The present invention relates to improved process for the preparation of 4-[[4-[[4-
[(E)-2-cyanoethenyl]-2>6-dimethylphenyl]amin0]-2-pyrimidinyl]aniino]ben2onitrile monohydrochloride compound of formula-la, represented by the following structural formula:
Back ground of the Invention
Rilpivirine, which is chemically known as of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amin0]-2-pyrimidinyl]amino]benzonitrile; is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and exhibits human immunodeficiency virus (HIV) replication inhibiting properties. Rilpivirine is used as its hydrochloride salt in the anti-HIV
formulations.
U.S. Patent No. 7,125,879 ("herein after referred as '879 patent") discloses HIV inhibiting pyrimidine derivatives such as Rilpivirine and its hydrochloride salt form.
The '879 patent further discloses various processes for the preparation of Rilpivirine, which includes condensation of 3-(4-amino-3,5-dimethyl phenyl)-acrylonitrile either in free' base or hydrochloride salt with 4-(4-chloroPyrimidin-2-ylamino)benz0nitrile at temperature of 150°C for 1 hour followed by treatment with mixture of 10% potassium carbonate, methylene chloride and methanol and then the product Rilpivirine was isolated by column chromatography.
The '879 patent discloses another process for the preparation of Rilpivirine by condensation of 3-(4-amino-3,5-dimethyl phenyl)-acrylonitrile hydrochloride salt with 4-(4-chl0ropyrimidin-2-ylamino)benzonitrile in acetonitrile at reflux temperature for 69 hours followed by resultant Rilpivirine hydrochloride product was isolated by filtration under hot condition at 55°C. Basification of the obtained solid with 10% aqueous solution of potassium carbonate followed by obtained Rilpivirine free base refluxed in 65 volumes of isopropanol

to obtain Rilpivirine. The said '879 patent has the following disadvantages:
• The '879 patent fails to disclose purity and impurity profile of the Rilpivin
obtained.
• Use of neat reaction conditions extremely at high temperature of about 150°C whi may lead to the formation of degradation impurities and involves tedio chromatographic purifications makes the process not viable for large see manufacturing.
• Reaction in presence of acetonitrile at reflux for a period about 69 hours. Tl prolonged period of reaction maintenance leads to an increase in the manufacture cycle time and decrease in the product yield and quality.
• Isolation of crude Rilpivirine hydrochloride at hot conditions such as filtration ( crude at temperature 55°C. Solid filtration at h,gh temperature is not viabl, particularly on commercial scale operations for producing API's and thus require utmost care to use.
In view of the above, there is a need in the art to develop an improved, economical! viable and efficient, simple process for the preparation of Rilpivirine hydrochlorid, compound of formula-la with high yield and purity.
Brief description of the Invention:
The first aspect of the present invention is to provide an improved process for the
preparation of 4-[[4.[[4-[(E)-2-cyanoethenyl].2,6-dimethylphenyl]amino]-2-Pyrimidinyl] amino]benzonitrile monohydrochloride compound of formula-la.
The second aspect of the present invention is to provide a process for the preparation of 4-(4-hydroxy pyrimidin-2-ylamino)benZamide compound of formula-5.
The third aspect of the present invention is to provide an improved process for the
preparation of 4-[[4-[[4-[(E)-2-cyanoe.henyl]-2,6-dimethylPhenyI]amino]-2-pyrimidinyl] aminojbenzonitrile compound of formula-1.
The fourth aspect of the present invention is to provide a process for the preparation
of 4-[[4-[[4-[(E)-2-cyan0ethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]
benzonitrile monohydrochloride compound of formula-la.

