Field of the Invention:

The present invention provides novel processes for the preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile represented by the following structural formula-1, its pharmaceutically acceptable acid-addition salts and intermediates thereof.

Background of the Invention:

4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino] benzonitrile hydrochloride commonly known as Rilpivirine hydrochloride is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type-1 (HIV-1) developed by Janssen-Cilag International N.V. It was approved in both US and Europe and is marketed under the brand name EDURANT. 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl] amino]-2-pyrimidinyl]amino] benzonitrile, its pharmaceutically acceptable salts and various processes for their preparation was first disclosed in US7125879B2. All the processes disclosed in the said patent involves the coupling of halo intermediate compounds with acrylnitrile.

Brief Description of the Invention:

The first aspect of the present invention is to provide a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile compound of formula-1 (Rilpivirine).

The second aspect of the present invention is to provide a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoemenyl]-2,6-dimemylphenyl]ammo]-2-pyrimidmyl]amino]benzonitrile compound of formula-1.

The third aspect of the present invention is to provide a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoemenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile compound of formula-1.

The fourth aspect of the present invention is to provide a process for the preparation of (E)-4-(4-(4-(2-cyanovinyl)-2,6-dimemylphenylanimo)pyriniidin-2-ylarnino)benzamide compound of formula-9.

The fifth aspect of the present invention is to provide a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile compound of formula-1.

The sixth aspect of the present invention is to provide a process for the preparation of (E)-3-(4-(2-(4-azidophenylamino)pyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylonitrile compound of formula-11.

The seventh aspect of the present invention is to provide a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile compound of formula-1.

The eighth aspect of the present invention is to provide a process for the preparation of (E)-4-(4-(4-(2-cyanovinyl)-2,6-dimethylphenylamino)pyrimidin-2-ylamino)benzamide compound of formula-9.

The ninth aspect of the present invention is to provide a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoemenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile compound of formula-1.

The tenth aspect of the present invention is to provide a process for the preparation of (E)-4-(4-(4-(2-cyanovmyl)-2,6-dmiemylphenylamino)pyrimidin-2-ylamino)benzoic acid compound of formula-10.

The eleventh aspect of the present invention is to provide a process for the preparation of (E)-3-(4-(2-(4-azidophenylanuno)pyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylonitrile compound of formula-11.

The twelfth aspect of the present invention is to provide a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoemenyl]-2,6-dimethylphenyl]ammo]-2-pyrimidmyl]amino]benzonitrile compound of formula-1.

The thirteenth aspect of the present invention is to provide a process for the preparation of (E)-4-(4-(4-(3-amino-3-oxoprop-l-enyl)-2,6-dimethylphenylamino)pyrimidin-2-ylamino)benzoic acid compound of formula-13.

The fourteenth aspect of the present invention is to provide a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile compound of formula-1.

The fifteenth aspect of the present invention is to provide a process for the preparation of (E)-3-(4-(2-(4-azidophenylamino)pyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylonitrile compound of formula-11.

The sixteenth aspect of the present invention is to provide a process for the preparation of 4-[[4^[4-[(E)-2-cyanoemenyl]-2,6-dimethylphenyl]amino]-2-pyrirnidinyl]amino]benzonitrile compound of formula-1.

The seventeenth aspect of the present invention is to provide novel intermediate compounds, which are useful in the synthesis of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile compound of formula-1 and its pharmaceutically acceptable salts.

Detailed Description of the Invention:

The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, 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 and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, t-butanol and the like; "polar solvents" such as water; and/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 and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia, alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide(KHMDS) and/or mixtures thereof.

The "suitable halogenating agent" used in the present invention can be selected from but not limited to phosphoryl chloride, phosphoryl bromide, thionyl chloride, phosphorous trichloride, phosphorous pentachloride, phosphorous tribromide, phosphorous pentabromide, oxalyl chloride, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), CCLt/PPh3, CBr4/PPh3 and the like. The "suitable dehydrating agent" used in the present invention can be selected from but not limited to phosphoryl chloride, cyanuric chloride, conc.sulfuric acid, trifluoroacetic anhydride. The "suitable reducing agent" used in the present invention wherever if necessary can be selected from but not limited to Pd/C, Pt/C, Pt02, Ni, Raney Ni, Fe, Fe in acidic media like HCl, acetic acid, NH4CI, Zn dust, Zn in acidic media like HCl, NH4CI or acetic acid, Sn-HCl, stannous chloride, NaBHU optionally in combination with charcoal, sodium cyanoborohydride, sodium triacetoxy borohydride, sodium trimethoxy borohydride, vitride, zinc borohydride, lithium borohydride, diborane, hydrazine hydrate, sodium aluminium hydride, sodium amalgam, borane-tetrahydrofuran complex and the like.

The "suitable amine source" used in the present invention can be selected from but not limited to ammonia gas, aq.ammonia, formamide, ammonium carbonate, ammonium formate, ammonium phosphate, ammonium acetate, ammonium chloride, ammonium hydroxide, ammonium sulfate and the like. The "suitable catalyst" used in the present invention can be selected from but not limited to Palladium based reagents such as Pd(OAc)2, Pd/C, Palladium chloride and the like optionally in combination with tri(alkyl or aryl or aralkyl)phosphines, ZnCl2,CuCl2, Cul, SnCU and the like. The "suitable deprotecting agent" used in the present invention can be selected from but not limited to acids such as hydrochloric acid, aq.phosphoric acid, trifluoroacetic acid, methane sulfonic acid, p-toluenesulfonic acid, acetyl chloride/alcohol and the like; organic or inorganic bases; Pd/C, Raney Ni, platinum oxide, platinum black, Rh/C, Ru, Ir and the like in combination with hydrogen.

