WO2013179105A1

WO2013179105A1 - Improved process for preparation of rilpivirine and pharmaceutically acceptable salts thereof

Info

Publication number: WO2013179105A1
Application number: PCT/IB2013/000628
Authority: WO
Inventors: Narasimha Rao Ketavarapu; Shashank Gopalrao POTDAR; Venkata Sunil Kumar Indukuri; Seeta Ramanjaneyulu Gorantla; Satyanarayana Chava
Original assignee: Laurus Labs Private Limited
Priority date: 2012-06-01
Filing date: 2013-05-30
Publication date: 2013-12-05

Abstract

Disclosed is an improved process for the preparation of rilpivirine hydrochloride. The process comprises a) reacting 3-(4-amino-3,5-dimethyl phenyl)-acrylonitrile hydrochloride and 4-[(4-chloropyrimidin-2-yl) amino] benzonitrile in the presence of a phase transfer catalyst followed by saltification with an acid and b) converting the rilpivirine acid addition salt into rilpivirine hydrochloride salt.

Description

IMPROVED PROCESS FOR PREPARATION OF RILPIVIRINE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

PRIORITY

This application claims the benefit under Indian Provisional Application No. 2201 /CHE/2012, filed on June 01, 2012 entitled "An improved process for the preparation of rilpivirine and pharmaceutically acceptable salts thereof, the contents of which is incorporated by reference herein.

FIELD OF THE INVENTION

The present invention generally relates to an improved process for preparing Rilpivirine or pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the same.

The present invention also provides acid addition salts of rilpivirine and processes for the preparation of the same.

BACKGROUND OF THE INVENTION

Rilpivirine, also known as 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]2- pyrimidinyl]amino]benzonitrile, is represented by the structural Formula I:

Formula I

Rilpivirine is approved as its monohydrochloride salt and is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1), available in the market under the brand name EDURANT™ in the form of Tablets. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine.

U.S. Patent No. 7,125,879 ("the '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 of Formula II either in free base or hydrochloride salt with 4-(4-chloropyrimidin-2-ylamino) benzonitrile of Formula III 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 Formula II as its hydrochloride salt with Formula III 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 process disclosed in the '879 patent is schematically represented as follows:

HCl Rilpivirine HCl Crude ^HC1

Formula II Formula III

10% Aq K₂C0₃

Rilpivirine HCl Rilpivirine Base

The synthesis of rilpivirine as discussed in the '879 patent has certain drawbacks as it involves:

i) The '879 patent fails to disclose purity and impurity profile of the rilpivirine obtained.

ii) Use of neat reaction conditions extremely at high temperature of about 150°C and involves tedious chromatographic purifications makes the process not viable for large scale manufacturing.

iii) Reaction in presence of acetonitrile at reflux for a period about 69 hours. The prolonged period of reaction maintenance leads to an increase in the manufacturing cycle time and decrease in the product yield and quality.

iv) Isolation of crude rilpivirine hydrochloride at hot conditions such as filtration of crude at temperature 55°C. Solid filtration at high temperature is not viable, particularly on commercial scale operations for producing API's and thus requires utmost care to use.

v) Use of large volumes of solvent for purification of rilpivirine free base, requires high capacity apparatus and thus involves more operational occupancy, which in turn result to an increase in the manufacturing cost, particularly on large scale production of rilpivirine.

U.S. Patent No. 7,399,856 ("the '856 patent) discloses a process for the preparation of rilpivirine by condensation of Formula II as its hydrochloride salt with Formula III in acetonitrile at reflux temperature for 24 hours followed by treatment with aqueous potassium carbonate solution at temperature 50°C and then the resultant rilpivirine base was filtered and refluxed in ethanol for 2 hours, filtered and followed by drying. However, the '856 patent has no disclosure about purity and impurities of rilpivirine obtained by the process.

IN Application No. 2340/CHE/2009 ("the '340 application") discloses a process for the preparation of rilpivirine contain less than 0.15% Z-isomer by condensation of Formula II with Formula III in N-methyl-2-pyrrolidinone in presence of 20% isopropanolic HC1 at temperature 85±3°C for 8 hours followed by treatment with 25% aqueous potassium carbonate solution to obtain rilpivirine. The obtained rilpivirine was purified in a mixture of acetonitrile, N-methyl-2-pyrrolidinone and water and then further purified in a mixture of acetone (30 volumes) and water (20 volumes) to obtain rilpivirine with purity more than 99% and Z-isomer is less than 0.15%.

The '340 application process involves multiple purifications of rilpivirine base and further involves large excess volumes of solvents for the purification, which is result to an increase in the manufacturing cost.

PCT publication No. 2012/143937 ("the '937 publication") discloses a process for the preparation of rilpivirine contain less than 0.1% Z-isomer by condensation of Formula II with Formula III in presence of acetonitrile as solvent, isolating rilpivirine free base at alkaline pH. The obtained rilpivirine was purifying with acetone and dimethyl sulfoxide solvent medium by heating the mixture to 50-55°C, adding hydrochloric acid followed by water and isolating rilpivirine hydrochloride having Z isomer less than 0.1% at a temperature of 25-30°C.

U.S. Patent No. 7,638,522 ("the '522 patent) discloses crystalline polymorphic forms of rilpivirine hydrochloride such as Form A, Form B, Form C and Form D and process for its preparation. The crystalline Form A, Form B, Form C and Form D are characterized by XRPD and DSC thermograms.

U.S. Patent publication No. 2011/150996 ("the '996 publication) discloses rilpivirine fumarate salt and pharmaceutical composition containing the same.

IN Application No. 856/CHE/2009 ("the '856 application") discloses organic acid addition salts of rilpivirine and process for the preparation of the same, wherein the organic acid salts are selected from the group consisting of Malonate, Succinate, Adipate, Fumarate, Malate, Maleate, Tartarate and Saccharinate. The organic acid salts of rilpivirine characterized by XRPD.

The rilpivirine compound of Formula I exist in 2 geometric isomers at the double bond of the cyanoethenyl chain, i.e. E configuration (E-isomer) and the Z configuration (Z- isomer). The E-isomer of rilpivirine substantially free of Z-isomer is the active compound.

Processes disclosed in the art either is not disclosed the content of Z-isomer in the rilpivirine or disclosed processes are not satisfactory to provide the rilpivirine within the acceptable levels of its Z-isomer with industrially viable processes.

Processes for preparation of rilpivirine resulting substantially free of Z-isomer with an industrially viable methods are good alternative for the large scale production of rilpivirine that solve the aforesaid drawbacks associated with processes described in the art.

Accordingly, there remains a need in the art for highly pure rilpivirine or its salts thereof substantially free of its impurities including Z-isomer, as well as purification processes for obtaining thereof.

OBJECT OF THE INVENTION The main object of the invention is to provide a simple, cost effective process for the preparation of rilpivirine or pharmaceutically acceptable salts thereof with high purity and yield without the formation of undesired impurities.

Another object of the invention is to provide a process for the preparation of rilpivirine or pharmaceutically acceptable salts thereof wherein the process includes phase transfer catalyst thereby substantially reducing the overall reaction time cycle, making the process suitable for commercial applications.

Yet another object of the invention is to provide a process for the preparation of rilpivirine or pharmaceutically acceptable salts thereof includes purification of rilpivirine free base with a novel solvent system, thereby minimizing the impurities including unwanted Z-isomer without involving hot filtrations, making the process more suitable for commercial applications. Further object of the invention is to provide a process for the preparation of rilpivirine or pharmaceutically acceptable salts thereof includes purification of rilpivirine free base via formation of novel acid addition salts of rilpivirine free base, thereby minimizing the impurities including unwanted Z-isomer, making the process more suitable for commercial applications.

SUMMARY OF THE INVENTION

The present invention encompasses an improved process for the preparation of rilpivirine or pharmaceutically acceptable salts thereof with high product yield and quality, wherein the improvements comprise use of phase transfer catalysts and purification techniques involving either purification of rilpivirine free base in one or more solvents or formation of acid addition salts of rilpivirine free base, thereby process more convenient and economical, particularly on commercial scale.

In one embodiment, the present invention provides a process for the preparation of rilpivirine or pharmaceutically acceptable salts thereof of Formula I, comprising:

Formula I

reacting 3-(4-amino-3,5-dimethyl phenyl)-acrylonitrile of Formula II either in free base or a salt thereof

Formula II

with 4-(4-chloropyrimidin-2-ylamino) benzonitrile of Formula III

Formula III

in presence of a phase transfer catalyst optionally in an organic solvent to obtain rilpivirine or a salt thereof.

In a second embodiment, the present invention provides an improved process for the preparation of rilpivirine or pharmaceutically acceptable salts thereof, comprising:

a) reacting 3-(4-amino-3,5-dimethyl phenyl)-acrylonitrile of Formula II either in free base or a salt thereof with 4-(4-chloropyrimidin-2-ylamino) benzonitrile of Formula III in presence of a phase transfer catalyst optionally in an organic solvent to obtain rilpivirine or a salt thereof;

b) optionally treating the rilpivirine or a salt thereof with a base to obtain rilpivirine base;

c) purifying the crude rilpivirine base in one or more solvents to obtain pure rilpivirine base; and

d) converting pure rilpivirine base into its pharmaceutically acceptable salts thereof. wherein one or more solvent includes but is not limited to alcohols, dipolar aprotic solvents, halogenated solvents, ketones, nitriles, water or mixtures thereof.

In a third embodiment, the present invention provides an improved process for the purification of rilpivirine or pharmaceutically acceptable salts thereof substantially free of its Z-isomer, comprising:

a) combining rilpivirine base in one or more solvents at ambient temperature to about reflux,

b) stirring the reaction mass for about 10 minutes to about 8 hours,

c) cooling the reaction mass to room temperature,

d) isolationg pure rilpivirine base; and

e) converting the pure rilpivirine base into its pharmaceutically acceptable salts thereof;

wherein the one or more solvent includes but is not limited to alcohols, dipolar aprotic solvents, halogenated solvents, ketones, nitriles, water or mixtures thereof.

In a fourth embodiment, the present invention provides an improved process for the preparation of rilpivirine or pharmaceutically acceptable salts thereof, comprising the steps of:

a) reacting 3-(4-amino-3,5-dimethyl phenyl)-acrylonitrile of Formula II either in free base or a salt thereof with 4-(4-chloropyrimidin-2-ylamino) benzonitrile of Formula III in presence of a phase transfer catalyst optionally in an organic solvent to obtain rilpivirine or a salt thereof,

b) optionally treating the rilpivirine or a salt thereof with a base to obtain rilpivirine base,

c) treating the rilpivirine base with an acid to obtain an acid addition salt of rilpivirine, d) converting the rilpivirine acid addition salt into its pharmaceutically acceptable salt thereof. In a fifth embodiment, the present invention provides an improved process for the preparation of rilpivirine or pharmaceutically acceptable salts thereof; preferably hydrochloride salt, comprising the steps of:

c) treating the rilpivirine base with an acid to obtain an acid addition salt of rilpivirine,

d) converting the rilpivirine acid addition salt into rilpivirine hydrochloride salt. wherein the acid is either an organic acid or an inorganic acid; preferably the acid is an organic acid and is selected form any organic acid that forms an acid addition salt with rilpivirine. Preferably the organic acid include but is not limited to oxalic acid, citric acid, tartaric acid, salicylic acid, glycolic acid, methane sulfonic acid, lactic acid, mandelic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid and the like.

In a sixth embodiment, the present invention provides an improved process for the purification of rilpivirine or pharmaceutically acceptable salts thereof substantially free of its Z-isomer, comprising: a) treating crude rilpivirine base with an acid to obtain an acid addition salt of rilpivirine and b) converting the rilpivirine acid addition salt into rilpivirine or pharmaceutically acceptable salts thereof;

wherein the acid is either an organic acid or an inorganic acid; preferably the acid is an organic acid and is selected form any organic acid that forms an acid addition salt with rilpivirine. Preferably the organic acid include but is not limited to oxalic acid, citric acid, tartaric acid, salicylic acid, glycolic acid, methane sulfonic acid, lactic acid, mandelic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid and the like.

In a seventh embodiment, the present invention provides rilpivirine acid addition salts, wherein the acid addition salts are selected from the group consisting of oxalic acid, citric acid, tartaric acid, salicylic acid, glycolic acid, methane sulfonic acid, lactic acid, mandelic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid and the like.

In an eighth embodiment, the present invention provides rilpivirine or pharmaceutically acceptable salts thereof having purity greater than about 99.5% by HPLC.

In a ninth embodiment, the present invention provides rilpivirine or pharmaceutically acceptable salts thereof substantially free of its Z-isomer.

In a tenth embodiment, the present invention provides rilpivirine or pharmaceutically acceptable salts thereof substantially free of a compound of Formula II, a compound of Formula III and an acid compound of Formula IV. In an eleventh embodiment, the present invention provides pharmaceutical composition comprising rilpivirine or pharmaceutically acceptable salts thereof prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention. Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of rilpivinne citrate salt as obtained in Example 7.

Figure 2 is the characteristic powder X-ray diffraction (XRD) pattern of rilpivirine oxalate salt as obtained in Example 9.

Figure 3 is the characteristic powder X-ray diffraction (XRD) pattern of rilpivirine tartrate salt as obtained in Example 11. Figure 4 is the characteristic powder X-ray diffraction (XRD) pattern of rilpivirine mesylate salt as obtained in Example 11.

Figure 5 is the characteristic powder X-ray diffraction (XRD) pattern of rilpivirine salicylate salt as obtained in Example 11.