Detailed description of the Invention:
As used herein the term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene and the like; "ether solvents-such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, Methylene glycol dimethyl ether, anisole, t-butyi methyl ether, 1,2-dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 1,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.
The term "suitable base" used herein the present invention until unless specified is selected from inorganic bases like "alkali metal hydroxides" such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "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 hydrides" such as sodium hydride, potassium hydride, lithium hydride md the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, sodium ert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the ike; ammonia; and organic bases such as triethyl amine, methyl amine, ethyl amine, 1,8-3iazabicyclo[5.4.0]undec-7-ene (DBU), l,5-Diazabicyclo(4.3.0)non-5-ene (DBN), lithium lioisoporpylamide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine,

diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-methyl-2-pyrrolidone, N-ethylmorpholine, piperidine, dimethylamino pyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1 -methylimidazole, 1,2,4-triazole, l,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.
The suitable hydrochloric acid source is selected from HC1 gas, aqueous HC1, dry HC1, ethylacetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl.
As used herein.the term "chlorinating agent" is selected from pivaloyl chloride, thionyl chloride, sulfuryl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and the like.
The first aspect of the present invention provides an improved process for the preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl] amino]benzonitrile monohydrochloride compound of formula-la, comprising of the following steps:
a) Reacting 4-aminobenzamide compound of formula-2 with aqueous cyanamide in presence of a suitable hydrochloric acid source and in a suitable solvent to provide 4-guanidinobenzamide hydrochloride compound of formula-3 a,
b) reacting the compound of formula-3a with (E)-ethyl 3-(dimethylamino)acrylate compound of formula-4 in the presence of a suitable base in a suitable solvent to provide 4-(4-hydroxypyrimidin-2-ylamino)benzamide compound of formula-5,
c) treating the compound of formula-5 with a suitable chlorinating agent in presence of a suitable base in a suitable solvent to provide 4-(4-chloropyrimidin-2-ylamino) benzonitrile compound of formula-6,
d) reacting 2,6-dimethylaniline compound of formula-7 with iodine in presence of a suitable base in a suitable solvent to provide 4-iodo-2,6-dimethylaniline. compound of formula-8,
e) reacting the compound of formula-8 with acrylonitrile in presence of palladium carbon, sodium acetate and a suitable base in a suitable solvent to provide (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile compound of formula-9, which is on further treating with a suitable hydrochloric acid source in a suitable solvent to provide (E> 3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride compound of formula-9a,

provide (E)-3-(4-amino-3)5-dimethylphenyl)acrylonitrile hydrochloride compound of formula-9a,
f) optionally, purifying the compound of formula-9a using a suitable solvent to provide pure compound of formula9a,
g) reacting the compound of formula-9a obtained in step-(e) or (f) with 4-(4-chloropyrimidin-2-ylamino)benzonitrile compound of formula-6 obtained in step-(c) in presence of acetic acid in a suitable solvent to provide 4-[[4-[[4-[(E)-2-
cyanoethenyl]-2)6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benZOnitrile compound of formula-1 or its hydrochloride salt compound of formula-la, h) optionally, purifying the compound of formula-la by treating it with a suitable base in a suitable solvent and then treating with acetic acid and suitable hydrochloric acid source in a suitable solvent to provide 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethyl
phenyl]amino]-2-pyrimidinyl]amino]benzonitrile hydrochloride compound of formula-la,
i) treating the compound of formula-la with a suitable base in a suitable solvent to
provide 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl] aminojbenzonitrile compound of formula-1,
j) treating the compound of formula-1 with a suitable hydrochloric acid source in a suitable solvent to provide 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl] amino]-2-pyrimidinyl] aminojbenzonitrile hydrochloride compound of formula-la. Wherein,
in step-a), e), h) and j) the suitable hydrochloric acid source is selected from HCI gas, aqueous HCI, dry HCI, ethylacetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl;
in step-b), d), e), h) and i) the suitable base is selected from organic or inorganic base;
in step-c) the suitable chlorinating agents is selected from pivaloyl chloride, thionyl chloride, sulfuryl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and the like and suitable base is selected from organic base such as N-methyl-2-pyrrolidone;
in step-a) to step-j) the suitable solvent is selected from chloro solvents, ester solvents,
hydrocarbon solvents, ketone solvents, ether solvents, polar aprotic solvents, alcohol