The first aspect of the present invention provides a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile compound of formula-1 (Rilpivirine), comprising of; a) Reacting the (E)-3 -(4-amino-3,5-dimethylphenyl)acrylamide compound of formula-2 with 4-halopyrimidin-2-ol in a suitable solvent to provide (E)-3-(4-(2-hydroxypyrimidin-4-yl amino)-3,5-dimethylphenyl)acrylamide compound of formula-5, b) halogenating the compound of formula-5 by treating it with a suitable halogenating agent in a suitable solvent to provide (E)-3-(4-(2-halopyrimidin-4-ylamino)-3,5-dimethylphenyl) acrylamide compound of general formula-6, d) reacting the compound of general formula-7 with 4-aminobenzonitrile in a suitable solvent to provide compound of formula-1. The (E)-3-(4-(2-hydroxypyrimidin-4-yl amino)-3,5-dimethylphenyl)acrylamide compound of formula-5 can also be prepared by reacting the 3-(4-halo-3,5-dimethylphenyl)acrylamide compound of general formula-3 with 6-aminopyrimidin-2-ol in a suitable solvent to provide compound of formula-5. The (E)-3-(4-amino-3,5-dimethylphenyl)acrylamide compound of formula-2 utilized in step-a) of the first aspect of the present invention can be synthesized by any of the processes known in the art such as for example by reacting the 4-halo-2,6-dimethylaniline (halogen= CI, Br or I) with acrylamide in presence of a suitable catalyst and a suitable base in a suitable solvent.

The (E)-3-(4-halo-3,5-dimethylphenyl)acrylamide compound of general formula-3 utilized in the above reaction can be synthesized by any of the processes known in the art. The compound of general formula-3 can be prepared by reacting the 4-halo-2,6-dimethylphenol with acrylamide in presence of a suitable base and a suitable catalyst in a suitable solvent followed by halogenating the obtained (E)-3-(4-hydroxy-3,5-dimethylphenyl)acrylanride with a suitable halogenating agent in a suitable solvent to provide (E)-3-(4-halo-3,5-dimethylphenyl)acrylamide compound of general formula-3. The second aspect of the present invention provides a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoemenyl]-2,6-dimemylphenyl]amino]-2-pyrimidmyl]amino]benzonitrile compound of formula-1, comprising of;

a) Reacting the (E)-3-(4-amino-3,5-dimethylphenyl)acrylamide compound of formula-2 with 4-halopyrimidin-2-ol in a suitable solvent to provide (E)-3-(4-(2-hydroxypyrimidin-4-ylamino)-3,5-dimethylphenyl) acrylamide compound of formula-5,

b) dehydration of compound of formula-5 by treating it with a suitable dehydrating agent in a suitable solvent to provide (E)-3-(4-(2-hydroxypyrimidm-4-ylamino)-3,5-dimethylphenyl) acrylonitrile compound of formula-8,

c) halogenating the compound of formula-8 by treating it with a suitable halogenating agent in a suitable solvent to provide (E)-3-(4-(2-halopyrimidin-4-ylamino)-3,5-dimethylphenyl) acrylonitrile compound of general formula-7,

d) reacting the compound of general formula-7 with 4-aminobenzamide in a suitable solvent to provide (E)-4-(4-(4-(2-cyanovinyl)-2,6-dimethylphenylamino)pyrimidin-2-ylamino)benzamide compound of formula-9,

e) dehydration of the compound of formula-9 by treating it with a suitable dehydrating agent in a suitable solvent to provide compound of formula-1.

The third aspect of the present invention provides a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile compound of formula-1, comprising of;

a) Reacting the (E)-3-(4-(2-halopyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylonitrile compound of general formula-7 with 4-azidoaniline in a suitable solvent to provide (E)-3-(4-(2-(4-azido phenylamino)pyrirnidin-4-ylaniino)-3,5-dimethylphenyl)acrylonitrile compound of formula-11,

b) treating the compound of formula-11 with a suitable alkali metal cyanide in a suitable solvent to provide compound of formula-1.

The fourth aspect of the present invention provides a process for the preparation of (E)-4-(4-(4-(2-cyanovinyl)-2,6-dimethylphenylarnmo)pyrimidin-2-ylamino)benzamide compound of formula-9, comprising of;

a) Reacting the (E)-3-(4-(2-halopyrirnidin-4-ylamino)-3,5-dimethylphenyl)acrylonitrile compound of general formula-7 with 4-aminobenzoic acid in a suitable solvent to provide (E)-4-(4-(4-(2-cyanovinyl)-2,6-dimethylphenylamino)pyrimidin-2-ylamino)benzoic acid compound of formula-10,

b) amidation of compound of formula-10 by treating it with a suitable amine source in a suitable solvent to provide compound of formula-9.

