A process for making trametinib

Abstract

The invention relates to a process for preparation of compound of formula (6) and Trametinib, compound of formula (1):

Description

[0001] A PROCESS FOR MAKING TRAMETINIB

[0002] This invention relate to processes for preparation of trametinib, compound of formula (1):

[0003] BACKGROUND OF THE INVENTION

[0004] Trametinib, chemically N-[3 - [3 -Cyclopropyl-5 -(2-fluoro-4-iodophenylamino)-6, 8-dimethyl- 2,4,7-trioxo-l,2,3,4,6,7-hexahydropyrido[4,3-d]pyrimidin-l-yl]phenyl]acetamide dimethyl of formula (1): is a mitogen-activated protein (MAP) kinase (MEK) inhibitor, which is used for the treatment of patients with unresectable or metastatic melanoma with BRAF V600 mutations as detected by an FDA-approved test. Trametinib is marketed as dimethyl sulfoxide solvate under trade name Mekinist by Novartis. Trametinib was first disclosed in W02005121142. Several processes for preparation of Trametinib are described in the prior art for example in

[0005] W02005121142 or WO2019215426 or CN109320513 applications. The process described in W02005121142 is depicted in following scheme:

[0006] The disadvantage of the process described in W02005121142 application is, that the reaction time in STEP A is relative lly long. Thus, there is still a need to find an improved process for preparation of Trametinib, a salt or a solvate thereof.

[0007] We have surprisingly found that use of the process according to presented invention can significanly shorten the reaction time in STEP A. The process of the presented invention also increases the yield and purity of obtained product in comparison with the process described in the prior art.

[0008] BRIEF DESCRIPTION OF THE PRESENT INVENTION

[0009] The presented invention relates to a process for preparation of Trametinib, compound of formula (1) or a salt or a solvate thereof, the process comprising: a. Reacting compound of formula (2) with compound of formula (3) to provide compound of formula (4): b. Transforming compound of formula (4) into Trametinib, a salt or a solvate thereof. The presented invention further relates to a process for preparation of Trametinib, compound of formula (1) or a salt or a solvate thereof, the process comprising: a. Reacting compound of formula (2) with compound of formula (3) to provide compound of formula (4): b. Reacting compound of formula (4) with compound of formula (5) to provide compound of formula (6): c. Transforming compound of formula (6) into Trametinib, a salt or a solvate thereof. The presented invention further relates to a process for preparation of Trametinib, compound of formula (1) or a salt or a solvate thereof, the process comprising: a. Reacting compound of formula (2) with compound of formula (3) to provide compound of formula (4); b. Reacting compound of formula (4) with compound of formula (5) to provide compound of formula (6); c. Transforming compound of formula (6) into Trametinib, a salt or a solvate thereof.

[0010] The solvate of compound of formula (1) is preferably dimethyl sulfoxide solvate.

[0011] The advantage of the presented invention is shorter reaction time to obtain compound of formula (6). Additionally to that compound of formula (6) in obtained in higher yield and improved impurity when compared to compound (6) obtained according to processes described in the prior art. The presented invention also relates to a process for preparation of Trametinib, compound of formula (1), a salt or a solvate thereof, the process comprising: a. Reacting compound of formula (2) with compound of formula (3 a) to provide compound of formula (6): wherein the reaction is performed in N-methyl-2 -pyrrolidone and the molar ratio between compound of formula (2) and compound of formula (3a) is higher than 1:3; b. Transforming compound of formula (6) into Trametinib, a salt or a solvate thereof. The solvate of compound of formula (1) is preferably dimethyl sulfoxide solvate.

[0012] The advantage of the presented invention is improved yield and purity of obtained compound of formula (6) in comparison with processes described in the prior art. The advantage of the process is also high solubility of reagents in N-methyl-2 -pyrrolidone thereby the amount of the solvent can be decreased that makes the reaction more environmental friendly and economical. DETAILED DESCRIPTION OF THE INVENTION

[0013] The presented invention relates to a process for preparation of Trametinib, compound of formula (1) or a salt or a solvate thereof, the process comprising: a. Reacting compound of formula (2) with compound of formula (3) to provide compound of formula (4): b. Transforming compound of formula (4) into Trametinib, a salt or a solvate thereof.

[0014] The solvate of compound of formula (1) is preferably dimethyl sulfoxide solvate. The presented invention further relates to a process for preparation of Trametinib, compound of formula (1) or a salt or a solvate thereof, the process comprising: a. Reacting compound of formula (2) with compound of formula (3) to provide compound of formula (4): b. Reacting compound of formula (4) with compound of formula (5) to provide compound of formula (6): c. Transforming compound of formula (6) into Trametinib or a salt or a solvate thereof.

[0015] The solvate of compound of formula (1) is preferably dimethyl sulfoxide solvate.