Figure 6 is the characteristic powder X-ray diffraction (XRD) pattern of rilpivirine glycolate salt as obtained in Example 11.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of rilpivirine or pharmaceutically acceptable salts thereof with high product yield and quality. In particular, the present invention provides a process to prepare rilpivirine hydrochloride wherein the process includes the use of phase transfer catalysts in the coupling reaction of Formula II and Formula III and/or purification techniques involving either purification of Rilpivirine free base in one or more solvents or formation of novel acid addition salts of rilpivirine, which avoids high temperature reactions for prolonged period of time and also avoids multiple purifications with large excess of organic solvents, thereby process more convenient and economical, particularly on commercial scale.

Formula I

Formula II

with 4-(4-chloropyrimidin-2-ylamino) benzonitrile of Formula III

Formula III

In another embodiment, the present invention provides an improved process for the preparation of rilpivirine or pharmaceutically acceptable salts thereof, comprising:

d) converting pure rilpivirine base into its pharmaceutically acceptable salts thereof, wherein one or more solvent includes but is not limited to alcohols, dipolar aprotic solvents, halogenated solvents, ketones, nitriles, water or mixtures thereof.

In another embodiment, the present invention provides an improved process for the preparation of rilpivirine or pharmaceutically acceptable salts thereof, comprising the steps of:

c) treating the rilpivirine base with an acid to obtain an acid addition salt of rilpivirine, d) converting the rilpivirine acid addition salt into its pharmaceutically acceptable salt thereof. wherein the acid is either an organic acid or an inorganic acid; preferably the acid is an organic acid and is selected form any organic acid that forms an acid addition salt with rilpivirine. Preferably the organic acid include but is not limited to oxalic acid, citric acid, tartaric acid, salicylic acid, glycolic acid, methane sulfonic acid, lactic acid, mandelic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid and the like.

The compounds of Formula II and Formula III are known in the art and can be produced by methods known and recognized by the organic chemist of ordinary skill in the art. For example, such a process is described in U.S. Patent No. 7,125,879 which is included by reference herein in its entirety.

The '879 patent disclose coupling reaction of Formula II and Formula III are carried at higher temperatures of about 150°C and/or for a period of about 69 hours. The prolonged period of reaction leads to an increase in the manufacturing cycle time and formation of unwanted reaction impurities. To overcome the difficulties associated with the processes described above, the inventors of the present invention have surprisingly found that use of phase transfer catalyst may reduce the coupling reaction time cycle, for instance from about 69 hours to about 16 hours, and improves the purity of the product and reduce the formation of Z-isomer as well.

Step a) of coupling reaction of Formula II and Formula III involves at least one phase transfer catalyst. Typically, the reaction comprises mixing Formula II and Formula III in the presence of at least one phase transfer catalyst in an organic solvent to form a reaction mixture; heating the reaction mixture to about ambient temperature to about reflux for a sufficient amount of time to effect the reaction; and isolating the product.

The Formula II can be taken as either in free base or a salt thereof, the salt may be any organic acid or inorganic acid that forms an acid addition salt with Formula II, preferably the Formula II is used as its hydrochloride salt form.

The phase transfer catalyst may be present in an amount of about 0.05 to about 1 mol equivalents to Formula III, and is preferably present in an amount of about 0.1 to about 0.5 mol equivalents to Formula III. Several classes of compounds are known to be capable of acting as phase transfer catalysts, for example quaternary ammonium compounds and phosphonium compounds, to mention just two. Phase transfer catalysts include, but are not limited to, at least one of tetramethyl ammoniumbromide, tetramethyl ammonium iodide, tetrabutylammonium bromide, tetrabutylammoniumchloride, tetrabutylammoniumiodide, tetrabutyl ammonium tribromide, tetrabutylammonium acetate, tetrabutylammonium fluoride, tetrabutylammonium hydroxide, tetrabutylphosphonium bromide, tetramethyl ammonium chloride, tetraethylammonium chloride, methyl triethylammonium bromide, tetrabutylammonium hydrogensulfate, tricaprylylmethylammonium chloride, benzyl trimethylammonium bromide, benzyltriethylammonium bromide, benzyltrimethyl ammonium chloride, benzyltriethylammonium chloride, cetyltrimethylammonium bromide, cetylpyridinium bromide, N-benzylquininium chloride, benzyltributyl ammonium bromide, benzyltriethylammonium bromide, hexadecyltriethylammonium chloride, hexadecyltrimethyl ammonium chloride, or octyltrimethylammonium chloride. The phase transfer catalysts are either-commercially available or readily synthesized by one of ordinary skill in the art. For example tricaprylylmethylammonium chloride, commonly known as Aliquat-336, is manufactured by Aldrich Chemical Company, Inc. Milwaukee, Wis.

Preferably, the phase transfer catalyst includes, but is not limited to, at least one of tetra butyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium chloride, tetra butyl ammonium tribromide, tetra butyl phosphonium bromide, triethylbenzyl ammonium chloride, tetra methyl ammonium iodide, tetra butyl ammonium acetate, Aliquat-336 or tetra butyl ammonium fluoride.

The organic solvent for step a) includes but are not limited to an alcohols such as C alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like; nitriles such as acetonitrile, propionitrile and the like; dipolar aprotic solvents such as dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-methyl- pyrrolidinone and the like; and mixtures thereof; preferably acetonitrile.

The reaction temperature should be sufficient to effect coupling reaction. Typically the reaction temperature may be from about ambient temperature to about reflux temperature. Preferably the reaction temperature is about 40°C to about 85°C. The reaction may take from about 2 hours to about 36 hours depending upon the phase transfer catalyst, solvent and temperature chosen, preferably about 16 hours. Then, the resultant reaction mass may be evaporated to obtain the crude rilpivirine as salt, preferably hydrochloride salt, which may be treated with another solvent at a temperature of about 35°C to about reflux temperature. The crude rilpivirine hydrochloride mixture may be cooled to about 30°C and separated by filtration from the reaction mixture.

The another solvent includes but is not limited to C_1-4 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like; nitriles such as acetonitrile, propionitrile and the like; dipolar aprotic solvents such as dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-methyl-pyrrolidinone and the like; and mixtures thereof; preferably methanol, ethanol, isopropaol, acetonitrile, and the like and mixtures thereof; more preferably methanol. Then, the resultant crude rilpivirine hydrochloride obtained from step a) treated with a base such as aqueous potassium carbonate solution at a temperature of about ambient temperature to about reflux for about 3 to 6 hours to obtain rilpivirine base. The resulting rilpivirine base as crude, obtained by the aforementioned process, may have a chemical purity of at least about 97%, as measured by HPLC and about 1-3 % of Z-isomer, as measured by HPLC.