The fifth aspect of the present invention provides a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoemenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile compound of formula-1, comprising of;

a) Reacting the (E)-3-(4-(2-halopyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylamide compound of general formula-6 with 4-aminobenzamide in a suitable solvent to provide (E)-4-(4-(4-(3-amino-3 -oxoprop-1 -enyl)-2,6-dimethylphenylamino)pyrimidin-2-ylamino)benzamide compound of formula-12,

b) dehydration of compound of formula-12 by treating it with a suitable dehydrating agent in a suitable solvent to provide compound of formula-1. The (E)-4-(4-(4-(3-amino-3-oxoprop-l-enyl)-2,6-dimethylphenylamino)pyrimidin-2-yl amino)benzamide compound of formula-12 can also be prepared by reacting the (E)-3-(4-(2-halo pyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylamide compound of general formula-6 with 4-aminobenzoic acid in a suitable solvent to provide (E)-4-(4-(4-(3-amino-3-oxoprop-l-enyl)-2,6-dimethylphenylamino)pyrimidin-2-ylamino)benzoic acid compound of formula-13, followed by amidation of the compound of formula-13 by treating it with a suitable amine source in a suitable solvent to provide (E)-4-(4-(4-(3-amino-3-oxoprop-l-enyl)-2,6-dimethylphenylamino) pyrimidin-2-ylamino)benzamide compound of formula-12.

The sixth aspect of the present invention provides a process for the preparation of (E)-3-(4-(2-(4-azidophenylamino)pyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylonitrile compound of formula-11, comprising of;

a) Reacting the (E)-3-(4-(2-halopyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylamide compound of general formula-6 with 4-azidoaniline in a suitable solvent to provide (E)-3-(4-(2-(4-azidophenylamino)pyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylamide compound of formula-14,

b) dehydration of compound of formula-14 by treating it with a suitable dehydrating agent in a suitable solvent to provide compound of formula-11.

The seventh aspect of the present invention provides a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoemenyl]-2,6-dimemylphenyl]amino]-2-pyrirnidinyl]amino]benzonitrile compound of formula-1, comprising of;

a) Reacting the (E)-3-(4-amino-3,5-dimethylphenyl)acrylamide compound of formula-2 with 4-halo-2-nitropyrimidine in a suitable solvent followed by optionally protecting the obtained (E)-3-(3,5-dimemyl-4-(2-riitropyiimidin-4-ylamino)phenyl)acrylamide with a suitable amine protecting group to provide compound of general formula-15, wherein, 'P' represents hydrogen or amine protecting groups selected from but not limited to tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), trifluoroacetyl (TFA), benzoyl (Bz), benzyl (Bn) group and the like; b) dehydration of compound of general formula-15 by treating it with a suitable dehydrating agent in a suitable solvent to provide compound of general formula-16,

c) reducing the compound of general formula-16 with a suitable reducing agent in a suitable solvent to provide compound of general formula-17,

d) reacting the compound of general formula 17 with 4-halobenzonitrile optionally in presence of a suitable base in a suitable solvent followed by optionally deprotecting the obtained compound by treating it with a suitable deprotecting agent to provide compound of formula-1.

in step-a) the suitable solvent is selected from polar-aprotic solvents, alcohol solvents, chloro solvents, polar solvents, nitrile solvents, ether solvents, ester solvents or their mixtures; in step-b) the suitable dehydrating agent is selected from phosphoryl chloride, cyanuric chloride, cone.sulfuric acid, trifluoroacetic anhydride; in step-c) the suitable reducing agent is selected from Pd/C, Pt/C, Pt02, Ni, Raney Ni, Fe, Fe in acidic media like HC1, acetic acid, NH4CI, Zn dust, Zn in acidic media like HC1, NH4CI or acetic acid, Sn-HCl, stannous chloride; and the suitable solvent is selected from alcohol solvents, ether solvents, hydrocarbon solvents, ester solvents, polar solvents, chloro solvents or their mixtures; in step-d) the suitable base is selected from inorganic bases; in step-b) and step-d) the suitable solvent is selected from nitrile solvents, ether solvents, polar-aprotic solvents, ester solvents or their mixtures. The deprotection of the amine in the above aspect can be done in step-c) or step-d) using a suitable deprotecting agent as defined above to provide corresponding free amine compounds.

The eighth aspect of the present invention provides a process for the preparation of (E)-4-(4-(4-(2-cyanovinyl)-2,6-dimethylphenylamino)pyrimidin-2-ylamino)benzamide compound of formula-9, comprising of;

a) Reducing the compound of general formula-15 with a suitable reducing agent in a suitable solvent to provide protected compound of general fomula-18,

b) dehydration of compound of general formula-18 by treating it with a suitable dehydrating agent in a suitable solvent to provide compound of general formula-17,

c) reacting the compound of general formula-17 with 4-halobenzamide optionally in presence of a suitable base in a suitable solvent followed by optionally deprotecting with a suitable deprotecting agent to provide compound of formula-9. Wherein, in step-a) the suitable reducing agent and the suitable solvent are same as defined in step-c) of the seventh aspect of the present invention; In step-b) the suitable dehydrating agent and the suitable solvent are same as defined in step-b) of the seventh aspect of the present invention; In step-c) the suitable base and the suitable solvent are same as defined in step-d) of the seventh aspect of the present invention; The other embodiment of the present invention provides a process for the preparation of (E)-4-(4-(4-(3-amino-3-oxoprop-l-enyl)-2,6-dimethylphenylamino)pyrimidin-2-ylamino)benzamide compound of formula-12, comprising of reacting the compound of general fomula-18 with 4-halobenzamide in a suitable solvent, followed by optionally deprotecting the obtained compound using a suitable deprotecting agent to provide compound of formula-12, In another embodiment of the present invention the (E)-3-(4-(2-(4-azidophenylamino) pyrimidm-4-ylaniino)-3,5-dimethylphenyl)acrylarnide compound of formula-14 can be prepared by reacting the compound of general fomula-18 with l-azido-4-halobenzene in a suitable solvent followed by optionally deprotecting the obtained compound using a suitable deprotecting agent to provide compound of formula-14.

