The following specification claims priority from Indian Patent Application bearing Number 2340/CHE/2009 dated Sept 29, 2009

FIELD OF THE INVENTION

The present invention relates to novel process for preparation of 4-(6-oxo-l,6-dihydro pyrimidin-2-yl-amino) benzonitrile, an intermediate of Rilpivirine. The present invention further relates to conversion of the said intermediate to Rilpivirine.

BACK GROUND OF THE INVENTION

Retroviruses are class of viruses which lower the immunity levels in mammals particularly Humans. Human Immuno deficiency Virus is one such retrovirus which causes AIDS. Short life cycle and high error rate causes the virus to mutate very rapidly, resulting in a high genetic variability of HIV. Antiretroviral drugs include Nucleoside reverse transcriptase inhibitors (NRTI's), Non-Nucleoside reverse transcriptase inhibitors (NNRTI's), HIV protease inhibitors, fusion inhibitors, maturation inhibitors. Compound 4-((4-((4-((1E)-2-Cyanoethenyl)-2,6-dimethylphenyl)amino)-2-pyrimidinyl)amino) benzonitrile [TMC278] is one such NNRTI, generically designated as Rilpivirine and has the following structural formula.

Rilpivirine is an investigational new drug developed by Tibotec, a biotechnology company in Belgium; for the treatment of HIV infection. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTIs). Rilpivirine prevents HIV from entering the nucleus of healthy CD4 cells. This prevents the cells from producing new virus and decreases the amount of virus in the body. Rilpivirine is being studied in combination with other HIV medicines in two groups of HIV-positive people: those starting HIV treatment for the first time and those in need of newer medicines to treat HIV that has become resistant to older options.

US 7,125,879 specifically discloses Rilpivirine. This patent discloses various processes for the preparation of heteroaryl amine compounds, in particular the preparation of Rilpivirine, one of which involves condensation of 3-(4-amino-3,5-dimethylphenyl)-acrylonitrile either in free base or hydrochloride salt with 4-(4-chloropyrimidin-2-ylamino)benzonitrile using potassium carbonate.

Synthetic communications 27 (11), 1943-1949, 1997 discloses two stage process for the preparation of 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino]benzonitrile, Rilpivirine intermediate, which comprises methylating the thiouracil and simultaneously treating the obtained thiomethyl uracil with aminobenzonitrile to get the desired compound. The disadvantage of the said process is liberation of highly toxic and flammable methyl mercaptane gas which is having extremely strong and has repulsive smell.

PCT publication WO 2006/125809, discloses a process for the preparation of 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino]benzonitrile, comprising the steps of reacting cyanamide with aminobenzonitrile to produce 4-cyanophenylguanidine which is further treated with diethyl-2-(ethoxymethylene)malonate or dimethyl-2-(ethoxymethylene) malonate to produce the desired compound. Use of toxic gas is avoided in this process but the main disadvantage of the process lies in carrying out the reaction at higher temperature over a period of 72 hours, which results in the formation of impure product. Further the process requires number of purification steps to get the final compound. Moreover maintaining reaction at higher temperature on a commercial scale is a difficult task.

Hence there is a long felt need to develop an improved and commercially viable process for the preparation of Rilpivirine.

OBJECTIVE OF THE INVENTION

The main object of the present invention is to provide novel process for the preparation of 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino]benzonitrile, an intermediate of Rilpivirine and its further conversion to Rilpivirine.

SUMMARY OF THE INVENTION

The main aspect of the present invention is to provide novel process for the preparation of 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino]benzonitrile, an intermediate of Rilpivirine by reacting 4-cyanophenylguanidine with N, N-dimethyl amino acrylate and optionally purifying the obtained 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino] benzonitrile.

Another aspect of the present invention is to provide an improved process for the preparation of Rilpivirine wherein 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino] benzonitrile is reacted with halogenating agent to give 4-(4-halo-pyrimidin-2-yl-amino) benzonitrile which is later condensed with (E)-3-(4-amino-3,5-dimethyl phenyl) acrylonitrile in a solvent medium to yield Rilpivirine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel process for preparation of 4-[(6-oxo-l,6-dihydro pyrimidin-2-yl)-amino]benzonitrile, an intermediate of Rilpivirine and further conversion of the said intermediate 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino]benzonitrile to Rilpivirine.