the preparation of 4-[[44[44(E)-2-cyanoethenyl]-2)6-dimethylphenyl]amino]-2-pyrimidinyl] amino]benzonitriIe monohydrochloride compound of formula-la, comprising of the following steps:
a) Reacting 4-aminobenzamide compound of formula-2 with aqueous cyanamide in presence of aqueous hydrochloric acid in isopropanol to provide 4-guanidinobenzamide hydrochloride compound of formula-3a,
b) reacting the compound of formula-3a with (E)-ethyl 3-(dimethylamino)acrylate compound of formula-4 in presence of sodium carbonate in water to provide 4-(4-hydroxypyrimidin-2-ylamino)benzamide compound of formula-5,
c) treating the compound of formula-5 with phosphorus oxychloride in presence of N- j
i
methyl-2-pyrrolidone in toluene to provide 4-(4-chloropyrimidin-2-ylamino) |
benzonitrile compound of formula-6,
d) reacting 2,6-dimethylaniline compound of formula-7 with iodine in presence of
sodium bicarbonate in dichloromethane to provide 4-iodo-2,6-dimethylaniline
compound of formula-8,
., e) reacting the compound of formula-8 with acrylonitrile in presence of palladium
carbon, sodium acetate and diisopropyl ethyl amine in dimethyl acetamide to provide
(E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile compound of formula-9, which is on
further treating with isopropanolic-hydrochloric acid (IPA-HC1) in a mixture of
isopropanol and methyl tertiarybutyl ether to provide (E)-3-(4-amino-3,5-
dimethylphenyl)acrylonitrile hydrochloride compound of formula-9a, |
f) purifying the compound of formula-9a using methanol to provide pure compound of formula9a,
g) reacting the compound of formula-9a obtained in step-(e) or (f) with 4-(4-chloro pyrimidin-2-ylamino)benzonitrile compound of formula-6 obtained in step-(c) in presence of acetic acid in N-methyl-2-pyrrolidone to provide 4-[[4-[[4-[(E)-2-
cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile hydrochloride compound of formula-la,
h) purifying the compound of formula-la by treating it with triethyl amine in dimethyl sulfoxide and then treating with acetic acid and hydrochloric acid in water to provide

h) purifying the compound of formula-la by treating it with triethyl amine in dimethyl sulfoxide and then treating with acetic acid and hydrochloric acid in water to provide
4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino] benzonitrile hydrochloride compound of formula-1 a,
i) treating the compound of formula-1 a with potassium carbonate in water to provide 4-
[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl] amino]benzonitrile compound of formula-1,
j) treating the compound of formula-1 with cone, hydrochloric acid in acetic acid to
provide 4-[[4-[[4-[(E)-2-cyanoethenyl]-2)6-dimethylphenyl]amino]-2-pyrimidinyl] aminojbenzonitrile hydrochloride compound of formula-la.
The second aspect of the present invention is to provide a process for the preparation of 4-(4-hydroxy pyrimidin-2-ylamino)benzarnide compound of formula-5, comprising of:
a) Reacting 4-aminobenzamide compound of formula-2 with aqueous cyanamide in presence of a suitable hydrochloric acid source and in a suitable solvent to provide 4-guanidinobenzamide hydrochloride compound of formula-3a,
b) reacting the compound of formula-3a with (E)-ethyl 3-(dimethylamino)acrylate compound of formula-4 in the presence of a suitable base in a suitable solvent to
provide 4-(4-hydroxypyrimidin-2-ylamino)benzamide compound of formula-5. Wherein,
in step-a) the suitable hydrochloric acid source is selected from HC1 gas, aqueous HC1, dry
HC1, ethylacetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl; in step-b) the suitable base is selected from organic or inorganic base. in step-a) to step-b) the suitable solvent is selected from chloro solvents, ester solvents,
hydrocarbon solvents, ketone solvents, ether solvents, polar aprotic solvents, alcohol
solvents and polar solvents like water or mixture thereof.
The preferred embodiment of the present invention provides a process for the preparation of 4-(4-hydroxy pyrimidin-2-ylamino)benzamide compound of formula-5, comprising of the following steps:

