Field of the Invention:

The present invention provides solid state forms of 2-[3,5-bis(trifluoromethyl)phen^
pyridin-3-yl]propanamide represented by the following structural formula-1 and process for preparation thereof.
Background of the Invention:

2-[3,5-Bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-l-yl)pyridin-3-yl]propanamide, commonly known as "Netupitant" is a selective NK1 receptor antagonist. In the United States, the combination drug Netupitant/Palonosetron (Akynzeo) is approved by the Food and Drug Administration for prevention of acute and delayed nausea and vomiting associated with cancer chemotherapy.
2-[3,5-Bis(trifluoromethyl)phenyl]-N52-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-l-yl)pyridin-3-yl]propanamide, its related compounds and process for their preparation is described in US6297375B1.
US6303790B1 patent has described process for the preparation of 2-[3,5-
Bis(trifluoromethyl)phenyl]-Ns2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-l-yl)pyridin-3-yl]propanamide and its various intermediate compounds.
Still, there is a significant need in the art to develop an improved process for the preparation of Netupitant which provides the product in better yield and improved quality.
As on date, no polymorphic forms have been reported in the literature for 2-[3,5-
bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-l-yl)pyridin-3-yl]propanamide. There is a significant need in the art to develop polymorphic forms of the said compound which are stable and having advantageous physical properties such as free flowability, greater stability and greater bioavailability.

Brief description of the invention:

The first aspect of the present invention is to provide amorphous form of 2-[3,5-
bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-l-yl)pyridin-3-yl]propanamide compound of formula-1.
The second aspect of the present invention is to provide process for the preparation of amorphous form of compound of formula-1.
The third aspect of the present invention is to provide amorphous solid dispersion comprising compound of formula-1 and at least one pharmaceutical^ acceptable excipient.
The fourth aspect of the present invention is to provide process for the preparation of amorphous solid dispersion comprising compound of formula-1 .and at least one pharmaceutically acceptable excipient.
The fifth aspect of the present invention is to provide crystalline polymorph of compound of formula-1, herein after designated as crystalline form-M.
The sixth aspect of the present invention is to provide a process for the preparation of compound of formula-1, comprising of reacting the N-methyl-6-(4-methylpiperazin-1-yl)-4-o-tolylpyridin-3-amine compound of formula-2 with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoic acid compound of formula-3 under suitable conditions to provide compound of formula-1.
The seventh aspect of the present invention is to provide a process for the preparation of compound of formula-1.
Brief description of the Drawings:

Figure-1: Illustrates the PXRD pattern of amorphous compound of formula-1 obtained
according to example-1.
Figure-2: Illustrates the PXRD pattern of amorphous compound of formula-1 obtained
according to example-2.
Figure-3: Illustrates the PXRD pattern of amorphous solid dispersion comprising compound
of formula-1 and povidone-K-30.
Figure-4: Illustrates the PXRD pattern of amorphous solid dispersion comprising compound
Figure-5: Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula-1 and HPMCAS.
Figure-6: Illustrates the PXRD pattern of amorphous solid dispersion comprising compound of formula-1 and HPC.
Figure-7: Illustrates the PXRD pattern of crystalline form-M of compound of formula-1.
Detailed description of the Invention:
The "suitable solvent" used in the present invention can be selected from but not limited to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, methyl ethyl ether, methyl phenyl ether, diisopropyl ether, methyl tert-butyl ether, dimethoxyethane, diethoxyethane, dibutoxyethane, tetrahydrofuran, 1,4-dioxane, alkyl ethers of ethylene glycol or propylene glycol selected from but not limited to ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono-n-butyl ether, propylene glycol methyl ether, propylene glycol ethyl ether, propylene glycol propyl ether, propylene glycol butyl ether and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, 2-butanol, tert-butanol, n-pentanol, ethane-1,2-diol, propane-1,2-diol; "polar solvents" such as water; formic acid, acetic acid or mixtures thereof.
The term "suitable base" used in the present invention refers to "inorganic bases" selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium
A

bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium 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; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; ammonia; "organic bases" like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, triisopropyl amine, tributylamine, tertbutyl amine, pyridine, 4-dimethylaminopyridine, imidazole, N-methylimidazole, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), N-methylmorpholine, l,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine and the like; "organolithium bases" such as methyl lithium, n-butyl lithium, lithium diisopropylamide and the like; "organosilicon bases" such as lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide and the like or their mixtures.
The first aspect of the present invention provides amorphous form of 2-[3,5-
bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-l-yl)pyridin-3-yl]propanamide compound of formula-1. The amorphous form of compound of formula-1 of present invention is characterized by its PXRD pattern as illustrated in figure-1.
The second aspect of the present invention provides process for the preparation of amorphous form of compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in a suitable solvent or mixture of solvents, D) optionally filtering the reaction mixture,
:) removing the solvent from the reaction mixture to provide amorphous form of compound of formula-1.
Wherein, in step-a) the suitable solvent is selected from but not limited to chloro solvents, ketone solvents, C2-C6 alcohol solvents, ester solvents, nitrile solvents, ether solvents or their mixtures; and the dissolution of compound of formula-1 in a suitable solvent

