluoromethoxy)-[l, -biphenyl]-3-carboxylic acid (5.50 kgs) at 25-30°C and stirred for 15 minutes at the same temperature. 1 -Hydroxybenzotriazole (0.25 kgs) was added to the reaction mixture. Diisopropylethylamine (3.0 kgs) was slowly added to the reaction mixture at 25-30°C. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (4.5 kgs) was added lot wise to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Water was added the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried for 5 hour at 60-65°C. Acetone (88 Its) was added to the obtained compound at 25-30°C and stirred for 20 minutes at the same temperature. Activated carbon (0.30 kgs) was added to the reaction mixture at 25-30°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed the bed with acetone. To the obtained filtrate, hydrochloric acid (3.0 Its) was added at 25-30°C and stirred the reaction mixture for 12 hours at the same temperature. Filtered the precipitated solid and washed with acetone. To the obtained compound, methanol (36 Its) was added at 25-30°C and stirred for 20 minutes at the same temperature. Water (72 Its) was slowly added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water. Methanol (36 Its) was added to the wet compound at 25-30°C and stirred for 30 minutes at the same temperature. Hydrochloric acid solution (1.0 Its of HC1 in 6.0 Its of water) and water (66 Its) was slowly added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.

Yield: 6.93 kgs; Purity by HPLC: 99.91%; Bromo amide impurity: Not detected; Desbromo amide impurity: Not detected; Regio isomer impurity I: Not detected; Trans isomer impurity:

0.03%; Regio isomer impurity; Not detected%. Unknown impurities: 0.04%.

Example-37: Preparation of crystalline form-S of N-(6-(cis-2,6-dimethylmorpholino) pyridin-3-yI)-2-methyl-4-(trifluoromethoxy)-[l,l'-biphenyl]-3-carboxamide

monophosphate: (Formula-lb)

Water (60 Its) and dichloromethane (65 Its) was added to N-(6-(cis-2,6-dimethyl morpholino)pyridin-3 -yl)-2-methyl-4'-(trifluoromethoxy)- [1 ,1 '-biphenyl] -3 -carboxamide hydrochloride salt (6.50 kgs) at 25-30°C. Sodium carbonate solution (1.50 kgs of sodium carbonate in 7 Its of water) was slowly added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Both the organic and aqueous layers were separated. Carbon (030 kgs) was added to the organic layer at 25-30°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed the bed with dichloromethane. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with acetonitrile. To the obtained compound, acetonitrile (91 Its) was added at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 20 minutes at the same temperature. Phosphoric acid (1.44 kgs) was added to the reaction mixture at 60-65°C. Cooled the reaction mixture to 25-30°C and stirred for 45 minutes at the same temperature. Further, cooled the reaction mixture to 0-5 °C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with acetonitrile. A mixture of water (16 Its) and acetonitrile (16 Its) was added to the obtained compound at 25-30°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with acetonitrile and dried to get the title compound. Yield: 7.27 kgs; Phosphate content: 16.58%; Purity by HPLC: 99.98%; Bromo amide impurity: Not detected; Desbromo amide impurity: Not detected; Regio isomer impurity I: Not detected; Trans isomer impurity: 0.01%; Regio isomer impurity; Not detected%; Unknown impurities: 0.01%.

The P-XRD pattern of the obtained compound was depicted in figure- 17.

Example-38: Preparation of N-(6-(cis-2,6-dimethyImorpholino)pyridin-3-yl)-2-methyl-

4'-(trifluoromethoxy)-[l,l'-biphenyI]-3-carboxamide diphosphate: (Formula-la)

Water (10 Its) and dichloromethane (15 Its) was added to N-(6-(cis-2,6-dimethyl morpholino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)-[l, -biphenyl]-3-carboxamide hydrochloride (1.50 kgs) at 25-30°C. Sodium carbonate solution (335.0 gms of sodium carbonate in 1.5 Its of water) was slowly added to the reaction mixture at 25-30°C and stirred for 30 minutes at same temperature. Both the organic and aqueous layers were separated. Carbon (75.0 gms) was added to the organic layer at 25-30°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed the bed with dichloromethane. Distilled off the solvent completely from the filtrate under reduced pressure. Acetonitrile (21 Its) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 60-65 °C and stirred for 20 minutes at the same temperature. Phosphoric acid (675.0 gms) was added to the reaction mixture at 60-65°C. Cooled the reaction mixture to 25- 30°C and stirred for 45 minutes at the same temperature. Further, cooled the reaction mixture to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with acetonitrile and dried to get the title compound.

Yield: 1.96 kgs; Phosphoric acid content: 27.2% w/w; Purity by HPLC: 99.97%; Bromo amide impurity: Not detected; Desbromo amide impurity: Not detected; Regio isomer impurity I: Not detected; Trans isomer impurity: 0.03%; Regio isomer impurity; Not detected%.

