DESC:FIELD OF INVENTION

The present invention provides a novel process for the preparation of Encorafenib, which process has many advantages over prior art processes such as reducing side reactions and improving the yield of the product.

BACKGROUND OF THE INVENTION

Encorafenib is chemically known as methyl N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3-(methane sulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2yl} carbamate and has the structural formula (I):

- Formula-I
Encorafenib is a kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively.

Encorafenib is approved by USFDA as BRAFTOVI capsule for oral administration; in
combination with Binimetinib or Cetuximab for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

Encorafenib was first disclosed in US 8,501,758 B2. According to US 8,501,758 B2 the process for the preparation of Encorafenib (I) involves two approaches, the first approach involved Methanesulfonyl chloride is reacted with solution of (S)-methyl-1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate in presence of DCM and pyridine to produce Encorafenib of formula (I) and other compounds.

The second approach involved reacting the (S)-Methyl-1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate with methane sulfonyl chloride in presence of 2-methyltetrahydrofuran and triethylamine provides bis-mesylated product, which further undergoes selective deprotection using aq. sodium hydroxide in presence of 2-Methyltetrahydrofuran to provide Encorafenib.

As per prior-art process, the present inventors observed that both approaches are not suitable for commercial scale due to involves isolation of other compounds of Methyl N-[(2S)-2-({4-[3-(5-chloro-2-fluoro-3-methanesulfonamidophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propyl]carbamate, N-{3-[4-(2-aminopyrimidin-4-yl)-1-(propan-2-yl)-1H-pyrazol-3-yl]-5-chloro-2-fluorophenyl}methanesulfonamide and bis-mesylated product. In selective de-protection of bis-mesylated product both mesyl groups are de-protected and isolated as a starting material as well as in both approaches involve the use of base such as pyridine and tri-ethylamine and organic solvents such as dichloromethane and 2-methyltetrahydrofuran and isolation compound involves column chromatography.

In view of the above cited prior art, the present inventors understood the need for a process for the preparation of Encorafenib having high purity and low level of impurities, which obviates the drawbacks of the prior art.

The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and to provide a new process for the preparation of Encorafenib provide a more economical, efficient, and environmentally friendly, having high purity and acceptable levels of impurities.

In view of this the present inventors have developed a process for the preparation of the Encorafenib without use of base, organic solvent and selective methylsulfonation.

The present invention gives Encorafenib high yields in low cost and economical and commercially applicable.

OBJECTIVES OF THE INVENTION

The objective of the present invention is to provide process for preparation of Encorafenib simple, environmental friendly and cost- effective.

Another object of the present invention is to provide a process for preparation of Encorafenib with high yield and purity.

Another object of the present invention is to provide a process for preparation of Encorafenib which involves selective mono-methanesulfonylation.

Another object of the present invention is to provide a process for preparation of Encorafenib which minimizes the impurities.

Another object of the present invention is to provide a process for preparation of Encorafenib in which the products obtained are easily isolated and purified.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of Encorafenib compound of formula I which comprising reacting compound of formula II with methane sulfonyl chloride in presence of water.

In an another aspect of the present invention provides a process for purification of Encorafenib compound of formula I which comprising:
a) dissolving Encorafenib in isopropyl alcohol solvent;
b) heating the reaction mixture to 80-90°C;
c) Isolating pure Encorafenib.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to process for the preparation of Encorafenib, which comprises, reacting (S)-methyl-1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl) pyrimidin-2-ylamino)propan-2-ylcarbamate of compound Formula II with methane sulfonyl chloride in presence of water to yield Encorafenib of formula I.