or mixture of solvents can be carried out at 25-30°C or by heating the reaction mixture to a temperature ranging from 30°C to reflux temperature of the solvents employed;
In step-c) suitable techniques which may be used for the removal of solvent from reaction mixture includes but not limited to evaporation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentration, atmospheric distillation, vacuum distillation, distillation by using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying, melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, addition of suitable anti-solvent to the reaction mixture followed by filtration of precipitated solid, cooling the clear solution to lower temperatures such as below 20°C to precipitate the solid followed by filtration or by any other suitable techniques.
The solvent may be removed at temperatures ranging from -40°C to 100°C optionally under reduced pressures.
The suitable anti-solvent in the above process is selected from but not limited to water, hydrocarbon solvents and the like.
The third aspect of the present invention provides amorphous solid dispersion comprising 2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-l-yl)pyridin-3-yl]propanamide compound of formula-1 and at least one pharmaceutically acceptable excipient.
Wherein, the excipient is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), polyvinylpyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate, methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxyethyl methyl cellulose succinate, hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose, cross linked sodium carboxy methyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose,

magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, a-,(3-,y-cyclodextrins, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates and the like.
In one embodiment, the suitable excipient is preferably'selected from povidone, HPC, HPMC, HPMCAS.
The fourth aspect of the present invention provides a process for the preparation" of amorphous solid dispersion comprising compound of formula-1 and at least one pharmaceutically acceptable excipient, comprising of;
a) Dissolving the compound of formula-1 and at least one excipient in a suitable solvent or mixture of solvents at a suitable temperature,
b) optionally filtering the solution,
c) removing the solvent from the reaction mixture to provide amorphous solid dispersion comprising compound of formula-1 and excipient.
Wherein, in step-a) the suitable excipient is same as defined in the third aspect of the present invention;
The suitable solvent is same as defined in step-a) of the second aspect of the present invention; the suitable temperature ranges from 0°C to reflux temperature of the solvent used;
After dissolving the compound of formula-1 and excipient in the solvent system, the solution may optionally be treated with charcoal or any other suitable material to remove color and/or to clarify the solution;

In step-c) the suitable techniques which may be used for the removal of solvent from
the reaction mixture are same as defined in step-c) of the second aspect of the present
invention; the solvent may be removed at temperatures ranging from -40°C to 100°C
optionally under reduced pressures.
) In the present invention, the ratio of the amount of weight of compound of formula-1
within the solid dispersion to the amount by weight of the excipient therein ranges from but not limited to about 1:0.05 to about 1:5.
The fifth aspect of the present invention provides crystalline polymorph of 2-[3,5-I bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-l-yl)pyridin-3-yl]propanamide compound of formula-1, herein after designated as crystalline form-M. The said polymorph is characterized by its PXRD pattern having peaks at 4.5, 8.4, 11.4, 16.7, 17.3, 20.7, 21.6, 22.9, 23.8 ± 0.2° of 2-theta. The crystalline form-M of the present invention is further characterized by its PXRD pattern as illustrated in figure-7.
An embodiment of the .present invention provides a process for the preparation of crystalline compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in methanol,
b) optionally filtering the reaction mixture,
c) distilling off the solvent completely from the reaction mixture and drying the material to provide crystalline compound of formula-1.
The other embodiment of the present invention provides alternate process for the preparation of crystalline compound of formula-1, comprising of;
a) Adding a suitable solvent to the compound of formula-1,
b) heating the reaction mixture,
c) cooling the reaction mixture,
d) filtering the solid,
e) optionally slurrying the solid in water,
f) drying the material to provide crystalline compound of formula-1.