Example-39: Preparation of Amorphous N-(6-(cis-2,6-dimethylmorpholino)pyridin-3-yl) -2-methyl-4'-(trifluoromethoxy)-[l,l'-biphenyl]-3-carboxamide diphosphate:

(Formula-la)

Methanol (150 ml) was added to N-(6-(cis-2,6-dimethylmorpholino)pyridin-3-yl) -2- methyl-4'-(trifluoromethoxy)-[l, -biphenyl]-3-carboxamide (5.0 gms) at 25-30°C and stirred for 30 minutes at the same temperature. Phosphoric acid (3.0 gms) was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. The reaction mixture was spray dried at below mentioned parameters to obtain amorphous N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide diphosphate:

Operation parameters:

Labultima Instrument

Inlet temperature: 65°C

Feed rate: 10 ml/min

Aspirator flow rate: 65%

Gas flow N₂ pressure: 3.0 kg/ cm²

Yield: 3.0 gms; The P-XRD pattern of the obtained compound was depicted in figure-11.

Claims

We Claim:

1. Amorphous N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoro methoxy) [l, -biphenyl]-3-carboxamide diphosphate.

2. Amorphous N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoro methoxy) [l,l '-biphenyl]-3-carboxamide diphosphate according to claim-1 is further characterized by its PXRD pattern as depicted in figure- 1 1.

3. Amorphous N- [6-(cis-2,6-dimethylmo holin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoro methoxy) [l ,l '-biphenyl]-3-carboxamide diphosphate according to claim-1 is substantially free of any of the crystalline forms of compound of formula- la.

4. A process for the preparation of amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl]-3-carboxamide diphosphate compound of formula- la, comprising of:

a) Dissolving N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [l ,l '-biphenyl]-3-carboxamide diphosphate in a suitable solvent, b) stirring the reaction mixture,

c) isolating the amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]- 2-methyl-4'-(trifluoromethoxy) [1 ,1 '-biphenyl]-3-carboxamide diphosphate compound of formula- la.

5. The process according to claim-4, wherein, in step-a) the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixtures thereof.

in step-c) isolation of compound of formula- la can be carried out by filtration, solvent dry distillation, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique or by adding suitable anti- solvent.

6. A process for the preparation of amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide diphosphate compound of formula- la, comprising of:

a) Dissolving N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' - (trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate in a mixture of methanol and dichloromethane,

b) stirring the reaction mixture,

c) isolating the amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]- 2-methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl]-3-carboxamide diphosphate compound of formula- la.

7. An improved process for the preparation of N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 ,1 '-biphenyl]-3-carboxamide diphosphate compound of formula- la,

a) Reacting 2-chloro-5-nitropyridine compound of formula-2 with cis-2,6-dimethyl morpholine compound of formula-3 in presence of a suitable base in a suitable solvent to provide cis-2,6-dimethyl-4-(5-nitropyridin-2-yl)morpholine compound of formula- 4,

b) reducing the compound of formula-4 with a suitable reducing agent in a suitable solvent to provide 6-((cis)-2,6-dimethylmorpholino)pyridin-3-amine compound of formula-5,

d) reacting the compound of formula-5 obtained in step-(b) or step-(c), with 2-methyl-4'- (trifluoromethoxy)-[l,r-biphenyl]-3-carboxylic acid compound of formula-8 in presence of suitable coupling agent and a suitable base in a suitable solvent to provide N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide compound of formula-1,

e) treating the compound of formula-1 with a suitable acid in a suitable solvent to provide its corresponding acid addition salt of compound of formula-1,

g) treating the acid addition salts compound of formula- 1 with a suitable base in a suitable solvent to provide pure N-[6-(cis-2,6-dimethyl mo holin-4-yl)pyridine-3-yl]- 2-methyl-4'-(trifluoromethoxy)[l, -biphenyl]-3-carboxamide compound of formula- 1,

h) treating the compound of formula- 1 with phosphoric acid in a suitable solvent to provide N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoro methoxy) [l,l '-biphenyl]-3-carboxamide diphosphate compound of formula-la.

