Claims:We claim:

1. A process for the preparation of Rilpivirine and its pharmaceutically acceptable salts comprising, reacting the compound of formula (IV) with a compound of formula (III) or salt thereof.

wherein R is sulfonyl group.

2. The process of claim 1, further comprising, purifying the compound of formula (I) by treating with an acid and then with base.

3. A Novel intermediate compound of formula (IV).

wherein R is sulfonyl group.

4. A process for the preparation of compound of formula (IV), comprising,
a) condensation of formula (VI) and compound of formula (VII) to obtain compound of formula (V);

b) optionally purifying the compound of formula (V);
c) reacting the compound of formula (V) with reagent “Z” to obtain compound of formula (IV);

wherein Z is RX or R-O-R; R is sulfonyl group; X is halogen.

5. The process according to claim 1, 3 and 4, wherein the sulfonyl group is selected from the group comprising of p-toluene sulfonyl, p-nitrobenzene sulfonyl, benzenesulfonyl, methane sulfonyl, trifluoromethane sulfonyl and 2,4-difluoro benzene sulfonyl.

6. The process according to claim 1 and 2, wherein the acid is selected from the group comprising of hydrochloric acid, sulfuric acid, acetic acid, formic acid, propionic acid, methane sulfonic acid, p-toluene sulfonic acid and triflic acid.

7. The process according to claim 2, wherein the base is selected from the group comprising of ammonium hydroxide, potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide.

8. A process for the preparation of crystalline Rilpivirine hydrochloride Form-A, comprising,
a) treating the Rilpivirine with hydrochloric acid;
b) optionally treating with an acid; and
c) isolating crystalline Rilpivirine hydrochloride Form-A.

9. The process according to claim 8, wherein acid used in step b) is selected from acetic acid, propionic acid and formic acid.
, Description:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Rilpivirine and its pharmaceutically acceptable salts thereof. The present invention further relates to novel intermediate of Rilpivirine and its preparation.

BACK GROUND OF THE INVENTION

Rilpivirine, which is chemically known as 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile, is represented by the formula (I).

Rilpivirine is approved as hydrochloride salt, with the brand name EDURANTTM by US Food and Drug Administration in the dosage form of Tablets having strength Eq 25 mg. Rilpivirine hydrochloride is a non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV), developed by Janssen.

The Rilpivirine compound of formula (I) exists in 2 geometric isomers at the double bond of the cyanoethenyl group i.e. E and Z isomers. The E-isomer is the active compound. The Z-isomer may form as an impurity.

US 7,125,879 (US ‘879) first discloses specifically Rilpivirine and its pharmaceutically acceptable salts. This patent disclosed different processes for the preparation of Rilpivirine, one of which involves reacting compound of formula (II) with compound of formula (III) either in free base or hydrochloride salt, which is as shown below:

According to the US ‘879 the reaction of compound of formula (II) and formula (III) requires either high reaction temperatures (like 150oC) or longer reaction time (such as 69 hours), which results Rilpivirine in ~60-65% yield.

The nucleophilic substitution reaction of chloro intermediate of formula (II) with compound of formula (III) involves slower reaction time and significant side reactions, which leads to the formation of major impurities such as Z-isomer, hydrolysis product and dimers. Removal of these impurities in later stages is very difficult and requires multiple purifications, which leads to decrease in the yield and making the process uneconomical.

US 7,399,856, IN 2340/CHE/2009, IN 5979/CHE/2015 and WO 2012/143937 disclose a process for the preparation of Rilpivirine hydrochloride by coupling of compound of formula (II) and formula (III).

Apart from that, US 9,126,949 (US ‘949) discloses a modified process for the preparation of Rilpivirine by coupling the compounds of formulae (II) and (III), in presence of p-toluene sulfonic acid as additive and ether as solvent. By using this, the reaction time has reduced but not able to achieve the low reaction temperature as well as good yield.

All the above reported literature, involves use of chloro intermediate of formula (II) as the starting material. Because of poor activity of the leaving group of formula (II) in the nucleophilic substitution reaction with compound of formula (III), slower the effective conversion and leads to the formation of more impurities.