Wherein, in step-a) the suitable solvent is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or mixtures thereof.
In step-b) the reaction mixture can be heated to a temperature ranges from 35°C to reflux temperature of the solvent used;
In step-c) the reaction mixture can be cooled to a suitable temperature ranges from 20°C to -70°C.
The compound of formula-1 which is utilized as starting material for the preparation of various polymorphic forms of the present invention can be prepared by any of the known processes or it can be prepared by the process as described in the present invention.
The solid state forms of compound of formula-1 of the present invention are useful for the preparation of various pharmaceutical compositions formulated in a manner suitable for the route of administration to be used where at least a portion of compound of formula-1 is present in the composition in particular polymorphic form mentioned.
The sixth aspect of the present invention provides a process for the preparation of compound of formula-1, comprising of reacting the N-methyl-6-(4-methylpiperazin-l-yl)-4-o-tolylpyridin-3-amine compound of formula-2 with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoic acid compound of formula-3 under suitable conditions to provide compound of formula-1.
Wherein, the above step is carried out in presence of a pyridinium based coupling agent in a suitable solvent optionally in presence of a suitable base that includes organic bases, inorganic bases, organolithium bases, organosilicon bases or their mixtures.
Wherein, the suitable pyridinium based coupling agent is represented by the following structural formula
wherein, 'X' represents halogen;
'R' represents Ci-C6 straight chain or branched chain alkyl group;
' Y" represents halide (X"), BF4", SbCl6" and the like.

The suitable solvent that can be used in .the above process is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or their mixtures. The suitable solvent is preferably selected from hydrocarbon solvents.
The reaction of compound of formula-2 with compound of formula-3 can also be
carried out in presence of a suitable coupling agent selected from but not limited to N,N'-
dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride" (EDC.HC1), N,N'-carbonyldiimidazole
(CDI), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid
hexafluorophosphate (HATU), 2-( 1 H-benzotriazol-1 -yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HBTU), 1 H-benzotriazolium 1 -[bis(dimethylamino)methylene]-
Schloro-hexafluorophosphate (1-) 3-oxide (HCTU), alkyl or aryl chloroformates such as
methyl chloroformate, ethyl chloroformate, benzylchloroformate, diphenylphosphoroazidate,
SOCl2, oxalyl chloride, POCl3, phosphorous pentachloride, 4-methyl-2-oxopentanoyl
chloride (i-BuCOCOCl), (benzotriazol-1 -yloxy)tris(dimethylamino)phosphonium
hexafluorophosphate (BOP), benzotriazol-1 -yl-oxytripyrrolidinophosphonium
hexafluorophosphate (PyBOP), methanesulfonyl chloride and the like optionally in
combination with 1-hydroxy-7-azatriazole (HOAt), 1-hydroxybenzotriazole (HOBt), 1-
hydroxy-1H-1,2,3-triazole-4-carboxylate (HOCt), 0-(benzotriazol-1 -yl)-N,N,N',N'-
tetramethyluronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS) and the like; and the reaction can be carried out in a suitable solvent optionally in presence of a suitable base as described above.
In the above processes, the coupling agent can be used in an amount of 1.0 to 3.0 mole ratio, preferably 1.2 to 2.5 mole ratio, more preferably 1.4 to 2.0 mole ratio per one mole of compound of formula-2 and the base can be used in an amount of 1.0 to 3.5 mole ratio, preferably 1.5 to 3.0 mole ratio, more preferably 2.0 to 2.5 mole ratio per one mole of compound of formula-2.

The seventh aspect of the present invention provides a process for the preparation of compound of formula-1, comprising of;
a) Amidation of 6-halonicotinic acid compound of general formula-4 by reacting it with an amine having the general formula R-NH2 or its acid addition salt to provide compound of general formula-5,
b) reacting the compound of general formula-5 with o-tolyl magnesium halide in presence of a suitable solvent followed by oxidation of the obtained compound with a suitable oxidizing agent in a suitable solvent to provide compound of general formla-6,
c) reacting the compound of general formula-6 with N-methyl piperazine optionally in presence of a solvent to provide compound of general formula-7,
d) deprotecting the compound of general formula-7 with a suitable deprotecting agent to provide 6-(4-methylpiperazin-1 -yl)-4-o-tolylnicotinamide compound of formula-8,
e) converting the compound of formula-8 to methyl 6-(4-methylpiperazin-1 -yl)-4-o-tolylpyridin-3-ylcarbamate compound of formula-9,
f) reducing the compound of formula-9 with a suitable reducing agent in a suitable solvent
to provide N-methyl-6-(4-methylpiperazin-l-yl)-4-o-tolylpyridin-3 -amine compound of formula-2,
g) reacting the compound of formula-2 with ' 2-(3,5-bis(trifluoromethyl)phenyl)-2-
methylpropanoic acid compound of formula-3 under suitable conditions to provide
compound of formula-1.
Wherein, step-a) comprises reaction of compound of general formula-4 with a suitable chlorinating agent selected from but not limited to thionyl chloride, oxalyl chloride, POCl3, PCI5, PCI3 and the like optionally in presence of a suitable solvent followed by reacting the obtained acid chloride with the amine described in step-a) in presence of a suitable solvent optionally in presence of a suitable base selected from but not limited to inorganic bases, organic bases, organolithium bases, organosilicon bases or their mixtures to provide compound of general formula-5;
In step-b) the suitable oxidizing agent is selected from but not limited to Mn(OAc)3, Cu(OAc)2, iodine, bromine, N-bromosuccinimide, Pd/C, Pt/C, DDQ (2,3-dichloro-5,6-dicyano-l,4-benzoquinone), chloranil (2,3,5,6-tetrachlorocyclohexa-2,5-diene-l,4-dione),
11