8. The process according to claim-7, wherein, in step-a), d) and g) the suitable base is selected from organic or inorganic base;

in step-b) the suitable reducing agents is selected from Sn in acidic media like HCl, Zn dust, Zn in acidic media like HCl or NH4CI, ammonium acetate or acetic acid, stannous chloride (SnCb), NaBH4, L1AIH4, L1BH4, diborane, borane-THF complex, hydrazine hydrate, hydrogenation catalysts such as Rhodium, sulfides, alkali metal dithionite, alkali metal dithionate and sodium amalgam;

in step-d) the suitable coupling agent is selected from thionyl chloride, (DCC) N,N- dicyclohexylcarbodimide, Ν,Ν'-diisopropylcarbodiimide, N-di-tert-butylcarbodiimide, 1 ,3-di-p-tolylcarbodiimide, bis(3-chloro-2-methylphenyl)carbodiimide, bis(otolylcarbo diimide), l-tert-butyl-3-ethylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbo diimide, bis(2,6-diisopropylphenyl)carbodiimide, bis(2,6-diethylphenyl)carbo diimide, N- cyclohexyl-N'-iso propylcarbodiimide, N-methyl-N'-phenylcarbodiimide, l-cyclohexyl-3- (2-(4-morpholinyl)ethyl)carbodiimide, N,N'-dicyclohexyl-N-methylcarbodiimidium iodide, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HC1), ((O- benzotriazol- 1 -y^-N_jN_jN^N -tetramethyluroniumtetrafluoroborate) (TBTU), 2-chloro-4,6- dimethoxy-l,3,5-triazine (CDMT), 2-chloro-l ,3-dimethylimidazolium chloride (DMC), alkyl chloroformate compounds (e.g. ethyl chloroformate, isobutyl chloroformate (IBCf), or the like) and optionally, in addition to the coupling agent, a catalytic auxiliary nucleophile may be used to activate the carboxyl group. Suitable catalytic auxiliary nucleophiles which can be used to promote the reaction include, but are not limited to 1 - hydroxybenzotriazole (HOBt), N-hydroxysuccinimede 5 (HOSu) and N-hydroxy-5- norbene-endo-2,3-dicarboxamide (HONB); in step-e) the suitable acid is selected from inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; and organic acid such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, 2-chloromandelate, p-toluene sulfonic acid, ethane- 1 ,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid and aspartic acid;

9. An improved process for the preparation of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl]-3-carboxamide diphosphate compound of formula- la,

b) reducing the compound of formula-4 with palladium carbon in ethyl acetate to provide 6-((cis)-2,6-dimethylmorpholino)pyridin-3-amine compound of formula-5,

d) reacting the compound of formula-5 with 2-methyl-4'-(trifluoromethoxy)-[l,r-bi phenyl] -3 -carboxylic acid compound of formula-8 in presence of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride and 1 -hydroxybenzotriazole in diisopropylethylamine and dimethylformamide to provide N-[6-(cis-2,6-dimethyl moipholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifiuoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide compound of formula- 1,

e) treating the compound of formula- 1 with hydrochloric acid in acetone to provide N-[6- (cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifiuoromethoxy) [ 1 , 1 ' - biphenyl] -3 -carboxamide hydrochloric acid salt compound of formula- lc, f) purifying the compound of formula- lc using a mixture of methanol and water, g) treating the compound of formula- lc of step-(e) or (f) with sodium hydroxide in water to provide pure N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide compound of formula- 1 , h) treating the compound of formula- 1 with phosphoric acid in acetonitrile to provide N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate compound of formula- la.

10. Crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate compound of formula- la characterized by its X-ray powder diffractogram having peaks at 4.9, 10.0, 12.7, 13.7, 15.1, 16.1, 17.3, 17.9, 18.7, 20.3, 21.8, 24.0 and 26.3 ± 0.2 degrees two-theta as illustrated in figure- 16.

11. A process for the preparation of crystalline form-M of N-[6-(cis-2,6-dimethyl morpholin- 4-yl)pyridine-3 -yl]-2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide diphosphate compound of formula- la, comprising of the following steps:

a) Adding suitable solvent to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [1 , 1 '-biphenyl] -3 -carboxamide,

b) heating the reaction mixture to suitable temperature,

c) adding phosphoric acid to the reaction mixture,

d) stirring the reaction mixture,

e) cooling the reaction mixture to suitable temperature,

f) stirring the reaction mixture and filtering the precipitated solid to provide crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide diphosphate compound of formula- la.

12. The process according to claim-1 1, wherein, in step-a) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, chloro solvents, ether solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents and polar solvents like water or mixture thereof; in step-b) the suitable temperature is ranging from 25°C to the reflux temperature of solvent used in the reaction;

in step-e) the suitable temperature is ranging from -15C to 15°C.

13. A process for the preparation of novel crystalline form-M of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -bipheny 1] -3 - carboxamide diphosphate compound of formula- la, comprising of the following steps: a) Adding methanol to N-[6-(cis-2,6-dimethylmo holin-4-yl)pyridine-3-yl]-2-methyl- 4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide,

b) heating the reaction mixture to 40-45°C,

c) adding phosphoric acid to the reaction mixture,

d) stirring the reaction mixture,

e) cooling the reaction mixture to 0-5 °C,

f) stirring the reaction mixture and filtering the precipitated solid to get crystalline form- M of N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoro methoxy) [Ι , -biphenyl] -3 -carboxamide diphosphate compound of formula-la.