In one embodiment, the present invention provides a novel process for the preparation of 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino]benzonitrile, an intermediate of Rilpivirine comprising the steps of:

a. reacting 4-cyanophenylguanidine with N,N-dimethyl amino acrylate to get 4-[(6-oxo-1,6-dihydropyrimidin-2-yl)-amino]benzonitrile, and

b. optionally purifying the obtained 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino] benzonitrile.

The process according to the present invention is schematically represented as below,
According to the present invention, 4-cyanophenylguanidine is reacted with N,N-(dimethyl-amino) acrylate to get 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino] benzonitrile.

According to the present invention, 4-cyanophenyl guanidine is reacted with ethyl-3-(dimethylamino) acrylate in absence or in presence of a solvent. Solvent is selected from cyclohexane, chlorobenzene, toluene and benzene and the like.

According to the present invention, 4-cyanophenylguanidine is reacted with N, N-dimethylaminoacrylate in absence or in presence of a solvent selected from hexane, cyclohexane, chlorobenzene, toluene, benzene. Reaction is maintained at temperatures such as 70-140°C. After reaction completion, product is filtered and dried to obtain 4-[(6-oxo-1,6-dihydropyrimidin-2-yl)-amino] benzonitrile.

According to the present invention, 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino] benzonitrile is optionally purified by treating the compound with water and a base selected from alkali metal hydroxides, alkali metal carbonates such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium carbonate. The reaction contents are maintained for 30-90 min. Insolubles are filtered. pH of the filtrate is adjusted to 7.0-7.5 by adding dilute acid selected from mineral acids such as hydrochloric acid, sulfuric acid and the like; or organic acids such as acetic acid. Reaction mass is stirred, filtered and washed with solvent selected from alcohol such as methanol, esters such as ethyl acetate and water or mixtures thereof.

In another embodiment, the present invention provides process for conversion of the above said intermediate 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino]benzonitrile to Rilpivirine comprising the steps of:

a) converting 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino]benzonitrile to 4-(4-halo-pyrimidin-2-yl-amino) benzonitrile;

b) condensing 4-(4-halo-pyrimidin-2-yl-amino) benzonitrile with 3-(4-amino-3,5-dimethyl- phenyl)-acrylonitrile to yield Rilpivirine.

The entire reaction is schematically represented below, According to the present invention, 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino]benzo-nitrile is treated with halogenating agents in a solvent to give 4-(4-halo-pyrimidin-2-yl-amino) benzonitrile. Preferably 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino]benzo-nitrile is chlorinated using phosphorous oxychloride or thionyl chloride at a temperature 70-90 °C. After completion of reaction, reaction mass is quenched into ice and stirred for one hour. The obtained product is filtered and washed with alcohol such as methanol, ethanol, isopropyl alcohol to give pure intermediate compound 4-(4-chloro-pyrimidin-2-yl-amino) benzonitrile.

According to the present invention, the obtained intermediate 4-(4-halo-pyrimidin-2-yl-amino) benzonitrile is treated with (E)-3-(4-amino-3,5-dimethyl phenyl)acrylonitrile in a solvent such as N-methyl-2-pyrrolidinone at temperatures such as 80-95°C for 6-10 hrs to obtain Rilpivirine.

According to the present invention, (E)-3-(4-amino-3,5-dimethyl phenyl)acrylonitrile used in the above condensation step is prepared by reaction of 4-iodo-2,6-dimethyl aniline with acrylonitrile using N,N-dimethyl acetamide and Palladium carbon (10%) at 100-140°C. Reaction mass is maintained for 6-10 hours. Insolubles are filtered and product is isolated to obtain (E)-3-(4-amino-3,5-dimethylphenyl) acrylonitrile.

According to the present invention, the obtained Rilpivirine is optionally purified by using general purification techniques such as crystallization, solvent-anti solvent method, slurry, acid base treatment thereof. Rilpivirine is treated with a polar solvent or mixtures thereof. The polar solvent is selected from ketones such as acetone, nitrile such as acetonitrile, esters such as ethylacetate, dimethyl formamide, tetrahydrofuran, N-methyl-pyrrolidinone, methanol and water or mixtures thereof. Reaction contents are heated to temperature 60-90°C for 2-5 hrs and cooled to 0-25 °C. The product obtained is filtered to isolate pure Rilpivirine.

