FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - AN IMPROVED PROCESS FOR PREPARING
RILPIVIRINE AND ITS INTERMEDIATE
2. Applicant(s)
(a) NAME : LUPIN LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : 159, CST Road, Kalina, Santacruz (East),
Mumbai - 400 098, State of Maharashtra
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of invention:
The present invention relates to improved process for the preparation of Rilpivirine and its intermediate.
Background of the invention:
Rilpivirine, which is chemically known as 4-{ [4-{ (1 E)-2-cyanoethenyl]-2,6-dimethylphenyl}amino)pyridine-2-yl]amino}benzonitrile (Formula I),

is a non-nucleoside reverse transcriptase inhibitor and exhibits human immunodeficiency virus (HIV) replication inhibiting properties. Rilpivirine is used as its hydrochloride salt in the anti-HIV formulations.
WO 03/016306 first disclosed the synthesis of Rilpivirine involving different routes for synthesis of 4-(2-cyanoethyl)-2,6-dimethylphenylamine. The first route involved protection of the amino group of 4-bromo-2,6-dimethylphenylamine by converting to N,N-dimethylmethanimidamide, followed by formylation involving n-butyl lithium and dimethylformamide. The resulting formyl derivative was treated with diethyl (cyanomethyl) phosphonate to give the cyanoethenyl compound which was deprotected using zinc chloride to yield the cyanoethenylphenylamine intermediate having an undisclosed E/Z ratio. This route involved an elaborate sequence of synthesis comprising protection of amine by its conversion into imide, use of a highly moisture

sensitive and pyrophoric base such as butyl lithium and a low yielding formylation reaction. All these factors made the process highly unviable on industrial scale.
The second route disclosed in WO 03/016306 employed 4-iodo-2,6- dimethylphenylamine as a
starting material for synthesis of cyanoethenylphenylamine intermediate, which involved
reaction of the dimethylphenylamine derivative with acrylonitrile for 12 hours at 130°C in
presence of sodium acetate and a heterogeneous catalyst such as palladium on carbon. Isolation
of the desired compound involved solvent treatment with multiple solvents followed by
evaporation. This route also does not give any details of the E/Z ratio of the unsaturated
intermediate product. Although this route avoids use of phosphine ligands, lengthy reaction time
and problem of availability of pure halo-phenylamine derivatives coupled with moderate yields
hampers the commercial usefulness of this route.
The third route disclosed in WO 03/016306 involved reaction of 4-bromo-2,6-dimethylphenylamine with acrylamide in presence of palladium acetate, tris(2-methylphenyl)phosphine and N,N-diethylethanamine. The resulting amide was dehydrated using phosphoryl chloride to give 4-(2-cyanoethenyi)-2,6- dimethylphenylamine in a moderate yield of 67% without mentioning the E/Z ratio. Although the E/Z isomer ratio for the cyanoethenyl derivative obtained from these routes is not specifically disclosed in the patent, however, reproducibility of the above mentioned reactions were found to provide an E/Z ratio between 70/30 and 80/20. Various other methods have also been reported in the literature for introduction of the cyanoethenyl group in Rilpivirine.
The fourth route disclosed in WO 03/016306 involved reaction of (2E)-3-(4-amino-3, 5-dimethylphenyl) acrylonitrile hydrochloride with [4-[(4-chloro-2-pyrimidinyl) amino] benzonitrile in presence of acetonitrile as a solvent for about 70 hrs at reflux temperature with moderate yields.