14. Acid addition salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) ' -biphenyl]-3-carboxamide compound of formula- 1 ,

Formula- 1

wherein, the acid addition salt is selected from salt of inorganic acids, such as hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; and salt of organic acids, such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, 2-chloromandelate, p-toluene sulfonic acid, ethane- 1,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid, with the proviso that acid is not mono hydrochloric acid and mono sulfuric acid.

15. Crystalline acid addition salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l, -biphenyl]-3-carboxamide compound of formula-1 , which include:

a) Crystalline form-M of hydrobromide salt compound of formula- Id which is characterized by its P-XRD pattern as depicted in figure- 1.

b) Crystalline form-M of paratoluene sulfonate salt compound of formula- le which is characterized by its P-XRD pattern as depicted in figure-2.

c) Crystalline form-S of paratoluene sulfonate salt compound of formula- le which is characterized by its P-XRD pattern as depicted in figure-3.

d) Crystalline form-M of oxalate salt compound of formula- If which is characterized by its P-XRD pattern as depicted in figure-4.

e) Crystalline form-S of oxalate salt compound of formula-1 f which is characterized by its P-XRD pattern as depicted in figure-5.

f) Crystalline form-M of maleate salt compound of formula- lg which is characterized by its P-XRD pattern as depicted in figure-6.

g) Crystalline form-S of maleate salt compound of formula- lg which is characterized by its P-XRD pattern as depicted in figure-7.

h) Crystalline form-M of methane sulfonate salt compound of formula- lh which is characterized by its P-XRD pattern as depicted in figure-8.

i) Crystalline form-S of methane sulfonate salt compound of formula- lh which is characterized by its P-XRD pattern as depicted in figure-9.

16. A process for the preparation of crystalline acid addition salts of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide compound of formula-1, comprising of the following steps:

a) Adding a suitable solvent to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [ 1,1 ' -biphenyl] -3 -carboxamide compound of formula- 1, b) adding a suitable acid to the reaction mixture,

e) filtering the precipitated solid to provide corresponding crystalline acid addition salts of N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoro methoxy) [l,l '-biphenyl]-3-carboxamide compound of formula- 1.

17. The process according to claim- 16, wherein, in step-a) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, chloro solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixture thereof;

in step-b) the suitable acid is selected from inorganic acids, such as hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; and organic acids, such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, 2-chloromandelate, p- toluene sulfonic acid, ethane- 1 ,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid.

in step-c) the suitable temperature is ranging from ambient temperature to the reflux temperature of solvent used in the reaction;

in step-d) the suitable temperature is ranging from about 0°C to 30°C.

18. A process for the preparation of crystalline form-A of N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide compound of formula- 1, comprising of:

a) Adding a suitable solvent to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide compound of formula- 1,

b) heating the reaction mixture to a suitable temperature, c) optionally, treating the reaction mixture with activated carbon and filtering the reaction mixture,

d) cooling the filtrate obtained in step-c) and stirring at a suitable temperature, e) filtering the precipitated solid to provide crystalline form-A of N-[6-(cis-2,6- dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [1,1 '- biphenyl]-3-carboxamide compound of formula- 1.

19. The process according to claim- 18, wherein, in step-a) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, chloro solvents, ether solvents, polar aprotic solvents, nitrile solvents, hydrocarbon solvents and polar solvents like water or mixture thereof;

in step-d) the suitable temperature is ranging from -10°C to 30°C.

20. A process for the preparation of crystalline form-A of N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3-yl]-2-methyl-4' -(trifluoromethoxy) [1 ,1 '-biphenyl]-3-carboxamide compound of formula- 1 , comprising of:

c) cooling the reaction mixture to 25-30°C and stirring the reaction mixture,

d) further cooling the reaction mixture to 0-5 °C and stirring the reaction mixture, e) filtering the precipitated solid to provide crystalline form-A of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 ,1 '-biphenyl] -3- carboxamide compound of formula- 1.

21. A.process for the preparation of crystalline form-A of N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide compound of formula- 1 , comprising of:

a) Adding acetonitrile to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl -4 '-(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide compound of formula-1 , b) heating the reaction mixture to 80-85 °C and stirring the reaction mixture,

e) further cooling the reaction mixture to 0-5 °C and stirring the reaction mixture, f) filtering the precipitated solid to provide crystalline form- A of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -y 1] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide compound of formula- 1.