H202, H202-urea, Na2C03-H202, Mn02, KMn04, RuCl2(PPh3)3, Cerium ammonium nitrate (CAN), HN03, Sulfur, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid and the like.
In step-d) the suitable deprotecting agent is selected from but not limited to methanesulfonic acid, acetic acid, sulfuric acid or their mixtures.
In step-e) the conversion of compound of formula-8 to compound of formula-9 is carried out by reacting the compound of formula-8 with an oxidizing agent such as hypohalite, N-halosuccinimide or a hypervalent iodobenzene, for example sodium hypochlorite, potassium hypochlorite, N-chlorosuccinimide, N-bromosuccinimide or iodobenzene diacetate in the presence of a base such as NaOH, NaOMe and the like in a suitable solvent.
In step-f) the suitable reducing agent is selected from but not limited to LiAlH4, NaBH4, BH3-THF and Red-Al.
In step-g) the reaction is carried out in presence of a pyridinium based coupling agent in a suitable solvent optionally in presence of a suitable base that includes organic bases, inorganic bases, organolithium bases, organosilicon bases or their mixtures; wherein, the pyridinium coupling agent is same as defined in the sixth aspect of the presence invention.
In step-a) to step-g) of the above process, the suitable solvent used is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or mixtures thereof.
The compound of formula-1 produced by the process of the present invention is having purity greater than 99%, preferably greater than 99.5%, more preferably greater than 99.7%, most preferably greater than 99.9% by HPLC with all the impurities well within the limits as suggested by ICH guidelines.
P-XRD Method of Analysis:
PXRD analysis of compound of formula-1 was carried out by using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.

HPLC Method of Analysis:
Apparatus: A liquid chromatographic system equipped with variable wavelength UV detector; Column: Kromasil CI8, 250 x 4.6 mm, 5 urn or equivalent; Column temperature: 45°C; Wave length: 250 nm; Injection volume: 5 uL; Elution: Gradient; Diluent: Acetonitrile:Water (90:10 v/v); Sample concentration: 1.0 mg/mL; Buffer: Transfer 2.0 mL of triethylamine and 1.74 gm of dipotassium hydrogen phosphate in 1000 mL of milli-Q-water, adjust the pH to 6.0 with dilute orthophosphoric acid and filter this solution through 0.22 urn Nylon membrane filter paper; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Water (90:10 v/v).
The present invention is schematically represented as follows;
Wherein, 'X' represents halogen atom; wherein, 'R' represents Ci-C6 straight chain or branched chain alkyl group.

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention. Examples:
Example-1: Preparation of amorphous form of compound of formula-1
A mixture of compound of formula-1 (0.5 gm) and dichloromethane (10 ml) was stirred for 5 min at 25-30°C. Distilled off the solvent completely from the obtained solution in a Buchi flask under reduced pressure and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-1. Yield: 300.0 mg.
Example-2: Preparation of amorphous form of compound of formula-1
A mixture of compound of formula-1 (4 gm) and dichloromethane (15 ml) was stirred for 5 min at 25-30°C and filtered the resulting solution. The obtained filtrate was spray dried to provide the title compound. PXRD pattern of the obtained compound is shown in figure-2. Yield: 2.0 gm.
Example-3: Preparation of amorphous solid dispersion comprising compound of formula-1 and povidone-K-30 (1:1)
A mixture of compound of formula-1 (0.5 gm), povidone-K-30 (0.5 gm) and dichloromethane (40 ml) was stirred for 5 min at 25-30°C. The obtained clear solution was transferred to a Buchi flask. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-3. Yield: 700.0 mg.
Example-4: Preparation of amorphous solid dispersion comprising compound of formula-1 and HPMC (1:1)
A mixture of compound of formula-1 (0.5 gm), HPMC (0.5 gm) and dichloromethane (40 ml) was stirred for 5 min at 25-30°C. The obtained clear solution was transferred to a Buchi flask. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-4. Yield: 560.0 mg.

