Field of Invention

The present invention relates to a novel process for the preparation of a nitrile compound which is a key intermediate in the preparation of an antiretroviral drug Rilpivirine. In particular it relates to a process for the preparation of (2E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile.

Background of the Invention

Rilpivirine is also known as "Edurant" a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). Rilpivirine is also used in combination with other antiretroviral drugs such as Emtricitabine and tenofovir, known as "Complera". The chemical name for Rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]2-pyrimidinyl]amino]benzonitrile monohydrochloride represented by formula I.

The compound (2E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile of formula II is key raw material in the preparation of Rilpivirine.

There are number of literatures available which describe the process for preparation of Rilpivirine using (2E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile as key intermediate. US patent 7125879 describes a process for the preparation of (2E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile of formula II as given in the below scheme-1:

A major drawback in above known process is the use of very expensive reagents such as palladium acetate. Also, the above reaction takes long time to complete and involves formation of hazardous tris(2-methyl phenyl) phosphoxide as by-products.

Thus there is a need to develop a process for the preparation of (2E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile, which is cost effective and easy to handle on a commercial scale. Especially there is a need to develop a process which obviates the use of expensive reagent palladium acetate and formation of hazardous by-products.

The present inventors has found a lead to develop a cost effective process for preparing (2E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile in good yield in short time, which obviates the use of expensive reagent palladium acetate and formation of hazardous by-products. Further, the intermediate (2E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile of formula II is converted into Rilpivirine in high purity and high yield.

Summary of the invention

Accordingly, the principal aspect of the present invention is to provide a process for the preparation of (2E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile of formula II which comprises:

a) acetylating the 2,6-dimethylaniline of formula VII with acetic anhydride in presence of a suitable solvent to obtain a N-(2,6-dimethylphenyl)acetamide of formula VI;

b) treating compound of formula VI with phosphorous oxychloride in DMF to obtain N-(4-formyl-2,6-dirnethylphenyl)acetamide of formula V;

c) reacting compound of formula V with acetic anhydride and sodium acetate to obtain (2E)-3-[4-(acetylamino)-3,5-dimethylphenyl]acrylic acid of formula IV;

d) amidating the compound of formula IV using thionyl chloride and ammonia to form (2E)-3-[4-(acetylamino)-3,5-dimethylphenyl]acrylamide of formula III ;and

e) dehydrating the compound of formula III to obtain (2E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile of formula II.

The present invention can be illustrated by the below reaction scheme:

In another aspect of the present invention, compound (2E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile of formula II is further converted into Rilpivirine of formula I as.

In another aspect, the present invention provides the following novel compounds:

Detail Description of The Invention

In an embodiment of the invention, the process of present invention can be illustrated by the following examples, which are not to limit the scope of invention.

Example 1: Preparation of (2E)-3-(4-amino-3,5-dimethylphenyl)prop-2-enenitrile

(a) Preparation of Af-(2,6-dimethylphenyl)acetamide
Dissolve 30 g of 2,6-dimethylaniline in 50 mL of acetic acid and 0.5 mL of pyridine. To this solution, add 30 mL of acetic anhydride. Heat to gentle reflux for 2 hours. After completion of the reaction, the reaction mass was cooled to 10° C and quenched to ice water. Stirred the mass for 30 minutes and filtered the solid. Dried the white colored solid at 52 °C under vacuum to yield 31 g of N-(2,6-dimethylphenyl)acetamide.

(b) Preparation of N-(4-formyl-2,6-dimethyIphenyl)acetamide
Vilsmeier Haack reagent was prepared by adding POCI3 (2.5 mL) and DMF (7.5 mL) at 0 °C. To this was added 20 g of JV-(2,6-dimethylphenyl)acetamide and stirred for 2 h at 10-15 °C and stirred for 2 h at 60-65 °C. After cooling to 25-30 °C, the reaction mass was quenched to saturated solution of sodium carbonate. The reaction mass was heated to 90 °C 1 h. Cooled the reaction mass to 25-30 °C and extracted the product using 100 mL of Chloroform. The residue after the distillation of Chloroform was JV-(4-formyl-2,6-dimethylphenyl)acetamide, 20 g.

(c) Preparation of (2E)-3-[4-(acetylamino)-3,5-dimethylphenyl]prop-2-enoic acid
Mixture of A44-formyl-2,6-dimethylphenyl)acetamide (25 g, 0.13 mol) and acetic anhydride (19.35 g, 0.189 mol).were taken in RBF. To this was added sodium acetate (6.54 g, 0.079 mol).The mixture was then heated to reflux for 4 h. After the reaction, the reaction mass was cooled to 80-100 °C and poured to ice cold water. The reaction mass was cooled to 10-15 °C, basified to pH= 8, using saturated sodium carbonate solution. Impurities are washed out by MDC. Cooled the Aq. layer to 10-15°C and acidified to pH= 2, using Cone HC1. The solid precipitated was filtered and dried at 45-50 °C under vacuum to get 18.8 g of (2£)-3-[4-(acetylamino)-3,5-dimethylphenyl]prop-2-enoicacid.

(d) Preparation of (2E)-3-[4-(acetylamino)-3,5-dimethylphenyl]prop-2-enamide
To (2£^-3-[4-(acetylamino)-3,5-dimethylphenyl]prop-2-enoic acid (15 g) was added thionyl chloride (50 mL), the mixture was refluxed for 3 h and then concentrated to residue to give (2£)-3-[4-(acetylamino)-3,5-dimethylphenyl]prop-2-enoyl chloride. The residue was added to liq. Ammonia (20 mL) which was pre cooled to 10 °C. Stirred the reaction mass for 30 min. The precipitate formed was filtered, washed with water and dried at 50 °C under vacuum to yield 14.2 g of (2£)-3-[4-(acetylamino)-3,5-dimethylphenyl]prop-2-enamide.

(e) Preparation of (2E)-3-(4-amino-3,5-dimethylphenyl)prop-2-enenitrile
POCl3 (10 mL) was cooled to 0 °C and 1 g of (2£)-3-[4-(acetylamino)-3,5-dimethylphenyl]prop-2-enamide was added. After 30 minutes cooling bath was removed and the mixture was stirred fo 15 min at 20 °C. The mixture was then added drop wise to water and heated to 50 °C. Maintained the temperature of the reaction mass for 30 min. Cooled the reaction mass to 10 °C. The pH was brought to 8 using Aq ammonia. The solid formed was filtered and dried at 35 °C under vacuum to yield 0.7 g of (2£)-3-(4-amino-3,5-dimethylphenyl)prop-2-enenitrile.

We claim:

1. A process for the preparation of (2E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile which comprises:
a) acetylating the 2,6-dimethylaniline with acetic anhydride in presence of a suitable solvent to obtain a N-(2,6-dimethylphenyl)acetamide of formula VI;

b) treating compound of formula VI with phosphorous oxychloride in DMF to obtain N-(4-formyl-2,6-dimethylphenyl)acetamide of formula V;

c) reacting compound of formula V with acetic anhydride and sodium acetate to obtain (2E)-3-[4-(acetylamino)-3,5-dimethylphenyl]acrylic acid of formula IV;

d) amidating the compound of formula IV using thionyl chloride and ammonia to form (2E)-3-[4-(acetylamino)-3,5-dimethylphenyl]acrylamide of formula III ;and

e) dehydrating the compound of formula III to obtain (2E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile.