DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF CRYSTALLINE ENCORAFENIB

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of crystalline Encorafenib from ketone or mixture of ketone and ester solvent.

BACKGROUND OF THE INVENTION

Encorafenib is chemically known as Methyl N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3(methanesulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino] propan-2yl}carbamate (Formula I):

Encorafenib is approved in the United States under the trade name BRAFTOVI™ (encorafenib) capsules, for oral use. BRAFTOVI is a kinase inhibitor indicated, in combination with Binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.

Encorafenib is first described in US Patent 8,501,758. The ’758 Patent discloses a process to prepare crystalline Encorafenib comprising dissolving the obtained residual oil in ethanol by warming to 78°C. Further, the resulting solution is cooled to 20°C over 3 h, and a precipitate is formed. The mixture is then cooled to 0°C. The obtained mixture is filtered and washed with ethanol. The solid is dried for 14 h at 40° C to obtain crystalline Encorafenib.

In another process, amine compound formed is treated with methanesulfonyl chloride to obtain Encorafenib as a crude product. This crude product is purified by silica gel chromatography (60:1 to 40:1 Dichloromethane/methanol) to obtain crystalline form of Encorafenib.

The article IPCOM000263600D discloses Crystalline form of Encorafenib, which is characterized by Powder X-ray Diffraction Pattern having peaks at 5.55, 16.52, 19.01, 21.67 and 22.65 degrees of angle 2?.

The inventors of the present application observed that the prior art processes end up with one or the other problems, for example, solvated forms, unstable and formation of high levels of impurities, when they have conducted experiments.

Therefore, there is a need to develop an improved process for the preparation of crystalline Encorafenib, which is simple, cost-effective, high purity, high yield and robust at commercial scale.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide an improved process for the preparation of crystalline Encorafenib having high purity and good yield on commercial scale.

SUMMARY OF THE INVENTION

In an embodiment, the present invention provides an improved process for the preparation of crystalline Encorafenib having purity greater than about 99.0% by HPLC comprises providing a solution of Encorafenib in a ketone solvent or mixture of ketone and ester solvents; and isolating the crystalline Encorafenib.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts the Powder X-Ray Diffraction pattern of crystalline Encorafenib of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, the present invention provides an improved process for the preparation of crystalline Encorafenib having purity greater than about 99.0% by HPLC comprises providing a solution of Encorafenib in a ketone solvent or mixture of ketone and ester solvents; and isolating the crystalline Encorafenib.

The solution of Encorafenib is provided either by dissolving the compound in a solvent or formed during previous reaction step. Encorafenib used for preparing solution may be obtained by any known processes of the prior art.

The ketone solvent used comprises acetone, butanone, methyl isobutyl ketone, and the ester comprise ethyl acetate, isopropyl acetate, methyl acetate and n-butyl acetate. The ketone and ester solvent mixture may be in the ratio of 1:1 to 1:10. The solution is prepared at a temperature of 20°C to 30°C or at a higher temperature of 30-100°C or 35 to 70°C or at a reflux temperature of the solvent used.

The solution obtained is treated with carbon in a solvent at 20 to 100°C or at a reflux of the solvent or 50-60°C. In an embodiment, the carbon treatment comprises heating of the solution to a reflux temperature followed by filtration passing through paper, glass fiber or other membrane material or a bed of clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

The isolation of the solid is carried out by using one or more techniques of crystallization such as distillation, addition of another solvent, recrystallization, and cooling. The distillation is used to remove the solvent completely or partially. Another solvent is used to dilute the solution or to induce precipitation of the solid. The solution/suspension obtained from distillation or addition of solvent is subjected for recrystallization or cooled. The solution/suspension is cooled to room temperature or below 10°C and stirred the solution for a period of 30 minutes to 4 hours or more to enhance the precipitation and purity of crystalline Encorafenib. The suspension is filtered and dried at a temperature of about 35 to 70 °C for a period of 2 hours to 15 hours or more without affecting the quality of the material.