The Encorafenib of formula I may be prepared by the prior-art process of first approach carried out by treating the (S)-Methyl-1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate with methane sulfonyl chloride in presence of Dichloromethane and pyridine comparative to the present process.
Process Bis-methylated impurity
Purity
prior- art process
6.09 % 89.74 %
present process
0.3 % 90.57 %

The Encorafenib of formula I may be prepared by the prior-art process of second approach carried out by treating the (S)-Methyl-1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate with methane sulfonyl chloride in presence of triethylamine and 2-methyltetrahydrofuran to give Bis mesylated compound (approximately 88 %) along with Encorafenib (approximately 3 %), which in-turn undergoes hydrolysis in presence of aq. Sodium hydroxide converting to starting material of (S)-Methyl-1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl) pyrimidin-2-ylamino)propan-2-ylcarbamate (approximately 28 %).

The present invention involves reacting (S)-methyl-1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl) pyrimidin-2-ylamino)propan-2-ylcarbamate of compound Formula II with methane sulfonyl chloride in presence of water to yield Encorafenib of formula I by reducing the formation of starting material impurity and Bis-methylated impurity comparative to the known process
Process Starting material impurity Purity Yield (%)
prior- art process
28.2 % 67.7 % 50 %
present process
3.82 % 90.57 % 60 %

In another embodiment of the present invention is therefore the yield of the Encorafenib has been increased to due to selective mono-sulfonylation. Bis-sulfonylated product was not observed so no need of hydrolysis reaction.

In another embodiment of the present invention is therefore no need to de-protection of Bis-methylsulfonation compound so isolation of intermediate compounds are minimized, as per present invention Sulfonylation of compound of formulation II in presence of water as solvent yields mono-sulfonylation compound of formula I.

In another embodiment of the present invention is therefore the reaction is carried out in water as solvent, No base or organic solvents are required, selective monosulfonylation, less number of steps, higher yield and low cost.

Use of water as a solvent has several advantages, including natural resource, easy to obtain, low in cost, biorenewable, non-flammable, preventing the generation of waste, avoiding the use of hazardous substances (e.g. halogenated and high boiling solvents) and minimization of energy requirements.

In another embodiment, the present invention provides a process for purification of Encorafenib compound of formula I, which comprises of dissolving Encorafenib in Isopropyl alcohol solvent by heating to 80-90°C; and then cooling the reaction mixture to room temperature. Precipitated solid has been filtered and dried to get pure Encorafenib.

Further, the present invention also avoids the use of base as well as organic solvents. This results economical friendly process as well as cost-effective process, high yield and number of synthetic steps will be reduced.

The invention of the present application will be explained in more detail with reference to the following examples, which should not be construed as limiting the scope of the invention in any manner.

Reference Example 1: Preparation of 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)

To a solution of (S)-methyl 1-(4-(3-(3-amino-5-chloro 2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (5g ), DCM (272 ml) and pyridine (91 ml), added Methane sulfonyl chloride (2.49 ml) and the mixture was stirred at 25-30°C for 16 h. After completing the reaction, aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate and washed with sodium chloride. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography using Ethyl acetate-Hexane to get 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.

Yield: 3.9 g, 66 %;
Purity by HPLC: 89.74 %;
Bis-methylated impurity: 6 %.

Reference Example 2: Preparation of 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)

Step A: A mixture of (S)-methyl 1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (3 g), 2-methyltetrahydrofuran (28 ml) and triethylamine (3.28 g) was cooled to 0 to -5°C and added methane sulfonyl chloride (1.86 g) drop wise and stirred for 20 min at 0 to -5°C. The mixture was allowed to warm to 18-20°C and stirred at this temperature for 20 min. water was added to the reaction mixture was added water over 30 min at 18-20°C and the mixture was stirred 10 min at 20°C. Then the pH was adjusted to between 6.0 and 6.5 using 2N HCl. The pH was then adjusted to 7-7.5 using saturated aqueous sodium bicarbonate solution. The mixture was stirred 10 min at 20°C. The layers were separated. The 2-methylTHF layer containing the title compound was used directly in step B.
Step B: 3N aqueous sodium hydroxide (10 mL) was added to the organic layer obtained in step A at 15-20°C. The mixture was vigorously stirred at 20-23°C for 30 minutes. The aqueous layer was discarded, HCl was added to the organic layer to adjust the pH to 6.0–6.5, then saturated aqueous sodium bicarbonate solution was added to adjust the pH -8.5. The aqueous layer was discarded. The organic layer was washed with aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure to give brown solution oil. The crude product was purified by column chromatography using Ethyl acetate-Hexane to get 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).