a) Reacting 4-aminobenzamide compound of formula-2 with aqueous cyanamide in
presence of aqueous hydrochloric acid in isopropanol to provide 4-guanidino
benzamide hydrochloride compound of formula-3a,
b) reacting the compound of formula-3a with (E)-ethyl 3-(dimethylamino)acrylate
5 compound of formula-4 in presence of sodium carbonate in water to provide 4-(4-
hydroxypyrimidin-2-ylamino)benzamide compound of formula-5.
The third aspect of the present invention is to provide an improved process for the
preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl].2(6-dimethylphenyl]amino]-2-Pyrimidinyl] 0 aminojbenzonitrile compound of formula-1, comprising of:
a) Reacting the (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride
compound of formula-9a with 4-(4-chloropyrimidin-2-ylamino)benzonitrile
compound of formula-6 in presence of acetic acid in N-methyl-2-pyrrolidone provide
4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-Pyrimidinyl]amino]
i benzonitrile compound of formula-1 or its hydrochloride salt compound of formula-
la,
b) optionally, purifying the compound of formula-1 a by treating it with a suitable base in
a suitable solvent and then treating with acetic acid and suitable hydrochloric acid
source in a suitable solvent to provide pure 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-
dimethyl phenyl]amino]-2-pyrimidinyl]amino]benzonitrile hydrochloride compound of formula-1 a,
c) treating the compound of formula-la with a suitable base in a suitable solvent to
provide 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl] aminojbenzonitrile compound of formula-1. Wherein,
in step-b) and c) the suitable base is selected from organic or inorganic base;
in step-b) the suitable hydrochloric acid source is selected from HC1 gas, aqueous HC1, dry HC1, ethylacetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl;
in step-b & c) the suitable solvent is selected from chloro solvents, ester solvents,
hydrocarbon solvents, ketone solvents, ether solvents, polar aprotic solvents, alcohol solvents and polar solvents like water, acetic acid or mixture thereof.

a) Reacting the (^-(^ino-S.S-dimethylphenyDacrylonitrile hydrochloride compound of formula-9a with ^-chloropyrimidin^-ylamino^enzomtrile compound of formula-6 in presence of acetic acid in N-methyl-2-pyrrolidone provide
4-[[4-[[4-[(E)-2-cyan0ethenyl]-2)6-dimethylphenyl]amino]-2-pyrimidinyl]amino] benzonitrile compound of formula-1 or its hydrochloride salt compound of formula-la,
b) purifying the compound of formula-la by treating it with triethyl amine in dimethyl sulfo.de and then treating with acetic acid and hydrochloric acid in water to provide
4-[[4-[[4-[(E)-2-cyanoethenyl]-2)6-dimethylphenyl]amino]-2-Pyrimidi„yl]amino] benzonitrile hydrochloride compound of formula-la,
0 treating the compound of formula-la with potassium carbonate in water to provide 4-
[[4-[[4-[(E)-2-cyanoethenyl]-2!6-dimethylphenyl]amin0]-2-pyrimidinyl]amino] benzonitrile compound of formula-1.
The fourth aspect of the present invention is to provide a process for the preparation
° 4"[[4-[[4-[(E>2-Cyanoe*enyl]-2;6-dimethylphenyl]amino]-2-pyrimidinyl]amino]
benzonitrile monohydrochloride compound of formula-,a comprising of, treating the compound of formula-1 with a suitable hydrochloric acid source in a suitable solvent to
provide 4-[[4-[[4-[(E)-2-cyanoethenyl]-2!6-dimethylphenyl]amino]-2-pyrimidi„y.]amino] benzonitrile hydrochloride compound of formula-1 a.
. Wherein, the suitable hydrochloric acid source is selected from HC, gas, aqueous HC1, dry HC, ethylacetate-HC, IPA-HCI, ethanol-HCl, methanol-HCl; and the suitable so vent is ^eced from chloro solvents, ester solvents, hydrocarbon solvents, ketone solvents, ether solvents, polar aprotic solvents, alcohol solvents and polar solvents like water
acetic acid or mixture thereof.
The preferred embodiment of the present invention is to provide a process for the preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylpheny.]amino]-2-Pyrimidinyll aminojbenzonitrile monohydrochloride compound of formula-la comprising of treating the compound of formula-1 with cone, hydrochloric acid in acetic acid to provide ^-[M-RE) 2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyI]amino]benZonitrile

