A process for making dabrafenib

Abstract

The invention relates to a process for preparation of Dabrafenib, compound of formula (1) or a salt or a solvate thereof:.

Description

[0001] A PROCESS FOR MAKING DABRAFENIB

[0002] The present invention relates to an improved process for preparation of Dabrafenib or a salt thereof or a solvate thereof.

[0003] BACKGROUND OF THE INVENTION

[0004] Dabrafenib, chemically N-[3-[5-(2-Aminopyrimidin-4-yl)-2-tert-butylthiazol-4-yl]-2- fluorophenyl]-2,6-difluorobenzenesulfonamide of formula (1); is a B-Raf (BRAF) protein inhibitor used for the oral treatment of previously untreated patients with

[0005] BRAF V600 mutated advanced or metastatic melanoma as a monotherapy. Dabrafenib is marketed as methane sulfonate (mesylate) salt under trade name Tafinlar by GlaxoSmithKline. Dabrafenib was first disclosed in WO2009137391 application. Several processes for preparation of Dabrafenib are described in the prior art for example in W02009137391 or CN103588767 or WO2016059548 or WO2023043292 applications. The last step of the process described in WO2009137391 is depicted in following scheme:

[0006] The main disadvantage of the process described in WO2009137391 and other applications is that after the depicted reaction is finished, the product is isolated from the reaction mixture and purified by extractions or by using a column chromatography. Both extractions and column purification are time consuming processes where high volumes of organic solvents are used. The other processes described in prior art also use organic solvents in the depicted reaction and in processes for isolation and purification of the product. There is still a need to find an improved process that is not using organic solvents either in the reaction or in a subsequent step of isolating and purification of the product and also simplifies the isolating step.

[0007] BRIEF DESCRIPTION OF THE PRESENT INVENTION

[0008] The presented invention relates to a process for preparation of Dabrafenib, compound of formula (1), or a salt or a solvate thereof, the process comprising: a. Reacting compound of formula (3) in a solvent with a brominating agent, preferably N- bromosuccinimide, wherein the molar ratio between compound of formula (3) and the brominating agent, preferably N-bromosuccininimide, is between 1:0.97 and 1:0.99; b. Adding compound of formula (4) in the reaction mixture to provide compound of formula (2): c. Transforming compound of formula (2) into Dabrafenib, compound of formula (1).

[0009] The presented invention also relates to a process for preparation of Dabrafenib, compound of formula (1), or a salt or a solvate thereof: the process comprising: a. Reacting compound of formula (2) with water solution of ammonia: b. Adding water into the mixture; c. Isolating a solid form of compound of formula (1).

[0010] The presented invention further relates to a process for preparation of Dabrafenib, compound of formula (1), or a salt or a solvate thereof: the process comprising:

[0011] Reacting compound of formula (2) with ammonia in a solvent mixture of water and tetrahydrofurane, wherein the weight ratio between water and tetrahydrofurane can be between 4: 1 and 5: 1

[0012] The salt of Dabrafenib is preferably methane sulfonate salt.

[0013] There are following advantages of the presented invention:

[0014] • Isolation of solid form of Dabrafenib is done by simple addition of water to the reaction mixture, no extraction process or purification by column chromatography is used contrary to the processes described in the prior art;

[0015] • In a preferred exmbodiment of the presented invention, the reaction is perfomed in water, no organic solvent is used; process is therefore more environmental friendly than processes described in prior art using organic solvents for preparation of Dabrafenib;

[0016] • In another rpefereed embodiment of the presented invention the reaction is perfomed in a mixture of water and tetrahydrofurane, that further improves the reacion yields and purity of obtained Dabrafenib;

[0017] • The reaction time in decreased in comparison with the processes described in the prior art;

[0018] • Yield and purity of Dabrafenib are improved in comparison with processes described in the prior art;

[0019] • Use of the process of presented invention for isolating the methane sulfonate salt of Dabrafenib decreases the amount of acetonitrile in prepared Dabrafenib methane sulfonate salt. BRIEF DESCRIPTION OF THE FIGURES