22. A process for the preparation of crystalline form-A of N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3-yl]-2-methyl-4' -(trifluoromethoxy) [l ,l '-biphenyl]-3-carboxamide compound of formula- 1, comprising of:

a) Adding isopropanol to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl -4 '-(trifluoromethoxy) [1 ,1 '-biphenyl] -3 -carboxamide compound of formula-1, b) heating the reaction mixture to 80-85°C and stirring the reaction mixture,

d) cooling the obtained filtrate obtained in step-c) to 25-30°C and stirring at the same temperature,

e) further, cooling the reaction mixture to 0-5 °C and stirring the reaction mixture, f) filtering the precipitated solid to provide crystalline form-A of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2 -methyl-4' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide compound of formula- 1.

23. Crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide hydrochloride salt compound of formula-lc characterized by its X-ray powder diffractogram having peaks at 3.43, 4.81 , 9.95, 10.81, 1 1.42, 13.55, 14.46, 16.69, 17.01, 17.48, 18.34, 19.10, 20.35, 21.96, 23.08, 23.48, 24.17, 24.44, 24.53, 25.24, 27.61 , 29.90, 30.94, 31.44, 34.94, 38.25, 40.64 and 41.40 ± 0.2 degrees two-theta as illustrated in figure-18.

24. Use of crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide hydrochloride salt compound of formula- lc in the preparation of pure compound of formula- 1 as well as compound of formula- l .

25. A process for the preparation of crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin- 4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide hydrochloric acid salt compound of formula- lc, comprising of the following steps :

a) Dissolving N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' - (trifluoromethoxy) [1 ,1 '-biphenyl] -3 -carboxamide compound of formula- 1 in a suitable first solvent,

b) optionally, treating the reaction mixture with activated carbon,

d) stirring the reaction mixture,

e) filtering the precipitated solid,

f) dissolving the solid obtained in step-e) in a suitable second solvent,

g) adding a suitable third solvent to the reaction mixture,

h) stirring the reaction mixture,

i) filtering the precipitated solid to provide crystalline form-M of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 ,1 '-biphenyl]-3- carboxamide hydrochloric acid salt compound of formula- lc.

26. The process according to claim-25, wherein, in step-a), f) and g) the suitable first, second and third solvent is selected from alcohol solvents, ether solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixture thereof;

in step-d) the suitable hydrochloric acid source is selected from HC1 gas, hydrochloric acid, aqueous hydrochloric acid, ethyl acetate-HCl, methanolic-HCl, ethanolic-HCl and IPA-HC1.

27. A process for the preparation of crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin- 4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide hydrochloric acid salt compound of formula- lc, comprising of the following steps:

a) Dissolving N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' - (trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide compound of formula- 1 in acetone, b) treating the reaction mixture with activated carbon,

c) filtering the reaction mixture through hyflow bed,

d) adding hydrochloric acid to the obtained filtrate,

e) stirring the reaction mixture,

f) filtering the precipitated solid,

g) dissolving the solid obtained in step-f) in methanol,

h) adding water to the reaction mixture,

i) stirring the reaction mixture,

j) filtering the precipitated solid to get crystalline form-M of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide hydrochloric acid salt compound of formula- lc.

28. A process for the preparation of crystalline form-S of N-[6-(cis-2,6-dimethyl morpholin-4- yl)pyridine-3-yl]-2-methyl-4' -(trifluoromethoxy) [1 ,1 '-biphenyl]-3-carboxamide monophosphate compound of formula- lb, comprising of the following steps:

a) Adding a suitable solvent to N-[6-(cis-2,6-dimethylmo holin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide,

b) heating the reaction mixture to a suitable temperature,

c) stirring the reaction mixture,

d) optionally, filtering the reaction mixture through hyflow bed,

e) adding phosphoric acid to the filtrate obtained in step-c or step-d),

f) cooling the reaction mixture to a suitable temperature,

g) stirring the reaction mixture and filtering the precipitated solid to provide crystalline form-S of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoro methoxy) [1 ,1 '-biphenyl] -3 -carboxamide monophosphate compound of formula-lb.

29. The process according to claim-28, wherein, in step-a) the suitable solvent is selected from alcohol solvents; hydrocarbon solvents, ketone solvents; ester solvents, chloro solvents, ether solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixture thereof;

in step-f) the suitable temperature is -10°C to 30°C.

30. A process for the preparation of crystalline form-S of N-[6-(cis-2,6-dimethyl morpholin-4- yl)pyridine-3-yl]-2-methyl-4' -(trifluoromethoxy) [1 ,1 '-biphenyl]-3-carboxamide monophosphate compound of formula- lb, comprising of the following steps:

a) Adding acetonitrile to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl- 4'-(trifluoromethoxy) [1,1 '-biphenyl]-3-carboxamide,

b) heating the reaction mixture to 55-60°C,

c) stirring the reaction mixture,

d) filtering the reaction mixture through hyflow bed,

e) adding phosphoric acid to the filtrate obtained in step-d),

f) cooling the reaction mixture to 0-5°C,

g) stirring the reaction mixture and filtering the precipitated solid to provide crystalline form-S of N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoro methoxy) [l,l '-biphenyl]-3-carboxamide monophosphate compound of formula-lb.