aminojbenzonitrile monohydrochloride compound of formula-1 a comprising of treating the compound of formula-1 with cone, hydrochloric acid in acetic acid to provide 4-[[4-[[4-[(E)-
2-cyanoethenyl]-2)6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile hydrochloride compound of formula-la.
The4-[[4-[[4-[(E)-2-cyanoethenyl]-2)6-dimethylphenyl]amino]-2-pyrimidinyl]amino] benzonitrile hydrochloride compound of formula-la produced by the present invention can be further micronized or milled in a conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The process of the present invention can be represented schematically as follows:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-l: Preparation of 4-Guanidinobenzamide hydrochloride (Formula-3a)
50% aqueous cyanamide (308.63 gms) was added to a mixture of 4-aminobenzamide (200 gms) compound of formula-2 and isopropanol (800 ml) at 25-30°C. Hydrochloric acid solution (160 ml) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 4 hours at the same temperature. Added another lot of hydrochloric acid solution (40 ml) to the reaction mixture at 80-85°C and stirred for 4 hours at the same temperature. Cooled the reaction mixture to -5 to 0°C and stirred for 1 V2 hour at the same temperature. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: 265.5 gms; M.R: 265-270°C.
Example-2: Preparation of 4-(4-hydroxy pyrimidin-2-ylamino)benzamide (Formula-5)
A mixture of water (400 ml), 4-guanidinobenzamide hydrochloride (100 gms), sodium carbonate (74 gms) and (E)-ethyl 3-(dimethylamino)acrylate (80 gms) compound of formula-4 were heated to 90-95°C and stirred for 40 hours at the same temperature. Cooled

the reaction mixture to 25-30°C and stirred for 1 i4 hour at the same temperature. Filtered the solid and washed with water and dried to get the title compound. Yield: 50.57 gms; M.R: 280-285°C.
Example-3: Preparation of 4-(4-chIoropyrimidin-2-ylamino)benzonitriIe (FormuIa-6)
Phosphorus oxychloride (199.8 gms) was slowly added to a pre-cooled mixture of toluene (300 ml), N-methyl-2-pyrrolidone (100 ml) and 4-(4-hydroxy pyrimidin-2-ylamino)benzamide (100 gms) at 0-5°C. Heated the reaction mixture to 80-85°C and stirred for 6 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Quenched the reaction mixture into aqueous ammonia solution at 0-5°C. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the solid and washed with water. To the obtained wet compound, water (300 ml) and sodium carbonate was added at 25-30X and stirred for 40 minutes at the same temperature. Filtered the reaction mixture, washed with water and dried to get the title compound. Yield: 65 gms. Purity: 88.0% by HPLC.
Example-4: Preparation of 4-Iodo-2,6-dimethylaniline (Formula-8)
A mixture of dichloromethane (250 ml), 2,6-dimethyl aniline (50 gms), sodium bicarbonate (34.7 gms) and iodine (114.5 gms) were stirred for 3 hours at 25-30°C . Quenched the reaction mixture using aqueous sodium thiosulphate solution at 25-30°C. Stirred the reaction mixture for 30 minutes at 25-30°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with aqueous sodium carbonate solution followed by water. Carbon (5 gms) was added to the organic layer at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed and washed with dichloromethane. Distilled off the solvent completely from the filtrate and then co-distilled with n-heptane. To the obtained compound, n-heptane (250 ml) was added at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with chilled n-heptane and dried to get the title compound. Yield: 80 gms; M.R: 49-52°C.