[0020] Figure 1 depicts XRPD pattern of a solid form of compound of formula (2) prepared according to Example 2 or 3

[0021] Figure 2 depicts XRPD pattern of a solid form of compound of formula (3) prepared according to Example 1

[0022] DETAILED DESCRIPTION OF THE INVENTION

[0023] The presented invention relates to a process for preparation of Dabrafenib, compound of formula (1) or a salt or a solvate thereof, the process comprising: a. Reacting compound of formula (3) in a solvent with a brominating agent, preferably N- bromosuccinimide, wherein the molar ratio between compound of formula (3) and the brominating agent, preferably N-bromosuccinimide, is between 1:0.97 and 1:0.99:

[0024] B-bromosuccinimide b. Adding compound of formula (4) in the reaction mixture to provide compound of formula (2): c. Transforming compound of formula (2) into Dabrafenib, compound of formula (1).

[0025] In a preferred embodiment, the molar ratio between the compound of formula (3) and the brominating agent, preferably N-bromosuccinimide, can be between 1:0.98 and 1:0.99.

[0026] The solvent used in step a. and b. can be preferably dimethylacetamide. The improvement of the presented process when comparing to the processes described in prior art is that in both steps a. and b. is performed in the same solvent, preferably in dimethylacetamide, that simplifies reaction in comparison with the processes described in prior art. The prior art processes use different solvents used in steps a. and b. and comprise extractions and solvents switch that are time consuming operations that are not suitable for large scale processes. The processes described in prior art uses 1 or more equivalents of the brominating agent in the reaction step between the compound of formula (3) and the brominating agent. We have surprisingly found that when the molar ratio between the compound of formula (3) and the brominating agent, preferably N-bromosuccinimide, is between 1:0.97 and 1:0.99, preferably between 1:0.98 and 1:0.99, reaction conversions are improved and reaction time is decreased in comparison with the processes described in the prior art.

[0027] It the following table reaction results reaction of between the compound of formula (3) and the brominating agent, preferably N-bromosuccinimide, are summarized.

[0028] * based on HPLC data It can be concluded that when ratio between compound of formula (3) and the brominating agent, preferably N-bromosuccinimide, according to presented invention is used, the reaction conversion is improved and reaction time is decreased.

[0029] The concentration of compound of formula (3) in the solvent, preferably dimethylacetamide, can be between 0.2 g / g and 0.4 g / g. Compound of formula (3) is mixed with the solvent, preferably dimethylacetamide and the mixture can be optionally cooled to a temperature between -20°C and 0°C. To the mixture a mixture ot the brominating agent, preferablz N-bromosuccinimide, in the solvent, preferably in dimethylacetamide, is added. The concentration of the brominating agent in the solvent can be between 0.2 g / g and 0.4 g / g. The bromination agent can be added in several portions, for example in 2 or 3 or 4 or 5 or 6 or 7 or 8 portions during for example between 30 minutes and 120 minutes. Obtained mixture is then stirred for between 20 and 120 minutes at a temperature between - 20°C and 0°C. To the mixture a mixture of compound of formula (4) in the solvent, preferably dimethylacetamide, is added. The concentration of compound of formula (4) in the solvent can be between 0.2 g / g and 0.4 g / g. The mixture is stirred at a temperature between -20°C and 0°C for between 20 minutes and 120 minutes and then is heated to a temperature between 50°C and 80°C and stirred at this temperature for between 45 minutes and 120 minutes. The mixture is cooled to a temperature between 0°C and 25°C. To the mixture ethylacetate and water solution of NaCl are added. The weight ratio between ethylacetate and water solution of NaCl can be between 0.7: 1 and 1: 1. The concentration of NaCl in water solution of NaCl can be between 0.08 g / g and 0.12 g / g. The weight ratio between added ethylacetate and NaCl water solution and the solvent used in reaction, preferably dimethylacetamide, can be between 3.5: 1 and 4.5: 1. Layers are separated. From the organic phase approximatelly 2 / 3 of the solvents is distilled off. To the rest a mixture of tetrahydrofurane and acetone is added. The weight ratio between tetrahydrofurane and acetone can be between 1:0.2 and 1:0.5, preferably it is between 1:0.3 and 1:0.4. The weight ration between added mixture of tetrahydrofurane and acetone and ethylacetate can be between 1:0.8 and 1: 1.2. The mixture can be optionally heated to a temperature between 40°C and 50°C and stirred at this temperature for between 10 and 60 minutes. To the mixture water is added. The weight ratio between water and the mixture of tetrahydrofurane and acetone can be between 1:0.8 and 1: 1. The mixture is cooled to a temperature between 0°C and 20°C to obtain a suspension. The suspension is filtered off and obtained solid compound of formula (2) can be optionally washed for example with a mixture of acetone and water and dried.