The ninth aspect of the present invention provides a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoemenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile compound of formula-1, comprising of;

a) Reacting the (E)-3-(4-amino-3,5-dimethylphenyl)acrylamide compound of formula-2 with 4-halo-2-(methylthio)pyrimidine in a suitable solvent to provide (E)-3-(3,5-dimethyl-4-(2-(methylthio)pyrimidin-4-ylamino) phenyl)acrylamide compound of formula-19,

b) dehydration of compound of formula-19 by treating it with a suitable dehydrating agent in a suitable solvent to provide (E)-3-(3,5-dimethyl-4-(2-(methylthio)pyrimidin-4-ylamino) phenyl)acrylonitrile compound of formula-20,

c) reacting the compound of formula-20 with 4-aminobenzonitrile in a suitable solvent to provide compound of formula-1.

The tenth aspect of the present invention provides a process for the preparation of (E)-4-(4-(4-(2-cyanovinyl)-2,6-dimethylphenylamino)pyrimidin-2-ylamino)benzoic acid compound of formula-10, comprising of reacting the compound of general formula-17 with 4-halobenzoic acid in a suitable solvent followed by optionally deprotecting the obtained compound with a suitable deprotecting agent to provide compound of formula-10.

The eleventh aspect of the present invention provides a process for the preparation of (E)-3-(4-(2-(4-azidophenylamino)pyrimidin-4-ylanimo)-3,5-dimethylphenyl)acrylonitrile compound of formula-11, comprising of reacting the compound of general formula-17 with l-azido-4-halobenzene in a suitable solvent followed by optionally deprotecting the obtained compound with a suitable deprotecting agent to provide compound of formula-11.

The twelfth aspect of the present invention provides a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoemenyl]-2,6-dimethylphenyl]amino]-2-pyrimidmyl]amino]benzonitrile compound of formula-1, comprising of; a) Reacting the 4-halo-2,6-dimethylaniline having the following structure wherein, 'X' is as defined above; with 4-(4-halopyrimidin-2-ylamino)benzamide compound of general formula-21 in a suitable solvent to provide 4-(4-(4-halo-2,6-dimethylphenylamino)pyrimidin-2-ylamino) benzamide compound of general formula-22,

b) reacting the compound of formula-22 with acrylamide optionally in presence of a suitable catalyst and a suitable base in a suitable solvent to provide (E)-4-(4-(4-(3-amino-3-oxoprop-l-enyl)-2,6-dimethylphenylamino)pyrimidin-2-ylamino)benzamide compound of formula-12,

c) dehydration of compound of formula-12 by treating it with a suitable dehydrating agent in a suitable solvent to provide compound of formula-1. The 4-(4-halopyrimidin-2-ylamino)benzamide compound of general formula-21 utilized in step-a) of the twelfth aspect of the present invention can be synthesized by reacting the 4-halopyrimidin-2-amine with 4-halobenzamide in a suitable solvent to provide 4-(4-halopyrimidin-2-ylamino)benzamide compound of general formula-21. In another embodiment of the present invention, the 4-(4-(4-halo-2,6-dimethylphenylamino) pyrimidin-2-ylamino)benzamide compound of general formula-22 can be prepared by reacting the 4-halo-2,6-dimethylaniline with 4-(4-halopyrimidin-2-ylamino)benzoic acid compound of general formula-27 with 4-halo-2,6-dimethylaniline to provide 4-(4-(4-halo-2,6-dimethylphenylamino)pyrimidin-2-yl amino)benzoic acid compound of general formula-23 followed by amidation of compound of general formula-23 with a suitable amine source in a suitable solvent to provide compound of general formula-22. The 4-(4-halopyrimidin-2-ylamino)benzoic acid compound of general formula-27 utilized in step-a) of the above embodiment can be synthesized by reacting the 4-halopyrimidin-2-amine with 4-halobenzoic acid in a suitable solvent to provide compound of general formula-27.

In another embodiment of the present invention, the (E)-4-(4-(4-(2-cyanovinyl)-2,6-dimethylphenylamino)pyrimidin-2-ylamino)benzamide compound of formula-9 can be prepared by reacting the 4-(4-aminopyrimidin-2-ylamino)benzamide compound of formula24 in a suitable solvent to provide compound of formula-9. The 4-(4-aminopyrimidin-2-ylamino)benzamide compound of formula-24 utilized in the above embodiment can be prepared by reacting the 2-halopyrimidin-4-amine with 4-aminobenzamide in a suitable solvent to provide compound of formula-24.

The thirteenth aspect of the present invention provides a process for the preparation of (E)-4-(4-(4-(3-amino-3-oxoprop-l-enyl)-2,6-dimethylphenylammo)pyrimidin-2-ylamino)benzoic acid compound of formula-13, comprising of;

a) Reacting the 2-halopyrimidin-4-amine with 4-aminobenzoic acid in a suitable solvent to provide 4-(4-aminopyrimidin-2-ylamino)benzoic acid compound of formula-26,

b) reacting the compound of formula-26 with 3-(4-halo-3,5-dimethylphenyl)acrylamide compound of general formula-3 in a suitable solvent to provide compound of formula-13.