Example-5: Preparation of amorphous solid dispersion comprising compound of formula-l and HPMCAS (1:1)
A mixture of compound of formula-l (0.5 gm), HPMCAS (0.5 gm) and dichloromethane (40 ml) was stirred for 5 min at 25-30°C. The obtained clear solution was i transferred to a Buchi flask. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-5. Yield: 520.0 mg. ExampIe-6: Preparation of amorphous solid dispersion comprising compound of formula-l and HPC (1:1)
A mixture of compound of formula-l (0.5 gin), HPC (0.5 gm) and dichloromethane (40 ml) was stirred for 5 min at 25-30°C. The obtained clear solution was transferred to a Buchi flask. Distilled off the solvent completely from the reaction mixture under reduced pressure and then dried the material to get the title compound. The PXRD pattern of the obtained compound is shown in figure-6. Yield: 400.0 mg. Example-7: Preparation of crystalline form-M of compound of formula-l
A mixture of compound of formula-l (0.5 gm) and methanol (20 ml) was stirred for 5 min at 25-30°C. Distilled off the solvent completely from the obtained solution in a Buchi flask under reduced pressure and then dried the material to provide the title compound. The PXRD pattern of the obtained compound is shown in figure-7. Yield: 250.0 mg.
Example-8: Purification of compound of formula-l
A mixture of compound of formula-l (30 gm) and dimethyl sulfoxide (150 ml) was heated to 90-95°C and stirred for 15 min at the same temperature. The obtained solution was filtered and washed with dimethyl sulfoxide. Cooled the filtrate to 25-30°C and stirred for 60 min at the same temperature. Filtered the precipitated solid and washed with dimethyl sulfoxide. Water (180 ml) was added to the wet solid. Heated the reaction mixture to 60-65°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 60 min at the same temperature. Filtered the solid, washed with water and dried to get the pure title compound. PXRD of the obtained compound is similar to figure-7. Yield: 18.0 gm.

ExampIe-9: Preparation of N-tert-butyI-6-chloronicotinamide (Formula-5a) Step-01: A mixture of 6-chloronicotinic acid compound of formula-4a (100 gm) and dichloromethane (500 ml) was stirred for 15 min at 25-30°C under N2 atmosphere and dimethylformamide (4.89 ml) was added to it. SOCl2 (138.82 ml) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 3 hrs at the same temperature. Distilled off the solvent from the reaction mixture and co-distilled with dichloromethane. Dichloromethane (400 ml) was added to the reaction mixture at 25-30°C under N2 atmosphere, stirred for 15 min at the same temperature and then kept aside. Step-02: Triethylamine (263.77 ml) and tert.butyl amine (133.24 ml) were added to pre-cooled dichloromethane (400 ml) at 0-5 °C under nitrogen atmosphere in another RBF and stirred the reaction mixture for 15 min at the same temperature. The dichloromethane solution obtained in above step-01 was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Water was slowly added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with dichloromethane. Separated the organic and aqueous layers, extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with aq.Na2C03 solution followed by with water. Distilled off the solvent completely from the organic layer and co-distilled with cyclohexane under reduced pressure. Cyclohexane (800 ml) was added to the obtained compound. Heated the reaction mixture to 70-75°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 90 min at the same temperature. Filtered the solid, washed with cyclohexane and dried the material to get the title compound. Yield: 107.3 gm; M.R: 104-107.2°C. Example-10: Preparation of N-tert-butyl-6-chloro-4-o-tolylnicotinamide (FormuIa-6a)
o-Tolyl magnesium chloride solution (352.6 ml; 1M solution in THF) was slowly added to a pre-cooled mixture of compound of formula-5a (25 gm) and tetrahydrofuran (50 ml) at 0-5°C under nitrogen atmosphere and stirred the reaction mixture for 45 min at the same temperature. Heated the reaction mixture to 45-50°C and stirred for 5 hrs at the same temperature. Cooled the reaction mixture to 0-5°C, methanol (50 ml) was slowly added to it and stirred the reaction mixture for 30 min at the same temperature. 4,5-Dichloro-3,6-
16