The Journal of Medicinal Chemistry (2005), 48, 2072-79 discloses Wittig or Wadsworth-Emmons reaction of the corresponding aldehyde with cyanomethyl triphenylphosphonium chloride to provide a product having an E/Z isomer ratio of 80/20. An alternate method of Heck reaction comprising reaction of aryl bromide with acrylonitrile in presence of tri-o-tolylphosphine and palladium acetate gave the same compound with a higher E/Z isomer ratio of 90/10. The method required further purification in view of the presence of a significant proportion of the Z isomer in the unsaturated intermediate. A similar method was disclosed in Organic Process Research and Development (2008), 12, 530-536. However, the E/Z ratio of 4-(2-cyanoethenyl)-2,6- dimethylphenylamine was found to be 80/20, which was found to improve to 98/2 (E/Z) after the compound was converted to its hydrochloride salt utilizing ethanol and isopropanol mixture.
Thus, there is a need to develop an improved and convenient process for preparation of Rilpivirine or its intermediate without involving use of phosphine reagent and commercially viable and industrially advantageous.
The present inventors found an efficient and economic catalyst system for Heck reaction used in the process for preparation of Rilpivirine or its intermediate using mono-, di- or triethanolamine as solvent, ligand and base and palladium acetate as catalyst under phosphane-free reaction conditions. Moreover, mono-, di- or triethanolamine could be recovered and recycled without significant loss in activity.

Summary of the invention:
According to one aspect, the present invention provides an improved process for the preparation of Rilpivirine or its pharmaceutically acceptable salt by reaction of 4-((4-((4-iodo-2,6-dimethy]phenyl)amino)pyrimidin-2-yl)amino)benzonitrile (compound C) with acrylonitrile in the presence of palladium catalyst and mono-, di- or triethanolamine as shown in scheme 1:

According to another aspect, the present invention provides an improved process for preparation of Rilpivirine or its pharmaceutically acceptable salt by reaction of 4-iodo-2, 6-dimethylaniline (compound A) with acrylonitrile in presence of mono-, di- or triethanolamine and palladium

catalyst and further converting to Rilpivirine or its pharmaceutically acceptable salt, as shown in scheme 2:

According to another aspect, the present invention provides an improved process for preparation of Rilpivirine by reaction of (2E)-3-(4-amino-3, 5-dimethylphenyl) acrylonitrile (compound D) or its pharmaceutically acceptable salt with [4-[(4-chloro-2-pyrimidinyl) amino] benzonitrile (compound B) in presence of mixture of solvent, as shown in scheme 3,


According to another aspect, the present invention provides an improved process for the preparation of (2E)-3-(4-amino-3, 5-dimethylphenyl) acrylonitrile (compound D) or its pharmaceutically acceptable salt by reaction of 4-iodo-2, 6-dimethylaniline (compound A) with acrylonitrile in presence of mono-, di- or triethanolamine and palladium catalyst, as shown in scheme 4:,


Detailed description:
According to one aspect, there is provided an improved process for the preparation of Rilpivirine or its salt comprising:
a) reacting 4-iodo-2, 6-dimethylaniline (compound A) with 4-[(4-chloropyrimidin-2-yl) amino]
benzonitrile (compound B) in the presence of suitable solvent to produce 4-((4-((4-iodo-2,6-
dimethylphenyl)amino)pyrimidin-2-yl)amino)benzonitrile (compound C) or its pharmaceutically
acceptable salt;
b) reacting 4-((4-((4-iodo-2,6-dimethylphenyl)amino)pyrimidin-2-yl)amino)benzonitrile
(compound C) or an acid addition salt with acrylonitrile in the presence of palladium catalyst and
mono-, di- or triethanolamine to produce Rilpivirine; and
c) optionally converting Rilpivirine to its pharmaceutically acceptable salt.
Exemplary solvents employed in step-(a) include, but are not limited to, water; acetonitrile; an alcohol, such as for example ethanol, 2-propanol, 2-propanol-HCI; N,N-dimethylformamide; N,N-dimethy!acetamide; 1-methyl-2-pyrrolidinone; 1,4-dioxane; propylene glycol monomethylether or mixtures thereof. Preferably the solvent is acetonitrile; an alcohol, such as for example ethanol, 2-propanol, 2-propanol-HCI; N,N-dimethylformamide; N,N-