[0030] The solid form of compound of formula (2) can be characterized by XRPD pattern having 20 values at 7.2°, 11.8°, 14.9° and 19.8° degrees 2 theta (± 0.2 degrees 2 theta), when measured with

[0031] CuKal radiation (X = 1.54060 A). The solid form of compound of formula (2) can be further characterized by by a XRPD pattern having 20 values at 7.2°, 9.1°, 11.8°, 14.9°, 17.0°, 19.8° and 27.1° degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid form can be also characterized by XRPD pattern described in the following table:

[0032] The solid form can be also characterized by XRPD pattern depicted in Figure 1. Dabrafenib, compound of formula (1) or a salt or a solvate thereof, can be prepared by a process comprising:

[0033] Reacting compound of formula (2) with ammonia in a solvent mixture of water and tetrahydrofurane, wherein the weight ratio between water and tetrahydrofurane can be between 4: 1 and 5: 1:

[0034] The concentration of compound of formula (2) in the mixture of water and tetrahydrofurane can be between 0.04 g / g and 0.07 g / g. The molar ratio between compound of formula (2) and ammonia can be between 1:60 and 1:80, preferrably it is 1:70. Compound of formula (2) is mixed with ammonia, water and tetrahydrofurane. Ammonia can be also used in form of a solution of ammonia in water for example 20-25% solution. The amount of water added to the reaction mixture is then reduced of the water added to the mixture in the form of water present in water solution of ammonia. The reaction is perfomed in closed reaction vessel. The mixture is heated to a temperature between 70°C and 80°C for between 4 and 8 hours at a pressure between 4 and 5 bar. The reaction mixture is concentrated to approximatelly 80% to 85% of original weight. The rest is cooled to a temperature between 0°C and 15°C to obtain a suspension. The suspension is filtered off and obtained solid form Dabrafenib can be optionally washed for example with water.

[0035] Using the process of ther presented invention further improves the yield and purity of obtained Dabrafenib in comparison with processes described in the prior art.

[0036] A solid form of Dabrafenib can be also prepared by a process comprising: a. Mixing Dabrafenib with ethylacetate and water; b. Isolating a solid form of Dabrafenib.

[0037] The concentration of the Dabrafenib in the mixture of ethylacetate and water can be between 0.1 g / g and 0.2 g / g. The weight ratio between ethylacetate and water can be between 5.5: 1 and 6.5: 1, preferably it is between 6: 1. Dabrafenib is mixed with a mixture of ethylacetate and water. The mixture is heated to a temperature between 60°C and 80°C. Layers are separated. To the organic layer ethylacetate can be optionally added to ensure that all water is removed in the subsequent concentration step. That improves the yield of solid form of Dabrafenib prepared in the process. The weight ratio between added ethylacetate and ethylacetate in mixture with water can be between 1: 1.8 and 1:2.2. The organic phase is concentrated to approximately 80%-85% of original weight. The mixture is cooled to a temperature between 0°C and 10°C and stirred for between 3 and 10 hours to provide a solid form of Dabrafenib, compound of formula (1).