dihydroxyphthalonitrile (40 gm) was added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-3 0°C and stirred for 3 hrs at the same temperature. The obtained reaction mixture was slowly added to aqueous sodium hydroxide solution (50 gm of sodium hydroxide in 375 ml of water) at 25-30°C and stirred for 30 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with ethyl acetate. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Combined the organic layers and washed with water. Distilled off the solvent from the organic layer under reduced pressure. Methanol (50 ml) and water (125 ml) were added to the obtained compound at 25-30°C and stirred the reaction mixture for 1 hr at the same temperature. Filtered the solid, washed with water and dried the material to get the title compound. Yield: 15.0 gm.
Example-11: Preparation of N-tert-butyI-6-(4-methylpiperazin-l-yl)-4-o-
tolylnicotinamide (Formula-7a)
A mixture of compound of formula-6a (10 gm) and N-methyl piperazine (22.5 gm) was heated to 115-120°C and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, water and ethyl acetate were added to it and stirred for 15 min at the same temperature. Separated the organic and aqueous layers, extracted the aqueous layer with ethyl acetate. Distilled off the solvent from the total organic layers under reduced pressure to get the title compound. Yield: 11.0 gm.
Example-12: Preparation of 6-(4-methylpiperazin-l-yl)-4-o-tolylnicotinamide (FormuIa-8)
A mixture of compound of formula-7a (4 gm) and methanesulfonic acid (8 ml) was heated to 95-100°C and stirred for 8 hrs at the same temperature. Cooled the reaction mixture to 25-30°C, water was added to it and slowly basified the reaction mixture using 10% aqueous sodium hydroxide solution. Ethyl acetate was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Distilled off the solvent completely from the total organic layer to get the title compound. Yield: 3.0 gm.
Example-13: Preparation of methyl 6-(4-methylpiperazin-l-yl)-4-o-toIylpyridin-3-ylcarbamate (Formula-9)

N-Bromosuccinimide (37.25 gm) was added to pre-cooled methanol (150 ml) at 0-5°C and stirred the reaction mixture for 10 min at the same temperature. NaOH (22.54 gm) was slowly added lot wise to the reaction mixture at 0-5°C and stirred for 1 hr at the same temperature. A solution of compound of formula-8 (50 gm) in methanol (350 ml) was slowly added to the reaction mixture at 0-5 °C and stirred the reaction mixture for 4 hrs at the same temperature. Dichloromethane and water were added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer and co-distilled with acetonitrile under reduced pressure. Acetonitrile (100 ml) was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Heated the reaction mixture to 80-85°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 1 hr at the same temperature. Filtered the solid, washed with chilled acetonitrile and dried the material to get the title compound. Yield: 36.8 gm; M.R: 125-130°C.
Example-14: Preparation of N-methyI-6-(4-methylpiperazin-l-yl)-4-o-tolylpyridin-3-amine (Formula-2)
A solution of Red-Al (103.9 gm) in toluene (200 ml) was slowly added to a pre-cooled mixture of compound of formula-9 (50 gm) and toluene (250 ml) at 0-5°C under nitrogen atmosphere and stirred the reaction mixture for 30 min at the same temperature. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 20 min at the same temperature. Slowly heated the reaction mixture to 50-55°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 0-5°C, slowly added chilled water to it and stirred for 20 min at the same temperature. Raised the temperature of the reaction mixture to 25-30°C and stirred for 15 min at the same temperature. Separated the organic and aqueous layers and extracted the aqueous layer with toluene. Washed the total organic layer with water and distilled off the solvent completely to get title compound. Yield: 43.0 gm. Example-15: Preparation of compound of formula-1
A solution of Red-Al (68.29 ml) in toluene (69 ml) was slowly added to a pre-cooled mixture of compound of formula-9 (23 gm) and toluene (115 ml) at 0-5°C under nitrogen

atmosphere and stirred the reaction mixture for 10 min at the same temperature. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 10 min at the same temperature. Heated the reaction mixture to 50-55°C and stirred for 4 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and was slowly added to pre-cooled ! aqueous sodium potassium tartrate solution (23 gm of sodium potassium tartrate in 230 ml of water) at 0-5°C and stirred the reaction mixture for 15 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with toluene. Combined the organic layers and washed with aqueous sodium potassium tartrate solution. 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoic acid compound of formula-3 (22.31 gm), 2-bromo-l-ethyl-pyridinium tetrafluoroborate (27.74 gm) followed by diisopropylethyl amine (23.6 ml) were added to the organic layer at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Heated the reaction mixture to 95-100°C and stirred for 4 hrs at the same temperature. Cooled the reaction mixture to 25-3 0°C, aqueous potassium carbonate solution was added to it and stirred the reaction mixture for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed to make it particle free. Both the organic and aqueous layers were separated and washed the organic layer with aqueous potassium carbonate solution followed by with water. Distilled off the solvent from the organic layer and co-distilled with n-heptane under reduced pressure. n-Heptane (92 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid, washed with n-heptane and dried the material to get the title compound. The PXRD pattern of the obtained compound is similar to figure-7. Yield: 32.0 gm; MR: 155-157°C. Example-16: Alternate process for the preparation of compound of formula-l
Oxalyl chloride (128.43 gm) was slowly added drop wise to a mixture of compound of formula-3 (134.7 gm), dichloromethane (300 ml) and dimethylformamide (4.92 gm) at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 45 min at the same temperature. Distilled off the reaction mixture under nitrogen atmosphere and co-distilled with dichloromethane. The obtained compound was slowly added to a pre-cooled mixture of compound of formula-2 (100 gm), diisopropylethyl amine (109.01 gm) and toluene (500 ml)