In another embodiment, the present invention provides an improved process for the preparation of rilpivirine or pharmaceutically acceptable salts thereof, comprising purifying the rilpivirine free base as obtained by the process described above or may be obtained by any known process, as a starting material or as an intermediate in one or more solvents to obtain pure rilpivirine base and converting the pure rilpivirine base into pharmaceutically acceptable salts thereof, preferably hydrochloride salt may have a purity equal to or greater than about 99.5% as determined by HPLC and substantially free of rilpivirine Z-isomer.

In another embodiment, the present invention provides an improved process for the purification of rilpivirine or pharmaceutically acceptable salts thereof substantially free of its Z-isomer, comprising:

a) combining any form of rilpivirine base or obtained by the process as described above in one or more solvents at ambient temperature to about reflux,

b) stirring the reaction mass for about 10 minutes to about 8 hours,

c) cooling the reaction mass to room temperature,

d) isolationg pure rilpivirine base; and

e) converting the pure rilpivirine base into its pharmaceutically acceptable salts thereof.

The one or more solvent includes but is not limited to an alcohols such as C_1-4 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like; dipolar aprotic solvents such as dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-methyl-pyrrolidinone, hexamethyl phosphoramide and the like; halogenated solvents such as methylene chloride, ethylene chloride, chloroform and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; water or mixtures thereof.

Preferably, the one or more solvent is selected from the group comprising methanol, ethanol, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-methyl- pyrrolidinone, water and mixtures thereof.

The temperature suitable for combining rilpivirine base in one or more solvents is about ambient temperature to about reflux; preferably about 60°C to 95°C. After sufficient period of stirring the reaction mass, preferably about 30 minutes, cooling the reaction mass to room temperature; preferably about 25°C and stirring the cooled mass for about 10 minutes to about 2 hours, preferably for about 30 minutes and isolating the thus obtained solids by methods known in the art, for example filtration and followed by step of optionally drying.

The resulting rilpivirine base, obtained by the aforementioned process, may have a chemical purity of at least about 99%, as measured by HPLC and less than about 0.2% of Z-isomer, as measured by HPLC.

The step e) of conversion of the pure rilpivirine base as obtained just as above into its pharmaceutically acceptable salts thereof; preferably hydrochloride salt further comprises:

i. providing a solution of rilpivirine base in a first solvent,

ii. optionally treating the resultant solution with charcoal,

iii. adding a second solvent to the resultant solution,

iv. co-distilling the first solvent from the solution and adding hydrochloric acid, v. adding an anti-solvent to precipitate the rilpivirine hydrochloride,

vi. isolating the rilpivirine hydrochloride salt.

The first solvent includes, but is not limited to acetic acid, acetone and the like and mixtures thereof, preferably acetone. The second solvent includes, but is not limited to acetic acid, Ν,Ν-dimethyl formamide, Ν,Ν-dimethyl acetamide, N-methylpyrrolidone and the like and mixtures thereof; preferably acetic acid.

The step i) of the foregoing process includes providing a solution of rilpivirine base includes dissolving pure rilpivirine base in a first solvent such as acetone, clarifying the obtained solution to remove colored and other suspended particles by treatment with charcoal at a temperature of about 35°C to about 70°C, and for a time ranging from about 30 mins to about 60 mins; preferably about 30mins.

The step iii) and iv) of the foregoing process includes adding a second solvent such as acetic acid and co-distilling the first solvent under vacuum thereby forming a solution of rilpivirine free base in a second solvent i.e. acetic acid.

Further, addition of hydrochloric acid may be in the form of an aqueous, anhydrous, gas form, for example aqueous hydrochloric acid or solvent containing hydrochloric acid or hydrochloric acid gas; preferably aqueous hydrochloric acid. The resultant rilpivirine hydrochloride can be isolated by conventional techniques such as solvent precipitation, solvent crystallization and the like; preferably solvent precipitation by adding an anti solvent such as water and separating the nlpivirine hydrochloride by methods known in the art, for example filtration.

The rilpivirine hydrochloride salt obtained by the process as described above may have a chemical purity of at least about 99.8%, as measured by HPLC and less than about 0.1% of Z-isomer, as measured by HPLC, preferably less than about 0.05% as measured by HPLC.

In another embodiment, the present invention provides an improved process for the preparation of rilpivirine or pharmaceutically acceptable salts thereof, comprising providing crude rilpivirine free base as obtained by the process described above or may be obtained by any known process, as a starting material or as an intermediate, and which may be converted into rilpivirine or pharmaceutically acceptable salts thereof through formation of rilpivirine acid addition salts of the invention, where the yield and the purity of the pharmaceutically acceptable salts thereof, preferably hydrochloride salt may have a purity equal to or greater than about 99.8% as determined by HPLC and substantially free of rilpivirine Z-isomer.

a) treating the crude rilpivirine base obtained by the process described above with an acid to obtain an acid addition salt of rilpivirine and

b) converting the rilpivirine acid addition salt into rilpivirine or pharmaceutically acceptable salts thereof.

The acid is either an organic acid or an inorganic acid; preferably the acid is an organic acid and is selected form any organic acid that forms an acid addition salt with rilpivirine. Preferably the organic acid include but is not limited to oxalic acid, citric acid, tartaric acid, salicylic acid, glycolic acid, methane sulfonic acid, lactic acid, mandelic acid, p-coumaric acid, ferulic acid, sinapic acid, caffeic acid and the like.

Treating rilpivirine free base with an acid of step a) further comprises providing a rilpivirine free base in a suitable medium and heating the mixture of the free base and acid at ambient temperature to about reflux; preferably at about 60°C to about 95°C. The suitable medium includes but is not limited to acetic acid, Ν,Ν-dimethyl formamide, Ν,Ν-dimethyl acetamide, N-methylpyrrolidone and the like; preferably acetic acid. Then, treating the resultant mixture with an acid followed by addition of an anti- solvent, for example water to the resultant mixture of rilpivirine base and an acid to precipitate the corresponding acid addition salt of rilpivirine. The reaction mixture may be optionally cooled and then, isolating the corresponding rilpivirine acid addition salt by conventional techniques, for example filtration, followed by optional step of drying the wet compound.

In another embodiment, the rilpivinne acid addition salt thus obtained may be optionally purified to obtain the rilpivirine acid addition salt substantially free of its Z-isomer. The purification of rilpivirine acid addition salts may be carried out by treating the rilpivirine acid addition salt with a suitable solvent. The suitable solvent may be include but is not limited acetic acid, Ν,Ν-dimethyl formamide, Ν,Ν-dimethyl acetamide, N- methylpyrrolidone; preferably acetic acid at ambient temperature to about reflux; preferably about 60°C to about 95 °C and precipitating the solid rilpivirine acid addition salt by decreasing the reaction mass temperature or adding an antisolvent, preferably adding an antisolvent such as water and isolating the rilpivirine acid addition salt by conventional techniques, for example filtration. The rilpivirine acid addition salts obtained by the process as described above may have a chemical purity of at least about 99.8%, as measured by HPLC and less than about 0.1% of Z-isomer, as measured by HPLC, preferably less than about 0.05% as measured by HPLC. The resultant rilpivirine acid addition salts of the invention can be converted into rilpivirine or pharmaceutically acceptable salts thereof; preferably hydrochloride salt by neutralizing the rilpivirine acid addition salts as obtained by the process described above with a suitable base such as sodium hydroxide, sodium carbonate, potassium carbonate and the like; preferably potassium carbonate to obtain rilpivirine free base, which is further converted into rilpivirine pharmaceutically acceptable salt form; preferably hydrochloride salt by process as described above.