[0038] The presented invention also relates to a process for preparation of Dabrafenib, compound of formula (1), or a salt or a solvate thereof: the process comprising: a. Reacting compound of formula (2) with water solution of ammonia: b. Adding water into the mixture; c. Isolating a solid form of compound of formula (1).

[0039] The salt of Dabrafenib is preferably methane sulfonate salt.

[0040] The concentration of compound of formula (2) in water solution of ammonia can be between 0.06 g / g and 0.1 g / g, preferably it is between 0.07 g / g and 0.08 g / g. Water solution of ammonia is preferably 25% (weight %) water solution of ammonia. The molar ratio between compound of formula (2) and ammonia can be between 1:45 and 1:50. The reaction is preferably perfomed in a closed reactor under a pressure (can be a pressure of ammonia from present water solution of ammonia or can be a pressure of an inert gas such as nitrogen or argon) between 5 and 6 bars, preferably under a pressure of 5.5 bars. Compound of formula (2) is mixed with water solution of ammonia (NH4OH). The mixture is preferably placed in a closed reactor and heated to a temperature between 90°C and 110°C. The mixture is then stirred at this temperature under a pressure between 5 and 6 bars, preferably under a pressure of 5.5 bars for between 1 and 2 hours. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is completed, the mixture is cooled to a temperature between 15°C and 30°C. To the mixture water is added. The weight ratio between added water and the water solution of ammonia can be between 0.4: 1 and 0.8: 1, preferably it is between 0.5: 1 and 0.6: 1. The mixture is then stirred for between 1 and 2 hours to obtain a suspension. The suspension is filtered off to provide the Dabrafenib, compound of formula (1) in a good yield and purity. Obtained Dabrafenib can be optionally washed with water and dried. In comparison with processes described in prior art (using either extractions or purification using column chromatography, both beeing time consuming and using high volumens of organic solvents) the process of the presented invention is simple and uses no organic solvent for preparation of Dabrafenib.

[0041] Dabrafenib methane sulfonate salt can be prepared by a process comprising: a. Mixing Dabrafenib with acetonitrile and water, wherein the weight ratio between acetonitrile and water is between 9: 1 and 11: 1; b. Adding methane sulfonic acid; c. Isolating solid form of Dabrafenib methane sulfonate salt at a temperature between 15 °C and 30°C, preferably between 20°C and 25°C.

[0042] The concentration of Dabrafenib in acetonitrile and water mixture can be between 0.07 g / g and 0.15 g / g. Dabrafenib is mixed with water and acetonitrile. The mixture is hetated to a temperature between 60°C and 70°C. To the mixture methane sulfonic acid is added. The concentration of the methane sulfonic acid in the mixture water and acetonitrile can be between 0.012 g / g and 0.016 g / g. The molar ratio between Dabrafenib and methane sulfonic acid can be between 1 : 1 and 1: 1.1, preferably it is between 1 : 1 and 1 : 1.05. The mixture is stirred at a temperature between 50°C and 60°C for between 4 and 10 hours. The mixture is cooled to a temperature between 15°C and 30°C, preferably between 20 and 25°C, and stirred at this temperature for between 1 and 10 hours to obtain a suspension. The suspension is fdtered off and obtained solid of compound of formula (1) can be optionally washed with for example acetonitrile and dried.

[0043] We have surprisingly found that using the process of the presented invention can significantly decrease the amount of acetonitrile in prepared Dabrafenib in comparison with the processes described in the prior art. When the process described in the prior art was used (reaction in acetonitrile only and isolation of the obtained methane sulfonate salt of Dabrafenib at 0-5°C), the content of acetonitrile in obtained solid was 12461 ppm that is not suitable for production of API or final product containing the API for treatment. The content of acetonitrile in methanesulfonate salt of Dabrafenib prepared according to presented invention is lower than 500 ppm, preferably lower than 300 ppm, more preferably lower than 150 ppm.