dimethylacetamide; propylene glycol monomethylether; l-methyl-2-pyrrolidinone or mixtures thereof. More preferably, the solvent is 2-propanol, 6 N HC1 in 2-propanol, acetonitrile or 1-methyl-2-pyrrolidinone; especially acetonitrile or l-methyl-2-pyrrolidinone.
Exemplary palladium catalyst employed in step-(b) include, but are not limited to, Pd(OAc)2, PdCl2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd2(dba)3, (tris(dibenzylidene acetone)dipalladium), palladium thiomethylphenylglutaramide metallacycle and the like, or a heterogeneous Pd catalyst, such as palladium on charcoal, palladium on metal oxides, palladium on zeolites; preferably Pd(OAc)2.
According to another aspect, there is provided an improved process for preparation of Rifpivirine or its salt comprising:
a) reacting 4-iodo-2, 6-dimethylaniline (compound A) with acrylonitrile in the presence of mono-, di- or triethanolamine and palladium catalyst to produce (2E)-3-(4-amino-3, 5-dimethylphenyl) acrylonitrile (compound D) or its pharmaceutically acceptable salt;
b) reacting (2E)-3-(4-amino-3, 5-dimethylphenyl) acrylonitrile (compound D) or acid addition salt thereof with [4-[(4-chloro-2-pyrimidinyl)] amino] benzonitrile (compound B) in presence of solvent to produce Rilpivirine; and
c) optionally converting Rilpivirine to its pharmaceutically acceptable salt.
Exemplary the palladium catalyst employed in step-(a) include, but are not limited to, Pd(OAc)2, PdCl2, Pd(PPh3)4) Pd(PPh3)2Cl2, Pd2(dba)3, (tris(dibenzylidene acetone)dipalladium), palladium thiomethylphenylglutaramide metallacycle and the like, or a heterogeneous Pd catalyst, such as palladium on charcoal, palladium on metal oxides, palladium on zeolites; preferably Pd(OAc)2.

Exemplary solvents employed in step-(b) include, but are not limited to, water; acetonitrile; an alcohol, such as for example ethanol, 2-propanol, 2-propanol-HCl; an acid, such as for example acetic acid; N,N-dimethylformamide; N,N-dimethylacetamide; l-methyl-2-pyrrolidinone; 1,4-dioxane; propylene glycol monomethylether or mixtures thereof. Preferably the solvent is acetonitrile; an alcohol, such as for example ethanol, 2-propanol, 2-propanol-HCl; an acid, such as for example acetic acid; N,N-dirnethylformamide; N,N-dimethylacetamide; propylene glycol monomethylether; l-methyl-2-pyrrolidinone or mixtures thereof. More preferably, acetonitrile, acetic acid or mixture thereof.
According to another aspect, there is provided an improved process for preparation of Rilpivirine or pharmaceutically acceptable salt thereof comprising:
a) reacting (2E)-3-(4-amino-3, 5-dimethylphenyl) acrylonitrile (compound D) or its
pharmaceutically acceptable salt with [4-[(4-chloro-2-pyrimidinyl)] amino] benzonitrile
(compound B) in presence of mixture of solvent to produce Rilpivirine; and
b) optionally converting Rilpivirine to its pharmaceutically acceptable salt.
Exemplary the mixtures of solvent employed in step-(a) include, but are not limited to acetonitrile and acetic acid.
The reaction according to step (a) is carried out for 1 -10 hours.
According to another aspect, there is provided an improved process for preparation of (2E)-3-(4-amino-3, 5-dimethylphenyl) acrylonitrile (compound D) or its pharmaceutically acceptable salt thereof comprising:

a) reacting 4-iodo-2, 6-dimethylaniline with acrylonitrile in presence of mono-, di- or
triethanolamine and palladium catalyst to produce (2E)-3-(4-amino-3, 5-dimethylphenyl)
acrylonitrile (compound D);
b) optionally converting (2E)-3-(4-amino-3, 5-dimethylphenyl) acrylonitrile (compound D) to its
acid addition salt.
Exemplary the palladium catalyst employed in step-(a) include, but are not limited to, Pd(OAc)2, PdCl2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd2(dba)3) (tris(dibenzyiidene acetone)dipalladium), palladium thiomethylphenylglutaramide metallacycle and the like, or a heterogeneous Pd catalyst, such as palladium on charcoal, palladium on metal oxides, palladium on zeolites; preferably Pd(OAc)2.
The pharmaceutically acceptable addition salts as mentioned hereinabove or hereinafter are
meant to comprise the therapeutically active non-toxic acid addition salt forms. The
pharmaceutically acceptable addition salts can conveniently be obtained by treating the base
form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g.
hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or
organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-
oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-l,2,3-
propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-
methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.
The present invention is further illustrated by foregoing examples, which should not be construed by way of limiting the scope of the present invention.