at 0-5 °C under nitrogen atmosphere and stirred the reaction mixture for 2 hrs at the same temperature. Water was added to the reaction mixture and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with toluene. Combined the organic layers and washed with 10% aqueous potassium carbonate solution. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with n-heptane. n-Heptane (600 ml) was added to the obtained compound. Heated the reaction mixture to 75-80°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid, washed with n-heptane and dried the material to get the title compound. The PXRD pattern of the obtained compound is similar to figure-7. Yield: 120.6 gm; M.R: 152-157°C. Example-17: Purification of compound of formula-1
A mixture of compound of formula-1 (10 gm) and dimethylsulfoxide (100 ml) was stirred for 15 min at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 1 hr at the same temperature. Slowly cooled the reaction mixture to 45-50°C and stirred for 1 hr at the same temperature. Filtered the solid and washed with dimethylsulfoxide. Water (160 ml) was added to the obtained compound at 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid, washed with water and dried the material to get the pure title compound. The PXRD pattern of the obtained compound is similar to figure-7. Yield: 6.5 gm; M.R: 152-157°C; Purity by HPLC: 99.9%.
Particle size distribution: D(0.1) is 2.82 urn; D(0.5) is 6.98 urn; D(0.9) is 20.92 urn. Example-18: Purification of compound of formula-l
A mixture of compound of formula-l (20 gm) and dimethylsulfoxide (120 ml) was stirred for 15 min at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 30 min at the same temperature. Slowly cooled the reaction mixture to 25-30°C and stirred for 90 min at the same temperature. Filtered the solid and washed with dimethylsulfoxide. Water (160 ml) was added to the obtained compound at 25-30°C and stirred for 1 hr at the same temperature. Filtered the solid, washed with water and dried to get pure title compound. PXRD pattern of obtained compound is similar to figure-7. Yield: 12.7 gm; M.R: 152-157°C. Particle size distribution: D(0.1) is 3.93 urn; D(0.5) is 10.51 um; D(0.9) is 29.28 urn.

We Claim:
1. A process for the preparation of 2-[3,5-bis(trifluoromethyl)phenyl]-N52-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-1 -yl)pyridin-3-yl]propanamide compound of formula-1, comprising of reacting the N-methyl-6-(4-methylpiperazin-l-yl)-4-o-tolylpyridin-3-amine compound of formula-2 with 2-(3,5-bis(trifluoromethyl)phenyl)-2-methylpropanoic acid compound of formula-3 in presence of a suitable pyridinium coupling agent in a suitable solvent optionally in presence of a suitable base to provide compound of formula-1.
2. The process according to claim 1, wherein
the pyridinium coupling agent is represented by the following structural formula
wherein, 'X' represents halogen; 'R' represents Cj-Ce straight chain or branched chain alkyl group; and ' Y"' represents halide (X"), BF4\ SbCV and the like;
the. suitable base is selected from organic bases, inorganic bases, organolithium bases, organosilicon bases or their mixtures;
the suitable solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or their mixtures.
, A process for the preparation of 2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-l -yl)pyridin-3-yl]propanamide compound of formula-1, comprising of; a) Amidation of 6-halonicotinic acid compound of general formula-4
wherein, 'X' represents halogen atom;

by reacting it with an amine having the general formula or its acid addition salt
R—NH2 wherein, 'R' represents Ci-C6 straight chain or branched chain alkyl group; to provide compound of general formula-5,
b) reacting the compound of general formula-5 with o-tolyl magnesium halide having the general formula
wherein, 'X' represents halogen atom;
in presence of a suitable solvent followed by oxidation of the obtained compound
with a suitable oxidizing agent in a suitable solvent to provide compound of general
formla-6,
c) reacting the compound of general formula-6 with N-methyl piperazine optionally in presence of a solvent to provide compound of general formula-7,