[0044] Dabrafenib methane sulfonate salt can be also prepared by a process comprising: a. Mixing Dabrafenib methane sulfonate salt with a mixture of acetonitrile and water, wherein the weight ratio between acetonitrile and water can be betweem 5: 1 and 8: 1, preferably it is between 6: 1 and 7: 1; b. Isolating Dabrafenib methane sulfonate salt at a temperature between 15 °C and 30°C, preferably between 20°C and 25°C.

[0045] Dabrafenib is mixed with acetonitrile and water. The concentration of Dabrafenib in acetonitrile and water can be between 0.07 g / g and 0.15 g / g. The mixture is heated to a temperature between 60°C and 70°C to obtain a solution. The solution is cooled to a temperature between 50°C and 60°C and stirred at this temperature for between 1 and 5 hour. The mixture is cooled to a temperature between 15°C and 30°C, preferably between 20°C and 25°C, and stirred at this temperature for between 1 and 10 hours to obtain a suspension. The suspension is filtered off and obtained Dabrafenib methane sulfonate salt can be optionally washed with for example with acetonitrile and dried.

[0046] We have surprisingly found that using the process of the presented invention can significantly decrease the amount of acetonitrile in prepared Dabrafenib methane sulfonate salt in comparison with the processes described in the prior art. When the process described in the prior art was used (reaction in acetonitrile only and isolation of the obtained methane sulfonate salt of Dabrafenib at 0-5 °C), the content of acetonitrile in obtained solid was 12461 ppm that is not suitable for production of API or final product containing the API for treatment. The content of acetonitrile in methanesulfonate salt of Dabrafenib prepared according to presented invention is lower than 500 ppm, preferably lower than 300 ppm, more preferably lower than 150 ppm.

[0047] The presented invention therefore also relates to Dabrafenib methane sulfonate salt comprising less than 500 ppm of acetonitrile, preferably less than 300 ppm of acetonitrile, more preferably less than 150 ppm of acetonitrile.

[0048] The invention will be further described with reference to the following examples.

[0049] EXAMPLES

[0050] Example 1: Preparation of N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6- difluorobenzenesulfonamide, compound of formula (3)

[0051] The reaction was performed under nitrogen.

[0052] 150 g of methyl 3-((2,6-difluorophenyl)sulfonamido)-2 -fluorobenzoate was mixed with 340 g of tetrahydrofurane. The mixture was cooled to -2 °C. 1200 g of Lithium hexamethyldisilazide was added during 70 minutes. To the mixture a solution prepared from 57 g of 2-chloro-4-methylpyrimidine in 600 g of tetrahydrofurane was added during 65 minutes at a temperature between (-2) and (-3)°C. The mixture was heated to 10 °C and stirred 30 minutes. A solution of 405 g of 36% HC1 and 495 g of water was added at a temperature between 10°C and 22.6°C. Layers were separated. Organic layer was evaporated to 550 g, to the rest 1200 g of acetone and 150 g of water was added. The mixture was heated to 50 °C. To the mixture 850 g of water was added during 30 minutes at a temperature between 52°C and 48 °C. The mixture was stirred for 30 minutes at the temperature between 48°C and 50°C. To the mixture 350 g of water was added during 20 minutes at a temperature between 52°C and 48°C. The mixture was cooled to 20 °C and stirred at this temperature for 14 hours. Obtained suspension was filtered off, obtained solid was washed with 140 g of acetone and 140 g of water. 165. 1 g of compound of formula (3) was prepared (86% yield, 99.7% purity, HPLC IN). XRPD patern of prepared solid corresponds to XRPD patern depicted in Figure 2. The solid form can be also characterized by XRPD patern described in following table:

[0053] Example 2: Preparation of N-(3-(2-(tert-butyl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2- fluorophenyl)-2,6-difluorobenzenesulfonamide, compound of formula (2) was cooled to -9 °C. To the mixture 60 g of N-bromosuccinimide in 180 g of dimethylacetamide at a temperature between -15°C and (-8.5 °C) during 45 minutes were added. The mixture was stirred for 30 minutes. A mixture of 39 g of compound of formula (4) in 150 g of dimethylacetamide was added during 50 minutes at a temperature between (-10°C) and (-5.5) °C. The mixture was stirred for 30 minutes at (-7 °C). The mixture was heated to 70 °C and stirred for 1 hour. The mixture was cooled to 15°C. To the mixture was added 600 g of ethylacetate and 750 g of water at (17-25) °C during 30 minutes. To the mixture 75 g of NaCl was added. Layers were separated at 22 °C. Organic phase was evaporated to 323 g. To the rest 150 g of tetrahydrofurane and 450 g of acetone were added. The solution was heated to 47 °C and 600 g of water was added during 15 minutes. The mixture was cooled to 5°C to obtain a suspension. The suspension was fdtered off, obtained solid was washed with a mixture 50 g of acetone and 50 g of water to provide 158.34 g of formula (2) in yield 86.53 % and purity 99.8% (HPLC IN). XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 1.

[0054] Example 3: Preparation of solid form of compound of formula (2)

[0055] 188 g of compound of formula (2) was mixed with 640 g of acetone and 160 g tetrahydrofurane. The mixture was heated to 52 °C. To the mixture 500 g of water was dropwise added during 10 minutes. The mixture was stirred during 15 minutes at 48-50°C. 140 g of water was added during 10 minutes at (52-48) °C. The mixture was cooled to 2 °C during 1.5 hour to obtain a suspension. The suspension was fdtered off, obtained solid was washed with 2x50 g mixture acetone-water (weight ratio 1: 1) and dried to provide solid form of compound of formula (2) in 79% yield.

[0056] Example 4: Preparation of Dabrafenib, compound of formula (1) ammonia). The mixture was stirred in closed reactor (glass Miniclave) at 96 - 98 °C for 1 h at 5.5 bar.

[0057] "The mixture was then was cooled to 20°C, 100 g of water was added. The mixture was then stirred for 1 hour. Obtained suspension was filtered, obtained solid was washed with 3x25 g of water and dried in vacuum dryer (65 °C, 100 mbar, for 14 hours). 13.05 g of compound of formula (1) (90.25 % of theoretical yield) was obtained in purity 99.59% (HPLC).

[0058] Example 5: Preparation of Dabrafenib, compound of formula (1)

[0059] The reaction was performed in an autoclave (closed reactor).

[0060] 150 g of compound of formula (2) was mixed with 2800 g of NH4OH (24.5 % solution of ammonia in water, 200 of water, 225 g of tetrahydrofurane. The mixture was heated to 75 °C and stirred for 5.5 hour at 4.2 bar. From the mixture solvent was evaporated to the final weight 2652 g. The mixture was cooled to 10°C and stirred to obtain a suspension. The suspension was filtered off, obtained solid was washed with 2x70 g of water to provide 185 g of the wet solid Dabrafenib hydrate in purity 98.3% (HPLC IN).

[0061] Example 6: Preparation of a solid form of Dabrafenib, compound of formula (1)

[0062] 185 g of Dabrafenib preferably prepared according to example 5 was mixed with 1200 g of ethylacetate and 200 g of water. The mixture was heated to 70 °C. Layers were separated. To the organic layer 600 g of ethylacetate was added. The organic layer was concentrated to final weight 1480 g. To the rest 200 g of ethylacetate was added and the mixture was cooled to 2°C and stirred at this temperature for 4 hour to obtain a suspension. The suspension was filtered off and obtained solid was washed with 120 g of ethylacetate to provide 131.6 g of Dabrafenib in form of ethylacetate solvate (yield 78.5%, purity 99.8% (HPLC IN)). Example 7: Preparation of methane sulfonate salt of Dabrafenib

[0063] 2.50 g of Dabrafenib, compound of formula (1), was mixed with 25 g of acetonitrile and 2.50 g of water. The mixture was heated to 62 °C. To the mixture 0.41 g of methane sulfonic acid was added. The mixture was stirred for 2 hours at 53°C and cooled to 22 °C during 5 hour to obtain a suspension. The suspension was fdtered off at 22°C and obtained solid was washed with 2x2.5 g of acetonitrile and dried (16 hours, 85 °C, 100 mbar) to provide 2.05g of Dabrafenib salt with methane sulfonic acid (81% yield, 99.94% purity HPLC IN). The content of acetonitrile in obtained solid was 156 ppm.