Examples:
Example 1:
Preparation of 4-({4-[(4-iodo-2, 6-dimethylphenyl) amino] pyrimidin-2-yl} amino)
benzonitrile
A mixture of 4-iodo-2, 6-dimethylaniline (0.217 mol) and 4-[(4-chloropyrimidin-2-yl) amino] benzonitrile (0.217mol) in N-methyl pyrrolidinone was stirred at 95-100°C for 12-15 hrs under nitrogen atmosphere. Reaction mixture was cooled to room temperature and isopropyl alcohol was added to crystallize the material. The precipitate was filtered off and dried. Yield: 63.2 g (70.0 %). Purity by HPLC 91.19%
Example 2:
Preparation of 4-[[4-[[4-(2-cynoethenyl)-2, 6-dimethylphenyl] amino]-2-pyrimidinyl]
amino] benzonitrile hydrochloride salt [Rilpivirine hydrochloride]
A mixture of 4-({4-[(4-iodo-2, 6-dimethylphenyl) amino] pyrimidin-2-yl} amino) benzonitrile (0.0566 mol), prepared according to Example 1, acrylonitrile (0.113 mol), Pd(OAc)2 (0.0063 mol) in triethanolamine was stirred under inert atmosphere at 95-98°C for 6- 8 hr. After completion of reaction, reaction mixture was cooled and isopropyl alcohol was added to crystallize the material. The obtained solid was dried to get 4-[[4-[[4-(2-cynoethenyl)-2, 6-dimethylphenyl] amino]-2-pyrimidinyl] amino] benzonitrile. Yield: 17.2 g (82.8%).
The resultant 4-[[4-[[4-(2-cynoethenyl)-2, 6-dimethylphenyl] amino]-2-pyrimidinyl] amino] benzonitrile was added into acetic acid and heated at 80-85°C to get dissolve. Filtered the

undissolved particle and transfer into another flask. Filtrate was heated at 70-75 °C. Concentrated hydrochloric acid is added followed by addition of demineralized water. Reaction mixture was cooled to room temperature to crystallize the material completely. The precipitate was filtered off and dried. Yield: 16.4 g (88.0%). Purity by HPLC 96.45%
Example 3:
Preparation of (2E)-3-(4-amino-3,5-dimethylphenyl) acrylonitrile hydrochloride
A mixture of 4-iodo-2, 6-dimethylaniline (1 mmol), acrylonitrile (1 mmol), Pd(OAc)2 (0.01 mmol) and triethanolamine (5 ml) was stirred under inert atmosphere at 100°C for 10 h. After completion of the reaction, reaction mixture was cooled and extracted with diethyl ether. The layers were separated. The separated layers were collected and organic solvent was evaporated. The mixture was added to isopropanol and heated to 60°C under nitrogen atmosphere. 6N solution of hydrochloric acid in isopropanol (20ml) was added and the mixture was stirred for 30 minutes. After cooling to room temperature reaction mixture was filtered and residue was washed with isopropyl alcohol. The resulting residue was dried under reduced pressure. Yield: 4.0 g (95%).
Example 4:
Preparation of 4-[[4-[[4-(2-cynoethenyl)-2, 6-dimethylphenyl] amino]-2-pyrimidinyl]
amino] benzonitrile hydrochloride salt [Rilpivirine hydrochloride]
A mixture of (2E)-3-(4-amino-3, 5-dimethylphenyl) acrylonitrile hydrochloride (50.0 g) and [4-[(4-chloro-2-pyrimidinyl) amino] benzonitrile (58.0g) in acetic acid and acetonitrile mixture was

prepared under nitrogen atmosphere. The mixture was stirred under nitrogen atmosphere at 85-90°C for 6-8 hours. After completion of reaction the mixture was cooled under stirring .The obtained solid was filtered and dried under vacuum at 45-50°C to obtain Rilpivirine hydrochloride. Yield: 60.0 g (75.0%). Purity by HPLC 99.57%