Example-5: Preparation of (E)-3-(4-amino-3)5-dimethylphenyl)acrylonitrile hydrochloride (FormuIa-9a)
Diisopropyl ethyl amine (22.2 gms) was added to 4-Iodo-2>6-dimethylaniline obtained in example-4 at 25-30°C and stirred for 15 minutes at the same temperature. Sodium acetate (33.8 gms) and followed by acrylo nitrile (54.32 gms) was added to the reaction mixture at 25-30°C. A mixture of RN-dimethyl acetamide (250 ml) and 5% Pd/C (9.0 gms) was added to the reaction mixture at 25-30°C under nitrogen atmosphere. Heated the reaction mixture to 120-125°C and stirred for 8 hours at the same temperature. Another lot of acrylo nitrile (43.64 gms) was added to the reaction mixture at 120-125°C and stirred for 22 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture through hy-flow bed and washed with toluene. To the obtained filtrate, toluene (400 ml) was added at 25-30°C. The reaction mixture was slowly added to pre-cooled water (850 ml) at 10-15°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture and both the organic and aqueous layers were separated from the obtained filtrate. The organic layer was washed with water at 10-15°C. Carbon (5.0 gms) was added to the organic layer at 25:30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed and washed with toluene. Distilled off the solvent completely from the filtrate under reduced pressure. Methyl tertiary butyl ether (350 ml) and isopropanol (100 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 60-65°C and isopropanolic hydrochloric acid solution (80 ml) was slowly added to the reaction mixture at the same temperature. Stirred the reaction mixture to 1 hour at 60-65°C. Cooled the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with a mixture of methyl tertiary butyl ether and isopropanol. To the obtained wet compound, methanol (175 ml) was added at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 37 gms. M.R: 210-220°C.
Example-6: Preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyI]amino]benzonitrile hydrochloride (Formula-la)

A mixture of N-methyl-2-pyrrolidone (300 ml), (E)-3-(4-amino-3,5-dimethylphenyl) acrylonitrile hydrochloride (100 gms) compound of formula-9a, 4-(4-chloropyrimidin-2-yl amino)benzonitrile (132 gms) compound of formula-6 and acetic acid (2.8 gms) were heated to 90-95°C and stirred for 8 hours at the same temperature. Cooled the reaction mixture to 10-15°C. Hydrochloric acid (60 ml) and water (900 ml) was slowly added to the reaction mixture at 10-15°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid and washed with water. To the obtained compound, a mixture of N-methyl-2-pyrrolidone (200 ml), water (700 ml), hydrochloric acid (100 ml) were added at 25-30°C and stirred for 1 hour at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 140 gms.
Example-7: Preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2)6-dimethylphenyI]amino]-2-pyrimidinyl)amino]benzonitrile(Formula-l)
Dimethyl sulfoxide (390 ml) was added to 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile hydrochloride obtained in example-6 at 25-30°C. Triethyl amine (67.3 ml) was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Acetic acid (390 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Hydrochloric acid (78.5 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Water (780 ml) was added to the reaction mixture at 25-30°C and stirred for 1 !/2 hour at the same temperature. Filtered the precipitated solid and washed with water. To the obtained wet compound, water (520 ml) and potassium carbonate (66.8 gms) was added at 25-30°C and stirred for 1 hour at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 115 gms; M.R: 242-245°C.
Example-8: Preparation of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylPheny!Jamino]-2-pyrimidinyl]amino]benzonitriIe hydrochloride (Formula-la)
A mixture of 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylPhenyl]amino]-2-pyrimidinyl]amino]benzonitrile (100 gms) and acetic acid (550 ml) was heated to 90-100°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture through hy-