d) deprotecting the compound of general formula-7 with a suitable deprotecting agent to provide 6-(4-methylpiperazin-l-yl)-4-o-tolylnicotinamide compound of formula-8,
e) converting the compound of formula-8 to methyl 6-(4-methylpiperazin-1 -yl)-4-o-tolylpyridin-3-ylcarbamate compound of formula-9,
f) reducing the compound of formula-9 with a suitable reducing agent in a suitable
solvent to provide N-methyl-6-(4-methylpiperazin-l-yl)-4-o-tolylpyridin-3-amine compound of formula-2,
g) reacting the compound of formula-2 with 2-(3,5-bis(trifluoromethyl)phenyl)-2-
methylpropanoic acid compound of formula-T in presence of a suitable pyridinium
coupling agent, in a suitable solvent optionally in presence of a base to provide
compound of formula-1.
%. The process according to claim 3, wherein
step-a) comprises reaction of compound of general formula-4 with a suitable chlorinating agent selected from thionyl chloride, oxalyl chloride, POCl3, PC15, PC13 optionally in presence of a suitable solvent followed by reacting the obtained acid chloride with the amine in presence of a suitable solvent optionally in presence of a suitable base to provide compound of general formula-5;
in step-b) the suitable oxidizing agent is selected from Mn(OAc)3, Cu(OAc)2, iodine, bromine, N-bromosuccinimide, Pd/C, Pt/C, DDQ (2,3-dichloro-5,6-dicyano-l,4-benzoquinone), chloranil (2,3,5,6-tetrachlorocyclohexa-2,5-diene-l,4-dione), H202, H202-urea, Na2C03-H202, Mn02, KMn04, RuCl2(PPh3)3, Cerium ammonium nitrate (CAN), HN03, Sulfur, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid;
in step-d) the suitable deprotecting agent is selected from methanesulfonic acid, acetic acid, sulfuric acid or their mixtures;
in step-e) the conversion of compound of formula-8 to compound of formula-9 is carried out by reacting the compound of formula-8 with an oxidizing agent such as hypohalite, N-halosuccinimide or a hypervalent iodobenzene, for example sodium hypochlorite, potassium hypochlorite, N-chlorosuccinimide, N-bromosuccinimide or iodobenzene diacetate in the presence of a base such as NaOH, NaOMe in a suitable solvent;

in step-f) the suitable reducing agent is selected from LiAlH4, NaBH4, BH3-THF and Red-Al;
in step-g) the suitable pyridinium coupling agent is as defined in claim 2; the suitable base is selected from organic bases, inorganic bases, organolithium bases, organosilicon bases or their mixtures;
in step-a) to step-g), the suitable solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents, formic acid, acetic acid or their mixtures.
5. Amorphous form of 2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-1 -yl)pyridin-3-yl]propanamide compound of formula-1, characterized by its PXRD diffractogram as illustrated in figure-1.
6. A process for the preparation of amorphous form of 2-[3,5-bis(trifluoromethyl)phenyl]-
N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-l-yl)pyridin-3-yl]propanamide compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in a suitable solvent or mixture of solvents,
b) optionally filtering the reaction mixture,
c) removing the solvent from the reaction mixture to provide amorphous form of compound of formula-1.
7. Amorphous ■ solid dispersion comprising 2-[3,5-bis(trifluoromethyl)phenyl]-N,2-
dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-l-yl)pyridin-3-yl]propanamide compound of formula-1 and at least one pharmaceutically acceptable excipient.
S. A process for the preparation of amorphous solid dispersion comprising 2-[3,5-
bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-l-yl)pyridin-3-yl]propanamide compound of formula-1 and at least one pharmaceutically acceptable excipient according to claim 7, comprising of;
a) Dissolving the compound of formula-1 and at least one excipient in a suitable solvent or mixture of solvents at a suitable temperature,
b) optionally filtering the solution,

c) removing the solvent from the reaction mixture to provide amorphous solid dispersion comprising compound of formula-1 and excipient.
9. A process for the preparation of crystalline 2-[3,5-bis(trifluoromethyl)phenyl]-N,2-
dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-l-yl)pyridin-3-yl]propanamide
compound of formula-1, comprising of;
a) Adding a suitable solvent to the compound of formula-1,
b) heating the reaction mixture,
c) cooling the reaction mixture,
d) filtering the solid,
e) optionally slurrying the solid in water,
f) drying the material to provide crystalline compound of formula-1.
10. The process according to claim 9, wherein, j
in step-a) the suitable solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or mixtures thereof.
in step-b) the reaction mixture can be heated to a temperature ranges from 35°C to reflux temperature of the solvent used;
in step-c) the reaction mixture can be cooled to a suitable temperature ranges from 20°C to -70°C.