Claims:We claim:

1. A process for the preparation of Osimertinib mesylate comprising the steps of:
a) reacting N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine with 3-chloropropanoyl chloride in presence of ketone solvent and water and without use of any base to obtain 3-chloro-N-[2-[2- dimethylaminoethyl-methyl-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimiddin-2-yl]amino]phenyl] propanamide,
b) in-situ reacting the 3-chloro-N-[2-[2- dimethylaminoethyl-methyl-4-methoxy-5-[[4-(1-methylindol-3-yl) pyrimiddin-2-yl]amino] phenyl] propanamide with triethylamine as a base in presence of ketone solvent to obtain Osimertinib,
c) converting the Osimertinib to Osimertinib mesylate.

2. The process as claimed in claim 1, wherein the ketone solvent employed is selected from acetone, Methyl isobutyl ketone and methyl ethyl ketone.
, Description:Field of the Invention:
The present invention relates to an improved process for the preparation of Osimertinib mesylate with high purity and high yield.

Background of the Invention:
Osimertinib is a kinase inhibitor, chemically known as N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl) pyrimidin-2-yl] amino} phenyl) prop-2-enamide mesylate and structurally represent as below:

Osimertinib is marketed as Osimertinib mesylate under the brand name TAGRISSO® and it is indicated for treatment of locally advanced or metastatic non-small cell lung Cancer.

Osimertinib mesylate is disclosed in US 8946235. Also disclosed the process for the preparation of the same by reactingN1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine with acryloyl chloride in presence of diisopropylethylamine followed by flash column chromatography purification to provide Osimertinib with low yield and purity.

US Patent No. 8946235 discloses Osimertinib mesylate salt and the process for its
preparation. This patent also discloses crystalline form-A and B of Osimertinib mesylate as well as crystalline form-A, B, C, D, E and K of Osimertinib free base.

However, the process disclosed in US’235 exhibit various disadvantages including tedious column chromatographic purifications which are time consuming and not recommended for industrial scale.

In view of the above drawbacks, there are still remains an unmet need for a process for the preparation of Osimertinib with high yield, purity and which is also applicable for multi-kilogram production.

Summary of the Invention:
One Aspect of the present invention is to provide a process for the preparation of Osimertinib mesylate.

Another aspect of the present invention is to provide a process for the preparation of Osimertinib mesylate comprising the steps of:
a) reacting N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl) pyrimidin-2-yl)benzene-1,2,4-triamine with 3-chloropropanoyl chloride in presence of ketone solvent and water and without use of any base to obtain 3-chloro-N-[2-[2- dimethylaminoethyl-methyl-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimiddin-2-yl]amino] phenyl] propanamide,
b) in-situ reacting the 3-chloro-N-[2-[2-dimethylaminoethyl-methyl-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimiddin-2-yl]amino]phenyl] propanamide with triethylamine as a base in presence of ketone solvent to obtain Osimertinib,
c) converting the Osimertinib to Osimertinib mesylate.

Detailed description of the Invention:
One embodiment of the present invention is to provide a process for the preparation of Osimertinib mesylate.

Another embodiment of the present invention is to provide a process for the preparation of Osimertinib mesylate comprising the steps of:
a) reacting N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl) pyrimidin-2-yl)benzene-1,2,4-triamine with 3-chloropropanoyl chloride in presence of ketone solvent and water and without use of any base to obtain 3-chloro-N-[2-[2- dimethylaminoethyl-methyl-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimiddin-2-yl]amino] phenyl] propanamide,
b) in-situ reacting the 3-chloro-N-[2-[2-dimethylaminoethyl-methyl-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimiddin-2-yl]amino]phenyl] propanamide with triethylamine as a base in presence of ketone solvent to obtain Osimertinib,
c) converting the Osimertinib to Osimertinib mesylate.

The process of the present invention can be represented schematically as follows:

According to the present invention, the ketone solvent employed is selected from acetone, Methyl isobutyl ketone and methyl ethyl ketone, preferably acetone.