The rilpivirine hydrochloride salt obtained by the process through rilpivirine acid addition salts as intermediate may have a chemical purity of at least about 99.8%, as measured by HPLC and less than about 0.1% of Z-isomer, as measured by HPLC, preferably less than about 0.05% as measured by HPLC.

The present invention provides a rilpivirine hydrochloride, obtained by the process described herein, having a chemical purity of at least about 98%, as measured by HPLC, preferably at least about 99%, as measured by HPLC, and more preferably at least about 99.8%, as measured by HPLC; substantially free of 4-[[4-[[4-[(Z)-2-cyanoethenyl]-2,6- dimethylphenyl]amino]2-pyrimidinyl]amino]benzonitrile (rilpivirine Z-isomer); and substantially free of one or more of a compound of Formula II, a compound of Formula III or an acid compound of Formula IV.

Rilpivirine Z-isomer

Formula IV

wherein the word "substantially free" refers to rilpivirine or its hydrochloride salt having less than about 0.1%, of rilpivirine Z-isomer or Formula II or Formula III or Formula IV, as measured by HPLC, more preferably less than about 0.05% of rilpivirine Z- isomer or Formula II or Formula III or Formula IV as measured by HPLC.

The '879 patent disclose coupling reaction of Formula II and Formula III is carried out at higher temperatures of about 150°C and/or for a period of about 69 hours, results rilpivirine contain substantial amounts of Z-isomer. In contrast, the process herein described, arrives at a rilpivirine, which may be involved a phase transfer catalyst to improve the rate of the reaction accordingly reaction time is greatly reduced and also involved novel rilpivirine acid addition salts thereby selectively minimize the content of Z-isomer. The process herein described also avoids precarious hot filtration, which is critical in the large scale operations. Particularly, the process herein described allows that a rilpivirine may be prepared substantially lower level of Z-isomer.

The '856 patent disclose coupling reaction of Formula II and Formula III is carried out for 24 hours in acetonitrile solvent at reflux. Even though the '856 patent disclosed shorter reaction time compared to the '879 patent, but no disclosure about purity and impurities of rilpivirine obtained by the process.

A comparative preparation of rilpivirine using the '879 and the '856 patent processes, yielded a rilpivirine, that had low purity levels than the present process. Further these processes yielded a final product that contained substantial amounts of residual Formula II, Formula III or Formula IV. These results are summarized in Table III and Table IV, as shown below under Examples 12 and 13 where values are reported as weight percent (w/w%) as determined by HPLC.

In another embodiment, the present invention provides rilpivirine acid addition salts, wherein the acid addition salts are selected from either organic acid or an inorganic acid. The acid may be selected from the group consisting of oxalic acid, citric acid, tartaric acid, salicylic acid, glycolic acid, methane sulfonic acid, lactic acid, mandelic acid, p- coumaric acid, ferulic acid, sinapic acid, caffeic acid and the like.

In another embodiment, the rilpivirine acid addition salt recovered using the process of the present invention is rilpivirine citrate salt.

In another embodiment, the present invention provides rilpivirine citarte salt.

In another embodiment, the present invention provides rilpivirine citrate salt characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 1.

In another embodiment, the rilpivirine acid addition salt recovered using the process of the present invention is rilpivirine oxalate salt.

In another embodiment, the present invention provides rilpivirine oxalate salt.

In another embodiment, the present invention provides rilpivirine oxalate salt characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 2.

In another embodiment, the rilpivirine acid addition salt recovered using the process of the present invention is rilpivirine tartrate salt. In another embodiment, the present invention provides rilpivirine tartrate salt.

In another embodiment, the present invention provides rilpivirine tartrate salt characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 3.

In another embodiment, the rilpivirine acid addition salt recovered using the process of the present invention is rilpivirine mesylate salt.

In another embodiment, the present invention provides rilpivirine mesylate salt.

In another embodiment, the present invention provides rilpivirine mesylate salt characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 4. In another embodiment, the rilpivirine acid addition salt recovered using the process of the present invention is rilpivirine salicylate salt.

In another embodiment, the present invention provides rilpivirine salicylate salt. In another embodiment, the present invention provides rilpivirine salicylate salt characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 5.

In another embodiment, the rilpivirine acid addition salt recovered using the process of the present invention is rilpivirine glycolate salt.

In another embodiment, the present invention provides rilpivirine glycolate salt.

In another embodiment, the present invention provides rilpivirine glycolate salt characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 6. In another embodiment, the rilpivirine acid addition salt recovered using the process of the present invention is rilpivirine ferulate salt.

In another embodiment, the present invention provides rilpivirine ferulate salt. In another embodiment, the rilpivirine acid addition salt recovered using the process of the present invention is rilpivirine L(+)-mandelate salt.

In another embodiment, the present invention provides rilpivirine L(+)-mandelate salt. In another embodiment, the rilpivirine acid addition salt recovered using the process of the present invention is rilpivirine D(-)-mandelate salt.

In another embodiment, the present invention provides rilpivirine D(-)-mandelate salt.

In another embodiment, the rilpivirine acid addition salt recovered using the process of the present invention is rilpivirine lactate salt.

In another embodiment, the present invention provides rilpivirine lactate salt.

The present invention provides rilpivirine or its hydrochloride salt, obtained by the above process, as analyzed using the high performance liquid chromatography ("HPLC") with the conditions described below:

Column : Symmetry shield, RP-18, 5 μπι

Column temperature : 30°C

Diluent : methanol : water (9:1) v/v

Flow rate : 10 mL/min

Detection wavelength : 300nm

Injection volume : ΙΟμΙ, Mobile phase:

A) methanol: buffer (8:2 v/v)

B) methanol: buffer (2:8 v/v)

Buffer: Sodium dihydrogen phosphate dihydrate in water at pH to 6.0 with o-phosphoric acid.

Gradient program

The present invention provides rilpivirine or its hydrochloride salt, obtained by the above process, as analyzed using the X-Ray powder diffraction with the conditions described as follows: an X-ray powder Diffractometer equipped with a Cu-anode ([λ] =1.54 Angstrom), X-ray source operated at 30kV, 15 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°20; step width=0.020°; and scan speed=2°/minute.

Another embodiment of the present invention is directed to a pharmaceutical composition containing at least the substantially pure rilpivirine or its hydrochloride salt disclosed herein and at least one pharmaceutically acceptable excipient. Such pharmaceutical composition may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc.