The fourteenth aspect of the present invention provides a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoemenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile compound of formula-1, comprising of; a) Reacting the N-(4-azidophenyl)-4-halopyrimidin-2-amine compound of general formula-28 wherein, 'X' is as defined above; with 4-halo-2,6-dimethylaniline in a suitable solvent to provide N2-(4-azidophenyl)-N4-(4-halo- 2,6-dimethylphenyl)pyrimidine-2,4-diamine compound of general formula-29,

b) reacting the compound of formula-29 with acrylnitrile optionally in presence of a suitable catalyst and a suitable base in a suitable solvent to provide (E)-3-(4-(2-(4-azidophenylamino) pyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylonitrile compound of formula-11,

c) treating the compound of formula-11 with a suitable alkali metal cyanide in a suitable solvent to provide compound of formula-1.

The fifteenth aspect of the present invention provides a process for the preparation of (E)-3-(4-(2-(4-azidophenylamino)pyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylonitrile compound of formula-11, comprising of reacting the (E)-3-(4-halo-3,5-dimethylphenyl)acrylonitrile compound of general formula-25 with N2-(4-azidophenyl)pyrimidine-2,4-diamine compound of formula-30 Formula-30 in a suitable solvent to provide compound of formula-11.

The sixteenth aspect of the present invention provides a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoemenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile compound of formula-1, comprising of reacting the 4-(4-aminopyrimidin-2-ylamino)benzonitrile compound of formula-31 with (E)-3-(4-halo-3,5-dimethylphenyl)acrylonitrile compound of general formula-25 in a suitable solvent to provide compound of formula-1. In the present invention, the usage of base and/or catalyst may be required in various reaction steps. The base wherever necessary can be selected from organic and inorganic bases as defined above and the suitable catalyst is same as defined above. Rilpivirine obtained by various processes of the present invention can be converted into its pharmaceutically acceptable acid-addition salts by treating it with a suitable acid in a suitable solvent. For example, Rilpivirine obtained by the present invention can be converted into its hydrochloride salt by treating it with a suitable HC1 source in a suitable solvent, wherein the suitable HC1 source can be selected from but not limited to HC1 gas, dry HC1, aqueous HC1, ethyl acetate-HCl, methanolic HC1, ethanolic HC1, isopropyl alcohol-HCl and the like.

In all of the above aspects of the present invention, wherever if necessary the 2°-amine groups of intermediate compounds can be optionally protected before coupling with halo intermediates using suitable amine protecting group. The protected compounds obtained as products in such reactions can be deprotected by treating with a suitable deprotecting agent in the subsequent reaction steps to provide free amine compounds.

The seventeenth aspect of the present invention provides novel intermediate compounds, which are useful in the synthesis of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrirnidinyl]amino]benzonitrile compound of formula-1 and its pharmaceutically acceptable salts. The said novel intermediate compounds of the present invention are represented below. wherein, the group 'Ri' can be selected from CN, CONH2; 'R2' can be selected from SMe, NH2, N02, X, OH; 'R3' can be selected from CONH2, COOH, N3; 'R4' can be selected from X, NH2; 'X' represents halogen such as CI, Br, I; 'P' represents hydrogen or amine protecting group selected from but not limited to tert-butyloxycarbonyl (boc), benzyloxycarbonyl (cbz), 9-fiuorenylmethyloxycarbonyl (FMOC), acetyl, trifluoroacetyl, benzoyl, benzyl groups and the like; Alternative processes for the preparation of Rilpivirine and its intermediate compounds are schematically represented in the below mentioned schemes. Scheme-I:

Scheme-II:

NYN X

H2NOCV^ ^N \^cQoH Formula-6
H H
N N N,
H H
NVN N
H2N-Q>~CONH2 (iS'N>iiNrN>rr^i
H2NOCWk "UN IAC
Li / Fnrmula-13
H2NOC
N3 I H H
rmula-14 (fS',%lVhV
^CONH2
I H2NOC^^ ^N ^
I H {J Formula-12
^aut\ %/y Y^"
H H
NVN N
Formula-ll
Rilpivirine

Scheme-Ill;

^^^N*^
NC -
Formula-20
H2N-Q-CN>

AN1
•L^N N No2
"^^ b) Protection H2N0C^Uk "UN
X^SMe Fon„«Ia-15
U J. Dehydration/ ^N / \ Reduction
X.N NYN02 A-^V^
Formula-19 Formula-16 Formula-18
/Dehydration \ Reduction
Dehydration
b) Deprotection NC'
QX-QcOCH , H b) Deprotection Ij T
Formula-10
O "\\ "cONH2
•a \ x i H
/amidation
N NYN ^
v ^N ^^C0NH2 Formula-9
a) Dehydration | b) HCI
HCI Rilpivirine HCI
XJ Ndn (Rilpivirine HCl)
Formula-ll
H

^COOH

19

Scheme-IV:


NH,
N NTN02
Formula-15
Reduction P N^N_NH2
u

H2NOC

Formula-2

XJ NOj
b) Protection n
H2NOC^
X^N_NH
^
'Y' 2

-X y Formula-18 4>>\ T^
H H
N_N_N
xxxx
COOH
H H
Formula-13
'amidation
cocnxH
Formula-14
H H
H2NOC
i'
H H
N_N_N
xxxx
Formula-11

H2NOC "^
NC

trtX
CONH,
Formula-12
CN
Dehydration Rilpivirine

20

Scheme-V:

H2N^N X

NH,
H2N
V
H
COOH
If ^ TT*1 ^N ^CONH2y
H H2N N^N.
H X^N^N

Formula-21 /
I H H /
COOH
Formula-26
Formula-27
fV"A"f{
FormuIa-22
. II H2NOC
FormuIa-3
fa
tfxx
H H
6;«^
^
Ofl
I Rilpivirine!
2. Formula-23
ft^*
3.
COOH
H H
amidation CONH2 NC
Formula-13
H H
axia
xxxx