Apart from that, Rilpivirine hydrochloride is also known to have polymorphism and exits in different crystalline forms i.e. Form A, Form B, Form C and Form D which are described in US 7956063 and US 8101629.

Thus keeping all these disadvantages of prior art in considerations, the present inventors have developed a robust process for the preparation of Rilpivirine and its pharmaceutically acceptable salts with high purity and high yield by using a novel intermediate.

This novel intermediate helps in shorten the reaction time and temperature as well as consistency in controlling the impurity formation, which leads to the increase in overall yield of the product.

OBJECTS OF THE INVENTION

The main objective of the present invention is to provide a novel intermediate compound of formula (IV) and its process for preparation.
Another objective of the present invention is to provide an improved process for the preparation of Rilpivirine and its pharmaceutically acceptable salts using novel intermediate compound of formula (IV).

Yet another objective of the invention is to provide the process for the preparation of crystalline Rilpivirine hydrochloride Form A.

SUMMARY OF THE INVENTION
The present invention provides an improved, economical, and industrially advantageous process for the preparation of Rilpivirine and its pharmaceutically acceptable salts thereof involving using novel intermediate of Formula (IV).

wherein,
R is sulfonyl group.

A first aspect of the present invention provides a novel intermediate compound of formula (IV) and its process for the preparation, comprising the steps of:
a) Condensing compound of formula (VI) with an compound of formula (VII) to obtain a compound of formula (V);

b) optionally purifying the compound of formula (V); and
c) reacting the compound of formula (V) with reagent “Z” to obtain a compound of formula (IV);

wherein Z is RX or R-O-R; R is sulfonyl group; X is halogen.

A second aspect of the present invention provides an improved process for the preparation of Rilpivirine and its pharmaceutically acceptable salts, comprising reacting the novel intermediate compound of formula (IV) with compound of formula (III) or salt thereof.

wherein R is sulfonyl group.

In accordance with yet another aspect of the present invention provides a process for the preparation of crystalline Rilpivirine hydrochloride Form-A, comprising,
a) treating the Rilpivirine with hydrochloric acid;
b) optionally treating with an acid; and
c) isolating crystalline Rilpivirine hydrochloride Form-A.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:
Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only, and is not intended to limit the scope of the present invention.

All terms as used herein in this application shall be understood in their ordinary meaning as known in the art or according to described herein.
As used herein the term “suitable solvent” in the present invention refers to “nitrile solvents” such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, benzonitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, 2-nitro ethanol, 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, cyclohexanol, benzyl alcohol, phenol or glycerol and the like; “Ketones solvent” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “Halogenated hydrocarbon” solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; “dipolar aprotic solvents” such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidinone and the like; “Ester solvents” such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate and the like; “Ether solvents” such as 1,3-dioxane, 1,4-dioxane, tertrahydropyran, tetrahydrofuran, ethyl methyl ether, diethyl ether, diisopropyl ether, di-tert-butyl ether, tert-butyl methyl ether, ethyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, propylene glycol monomethylether, dimethoxymethane and the like; polar solvents such as water or mixtures thereof.

The term “acid” used herein the present invention is selected from group comprising of hydrochloric acid, sulfuric acid, acetic acid, oxalic acid, citric acid, tartaric acid, salicylic acid, glycolic acid, lactic acid, formic acid, propionic acid, methane sulfonic acid, p-toluene sulfonic acid, mandelic acid, triflic acid and the like.

As used herein the term “base” is selected from the group comprising of potassium carbonate, sodium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, sodium hydride, potassium hydride , lithium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, triethyl amine, methyl amine, ethyl amine, isopropyl amine and the like.

The term “Pharmaceutically acceptable salt” according to the present invention includes salt of Rilpivirine or its intermediates with organic and/or inorganic acids.

The “halogen” used herein the present invention is selected from chlorine, fluorine, bromine and iodine.

One embodiment of the present invention provides a novel intermediate compound of formula (IV) and its process for the preparation comprising,
a) condensing compound of formula (VI) with compound of formula (VII) to obtain compound of formula (V);

b) optionally purifying the compound of formula (V);
c) reacting the compound of formula (V) with reagent “Z” to obtain compound of formula (IV);

wherein Z is RX or R-O-R; R is sulfonyl group; X is halogen.