[0064] Example 8: Preparation of methane sulfonate salt of Dabrafenib

[0065] 5 g of methane sulfonate salt of Dabrafenib was mixed with 70 g of acetonitrile and 5.5 g of water. The mixture was heated to 75°C and then cooled to 53°C. The mixture was stirred at 53°C for 2 hours. The mixture was cooled to 22°C during 3 hours The mixture was stirred at 22°C for 16 hours to obtain a suspension. The suspension was fdtered off and the product was dried (85°C, 100 mbar, 16 hours) to provide 4.15 g of methane sulfonate salt of Dabrafenib (83% yield). Obtained product contained 105 ppm of acetonitrile.

Claims

CLAIMS1. A process for preparation of Dabrafenib, compound of formula (1) or a salt or a solvate thereof, the process comprising: a. Reacting compound of formula (3) in a solvent with a brominating agent, wherein the molar ratio between compound of formula (3) and the brominating agent is between 1:0.97 and 1:0.99; b. Adding compound of formula (4) in the reaction mixture to provide compound of formula (2):c. Transforming compound of formula (2) into Dabrafenib, compound of formula (1) or a salt or a solvate thereof2. The process according to claim 1, wherein the molar ratio between compound of formula (3) and the brominating agent is between 1:0.98 and 1:0.99.

3. The process according to claim 1 or 2 wherein the brominating agent is N-bromosuccinimide.

4. A process for preparation of Dabrafenib, compound of formula (1), or a a salt or a solvate thereof:the process comprising:a. Reacting compound of formula (2) with water solution of ammonia:b. Adding water into the mixture.

5. The process according to claim 4 wherein the water solution of ammonia is 25% solution.

6. The process according to claim 4 or 5 wherein the step b. further comprises isolating a solid form of compound (1).

7. The process according to any one of claims 4 to 6 wherein step a. is perfomed at pressure between 5 and 6 bars.

8. A process for preparation of Dabrafenib, compound of formula (1), or a salt or a solvate thereof:the process comprising reacting compound of formula (2) with ammonia in a solvent mixture of water and tetrahydrofurane, wherein the weight ratio between water and tetrahydrofurane can be between 4: 1 and 5: 1:

9. The process according to claim 8 wherein the ammonia is a solution of ammomnia in water.

10. The process according to claims 8 or 9 wherein reaction is perfomed at a pressure between 4 and 5 bars.

11. The process according to claim 1 or 4 or 8 wherein the salt of Dabrafenib is methane sulfonate salt.

12. A process for preparation of methane sulfonate salt of Dabrafenib comprising: a. Mixing Dabrafenib with acetonitrile and water, wherein the weight ratio between acetonitrile and water is between 9: 1 and 11: 1; b. Adding methane sulfonic acid; c. Isolating Dabrafenib methane sulfonate salt at a temperature between 15°C and 30°C.

13. The process according to claim 12 wherein Dabrafenib methane sulfonate salt is isolated at a temperature between 20°C and 25 °C.

14. A process for preparation of methane sulfonate salt of Dabrafenib comprising: a. Mixing Dabrafenib methane sulfonate salt with a mixture of acetonitrile and water, wherein the weight ratio between acetonitrile and water is betweem 5: 1 and 8: 1; b. Isolating Dabrafenib methane sulfonate salt at a temperature between 15 °C and 30°C.

15. The process according to claim 14 wherein the weight ratio between acetonitrile and water is between 6: 1 and 7: 1.

16. The process according to claim 14 or 15 wherein the temperature in step b. is between 20°C and 25°C.

17. Dabrafenib methane sulfonate salt comprising less than 500 ppm of acetonitrile.

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