Amidation
Formula-10
COOH
CONH2 \Dehydration
^AKty-a
""itfxx
NC Formula-25
NC ^- - - H2NOC
Formula-12
Formula-25 COOH
H2NV,N_N

XXTX
Formula-26
I
'HjNOCV^*^ (Rilpivirine^ H Formula-3
CONH2
xxxx
Formula-21
+
CONH2 NH
FormuIa-24
H XVNVN
f
N^X I
NH2
"WX
I +
CONH2
J H2NOC"
Formula-2
CONH2
Formula-24
21

Scheme-VI:

H
NH,
-a tx.
X,
1
H2N N X H
Formula-28
N,
•UN H2N N N
CN
H H
+ —^ IUN UV
Formula-31

xXXO €LN NC^NH2
Acrylnitrile
Acrylamide
Formula-29
If *T jf^ alkalimetal
\ H
H H
N^N^N
txxx

NC Formula-25
N cyanide
•3 i
H2NOC
NC
Formula-14
Formula-11
(Rilpivirine J
I "I + Formula-25
AfX H2N N YNY^ J«^X HZN^N^N^^
H2NOC
Formula-30
Formula-30
/
H2N^NYX ' /=\ ki
Formula-3

Wherein, in all the above schemes, 'X' represents halogen such as CI, Br, I; and 'P' represents hydrogen or amine protecting group selected from but not limited to tert-butyloxycarbonyl (boc), benzyloxycarbonyl (cbz), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl, trifluoroacetyl, benzoyl, benzyl groups and the like. The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation to the scope of the invention. Examples:

Example-1: Preparation of (E)-3-(3,5-dimethyl-4-(2-nitropyrimidin-4-ylamino)phenyl) acrylamide (Formula-15a) N-methyl pyrrolidone (25 ml) followed by 4-chloro-2-nitropyrimidine (4.1 gm) were added to (E)-3-(4-amino-3,5-dimethylphenyl)acrylamide compound of formula-2 (5 gm) at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 10 hrs at the same temperature. Potassium carbonate solution was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Dichloromethane was added to the reaction mixture and stirred for 30 min. Both the 22 organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 5.7 gm.

Example-2: Preparation of (E)-3-(4-(2-aminopyrimidin-4-ylamino)-3,5-dimethylphenyI) acrylamide (Formula-18a) (E)-3 -(3,5-dimethyl-4-(2-nitropyrimidin-4-ylamino)phenyl)acrylamide compound of formula-15a (3 gm) and methanol (30 ml) were charged into a par hydrogenator at 25-30°C. 5% Pd/C (1 gm) was added to the reaction mixture under nitrogen atmosphere at 25-30°C. 3-4 Kg/Cm2 hydrogen gas pressure was applied to the reaction mixture at 25-30°C and stirred for 6 hrs at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Distilled off the solvent completely from the filtrate under reduced pressure to get the title compound. Yield: 2.0 gm.

Example-3: Preparation of (E)-3-(4-(2-aminopyrimidin-4-ylamino)-3,5-dimethylphenyl) acrylonitrile (Formula-17a) Phosphorous oxychloride (4.3 gm) was drop wise added to a pre cooled mixture of (E)-3-(4-(2-aminopyrimidin-4-ylamino)-3,5-dimethyl phenyl)acrylamide compound of formula-18a (2 gm) and acetonitrile (20 ml) at 0-5°C under nitrogen atmosphere. Slowly heated the reaction mixture to 80-85°C and stirred for 6 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Ethyl acetate was added to the obtained compound and the resulting reaction mixture was neutralized with aq.sodium hydroxide solution. Both the organic and aqueous layers were separated and the organic layer was washed with saturated sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 1.49 gm.

ExampIe-4: Preparation of (E)-4-(4-(4-(2-cyanovinyI)-2,6-dimethyIphenyIammo)pyrimidin-2-ylamino)benzamide (Formula-9) Potassium carbonate (2.8 gm) was added to a mixture of (E)-3-(4-(2-aminopyrimidin-4-yl amino)-3,5-dimethylphenyl)acrylonitrile compound of formula-17a (3 gm) and 1,4-dioxane (30 ml) at 25-3 0°C under N2 atmosphere. Heated the reaction mixture to reflux temperature and stirred for 1 hr at the same temperature. A solution of 4-bromobenzamide (4.5 gm) in 1,4-dioxane (30 ml) was added drop wise to the reaction mixture at reflux temperature and stirred for 5 hrs at the same temperature. Distlled off the solvent completely from the reaction mixture under reduced pressure. Ethyl acetate was added to the obtained compound and the rection mixture was washed with saturated sodium chloride solution. Distilled off the solvent completely from the reaction mixture under reduced pressure to get the title compound. Yield: 3.47 gm. ExampIe-5: Preparation of 4-(4-chIoropyrimidin-2-ylamino)benzamide (Formula-21a) Potassium carbonate (4.9 gm) was added to a mixture of 4-chloropyrimidin-2-amine (3 gm) and tetrahydrofuran (30 ml) at 25-30°C under nitrogen atmosphere. Heated the reaction mixture to reflux temperature and stirred for 1 hr at the same temperature. A solution of 4-bromobenzamide (8 gm) in tetrahydrofuran (15 ml) was added dropwise to the reaction mixture at refluxtemperature and stirred for 6 hrs at the same temperature. Distlled off the solvent completely from the reaction mixture under reduced pressure. Ethyl acetate was added to the obtained compound and the rection mixture was washed with saturated sodium chloride solution. Distilled off the solvent completely from the reaction mixture under reduced pressure to get the title compound. Yield: 4.6 gm.