31. A process for the preparation of crystalline form-S of N-[6-(cis-2,6-dimethyl morpholin-4- yl)pyridine-3 -yl] -2-methyl-4' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide monophosphate compound of formula- lb, comprising of the following steps:

a) Adding a mixture of isopropanol and methanol to N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3-yl]-2-methyl-4' -(trifluoromethoxy) [1 ,1 '-biphenyl] -3 -carboxamide, b) heating the reaction mixture to 55-60°C,

c) stirring the reaction mixture,

d) adding phosphoric acid to the reaction mixture,

e) cooling the reaction mixture to 0-5°C, f) stirring the reaction mixture and filtering the precipitated solid to provide crystalline form-S of N- [6-(cis-2,6-dimethylmo holin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoro methoxy) [l,l '-biphenyl]-3-carboxamide monophosphate compound of formula-lb.

32. A process for the preparation of crystalline form-S of N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3 -yl]-2-methyl-4' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide monophosphate compound of formula- lb, comprising of the following steps:

a) Adding methanol to N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl- 4 '-(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide diphosphate,

b) heating the reaction mixture to 55-60°C,

c) stirring the reaction mixture,

d) cooling the reaction mixture to 25-30°C,

e) filtering the precipitated solid to provide crystalline form-S of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide monophosphate compound of formula- lb.

33. Amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide diphosphate compound of formula- la in combination with one or more pharmaceutical acceptable carriers.

34. Amorphous solid dispersion of N-[6-(cis-2,6-dimethylmo holin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [1 ,1 '-biphenyl] -3 -carboxamide diphosphate according to claim-33, wherein, the pharmaceutical acceptable carrier is a polymeric carrier, starches, modified starches, cellulose, methyl cellulose (MC), Microcrystalline cellulose (MCC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC -AS), polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxy alkylene derivatives, polymethacrylates, polyvinyl pyrrolidone (PVP), PVP K-30, polyvinyl acetate (PVAc), PVP vinylacetate-copolymer (PVP-VA), Kollidon VA 64 (a vinylpyrrolidone-vinyl acetate copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, isomalt, cyclodextrins such as cc-cyclodextrins, β-cyclodextrins, γ- cyclodextrins, hydroxyl-propyl-cyclodextrins, hydroxyl propyl-cyclodextrin, sodium carboxymethyl cellulose cross-linked polyacrylic acid (carbipol), or a mixture thereof.

35. Amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate compound of formula- la in combination with one or more pharmaceutical acceptable carrier, which includes:

a) Amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]- 2-methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate in combination with HPMC which is characterized by its P-XRD pattern as depicted in figure- 12.

b) Amorphous solid dispersion of N-[6-(cis-2,6-dimethylmoφholin-4-yl)pyridine-3-yl]- 2-methyl-4' -(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate in combination with PVP K-30 which is characterized by its P-XRD pattern as depicted in figure-13.

c) Amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]- 2-methyl-4'-(trifluoromethoxy) [l ,l '-biphenyl]-3-carboxamide diphosphate in combination with HPMC AS which is characterized by its P-XRD pattern as depicted in figure- 14.

d) Amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]- 2-methyl-4'-(trifluoromethoxy) [Ι,Γ-biphenyl] -3 -carboxamide diphosphate in scombination with HPC which is characterized by its P-XRD pattern as depicted in figure-15.

36. A process for the preparation of amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -bipheny 1] -3 - carboxamide diphosphate compound of formula- la in combination with one or more pharmaceutical acceptable carrier, comprising of:

a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide diphosphate and one or more pharmaceutical acceptable carrier in a suitable solvent, b) stirring the reaction mixture,

c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl]-3-carboxamide diphosphate compound of formula- la with one or more pharmaceutical acceptable carrier.

37. The process according to claim-36, wherein, in step-a) the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixture thereof and suitable pharmaceutical acceptable carrier is selected from starches, modified starches, cellulose, methyl cellulose (MC), Microcrystalline cellulose (MCC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMC-AS), polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxy alkylene derivatives, polymethacrylates, polyvinyl pyrrolidone (PVP), PVP K-30, polyvinyl acetate (PVAc), PVP vinylacetate-copolymer (PVP-VA), Kollidon VA 64 (a vinylpyrrolidone-vinyl acetate copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, isomalt, cyclodextrins such as cc-cyclodextrins, β-cyclodextrins, γ- cyclodextrins, hydroxyl-propyl-cyclodextrins, hydroxyl propyl-cyclodextrin, sodium carboxymethyl cellulose cross-linked polyacrylic acid (carbipol), or a mixture thereof.