The following examples will further illustrate the invention, without, however, limiting it thereto. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any manner.

EXAMPLES

Example 1: Process for the preparation of 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-
amino] benzonitrile 150 ml of chlorobenzene was added to 25 gms of 4-cyanophenyl guanidine in a reaction vessel. To the resulting solution 22.3 gms of ethyl-3-(dimethylamino) acrylate was added. The obtained reaction mass was maintained for about 24 hours at 125-135°C. The reaction mass was cooled to 30°C after completion of the reaction. Filtered the obtained reaction mass, washed the solid with methanol and dried the solid to get 25 gms of 4-[(6-oxo-1,6-dihydropyrimidin-2-yl)-amino]benzonitrile.

Example 2: Purification of 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino]benzonitrile
25 gms of 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino]benzonitrile was dissolved in water at 30°C and aqueous sodium hydroxide solution was added. The reaction mass was stirred for about 1 hour at 30-35°C. Filtered the reaction mass and removed the insoluble materials. pH of the filtrate was adjusted to 7.0 to 7.5 by adding dilute hydrochloric acid. Stirred the reaction mass, filtered, washed with water and methanol and dried to get 20 gms of 4-[(6-oxo-1,6-dihydropyrimidin-2-yl)-amino]benzonitrile.

Example 3: Process for the preparation of 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino] benzonitrile 4-Cyanophenyl guanidine (100gm) was added to a reaction vessel followed by addition of purified water (800ml). Ethyl-3-(dimethylamino) acrylate (98.2gm) was added. Reaction mass was heated to 97±2 and vigorously stirred for 5 Hrs. Reaction mass was cooled to room temperature and allowed to stir for 1 hour to crystallize the 4-(6-oxo-l,6-dihydropyrimidin-2-ylarnino) benzonitrile. Product was filtered and washed with water (100ml) followed by methanol (200ml). The obtained product was dries at 50°C to give 4-(6-oxo-l,6-dihydropyrimidin-2-ylamino) benzonitrile (70gm) (HPLC Purity >98%, HPLC assay > 98%).

Example 4: Preparation of 4-(4-chloropyrimidin-2-ylamino)benzonitrile In a clean and dry reaction vessel 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-aminojbenzonitrile (100gm) was added followed by acetonitrile (300ml). The contents were heated to 73±3°C and phosphorous oxychloride (108.6gm) was added to the reaction mass over one hour. Reaction mass was maintained at 70-75°C until completion. Reaction mass was cooled and quenched into ice (100gm) and stirred for one hour. The obtained product was filtered and washed with purified water (200ml). Further filtered material was washed with 1% sodium hydroxide solution (100ml). Finally washed with methanol (100ml) and dried at 50°C to give 4-(4-chloropyrimidin-2-ylamino)benzonitrile (105gm). HPLC Purity > 98% and HPLC assay > 98%.

Example 5: Preparation of 4-{[4-({4-[(E)-2-Cyanovinyl]-2,6-dimethylphenyl} amino) pyrimidin-2-yl] amino} benzonitrile [Rilpivirine]

In a clean and dry reaction vessel N,N-Dimethyl acetamide (250ml) was added along with sodium acetate (39.9gm) followed by 4.3gm of 10% palladium on Carbon. Reaction mass was heated to 137°C and mixture of 4-Iodo-2,6-dimethylaniline (100gm) and acrylonitrile (32.2gm) were prepared in N,N-Dimethyl acetamide (150ml) in about 2 hours. Reaction mass was maintained for 8 hours the reaction mass was cooled. Insolubles were filtered and to the filtrate, toluene (300ml) and purified water (400ml) were added. Product was extracted into the organic layer. Organic layer obtained after extractions and washings was collected and distilled under vacuum to get residue containing (E)-3-(4-amino-3,5-dimethyl phenyl)acrylonitrile. N-Methyl-2-Pyrrolidinone (300ml) was added followed by addition of 4-(4-chloropyrimidin-2-ylamino)benzonitrile (79.3gm). 20% Isopropanolic HC1 (62.8gm) was added. Reaction mass was heated to 85±3°C and maintained for 8 hours at same temperature and 4-(4-chloropyrimidin-2-ylamino)benzonitrile was monitored by HPLC till it is NMT 1.0%. On reaction completion reaction mass was cooled and 25% potassium carbonate solution (475ml). Reaction mass was filtered and washed with acetonitrile (100ml). The obtained product can be further purified in a solvent mixture consisting of acetonitrile (480ml), N-Methyl-2-pyrrolidinone (60ml) and purified water (60ml) by heating the above wet compound to 80°C and then cooling to 10°C and filtered and dried under vacuum at 50°C to get 4-{[4-({4- [(E)-2-Cyano vinyl] -2,6-dimethylphenyl} amino)pyrimidin-2-yl] amino } benzonitrile [Rilpivirine]. Yield (80gm) and HPLC >99%.