In a specific embodiment, the present invention provides an improved process for the preparation of crystalline Encorafenib having purity greater than about 99.0% by HPLC, which comprises:
a) providing a solution of Encorafenib in a solvent of acetone or ethyl acetate or mixture thereof at 35 to 70°C;
b) optionally, treating the solution with carbon; and
c) cooling the solution to precipitate the crystalline Encorafenib.

The resultant crystalline Encorafenib is characterized by Powder X-ray Diffraction Pattern and shown the peaks at 5.55, 16.52, 19.01, 21.67 and 22.65 degrees of angle 2?. The crystalline Encorafenib prepared by the process of the present application has purity greater than 99.0% or greater than 99.9% by HPLC.

Having described the invention with reference to certain aspects and embodiments, which will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES

Example 1: Process for the preparation of crystalline Encorafenib

Encorafenib technical (100 g) was charged in acetone (800 ml) under nitrogen atmosphere at room temperature. The reaction mass was stirred at room temperature and further stirred to 50-60°C for 30±5 min to get clear solution. After getting clear solution, the reaction mass was cooled to 40-50°C. Carbon slurry (15 g carbon in 200 ml acetone) was added to the reaction mass and it was stirred at 50-60 °C for 30±5 min. The carbon was filtered through hyflo bed and washed with pre-heated acetone (300 ml). The filtrate was passed through micron filter and acetone was completely distilled out under reduced pressure at below 45°C and it was cooled at 20-30°C. In the above flask, acetone (100 ml) was charged at 20-30°C and it was stirred for 15±5 min. Later, ethyl acetate (250 ml) was added to the above reaction mass, and it was stirred at 50-60°C for 30±5 min. The reaction temperature was reduced to 20-30°C and stirred for the next 180±10 min. The solid was precipitated and it was filtered. The solid was washed with acetone (20 ml +100 ml) and dried under the reduced pressure for 12 h at 50-60°C. 79.2 g of crystalline Encorafenib (Yield: 88%) was obtained with purity 99.91%.

Example 2: Process for the preparation of crystalline Encorafenib using acetone and ethyl acetate mixture (1:1)

Encorafenib technical (25 g) was charged in acetone (200 ml) at room temperature under nitrogen atmosphere. The reaction temperature was raised to reflux, and the reaction mass was stirred for 30±5 min. to get a clear solution. The reaction mass was cooled to 45-50°C and carbon slurry (3.75 g carbon in 50 ml acetone) was added and heating the reaction mass to reflux (50-60°C) for 30±5 min. The carbon slurry was filtered through hyflo bed and wash with pre-heated acetone (75 ml). Further, the filtrate through was passed through micron filter and acetone was completely distilled off from the filtrate under reduced pressure below 45°C. After distillation, the reaction mass was diluted with acetone (25 ml) and ethyl acetate (25 ml) and stirred at 50-60°C for 30±5 min. After stirring, the reaction mass was slowly cooled to 20-30°C and stirred for 180±10 min. The solid was obtained and it was filtered and washed with acetone (2.5 ml +2.5 ml). The obtained compound was dried under reduced pressure for 12 h at 50-60°C. 19.25 g of crystalline Encorafenib (Yield: 70%) was obtained with purity: 99.89%.

Example 3: Process for the preparation of crystalline Encorafenib using acetone and ethyl acetate mixture (1:5)

Encorafenib technical (25 g) was charged in acetone (200 ml) at room temperature under nitrogen atmosphere. The reaction temperature was raised to 50-60°C and the reaction mass was stirred for 30±5 min to get a clear solution. After getting clearing solution, the reaction mass was cooled to 45-50°C and carbon slurry (3.75 g carbon in 50 ml acetone) was added. The reaction temperature was raised to 50-60 °C and maintained for 30±5 min. The carbon was filtered through hyflo bed and washed with pre-heated acetone (75 ml). Further the filtrate was passed through micron filter and acetone was completely distilled out from the filtrate under reduced pressure at below 45°C. After distillation, acetone (25 ml) was charged followed by ethyl acetate (125 ml) to the above reaction mass at 30-45°C. The reaction temperature was raised to 50-60°C and stirred for 30±5 min. Further the reaction mass was cooled to 20-30°C and stirred for 180±10 min. The solid was precipitated, which was filtered and washed with acetone (2.5 ml +12.5 ml). The solid compound was dried under reduced pressure for 12 h at 50-60°C. 22.5 g of crystalline Encorafenib (Yield: 90%) was obtained with purity: 99.40%.