38. A process for the preparation of amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3 -yl] -2-methyl-4' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 - carboxamide diphosphate compound of formula- la in combination with one or more pharmaceutical acceptable carrier, comprising of:

i). amorphous solid dispersion of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]- 2-methyl-4' -(trifluoromethoxy) [1 ,1 '-biphenyl] -3 -carboxamide diphosphate in combination with HPMC, comprising of:

a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide diphosphate and HPMC in a mixture of methanol and dichloromethane, b) stirring the reaction mixture,

c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide diphosphate compound of formula- la in combination with HPMC. ii) . amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-

2-methyl-4' -(trifluoromethoxy) [1 ,1 '-biphenyl]-3-carboxamide diphosphate compound of formula- 1 a in combination with PVP K-30, comprising of:

a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide diphosphate and PVP K-30 in a mixture of methanol and dichloromethane,

b) stirring the reaction mixture,

c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 ,1 '-biphenyl]-3-carboxamide diphosphate compound of formula- la in combination with PVP K-30. iii) . amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-

2-methyl-4' -(trifluoromethoxy) [1 ,1 '-biphenyl] -3 -carboxamide diphosphate compound of formula-la in combination with HPMC AS, comprising of:

a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4' -(trifluoromethoxy) [l ,l '-biphenyl]-3-carboxamide diphosphate and HPMC AS in a mixture of methanol and dichloromethane,

b) stirring the reaction mixture,

c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4' -(trifluoromethoxy) [1 ,1 '-biphenyl]-3-carboxamide diphosphate compound of formula- la in combination with HPMC AS. iv) . amorphous solid dispersion of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-

2-methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide diphosphate compound of formula- la in combination with HPC, comprising of: a) Dissolving a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide diphosphate and HPC in a mixture of methanol and dichloromethane,

b) stirring the reaction mixture,

c) isolating amorphous solid dispersion of N-[6-(cis-2,6-dimethylmo holin-4-yl) pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide diphosphate compound of formula- la in combination with HPC.

39. An improved process for the preparation of 2-methyl-4'-(trifluoromethoxy)-[l, - biphenyl]-3-carboxylic acid compound of formula-8, comprising of reacting 3-bromo-2- methyl benzoic acid compound of formula-6 with (4-(trifluoromethoxy)phenyl)boronic acid compound of formula-7 in the presence of palladium catalyst in a suitable base in a suitable solvent to provide 2-methyl-4'-(trifluoromethoxy)-[ 1,1 '-biphenyl] -3 -carboxylic acid compound of formula-8.

40. The process according to claim-39, wherein, the suitable base is selected from inorganic or organic base and suitable solvent is selected from ketone solvents, ester solvents, hydrocarbon solvents, chloro solvents and polar solvents like water or mixture thereof.

41. An improved process for the preparation of 2-methyl-4'-(trifluoromethoxy)-[l,r- biphenyl]-3-carboxylic acid compound of formula-8, comprising of reacting 3-bromo-2- methyl benzoic acid compound of formula-6 with (4-(trifluoromethoxy)phenyl)boronic acid compound of formula-7 in the presence of palladium catalyst in potassium carbonate in water to provide 2-methyl-4'-(trifluoromethoxy)-[l,r-biphenyl]-3-carboxylic acid compound of formula-8.

42. A process for the preparation of amorphous N-[6-(cis-2,6-dimethylmorpholin-4-yl) pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 ,1 '-biphenyl] -3 -carboxamide compound of formula- 1, comprising of:

a) Dissolving N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' - (trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide in a suitable solvent,

b) stirring the reaction mixture, c) isolating the amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]- 2-methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide compound of formula- 1.

43. The process according to claim-42, wherein, in step-a) the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixtures thereof;

in step-c) the isolation of compound of formula- 1 can be carried out by filtration, solvent dry distillation, spray drying, agitated thin film drying ("ATFD"), freeze drying (lyophilization), and the like or any other suitable technique or by adding suitable anti- solvent.

44. A process for the preparation of amorphous form of N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl]-3-carboxamide compound of formula- 1 , comprising of:

a) Dissolving N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2-methyl-4 ' - (trifluoromethoxy) [ 1 , 1 ' -biphenyl] -3 -carboxamide in methanol,

b) stirring the reaction mixture,

c) isolating the amorphous form of N-[6-(cis-2,6-dimethylmo holin-4-yl)pyridine-3-yl]- 2-methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide compound of formula- 1.