WE CLAIM:
1. An improved process for preparation of Rilpivirine or a pharmaceutically acceptable salt,
which comprises:
a) reacting of 4-iodo-2, 6-dimethylaniline (compound A) with 4-[(4-chloropyrimidin-2-yl)
amino] benzonitrile (compound B) in the presence of suitable solvent to produce 4-((4-((4-iodo-
2,6-dimethylphenyl)amino)pyrimidin-2-yl)amino)benzonitrile (compound C);
b) reacting of 4-((4-((4-iodo-2,6-dimethylphenyl)amino)pyrimidin-2-yl)amino)benzonitrile
(compound C) obtained in step-a) with acrylonitrile in presence of palladium catalyst and mono-
, di- or triethanolamine to produce Rilpivirine; and
c) optionally converting Rilpivirine to its pharmaceutically acceptable salt.
2. The process of claim 1, wherein the solvent used in step- a) is selected from the group consisting of water, acetonitrile, ethanol, 2-propanol, 2-propanol-HCl, N,N-dimethylformamide; N,N-dimethylacetamide, 1 -methyl-2-pyrrolidinone, 1,4-dioxane, propylene glycol monomethylether or mixtures thereof.
3. An improved process for preparation of Rilpivirine or a pharmaceutically acceptable salt, which comprises;
a) reacting of 4-iodo-2, 6-dimethylaniline (compound A) with acrylonitrile in the presence of mono-, di- or triethanolamine and palladium catalyst to produce (2E)-3-(4-amino-3, 5-dimethylphenyl) acrylonitrile (compound D) or its pharmaceutically acceptable salt;

b) reacting of (2E)-3-(4-amino-3, 5-dimethylphenyl) acrylonitrile (compound D) or its
pharmaceutically acceptable salt obtained in step-a) with [4-[(4-chloro-2-pyrimidinyl)] amino]
benzonitrile (compound B) in presence of solvent to produce Rilpivirine; and
c) optionally converting Rilpivirine to its pharmaceutically acceptable salt.
4. The process of claim 3, wherein the solvent used in step- b) is selected from the group consisting of water, acetonitrile, ethanol, 2-propanol, 2-propanol-HCl, acetic acid, N,N-dimethylformamide, N,N-dimethylacetamide, l-methyl-2-pyrrolidinone, 1,4-dioxane, propylene glycol monomethylether or mixtures thereof.
5. An improved process for preparation of Rilpivirine or its pharmaceutically acceptable salt, which comprises reacting of (2E)-3-(4-amino-3, 5-dimethylphenyI) acrylonitrile (compound D) or its pharmaceutically acceptable salt with [4-[(4-chloro-2-pyrimidinyl) amino] benzonitrile (compound B) in presence of mixture of solvent.
6. The process of claim 5, wherein the mixture of solvent is selected from acetonitrile and acetic acid.
7. An improved process for preparation of (2E)-3-(4-amino-3, 5-dimethylphenyl) acrylonitrile (compound D) or its pharmaceutically acceptable salt, which comprises:

a) reacting of 4-iodo-2, 6-dimethyIaniline (compound A) with acrylonitrile in presence of mono-, di- or triethanolamine and palladium catalyst to produce (2E)-3-(4-amino-3, 5-dimethylphenyl) acrylonitrile; and
b) optionally converting compound D to its pharmaceutically acceptable salt.
8. The Palladium catalyst used according to any of the above claims is selected from Pd(OAc)2,
PdCl2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd2(dba)3, (tris(dibenzylidene acetone)dipalladium), palladium

thiomethylphenylglutaramide metallacycle and the like, or a heterogeneous Pd catalyst, such as palladium on charcoal, palladium on metal oxides, palladium on zeolites.