In one embodiment, the rilpvirine or its hydrochloride salt disclosed herein for use in the pharmaceutical compositions of the present invention can have a D₅o and D₉₀ particle size of less than about 400 microns, preferably less than about 200 microns, more preferably less than about 150 microns, still more preferably less than about 50 microns and most preferably less than about 15 microns. The particle sizes of the rilpvirine or its hydrochloride salt prepared according to the present invention can be obtained by any milling, grinding, micronizing, or other particle size reduction method known in the art to bring the solid state rilpvirine or its hydrochloride salt into any of the desired particle size range. EXAMPLES

The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

EXAMPLE 1

Preparation of Rilpivirine hydrochloride (crude) using tetra butyl ammonium acetate as Phase transfer catalyst.

A I L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was purged with N₂. The flask was charged 3-(4-amino-3,5-dimethyl phenyl)- acrylonitrile hydrochloride of Formula II (28.9 gms), 4-[(4-chloropyrimidin-2-yl) amino] benzonitrile of Formula III (20 gms), tetra butyl ammonium acetate (13 gms) and acetonitrile (360 ml). The reaction temperature was raised to reflux and maintained for 16 hours and product formation was monitored by HPLC (product: 81%, Z- isomer: 10%). Acetonitrile was distilled completely under reduced pressure at below 50°C and the obtained residue was charged methanol (100 ml) and the reaction temperature was raised to reflux and maintained for about 30 minutes. The reaction mixture was allowed to cool to 35°C and stirred for about 60 minutes at 25°C to 35°C. Precipitated solid was filtered and washed with methanol (20 ml). The wet product was dried at about 50°C to about 55°C under reduced pressure to provide the title compound as crude.

Yield: 29 gms.

HPLC purity: 96.21%,

Z-isomer: 3.06%, Formula II: 0.20%, Formula III: 0.13%, Formula IV: 0.12%

EXAMPLE 2

Preparation of Rilpivirine hydrochloride (crude) using Aliquat 336

A I L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was purged with N₂. The flask was charged 3-(4-amino-3,5-dimethyl phenyl)- acrylonitrile hydrochloride of Formula II (2.9 gms), 4-[(4-chloropyrimidin-2-yl) amino] benzonitrile of Formula III (2 gms), Aliquat 336 (1.75 gms) and acetonitrile (36 ml). The reaction temperature was raised to reflux and maintained for about 16 hours and product formation was monitored by HPLC (product: 76.4%, Z-isomer 9.74%). Acetonitrile was distilled completely under reduced pressure at below 50°C and the obtained residue was charged methanol (10 ml) and the reaction temperature was raised to reflux and maintained for about 30 minutes. The reaction mixture was allowed to cool to 35°C and stirred for about 60 minutes at 25°C to 35°C. Precipitated solid was filtered and washed with methanol (2 ml). The wet product was dried at about 50°C to about 55°C under reduced pressure to provide the title compound as crude.

Yield: 3 gms.

HPLC purity: 95.41%

Z-isomer: 3.02%, Formula II: 0.43%, Formula III: 0.06%, Formula IV: 0.52%

EXAMPLE 3

Preparation of Rilpivirine hydrochloride (crude) from 2 gms of Formula III using a procedure analogous to that employed in Example 2, using different phase transfer catalysts as described in the following Table I:

Table I:

EXAMPLE 4

Preparation of Rilpivirine free base

A I L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was purged with N₂. The flask was charged rilpivirine hydrochloride crude, obtained from Example 1 (23 gms), 10% aqueous potassium carbonate solution (21.09 gms of potassium carbonate was dissolved in 208.90 ml of water). The reaction mixture was stirred for 3 hours at room temperature and filtered and washed with water (50 ml). The wet product was dried at about 50°C to about 55°C under reduced pressure to provide the title compound.

Yield: 18.6 gms

HPLC Purity: 95.77% Z-isomer: 2.82%, Formula II: 0.03%, Formula III: 0.04%, Formula IV: 0.08%

EXAMPLE 5

Purification of Rilpivirine free base

A I L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was purged with N₂. The flask was charged rilpivirine free base, obtained from Example 4 (20.0 gms) and N-methylpyrrolidone, ethanol and DM water mixture (100 ml) in the ratio of 3:5:2. The reaction temperature was raised to 80°C to 85°C and maintained for 30 min. The reaction mixture was allowed to cool to 25°C to 35°C and stirred for 1 hour. Precipitated solid was filtered and washed with N-methylpyrrolidone, ethanol and DM water mixture (40 ml) in the ratio of 3:5:2. The product was dried at about 80°C to provide the title compound.

Yield: 17.4 gms

HPLC Purity: 99.74%

Z-isomer: 0.15%, Formula II: Not detected, Formula III: Not detected, Formula IV: Not detected

Purification of rilpivirine free base using a procedure analogous to that employed in Example 5, using different solvents as described in the following Table:

EXAMPLE 6

Preparation of Rilpivirine hydrochloride.

A I L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was purged with N₂. The flask was charged pure rilpivirine base, obtained from Example 5 (15.0 gms) in acetone (450 ml). The reaction mass was raised at a temperature of about 55°C to get a clear solution and filtered to obtain reaction mass. The resulting reaction mass was charged acetic acid (120 ml) and distilled out acetone under vaccum till ~7V acetic acid remains in the flask. The reaction mass was Heated to about 65°C. Aqueous hydrochloric acid (4.05 ml) was added at 65°C and then water (120 ml) was added. The reaction mixture was allowed to cool to 25 °C to 35°C and stirred for 1 hour. Precipitated solid was filtered and washed with water (30 ml). The wet product was dried at about 50°C under vaccume to provide the title compound.

Yield: 15.0 gms

HPLC Purity: 99.95%

Z-isomer: 0.02%, Formula II: Not detected, Formula III: Not detected, Formula IV: Not detected

EXAMPLE 7

Preparation of Rilpivirine citrate salt. A I L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was purged with N₂. The flask was charged rilpivirine free base, obtained from Example 4 (6 gms) and acetic acid (33 ml). The reaction temperature was raised to 90°C to 95°C and citric acid (4.2 gms) was added at same temperature. The reaction mixture was stirred for 10 minutes and water (33 ml) was added at temperature 65°C to 70°C. The reaction mixture was allowed to cool to 25°C to 35°C and stirred for 1 hour. Precipitated solid was filtered and washed with water (8 ml). The wet product was dried at about 60°C to about 65°C under reduced pressure to provide the rilpivirine citrate salt (Yield: 6.6 gms). The dry compound was taken in a 1 L round bottom flask and was charged acetic acid (24 ml). Heated to about 85°C and stirred for 30 minutes. The reaction mixture was allowed to cool to 25°C to 35°C and stirred for 1 hour. Precipitated solid was filtered and washed with water (90 ml). The wet product was dried at about 60°C to about 65°C under reduced pressure to provide the title compound.