flow bed and washed with hot acetic acid. Heated the obtained filtrate to 55-60°C. Hydrochloric acid (40 ml) was slowly added to the reaction mixture at 55-60°C and stirred for 30 minutes at the same temperature. Water (600 ml) was slowly added to the reaction mixture at 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°c and stirred for 30 minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 85 gms. Purity: 99.9% by HPLC.
The PXRD pattern of obtained the compound is matching with the PXRD pattern of crystalline Form-Aof Rilpivirine HC1 disclosed in US7638522B2.
Example-9: Preparation of (E/Z)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride (Formula-9a):
A mixture of (E/Z)-3-(4-amino-3,5-dimethylphenyl)acrylamide (100 gms), toluene (300 ml) and N-methyl pyrrolidone (100 ml) was stirred for 10 minutes at 25-30°C. Cooled the reaction mixture to 0-5°C and phosphoryl chloride (73.7 ml) was slowly added to the reaction mixture at below 25-30°C and stirred the reaction mixture for 6 hours at the same temperature. The reaction mixture was slowly added to a pre-cooled aqueous ammonium hydroxide [200 ml of ammonia in 300 ml of water] at 20-25°C and stirred the reaction mixture for 3 hours at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 95 gms.
Example-10: Preparation of (E/Z).3-(4-amino-3,5-dimethylpheny])acrylamide (Formula-13):
A mixture of 2-chloro acetamide (100 gms), toluene (300 ml) and triphenylphosphine (280.4 gms) was heated to 105-110°C and stirred for 6 hours at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 90 minutes at the same temperature. Filtered the precipitated solid and washed with toluene. Tetrahydrofuran (500 ml) was added to the obtained wet compound at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 15 minutes at the same temperature. Potassium-tertiary butoxide was slowly added to the reaction mixture at 0-5°C and stirred for 45 minutes at the same temperature. 4-amino-3,5-

dimethylbenzaldehyde (160 gms) was added to the reaction mixture at 0-5X. Heated the reaction mixture to 45-50°C and stirred for 5 hours at the same temperature. Water was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Ethyl acetate was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same > temperature. Both the organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate. Combine the organic layers and washed with water. Distilled off the solvent completely from the organic layer under reduced pressure. Methanol (600 ml) was added to the obtained residue and stirred for 3 hours at 0-5°C. Filtered the precipitated solid, washed with methanol and dried to the title compound. Yield: 175 gms; M.R: 185-190°C.
Example-11: Preparation of (E)-4-((4-((4-(2-cyanovinyI)-2,6-dimethylphenyl)amino) pyrimidin-2-yl)amino)ben2onitrile(Formula-l):
A mixture of N-methylpyrrolidone (300 ml), (E)-3-(4-amino-3,5-dimethylphenyl)acetonitrile hydrochloride (100 gms), 4-((4-chloropyrimidin-2-yl)amino) benzonitrile (132 gms) and acetic acid (2.8 ml) was heated to 90-95°C and stirred for 7 hours at the same temperature. Cooled the reaction mixture to 10-15°C, aqueous acetone solution [200 ml of acetone in 800 ml of water] was slowly added to the reaction mixture and stirred for 45 minutes at the same temperature. Filtered the solid and washed with water. Dimethylsulfoxide (375 ml) was added to the obtained wet compound at 25-30°C. Triethylamine (78 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Acetic acid (375 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Aqueous hydrochloric acid solution (90 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Water (750 ml) was added to the reaction mixture at 25-30°C and stirred for 90 minutes at the same temperature. Filtered the solid and washed with water. Dimethylsulfoxide (78 ml) was added to the obtained wet compound at 25-30°C. Triethylamine (78 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Acetic acid (375 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Aqueous hydrochloric acid solution (90 ml) was added to the reaction mixture at 25-30°C and stirred for 30 minutes

at the same temperature. Water (750 ml)was added to the reaction mixture at 25-30°C and stirred for 90 minutes at the same temperature. Filtered the solid and washed with water.
Dimethylsulfoxide (350 ml) was added to the obtained dry compound at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the solid and washed with methanol. Aqueous potassium carbonate solution [53 gm in 500 ml of water] was added to the obtained wet compound at 25-30°C and stirred for 60 minutes at the same temperature. Filtered the compound, washed with water and dried to get the title compound.
Yield: 120 gms; M.R: 242-245°C. Purity: 99.85 % by HPLC.
The PXRD pattern of the obtained compound is matching with the PXRD pattern of crystalline Form-II of Rilpivirine freebase disclosed in US8426434B2.
Example-12: Purification of 4-(4-chloropyrimidin-2-ylamino)ben2onitrile (Formula-6):
A mixture of 4-(4-chloropyrimidin-2-ylamino)benzonitrile, methanol (450 ml) and dimethyl sulfoxide (50 ml) was heated to 55-60°C and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 60 minutes at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound.
Yield: 74 gms. Purity: 97% by HPLC.