Example-6: Preparation of (E)-4-(4-(4-(3-amino-3-oxoprop-l-enyl)-2,6-dimethylphenylamino) pyrimidin-2-ylamino)benzamide(Formula-12) Potassium carbonate (2.6 gm) was added to a mixture of (E)-3-(4-(2-aminopyrimidin-4-yl amino)-3,5-dimethylphenyl) acrylamide compound of formula-18a (3 gm) and 1,4-dioxane (30 ml) at 25-30°C under N2 atmosphere. Heated the reaction mixture to reflux temperature and stirred for 1 hr at the same temperature. A solution of 4-bromobenzamide (4.2 gm) in 1,4-dioxane (30 ml) was added drop wise to the reaction mixture at reflux temperature and stirred for 6 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Ethyl acetate was added to the obtained compound and the reaction mixture was washed with saturated sodium chloride solution. Distilled off the solvent completely from the reaction mixture under reduced pressure to get the title compound. Yield: 3.4 gm.

Example-7: Preparation of (E)-4-(4-(4-(3-amino-3-oxoprop-l-enyl)-2,6-dimethylphenylamino) pyrimidin-2-yIamino)benzamide (Formula-12) N-methyl pyrrolidone (10 ml) followed by 4-(4-chloropyrimidin-2-ylamino)benzamide compound of formula-21a (1.6 gm) were added to (E)-3-(4-amino-3,5-dimethylphenyl)acrylamide compound of formula-2 (2 gm) at 25-3 0°C. 20% isopropyl alcohol-HCl (2 ml) was added to the reaction mixture. Heated the reaction mixture to 80-85°C and stirred for 10 hrs at the same temperature. Aqueous potassium carbonate solution was added to the reaction mixture at 25-3 0°C and stirred for 15 min at the same temperature. Dichloromethane was added to the reaction mixture and stirred for 30 min. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 3.38 gm.

Example-8: Preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethyIphenyl]amino]-2-pyrimidinyl] amino]benzonitrile (Formula-1) Potassium carbonate (2.07 gm) was added to a mixture of (E)-3-(4-(2-aminopyrimidin-4-yl amino)-3,5-dimethylphenyl)acrylonitrile compound of formula-17a (2 gm) and tetrahydrofuran (20 ml) at 25-30°C under nitrogen atmosphere. Heated the reaction mixture to reflux temperature and stirred for 1 hr at the same temperature. A solution of 4-bromobenzonitrile (1.57 gm) in tetrahydrofuran (4 ml) was added drop wise to the reaction mixture at 65-70°C and stirred for 5 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and distilled off the solvent completely under reduced pressure. Ethyl acetate was added to the obtained compound and the reaction mixture was washed with saturated sodium chloride solution. Distilled off the solvent completely from the reaction mixture under reduced pressure to get the title compound. Yield: 2.0 gm.

Example-0: Preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl] amino] benzonitrile (Formula-1) Phosphorous oxychloride (4.7 gm) was drop wise added to a pre-cooled mixture of (E)-4-(4-(4-(2-cyanovinyl)-2,6-dimethylphenylamino)pyrimidin-2-ylamino)benzamide compound of formula-9 (3 gm) and acetonitrile (30 ml) at 0-5°C under N2 atmosphere. Slowly raised the temperature to 25-30°C and stirred for 2 hrs. The reaction mixture was further heated to 80-85°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and distilled off the solvent completely from the reaction mixture under reduced pressure. Ethyl acetate was added to the obtained compound and the resulting reaction mixture was neutralized with aq.sodium hydroxide solution. Both the organic and aqueous layers were separated and the organic layer was washed with saturated sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 2.28 gm.

Example-10: Preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-py rimidinyl] amino] benzonitrile (Formula-1) Phosphorous oxychloride (9.1 gm) was drop wise added to a pre-cooled mixture of (E)-4-(4-(4-(3-amino-3-oxoprop-l-enyl)-2,6-dimethylphenylamino)pyrimidin-2-ylamino)benzamide compound of formula-12 (3 gm) and acetonitrile (45 ml) at 0-5 °C under N2 atmosphere. Slowly heated the reaction mixture to 80-85°C and stirred for 8 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Ethyl acetate was added to the obtained compound and the reaction mixture was neutralized with aq.NaOH solution. Both the organic and aqueous layers were separated and the organic layer was washed with saturated NaCl solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 2.18 gm.

Example-11: Preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl] amino] benzonitrile (Formula-1) Trifluoroacetic anhydride (2 gm) was slowly added to a mixture of (E)-4-(4-(4-(3-amino-3-oxoprop-l-enyl)-2,6-dimethylphenylamino)pyrimidin-2-ylamino)benzamide of formula-12 (2 gm) and ethyl acetate (20 ml) at 0-5°C and stirred for 60 min at the same temperature. Another 0.42 gm of trifluoroacetic anhydride was slowly added to the reaction mixture at 0-5°C and stirred for 60 min at the same temperature. Quenched the reaction mixture with ammonium bicarbonate at below 10°C. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 30 min at the same temperature. Filtered the reaction mixture and distilled off the solvent completely from the filtrate under reduced pressure. The obtained compound is recrystallized from isopropyl alcohol to get pure title compound. Yield: 1.45 gm.

Example-12: Preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl] amino] benzonitrile hydrochloride A mixture of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl] amino]benzonitrile (2 gm) and acetic acid (11 ml) was heated to 85-90°C. Filtered the reaction mixture and washed with acetic acid. Hydrochloric acid (1 ml) was added to the reaction mixture at 80-85°C and stirred for 30 min at the same temperature. Water was added to the reaction mixture at 80-85°C and slowly cooled the reaction mixture to 25-30°C. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 2.1 gm.

We Claim:

1. A process for the preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile compound of formula-1, comprising of; a) Reacting the (E)-3-(4-amino-3,5-dimethylphenyl)acrylamide compound of formula-2 with 4-halo-2-nitropyrimidine in a suitable solvent followed by optionally protecting the obtained (E)-3-(3,5-dimethyl-4-(2-nitropyrimidin-4-ylamino)phenyl)acrylamide with a suitable amine protecting group to provide compound of general formula-15, wherein, 'P' represents hydrogen or amine protecting group; b) reducing the compound of general formula-15 with a suitable reducing agent in a suitable solvent to provide compound of general fomula-18, c) dehydration of compound of general fomula-18 with a suitable dehydrating agent in a suitable solvent to provide compound of general formula-17, d) reacting the compound of general formula-17 with 4-halobenzomtnle optionally m presence of a suitable base in a suitable solvent followed by optionally deprotecting die obtained compound with a suitable deprotecting agent to provide compound of formula-1.

2. The process according to claim 1, wherein, in step-a) the suitable solvent is selected from polar-aprotic solvents, alcohol solvents, chloro solvents, polar solvents, nitrile solvents, ether solvents, ester solvents or their mixtures; in step-b) the suitable reducing agent is selected from Pd/C, Pt/C, Pt02, Ni, Raney Ni, Fe, Fe in acidic media like HC1, acetic acid, NH4C1, Zn dust, Zn in acidic media like HC1, NH4CI, acetic acid, Sn-HCl, stannous chloride; and the suitable solvent is selected from alcohol solvents, ether solvents, hydrocarbon solvents, ester solvents, polar solvents, chloro solvents or their mixtures; in step-c) the suitable dehydrating agent is selected from phosphoryl chloride, cyanuric chloride, conc.sulfuric acid, trifluoroacetic anhydride; in step-d) the suitable base is selected from inorganic bases; in step-c) and step-d) the suitable solvent is selected from nitrile solvents, ether solvents, polar-aprotic solvents, ester solvents or their mixtures.

3. A process for the preparation of (E)-3-(3,5-dimethyl-4-(2-nitropyrimidin-4-ylamino)phenyl) acrylamide compound of formula-15a, comprising of reacting the (E)-3-(4-amino-3,5- dimethylphenyl)acrylamide compound of formula-2 with 4-halo-2-nitropyrimidine in a suitable solvent optionally in presence of a suitable base to provide compound of formula-15a.

4. The process according to claim 3, wherein the suitable solvent is selected from polar-aprotic solvents, alcohol solvents, chloro solvents, polar solvents, nitrile solvent or their mixtures and the suitable base is selected from hydroxides, alkoxides, carbonates, bicarbonates of alkali metals.

5. A process for the preparation of compound of general formula-18, comprising of reducing the compound of general formula-15 with a suitable reducing agent in a suitable solvent to provide compound of general formula-18.

6. The process according to claim 5, wherein the suitable reducing agent is selected from Pd/C, Pt/C, Pt02, Ni, Raney Ni, Fe, Fe in acidic media like HC1, acetic acid, NH4CI, Zn dust, Zn in acidic media like HC1, NH4CI, acetic acid, Sn-HCl, stannous chloride and the suitable solvent is selected from alcohol solvents, ether solvents, hydrocarbon solvents, ester solvents, polar solvents, chloro solvents or their mixtures.

7. A process for the preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2- pyrimidinyl]amino]benzonitrile compound of formula-1, comprising of; a) Reacting the (E)-3-(4-amino-3,5-dimethylphenyl)acrylamide compound of formula-2 with 4-(4-halopyrimidin-2-ylamino)benzamide compound of general formula-21 in a suitable solvent to provide (E)-4-(4-(4-(3-amino-3-oxoprop-l-enyl)-2,6-dimethylphenylamino) pyrimidin-2-ylamino)benzamide compound of formula-12, b) dehydration of compound of formula-12 in presence of a suitable dehydrating agent to provide compound of formula-1, c) optionally converting the compound of formula-1 into its hydrochloride salt of formula-1 a.

8. A process for the preparation of 4-(4-halopyrimidin-2-ylamino)benzamide compound of general formula-21, comprising of reacting the 4-halopyrimidin-2-amine with 4-halo benzamide in presence of a suitable base in a suitable solvent to provide compound of general formula-21.

9. A process for the preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile compound of formula-1, comprising of dehydrating the (E)-4-(4-(4-(3 -amino-3-oxoprop-1 -enyl)-2,6-dimethylphenylamino)pyrimidin-2-ylamino)benzamide compound of formula-12 with trifluoroacetic anhydride optionally in presence of a suitable base in a suitable solvent to provide compound of formula-1.

10. Compounds represented by the following structural formulae; wherein, 'Rf can be selected from CN, CONH2; 'R2' can be selected from SMe, NH2, N02, X, OH; 'R3' can be selected from CONH2, COOH, N3; 'R4' can be selected from X, NH2; 'X' represents halogen such as CI, Br, I; 'P' represents hydrogen or amine protecting group; with the proviso that if 'P' is hydrogen, then 'R3' is not CONH2.