Yield: 3.4 gms

HPLC Purity: 99.64%

Z-isomer: 0.09%, Formula II: Not detected, Formula III: Not detected, Formula IV: Not detected

The XRPD is set forth in Fig. 01

EXAMPLE 8

Preparation of Rilpivirine hydrochloride.

A I L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was purged with N₂. The flask was charged rilpivirine citrate salt, obtained from Example 7 (3 gms), 30 ml of 10% aqueous potassium carbonate solution (2.73 gms of potassium carbonate was dissolved in 27.3 ml of water). The reaction mixture was stirred for 3 hours at room temperature and filtered and washed with water (6 ml). The wet product was dried at about 50°C to about 55°C under reduced pressure to provide rilpivirine base (Yield: 2 gm). The dry compound was taken in a round bottom flask and was charged acetic acid (10 ml). Heated to about 85°C and stirred for 20 minutes. Aqueous hydrochloric acid (0.6 ml) was added at 85°C and then water (12 ml) was added. The reaction mixture was allowed to cool to 25°C to 35°C and stirred for 1 hour. Precipitated solid was filtered and washed with water (2 ml). The wet product was dried at about 60°C to about 65°C under reduced pressure to provide the title compound.

Yield: 2.1 gms

HPLC Purity: 99.93%

Z-isomer: 0.06%, Formula II: Not detected, Formula III: Not detected, Formula IV: Not detected

EXAMPLE 9

Preparation of Rilpivirine oxalate salt.

A I L round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was purged with N₂. The flask was charged rilpivirine free base, obtained from Example 4 (3 gms) and acetic acid (16.5 ml). The reaction temperature was raised to 90°C to 95°C and oxalic acid (0.87 gms) was added at same temperature. The reaction mixture was stirred for 10 minutes and water (16.5 ml) was added at temperature 65°C to 70°C. The reaction mixture was allowed to cool to 25°C to 35°C and stirred for 1 hour. Precipitated solid was filtered and washed with water (4 ml). The wet product was dried at about 60°C to about 65°C under reduced pressure to provide the title compound. Yield: 3.3 gms.

HPLC Purity: 98.89%

Z-isomer: 0.63%

The XRPD is set forth in Fig. 02 EXAMPLE 10

Preparation of Rilpivirine ferulate salt.

A round bottom flask fitted with a mechanical stirrer, thermometer socket, addition funnel was purged with N₂. The flask was charged rilpivirine free base, obtained from Example 4 (1 gm) and acetic acid (5.5 ml). The reaction temperature was raised to 90°C to 95 °C and ferulic acid (0.61 gms) was added at same temperature. The reaction mixture was stirred for 10 minutes and water (5.5 ml) was added at temperature 65 °C to 70°C. The reaction mixture was allowed to cool to 25°C to 35°C and stirred for 1 hour. Precipitated solid was filtered and washed with water (2 ml). The wet product was dried at about 60°C to about 65 °C under reduced pressure to provide the title compound. Yield: 1.3 gms.

HPLC Purity: 98.95%

Z-isomer: 0.54%

EXAMPLE 11

Preparation of Rilpivirine salts using a procedure analogous to that employed Example 10, using different acid addition salts as described in the following Table II:

Table II:

EXAMPLE 12

Comparative preparation of Rilpivirine according to Example B1A of U.S. Patent No. 7,125,879.

A mixture of 8.7 gms of 3-(4-amino-3,5-dimethyl phenyl)-acrylonitrile hydrochloride of Formula II and 10 gms of 4-[,(4-chloropyrimidin-2-yl) amino] benzonitrile in 160 ml acetonitrile was prepared under nitrogen atmosphere. The mixture was stirred and refluxed for 65 hrs, then allowed to cool to 55°C. The mixture was filtered and the residue was wash with 50 ml of acetonitrile, followed by drying under reduced pressure at 50°C overnight to obtain crude rilpivirine HC1 salt. 12 gms of the obtained solid was brought in 120 ml of K₂C0₃ 10% aqueous solution. The mixture was stirred at room temperature followed by filtration. The obtained residue was washed twice with water followed by drying at 50°C under reduced pressure. The residue was brought in 237 ml isopropanol and the mixture was refluxed for overnight, then allowed to cool to room temperature and filtered. The residue was dried at 50°C under reduced pressure. Yield: 3.9 gms.

Below are measurements using HPLC of rilpivirine prepared as in Example 12, with the process used in the '879 patent in a process for the preparation of rilpivirine. The numerical values (%wt/wt) set forth below in Table III summarize purity and impurity levels after 65 hours reaction maintenance, at crude rilpivirine HCl salt stage, at before IPA purification and at final stage (after IPA purification).

Table III:

EXAMPLE 13

Comparitive preparation of Rilpivirine according to Example Bl (b) of U.S. Patent No. 7,399,856.

A mixture of 9.39, g (0.045mol) of 3-(4-amino-3,5-dimethyl phenyl)-acrylonitrile hydrochloride of Formula II and 10.38 g (0.045mol) of 4-[(4-chloropyrimidin-2-yl) amino] benzonitrile of Formula III in 90 ml acetonitrile was prepared under nitrogen atmosphere. The mixture was stirred and refluxed for 24 hrs, then allowed to cool to 50°C. A solution of potassium carbonate (12.44 gms) in water (45 ml) was added over a period of 20 min at 40°C to 50°C, followed by stirring for 1 hr at 50°C.The precipitate was separated and washed twice with 4.5 ml acetonitrile, followed by drying at 50°C under reduced pressure. Yield: 8.33 gms.

The obtained solid and 40 ml of Ethanol were mixed and refluxed for 2 hrs, then allowed to cool to room temperature. The precipitate was filtered and the residue was washed with 0.5 ml Ethanol. The obtained residue was dried overnight at 50°C under reduced pressure. Yield: 7.5 gms of rilpivirine base.

Below are measurements using HPLC of rilpivirine prepared as in Example 13, with the process used in the '856 patent in a process for the preparation of rilpivirine. The numerical values (%wt/wt) set forth below in Table IV summarize purity and impurity levels after 24 hours reaction maintenance, at crude stage (before ethanol treatment) and at final stage (after ethanol purification).

Table IV:

After 24 hours Rilpivirine base Rilpivirine base maintenance (before ethanol (after ethanol treatment) purification)

Formula II 17.16% 0.26% Not Detected

Formula III 55.21% 78.78% 78.04%

Formula IV 1.46% 0.26% 0.14%

Z-isomer 3.28% 0.42% 0.35%

Rilpivirine 20.46% 19.92% 19.04%

Tables III and IV show that levels of purity and impurities of rilpivirine hydrochloride obtained from the '879 and the '856 patents, in contrast to the process described herein, are lower than levels of purity and higher than the levels of Z-isomer, Formula II, Formula III or Formula TV of rilpivirine hydrochloride, obtained by using a phase transfer catalyst and rilpivirine acid addition salts, as process described herein.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.

Claims

WE CLAIM

Claim 1. A process for the preparation of rilpivirine or pharmaceutically acceptable salts thereof of Formula I, comprising:

Formula I

Formula II with 4-(4-chloropyrimidin-2-ylamino) benzonitrile of Formula III

Formula III in presence of a phase transfer catalyst optionally in an organic solvent to obtain rilpivirine or a salt thereof.

Claim 2: The process of claim 1, wherein the 3-(4-amino-3,5-dimethyl phenyl)- acrylonitrile of Formula II is its hydrochloride salt.

Claim 3: The process of claim 1, wherein the phase transfer catalyst is selected from the group comprising tetra butyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium chloride, tetra butyl ammonium tribromide, tetra butyl phosphonium bromide, triethylbenzyl ammonium chloride, tetra methyl ammonium iodide, tetra butyl ammonium acetate, Aliquat-336 or tetra butyl ammonium fluoride.

Claim 4: The process of claim 1, wherein the organic solvent is selected from the group comprising an alcohols such as C alcohols such as methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol and the like; nitriles such as acetonitrile, propionitrile and the like; dipolar aprotic solvents such as dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidinone and the like; and mixtures thereof. Claim 5: The process of claim 1, wherein the organic solvent is acetonitrile.

Claim 6: The process of claim 1, wherein the resultant rilpivirine or pharmaceutically acceptable salt is rilpivirine hydrochloride. Claim 7: The process of claim 6, further comprising the steps of:

a) treating the rilpivirine hydrochloride with a base to obtain rilpivirine base;

b) purifying the rilpivirine base in one or more solvents to obtain pure rilpivirine base; and

c) converting pure rilpivirine base into its pharmaceutically acceptable salts thereof.

Claim 8: The process of claim 7, wherein the base is potassium carbonate.

Claim 9: The process of claim 7, wherein the one or more solvents are selected from the group comprising alcohols, dipolar aprotic solvents, halogenated solvents, ketones, nitriles, water and mixtures thereof.

Claim 10: The process of claim 9, wherein the one or more solvents are selected from the group comprising methanol, ethanol, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-methyl-pyrrolidinone, water and mixtures thereof.

Claim 11 : The process of claim 7, wherein the pure rilpivirine base is substantially free of its Z-isomer.

Claim 12: A process for purification of rilpivirine free base substantially free of Z- isomer, comprising the steps of: a) combining rilpivirine base in one or more solvents at ambient temperature to about reflux,

b) stirring the reaction mass for about 10 minutes to about 8 hours,

c) cooling the reaction mass to room temperature, and

d) isolationg pure rilpivirine base.

wherein the one or more solvents are selected from the group comprising alcohols, dipolar aprotic solvents, halogenated solvents, ketones, nitriles, water and mixtures thereof. Claim 13: The process of claim 12, wherein the one or more solvents are selected from the group comprising methanol, ethanol, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-methylpyrrolidinone, water and mixtures thereof. Claim 14: The process of claim 12, wherein the one or more solvents are a mixture of N-methylpyrrolidone, ethanol and water.

Claim 15: The process of claim 12, wherein the temperature is about 60°C to 95°C. Claim 16: The process of claim 12, wherein the reaction mass is stirred for about 30 minutes.

Claim 17: The process of claim 12, where in the resultant rilpivirine base contains less than 0.2% of Z-isomer, as measured by HPLC.

Claim 18: A process for the preparation of rilpivirine hydrochloride, comprising: providing a solution of rilpivirine base, obtained from the process, of any of claims 1-17, and converting to rilpivirine hydrochloride using hydrochloric acid. Claim 19: A process for the preparation of rilpivirine hydrochloride, comprising: i. providing a solution of rilpivirine base in a first solvent,

ii. optionally treating the resultant solution with charcoal,

iii. adding a second solvent to the resultant solution,

iv. co-distilling the first solvent from the solution and adding hydrochloric acid, v. adding an anti-solvent to precipitate the rilpivirine hydrochloride, and

vi. isolating the rilpivirine hydrochloride salt.

Claim 20: The process of claim 19, wherein the first solvent is selected from acetic acid, acetone and mixtures thereof.

Claim 21 : The process of claim 19, wherein the first solvent is acetone.

Claim 22: The process of claim 19, wherein the second solvent is selected from the group comprising acetic acid, Ν,Ν-dimethyl formamide, Ν,Ν-dimethyl acetamide, N- methylpyrrolidone and mixtures thereof.

Claim 23: The process of claim 19, wherein the second solvent is acetic acid. Claim 24: The process of claim 19, wherein the hydrochloric acid is in the form of an aqueous, anhydrous, gas form. Claim 25: The process of claim 24, wherein the hydrochloric acid is aqueous hydrochloric acid.

Claim 26: The process of claim 19, wherein the anti-solvent is water,

Claim 27: An improved process for the preparation of rilpivirine hydrochloride salt of Formula I

Formula I

comprising:

a) reacting 3-(4-amino-3,5-dimethyl phenyl)-acrylonitrile of Formula II either free base or a salt thereof

with 4-(4-chloropyrimidin-2-ylamino) benzonitrile of Formula III

Formula III

in presence of a phase transfer catalyst optionally in an organic solvent to obtain rilpivirine or a salt thereof;

d) converting pure rilpivirine base into its hydrochloride salt.

wherein one or more solvent includes but is not limited to alcohols, dipolar aprotic solvents, halogenated solvents, ketones, nitriles, water or mixtures thereof.

Claim 28: The process of claim 27, wherein the phase transfer catalyst is selected from the group comprising tetra butyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium chloride, tetra butyl ammonium tribromide, tetra butyl phosphonium bromide, triethylbenzyl ammonium chloride, tetra methyl ammonium iodide, tetra butyl ammonium acetate, Aliquat-336 or tetra butyl ammonium fluoride.

Claim 29: The process of claim 27, wherein the organic solvent is acetonitrile.

Claim 30: The process of claim 27, wherein the one or more solvents are selected from the group comprising methanol, ethanol, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-methyl-pyrrolidinone, water and mixtures thereof. Claim 31 : The process of claim 27, wherein the one or more solvents are a mixture of N-methylpyrrolidone, ethanol and water.

Claim 32: Rilpivirine hydrochloride having a chemical purity greater than or equal to about 99.8% as measured by HPLC.

Claim 33: Rilpivirine hydrochloride having less than about 0.1% as measured by HPLC of Z-isomer.

Claim 34: Rilpivirine hydrochloride substantially free of 3 -(4-amino-3, 5 -dimethyl phenyl)-acrylonitrile of Formula II, 4-(4-chloropyrimidin-2-ylamino) benzonitrile of Formula III and a compound of Formula IV.