Example 6: Preparation of 4-{[4-({4-[(E)-2-Cyanovinyl]-2, 6-dimethylphenyl} amino) pyrimidin-2-yl] amino} benzonitrile

The compound 4-{[4-({4-[(E)-2-Cyanovinyl]-2, 6-dimethylphenyl} amino) pyrimidin-2-yl] amino} benzonitrile (100gm) was dissolved in acetone 3000ml in a reaction vessel. The clear solution was filtered, concentrated partially under vacuum, cooled to 40°C. To

this reaction mass, purified water (2000 ml) was added. The reaction mass was further cooled to 12°C; filtered and dried under vacuum at 50°C to give pure 4-{[4-({4-[(E)-2-Cyanovinyl]-2, 6-dimethylphenyl} amino) pyrimidin-2-yl] amino} benzonitrile. HPLC area% > 99% and Z-isomer <0.15%

We Claim:

1. A process for the preparation of 4-((4-(4-((1 E)-2-Cyanoethenyl)-2,6-dimethyl phenyl) amino)-2-pyrimidinyl)amino)benzonitrile [Rilpivirine] comprising the steps of:

a) reacting 4-cyanophenyl guanidine with ethyl-3-(dimethyl amino)acrylate to obtain 4-(6-oxo-l ,6-dihydropyrimidin-2-yl)benzonitrile;

b) optionally purifying 4-[(6-oxo-l ,6-dihydropyrimidin-2-yl)-amino]benzonitrile;

c) reacting 4-[(6-oxo-1,6-dihydropyrimidin-2-yl)-amino]benzonitrile with halogenating agent to give 4-(4-halo-pyrimidin-2-yl-amino) benzonitrile;

d) condensing 4-(4-halo-pyrimidine-2-yl-amino) benzonitrile with 3-(4-amino-3,5-dimethyl-phenyl)-acrylonitrile to yield Rilpivirine; and

e) optionally purifying the obtained Rilpivirine.

2. The process according to claim 1, wherein, 4-cyanophenyl guanidine is reacted with ethyl-3 -(dimethylamino) acrylate in absence or in presence of a solvent selected from cyclohexane, chlorobenzene, toluene and benzene.

3. The process according to claim 1, wherein, 4-[(6-oxo-l ,6-dihydropyrimidin-2-yl)-aminojbenzonitrile is optionally purified comprising the steps of:

a) treating 4- [(6-oxo-1,6-dihydropyrimidin-2-yl)-amino]benzonitrile with water and a base selected from alkali metal hydroxides, alkali metal carbonates;

b) filtering the insolubles and adjusting pH using an acid; and

c) isolating pure 4-[(6-oxo-1,6-dihydropyrimidin-2-yl)-amino]benzonitrile.

4. The process according to claim 1, wherein 4-[(6-oxo-l,6-dihydropyrimidin-2-yl)-amino]benzonitrile is reacted with halogenating agent like phosphorous oxychloride to obtain 4-(4-chloropyrimidin-2-ylamino)benzonitrile.

5. A process for the preparation of 4-[(6-oxo-1,6-dihydropyrimidin-2-yl)-amino] benzonitrile comprising the steps of:

a) reacting 4-cyanophenyl guanidine with ethyl-3 -(dimethyl-amino)acrylate to obtain 4-[(6-oxo-l ,6-dihydropyrimidin-2-yl)-amino]benzonitrile; and

b) optionally purifying 4-(6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile.

6. A process for the purification of Rilpivirine comprising the steps of:

a) treating Rilpivirine in a solvent or mixtures thereof; and

b) isolating pure Rilpivirine.

7. The process according to claim 6, wherein solvent used is a polar solvent.

8. The process according to claim 7, wherein the polar solvent is selected from nitriles, ketones, water or mixtures thereof.