45. N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)

[1,1 '-biphenyl] -3 -carboxamide diphosphate compound of formula- la according any of the preceding claims having purity greater than 99.97% by HPLC.

46. A process for the preparation of pure N-[6-(cis-2,6-dimethylmo holin-4-yl)pyridine-3- yl]-2-methyl-4' -(trifluoromethoxy) [1,1 '-biphenyl] -3 -carboxamide compound of formula- 1, comprising of treating compound of formula- 1 with a suitable acid in a suitable solvent to provide corresponding acid addition salt of compound of formula- 1, followed by treating the acid addition salts compound of formula- 1 with a suitable base in a suitable solvent to provide pure N-[6-(cis-2,6-dimethylmoφholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide compound of formula-1.

47. The process according to claim-46, wherein the suitable acid is selected from inorganic acids, such as hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; and organic acids, such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, 2-chloromandelate, p-toluene sulfonic acid, ethane- 1 ,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2- sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid and suitable base is selected from organic or inorganic base and suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents and polar solvents like water or mixtures thereof.

48. A process for the preparation of pure N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3- yl]-2-methyl-4'-(trifluoromethoxy) [l ,l '-biphenyl]-3-carboxamide compound of formula- 1, comprising of treating the compound of formula-1 with hydrochloric acid in a mixture of acetone, methanol and water to provide hydrochloride salt compound of formula- lc, followed by treating the compound of formula- lc with aqueous sodium carbonate solution in a mixture of water and dichloromethane to provide pure N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1 ,1 '-biphenyl]-3- carboxamide compound of formula-1.

49. Amorphous N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoro methoxy) [l,l '-biphenyl]-3-carboxamide diphosphate having particle size distribution of D₉₀ < 100 μιη.

50. An improved process for the preparation of 6-((cis)-2,6-dimethylmoφholino)pyridin-3- amine compound of formula-5, comprising of:

a) reducing cis-2,6-dimethyl-4-(5-nitropyridin-2-yl)moφholine compound of formula-4 with a suitable reducing agent in a suitable solvent selected form ester solvents to provide 6-((cis)-2,6-dimethylmorpholino)pyridin-3-amine compound of formula-5, b) optionally, purifying the compound of formula-5 with a suitable solvent to provide pure compound of formula-5.

51. The process according to claim-50, in step-a) the suitable reducing agents is selected from Sn in acidic media like HC1, Zn dust, Zn in acidic media like HC1 or NH4CI, ammonium acetate or acetic acid, stannous chloride (SnCh), NaBth, L1AIH4, L1BH4, diborane, borane-THF complex, hydrazine hydrate, hydrogenation catalysts such as Rhodium, sulfides, alkali metal dithionite, alkali metal dithionate and sodium amalgam; in step-b) the suitable solvent is selected from alcohol solvents, chloro solvents, nitrile solvents, ester solvents, hydrocarbon solvents, chloro solvents, ketone solvents, ether solvents, polar parotic solvents, polar solvents like water or mixture thereof.

52. An improved process for the preparation of 6-((cis)-2,6-dimethylmorpholino)pyridin-3- amine compound of formula-5, comprising of:

a) reducing cis-2,6-dimethyl-4-(5-nitropyridin-2-yl)morpholine compound of formula-4 with Pd/C in ethyl acetate to provide 6-((cis)-2,6-dimethylmorpholino)pyridin-3- amine compound of formula-5,

b) purifying the compound of formula-5 with n-heptane to provide pure compound of formula-5. -

53. Use of acid addition salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2- methyl-4'-(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide compound of formula- 1 in the preparation of pharmaceutical composition.

54. N- [6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3 -yl] -2 -methyl -4 ' -(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide monophosphate compound of formula-lb having particle size distribution of D₉₀ < 150 μπι, preferably < 100 μπν, more preferably < 50 μ^ηι.

55. Use of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoro methoxy) [l,l '-biphenyl]-3-carboxamide monophosphate compound of formula-lb in the preparation of pharmaceutical composition.

56. The process according to any of the preceding claims, N-[6-(cis-2,6-dimethylmorpholin-4- yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl]-3-carboxamide diphosphate compound of formula- la having any of the impurity such as desbromo amide impurity, bromo amide impurity, trans isomer impurity, regio isomer impurity, regio isomer impurity-1 < 0.1% by HPLC.

57. Use of Amorphous N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'- (trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate compound of formula- la in the preparation of pharmaceutical composition.

58. N- [6-(cis-2,6-dimethylmo holin-4-yl)pyridine-3 -yl] -2-methyl-4 ' -(trifluoromethoxy) [l,l '-biphenyl]-3-carboxamide diphosphate compound of formula- la obtained according to the preceding claims having particle size distribution of D₉₀ < 150 μη , preferably < 100 μηι; more preferably < 50 μιη.