Example 4: Process for the preparation of crystalline Encorafenib using acetone

Encorafenib technical (25 g) was charged in acetone (200 ml) at room temperature under nitrogen atmosphere. The reaction temperature was raised to 50-60°C and the reaction mass was stirred for 30±5 min to get a clear solution. After getting a clear solution, the reaction mass was cooled to 45-50°C. In the reaction mass, carbon slurry (3.75 g carbon in 50 ml acetone) was added. The reaction temperature was raised to 50-60°C and stirred for 30±5 min. The carbon was filtered through hyflo bed and washed with pre-heated acetone (75 ml). Further filter the filtrate was passed through micron filter and acetone was completely distilled out from the filtrate under reduced pressure below 45°C. After distillation, the reaction mass was cooled to 20-30°C and acetone (50 ml) was charged. The reaction mass was stirred for 15±5 min at same temperature and further temperature was raised to 50-60°C. The reaction mass was stirred at 50-60 °C for 30±5 min. Later it was cooled to 20-30°C and continued to stir for 180±10 min. The solid was obtained. It was filtered and washed with acetone (12.5 ml). The obtained compound was dried under reduced pressure for 12 h at 50-60°C. 19.25 g of crystalline Encorafenib (Yield: 77%) was obtained with purity: 99.94%.

Example 5: Process for the preparation of crystalline Encorafenib using ethyl acetate

Encorafenib technical (25 g) was charged in ethyl acetate (200 ml) at room temperature in nitrogen atmosphere. The reaction temperature was raised to 50-60°C and the reaction mass was stirred for 30±5 min. After stirring, ethyl acetate was completely distilled off under reduced pressure below 45°C. Ethyl acetate (62.5 ml) was charged into the reaction flask and the reaction temperature was raised to 50-60°C and stirred for 30±5 min. The reaction mass was cooled to 20-30°C and it was stirred for 180±10 min. The solid was precipitated. The solid was filtered and washed with ethyl acetate (12.5 ml). The obtained compound was dried under reduced pressure for 12 h at 50-60°C. 22.5 g of crystalline Encorafenib (Yield: 90%) was obtained with purity: 99.0%. ,CLAIMS:WE CLAIM:

1. A process for the preparation of crystalline Encorafenib having purity greater than about 99.0% by HPLC comprises providing a solution of Encorafenib in a ketone solvent or mixture of ketone and ester solvent; and isolating the crystalline Encorafenib.

2. The process as claimed in claim 1, wherein the ketone solvent comprises acetone, butanone, methyl isobutyl ketone and ester solvent comprise ethyl acetate, isopropyl acetate, methyl acetate and n-butyl acetate.

3. The process as claimed in claim 1, wherein the solution is prepared at a temperature of 20 - 100? or reflux temperature of the solvent.

4. The process as claimed in claim 1, wherein the ketone solvent is acetone, and the ester solvent is ethyl acetate.

5. The process as claimed in claim 1, wherein the solution is further treated with carbon.

6. The process as claimed in claim 1, wherein the isolation of solid is obtained by using distillation, addition of another solvent, recrystallization, cooling or combination thereof.

7. A process for the preparation of crystalline Encorafenib having purity greater than about 99.0% by HPLC comprises:
a) providing a solution of Encorafenib in a solvent of acetone or ethyl acetate or mixture thereof at 35 to 70°C;
b) optionally, treating the solution with carbon; and
c) cooling the solution to precipitate the crystalline Encorafenib.

8. The process as claimed in claim 7, wherein the carbon treatment is carried out at a temperature of about 20 to 100°C.