The starting compounds of Formulae (VI) or (VII) may be obtained by known processes in literature or person skilled in the art.

The reaction of step a) is carried by condensing compound of Formula (VI) with compound of Formula (VII) in the presence of a solvent.

In an embodiment, the solvent used in step a) is selected from group comprising of acetic acid, monochloro acetic acid, trichloro acetic acid, propionic acid, butyric acid, isobutyric acid, n-pentanoic acid, hexanoic acid, pivalic acid, 1,4-dioxane, 1,2-dimethoxy ethane and diglyme.

In an embodiment, the above reaction step a) may be carried out at temperatures ranging from about 50 oC -130oC, preferably 80-110oC.

After the completion of the reaction, the compound of Formula (V) may optionally be isolated and purified as per the methods known in the art or by the procedures disclosed in the present application or the reaction mixture comprising the compound of Formula (V) may be taken forward for the next steps, without isolating the compound of Formula (V).

In an embodiment, the purification of compound of formula (V) in step b) is carried out by dissolving in a suitable solvent and then isolating by conventional methods known in the art.

The reaction of step c) carried by reacting the compound of formula (V) with reagent “Z” to obtain compound of formula (IV) in presence of suitable solvent and base.
The reagent “Z” used in the above step c) is selected from RX or R-O-R, wherein the R is sulfonyl group and X is halogen.

In an embodiment of the present invention, sulfonyl groups used in compound of formula (IV) are selected from the group comprising of p-toluene sulfonyl, p-nitrobenzene sulfonyl, benzenesulfonyl, methane sulfonyl, trifluoromethane sulfonyl and 2,4-difluoro benzene sulfonyl.

In a further embodiment, the solvent used in step c) is selected from group comprising of acetonitrile, dichloromethane, tetrahydrofuran, ethylacetate, acetone and N-methylpyrrolidone.

In an embodiment, the base used in step c) is selected from group comprising of ammonium hydroxide, potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide.

In yet another embodiment of the present invention provides the compound of formula (IV) is further reacted with compound of formula (III) or a salt thereof, to obtain Rilpivirine and its pharmaceutically acceptable salts thereof.

wherein R is sulfonyl group.

In an embodiment of the present invention, the compound of formula (III) or a salt thereof can be prepared by the methods described in the literature.

In an embodiment of the present invention, use of novel intermediate of compound of formula (IV) for reaction with formula (III) is more effective as sulfonyl leaving group of compound of formula (IV) will actively participate in the nucleophilic substitution reaction and helps to complete the reaction in shorter time at lower temperatures as compared to intermediate compound of formula (II).

In accordance with the above embodiment, reaction of compound of Formula (IV) with compound of Formula (III) is carried in the presence of a suitable solvent and optionally in presence of an acid.

The suitable solvent used in the above reaction is selected from the group comprising of acetonitrile, dichloromethane, tetrahydrofuran, ethylacetate, acetone and N-methylpyrrolidone.

The acid used in the above reaction is selected from the group comprising of hydrochloric acid, sulfuric acid, acetic acid, formic acid, propionic acid, methane sulfonic acid, p-toluene sulfonic acid and triflic acid.

In an embodiment, the above reaction step may be carried out at temperatures ranging from about 70°C to about 95oC, more preferably 80-85oC and the reaction will complete in 8-14 hours, preferably 10-12 hrs.

In accordance with an embodiment, the Rilpivirine obtained according to the present invention has high yield such as more than 75%, preferably more than 80% and high purity such as about 97-99% purity with Z-isomer content less than 1%, preferably less than 0.5%, more preferably less than 0.1%.
In an embodiment of the present invention the Rilpivirine obtained can be isolated as free base or it’s salt and then optional purification by using conventional methods known in the art or by procedures described herein.

In other embodiment of the present invention, the purification of Rilpivirine can be carried out by subjecting the Rilpivirine free base or its salt to acid-base treatment.

The acid used for the above purification is selected from the group comprising of hydrochloric acid, acetic acid, methane sulfonic acid and p-toluene sulfonic acid. The base used for the purification is selected from the group comprising of ammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.