Osimertinib mesylate produced according to the present invention having the following impurities less than about 0.05% by HPLC:

3-Chloro-N-[2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]propanamide (Impurity-IA)
N-[2-[[2-(Dimethylamino)ethyl]methylamino]-5-[[4-(1H-indol-3-yl)-2-pyrimidinyl] amino]-4-methoxyphenyl]-2-propenamide
(Impurity-A)

N-[2-(Dimethylamino)-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl] amino]phenyl]-2-propenamide
(Impurity-B)
N-[2-Fluoro-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino] phenyl]-2-propenamide
(Impurity-C)

N-[2,4-Dimethoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-propenamide
(Impurity-D)
N-[2-[[2-(Dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]acetamide
(Impurity-E)

N-[2-[2-dimethylaminoethyl(methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl) pyrimidin-2-yl]amino]phenyl]-3-[2-[2-dimethylaminoethyl(methyl)amino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]-N-prop-2-enoyl-anilino] propanamide.
(Impurity-F)

Advantages of the present invention:
? In-situ preparation of Osimertinib involves mild base triethylamine and cheaper solvent Acetone.
? Yield is significantly improved to 86.5% compared to reported yield of 62%.
? Purification of Osimertinib base developed to achieve purity more than 99% and individual impurity less than 0.15% with yield: 86%.
? Impurities especially IMP-A, IMP-B, IMP-C, IMP-D, IMP-E, IMP-F are eliminated during purification.
? Yield is improved for Osimertinib mesylate as 96.7% compared to reported yield of 83.5%.

The process described in the present invention was demonstrated in examples illustrated as below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Example-1: Preparation of Osimertinib
Added the N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl) pyrimidin-2-yl)benzene-1,2,4-triamine (100g) followed by Acetone (500ml) and DM water (200ml) into a 1L multi-neck RB flask equipped with mechanical stirrer, thermometer socket and reflux condenser room temperature and then cooled the slurry mass to 0±3°C. Simultaneously, dissolved the 3-Chloropropionyl chloride (34.2 g) in acetone (50 ml) and added to the above reaction mass at -3 to 5°C in about 30min - After addition, warmed the slurry mass to 25-30°C, maintained for about 60min after that add Triethylamine (227g) to the reaction mass in about 15min at 25-45°C then heated the reaction mass to 55-60°C and maintained for 15±0.5 h and Thereafter, cooled the reaction mass to 25-30°C then added aqueous Methanol (1200ml) in about 30min and maintain for 5-5.5h. Then collected the wet product (116g) and dried under reduced pressure. Suspended above crude product (97g) in acetonitrile (400ml) and heated to 50-55°C then maintained for about 15min for dissolution. Thereafter, cooled to 25-30°C and maintained for 3-3.5h then cool to 0-5°C and maintained for about 1 hr .Thereafter, filter the product, washed with pre cooled acetonitrile (100ml) and suck dried for about 10min. Yield: 86.5 g; 77.14% by theory, 86.5% w/w. HPLC purity: 99.52%., IMP-A:0.00%, IMP-B: 0.03%,IMP-C: 0.00%, IMP-D: 0.06%, IMP-E: 0.02%, IMP-F: 0.10%,

Example-2: Preparation of Osimertinib mesylate
Added the Osimertinib (75 g) fallowed by acetone (750 ml) in to a 1.0 L multi-neck RB flask equipped with mechanical stirrer, thermometer socket and reflux condenser at 25-30°C the heated the reaction mixture to 50-55°C then maintained about 30 min. Thereafter, added activated carbon (2.5 g) to the above solution at 50-55°C, maintained above15-20 min, filtered the hot solution over hyflo bed and washed with acetone (100 ml).Collected the hot filtrate and washings transferred in to another 1.0 L multi-neck RB flask equipped with mechanical stirrer, thermometer socket and reflux condenser at above 35°C. Added the DM water (25 ml) then heated the reaction mixture to 50-55°C and maintained about 30 min. after that added the methane sulfonic acid (14.4 g) to the above reaction mass at 50-55°C in about 10min. Maintained at 50-55°C for about 3-3.5 h, and cooled to 25-30°C in about 1.5-1.75h then filtered the product, washed with acetone (125 ml) and suck dried for about 15 min. product dried under vacuum at 80°C for 8-10 hr. Yield : 86.5 g; theory: 96.73%,HPLC purity: 99.84 %. IMP-A: 0.00%, IMP-B: 0.02%, IMP-C: 0.00%, IMP-D: 0.02%, IMP-E: 0.02%, IMP-F: 0.04%,