Yield: 1.75 g; 50 %;
Purity by HPLC: 67.7 %;
Impurity: (S)-methyl 1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate: 28.2 %

Example-1: Preparation of 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)

Methanesulfonyl chloride (100 ml) was added to a mixture of (S)-methyl 1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-yl carbamate and water at 25-35°C and stirred for 18 hours. After completion of the reaction, pH of the reaction mixture was adjusted to 8-8.2 using 10% Sodium carbonate solution. The reaction mixture was extracted with dichloromethane and distilled off the solvent completely to get residue. A mixture of methanol (100 ml) and water (100 ml) was added to the residue at 25-35°C and stirred for 8 hours. Filter the solid and wash with and water and then dried to get 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 compound of formula I.

Yield: 14 g. 60 %;
Example-2: Preparation of methyl N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3-(methane sulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino] propan-2yl}carbamate (Formula I)
To a stirred solution of (S)-methyl 1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl) pyrimidin-2-ylamino) propan-2-ylcarbamate (3 g) in water (30 ml) was added methane sulfonyl chloride (22.2 g) and stirred at 25-30°C. After completion of the reaction, the reaction mixture was neutralized with aqueous sodium carbonate solution and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue was purified by column chromatography using Ethyl acetate and Hexane to get 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).

Yield: 2.1 g, 60%;
Purity by HPLC: 90.57 %;
Bis-methylated impurity: 0.3;
Starting material impurity : 3.82 %

Example-3: Preparation of (S)-Methyl 1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate

2-Chloro-4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)-pyrimidine was added to Dimethylsulfoxide (300 ml), (S)-methyl 1-aminopropan-2-ylcarbamate hydrochloric acid salt (63 g) and sodium carbonate (91.2 g) at 25-35°C. The reaction mixture was heated to 93-103°C and stirred for 8 hours. After completion of the reaction, the reaction mixture was cooled to 40-50°C and water was added to the reaction mixture and stirred for 2 hours at 25-35°C. Filtered the precipitated solid, Toluene (200 ml) and n-Heptane (200 ml) were added to the obtained solid and stirred for 2 hours at 25-35°. Filtered the solid and dried to get (S)-Methyl 1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate.
Yield: 120-124 g; 94.4%
Purity by HPLC: 98%

Example-4: Preparation of (S)-Methyl 1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate.
(S)-Methyl 1-(4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (50 g) was added to Toluene (250 ml), Tert-butyl 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (46.03 g), sodium carbonate (35.8g) at 25-35°C and stir for 10 minutes. Pd(dppf)Cl2 (0.42 g) was added at 25-35°C and heated 60-70oC and maintained for 10-20 minutes, the temperature of the reaction mixture raised to 85-95°C and maintained for 7 hours, the reaction mixture was cooled to 25-35°C. Filtered the reaction mixture through Hi-flow and separate the organic layer. The organic layer was treated with Activated carbon and then filtered to remove the activated carbon. Conc. HCl (75 ml) was added to the filtrate and stirred for 4 hours at 25-35°C. Water was added to the reaction mixture and separated both the organic and aqueous layers; the aqueous layer was treated with aq. Sodium carbonate solution and then extracted into Ethyl acetate. Distilled off the solvent completely from organic layer, Toluene (250 ml) and n-Heptane (250 ml) were added to the obtained residue at 25-35°C and stirred for 6 hours. Filtered the solid and then dried to get (S)-Methyl 1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate.

Yield: 43-45 g; 82.6%;
Purity by HPLC: 98%.

Example-5: Preparation of 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) .