In further embodiment of the present invention, the Rilpivirine hydrochloride can be isolated as crystalline Form-A, comprising,
a) treating the Rilpivirine with hydrochloric acid;
b) optionally treating with an acid; and
c) isolating crystalline Rilpivirine hydrochloride Form-A.

In an embodiment, the above step a) is carried out in presence of suitable solvent and the hydrochloric acid. The hydrochloric acid is either alcoholic hydrochloride or aqueous hydrochloride.

In accordance with the above embodiment, the suitable solvent is alcohol solvent selected from the group comprising of methanol, ethanol, 2-propanol, butanol, tert-butyl alcohol, isobutyl alcohol and mixtures thereof.

The acid used in step b) is selected from the group comprising of acetic acid, formic acid, propionic acid and mixtures thereof.

In a further embodiment the isolation of step c) is carried out by using conventional methods known in the art.

In an embodiment of the present invention, provides the crystalline Rilpivirine hydrochloride Form-A as stable product and in pure form.

The Rilpivirine hydrochloride prepared by the present invention can be further micronized or milled in 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 following non-limiting examples will serve to further illustrate the nature of the Invention but should not be construed as limiting the scope of present invention in any way.

Example 1:
Preparation of 4-[(4-hydroxypyrimidin-2-yl)amino]benzonitrile

2-Methylthio-4-pyrimidinone (100 gm) and 4-aminobenzonitrile (125 gm) were added to propionic acid. The mixture was heated to 100oC and stirred for few hours. The solution was then cooled to room temperature, filtered and dried under vacuum to afford 4-[(4-hydroxypyrimidin-2-yl)amino]benzonitrile in 75% yield.

Example 2
Preparation of 2-(4-cyanophenylamino) pyrimidin-4-yl-methylbenzenesulfonate

To a solution of 4-[(4-hydroxypyrimidin-2-yl)amino]benzonitrile (100gm) in acetonitrile, added triethylamine (100 gm). The reaction mass was cooled to 0-5oC and 4-toluenesulfonyl chloride (113 gm) was added and reaction was maintained for few hours. Water was added to the reaction mass, the resulting solid was filtered and washed with water and dried to afford 2-(4-cyanophenylamino)pyrimidin-4-yl-methylbenzenesulfonate in 90% yield.

Example 3
Preparation of 4-{[4-({4-[(E)-2-cyanovinyl]-2,6-dimethylphenyl}amino) pyrimidin-2-yl]amino}benzonitrile
(E)-3-(4-Amino-3,5-dimethylphenyl)acrylonitrile hydrochloride (85 g) was added to dichloromethane and water. Liquor ammonia (210 ml) was added to the reaction mass and layers were separated. Aqueous layer was extracted with dichloromethane and the combined organic layers were washed with water. Organic layer was distilled out completely under vacuum. Acetonitrile and 2-(4-cyanophenylamino)pyrimidin-4-yl-methylbenzenesulfonate (prepared according to example 2) (156 g) were added to the above reaction mass and heated to 70-80oC. Acetic acid was added and stirring the reaction mass at same temperature for 10 hrs. Water was added, stirred at the same temperature, the reaction mass was cooled to room temperature and filtered. dimethylformamide was added to the obtained solid and heated to 45-60oC. Methanesulfonic acid (97.8 g) was added to the reaction mass and stirred for 20-50 min. The reaction mass was cooled to room temperature, filtered and dried under vacuum. Adding acetic acid (780 ml) to the obtained dried compound. The reaction mass was cooled and then filtered. Liquor ammonia (156 ml) was added to the aqueous slurry of wet residue, stirred and filtered. The material was dried under vacuum to afford Rilpivirine in 70% yield having Z-isomer 0.03%.
Example 4
Preparation of Rilpivirine Hydrochloride
Heated the Rilpivirine (100 g) solution in IPA (500 ml) to 50-55oC. IPA.HCl was added to the reaction mass, maintained for few hours and distilled off completely under vacuum. Acetic acid (500 ml) was added to the reaction mass, then heated to 80-85oC and maintained for few hours. It was then cooled to room temperature and stirred. The solid was filtered and dried under vacuum to afford pure Rilpivirine hydrochloride in 92% yield.