Pyridine (4.36 ml) and Dimethylaminopyridine (0.013 g) were added to a mixture of (S)-methyl 1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl) pyrimidin-2-ylamino) propan-2-ylcarbamate (5 g) and Dichloromethane (50). Methane sulfonyl chloride (1.25 ml) was added to the reaction mixture at 25-35°C and maintained for 22 hours, After the reaction was completed charged aq, Hydrochloric acid solution and stirred for 15 minutes and separated the layers. The organic layer was washed with sodium bicarbonate solution and water. Activated carbon was added and filtered the reaction mixture and distilled off the solvent from the filtrate. Isopropyl alcohol (25 ml) was added to the residue obtained and stirred for 2 hours and sucked for 30 minutes. Dichloromethane (50 ml) followed by activated carbon were added to the wet solid and stirred for 15 minutes. Filtered the reaction mixture and distilled off the solvent completely under reduced pressure. Methanol (50 ml) was added to the obtained solid and stirred for 2 hours. Filtered the reaction mixture and dried the solid to get 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)

Yield: 2.95 g; 50.51 %;
Purity by HPLC: 99.66 %.

Example-6: Preparation of methyl N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3-(methane sulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino] propan-2yl}carbamate (Formula I) .

Pyridine (90.9 ml) followed by Methane sulfonyl chloride (2.49 ml) were added to a mixture of methyl 1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (5 g) and Dichlorometheane (272.7 ml) and stirred for 18 hours at 25-30°C. After the reaction was completed, Ethyl acetate and aq. sodium bicarbonate solution were added to the reaction mixture and both the organic and aqueous layers were separated. The organic layer was washed with sodium chloride solution and dried with sodium sulfate. Distilled off the solvent from organic layer and co-distilled with Ethanol. Ethanol (30 ml) was added to the obtained solid and raised the temperature to 70-80°C and stirred for 45 minutes. Cooled the reaction mixture to 0°C and stirred for 2 hours. Filtered the reaction mixture, washed with ethanol and then dried to get methyl N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3-(methane sulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino] propan-2yl}carbamate (Formula I).

Yield: 3.9 g; 66.72 %;
Purity by HPLC: 99.23%

Example-7: Preparation of methyl N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3-(methane sulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino] propan-2yl}carbamate (Formula I)

Dimethylaminopyridine (0.119 g) and pyridine (39.2 ml) were added to a mixture of methyl 1-(4-(3-(3-amino-5-chloro-2-fluorophenyl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (45 g) and Dichloromethane (450 ml) at 25-35°C and stirred for minimum 10 minutes. Methane sulfonyl chloride (11.3 ml) was added to the reaction mixture at 25-35°C and stirred for 22 hours. After the reaction was completed, the organic layer was treated with aqueous Hydrochloric acid solution followed by aqueous sodium bicarbonate solution and water. Activated carbon was added to organic layer and filtered the reaction mixture and washed with Dichloromethane. Distilled off the solvent completely and co-distilled off the solvent Isopropyl alcohol. Isopropyl alcohol (360 ml) was added to the solid obtained and stirred for 2 hours at 25-35°C. Filtered the solid and suck dried to get solid. Dichloromethane (450 ml) followed by activate carbon were added to the solid and stirred for 30 minutes at 25-35°C. Filtered and distilled of the filtrate and then co-distilled with Isopropyl alcohol. Isopropyl alcohol (360 ml) was added, heated to 80-90°C and stirred for 1 hour. Cool the reaction mixture to 25-35° and stirred for 4 hours. Filtered the solid and then dried to get methyl N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3-(methane sulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino] propan-2yl}carbamate (Formula I).

Yield: 42 g; 75.09%;
Purity by HPLC: 99.8% ,CLAIMS:1. A process for the preparation of Encorafenib compound of formula I
I,
which comprising reacting compound of formula II

with methane sulfonyl chloride in presence of water.

2. A process for purification of Encorafenib compound of formula I
which comprises:
a) dissolving Encorafenib in isopropyl alcohol solvent;
b) heating the reaction mixture to 80-90°C;
c) cooling the reaction mixture to room temperature; and
d) isolation pure Encorafenib.