[0016] The presented invention relates to a process for preparation of Trametinib, compound of formula (1), a salt or a solvate thereof, the process comprising: a. Reacting compound of formula (2) with compound of formula (3) to provide compound of formula (4): b. Transforming compound of formula (4) into Trametinib, a salt or a solvate thereof.

[0017] The solvate of compound of formula (1) is preferably dimethyl sulfoxide solvate.

[0018] LG, leaving group, can be selected from a halogen such as Cl or Br or I or an substituted or unsubstituted alkyl Ci-Cio alkyl sulfonate or Ce-Cio aryl sulfonate. Substituted or unsubstituted alkyl Ci-Cio alkyl sulfonate or Ce-Cio aryl sulfonate can be selected for example from methanesulfonate or ethane sulfonate or benzenesulfonate or 4-methyl benzene sulfonate or perfluoroalkylsulfonate such as triflate.

[0019] The reaction between compounds of formula (2) and formula (3) can be preferably done in a solvent for example in dimethylacetamide or N-methyl-2-pyrollidone or dimethyl sulfoxide or dimethylformamide. The reaction between compounds of formula (2) and formula (3) can be also performed without use of a solvent. The concentration of compound of formula (2) in the solvent can be between 0.15 g / g and 0.5 g / g, preferably it is between 0.3 g / g and 0.4 g / g. The concentration of compound of formula (3) in the solvent can be between 0.15 g / g and 0.4 g / g, preferably it is between 0.2 g / g and 0.3 g / g. The molar ratio between compounds of formula (2) and formula (3) can be between 1:4 and 1:6, preferably it is between 1:4 and 1:5. The reaction is preferably performed in a presence of a base. The base can be selected form an organic or an inorganic base, for example diisopropylethyl amine or 2,6-lutidine. The base is preferably 2,6-lutidine. Compound of formula (3) can be also used as the base in the reaction between compounds of formula (2) and (3). The concentration of the base in the solvent can be between 1.3 g / g and 2 g / g, preferably it is between 1.4 g / g and 1.8 g / g. The molar ratio between the base and the compound of formula (2) can be between 2.5: 1 and 5: 1, preferably it is between 2.9: 1 and 3.5: 1. Compound of formula (2) is mixed with compound of formula (3), the base and the solvent. The mixture is stirred at a temperature between 100°C and 140°C for between 1 and 2 hours to provide the compound of formula (4). The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is completed, compound of formula (4) can be optionally isolated for example by distilling off the solvent or by addition of an antisolvent (solvent in which compound of formula (4) is poorly soluble). In a prefered embodiment compound of formula (4) is not isolated form the reaction mixture.

[0020] The compound of formula (4) is then reacted with compound of formula (5) to provide compound of formula (6):

[0021] The reaction is preferably performed in a solvent. The solvent is preferably the same solvent as was used in the previous step selected for example from dimethylacetamide or N-methyl-2- pyrollidone or dimethyl sulfoxide or dimethylformamide. The reaction can be also performed without use of a solvent. The concentration of compound of formula (4) in the solvent can be between 0.15 g / g and 0.5 g / g, preferably it is between 0.2 g / g and 0.4 g / g. The concentration of compound of formula (5) in the solvent can be between 0.3 g / g and 0.7 g / g, preferably it is between 0.4 g / g and 0.6 g / g. The molar ration between compounds of formula (4) and formula (5) can be between 1:7 and 1: 11, preferably it is between 1:8 and 1: 10. Compound of formula (4) and compound of formula (5) are mixed with the solvent and the mixture is stirred for between 5 and 15 minutes to provide the compound of formula (6). 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 60°C and 80°C, preferably between 65°C and 75°C. To the mixture of methanol and water is added. The volume ratio between methanol and water can be between 1:0.8 and 1: 1.2, preferably it is 1: 1. The volume ratio between the solvent used in the reaction and the methanol / water mixture can be between 1:5 and 1:8, preferably it is between 1:6 and 1:7. The mixture is stirred for between 30 and 120 minutes to provide a suspension. The suspension was fdtered off to provide compound of formula (6).

[0022] A solid form of compound of formula (6) can be prepared by a process comprising: a. Dissolving compound of formula (6) in N-methyl-2 -pyrrolidone or dimethylformamide; b. Adding a mixture of butyl acetate and heptane; c. Isolating the solid form of compound of formula (6).

[0023] The concentration of compound of formula (6) in N-methyl-2 -pyrrolidone or dimethylformamide can be between 0. 1 g / g and 0.2 g / g. Compound of formula (6) is dissolved in N-methyl-2 - pyrrolidone or dimethylformamide preferably at a temperature between 100°C and 130°C. The mixture can be optionally fdterred via for example cellite. Filtrate is optionally cooled to a temperature between 80°C and 100° and to the filtrate a mixture of butyl acetate and heptane is added. The weight ratio between butyl acetate and heptane can be between 1:0.8 and 1: 1.2, preferably it is 1: 1. The weight ration between N-methyl-2-pyrrolidone or dimethylformamide and the mixture of butyl acetate / heptane can be between 0.4: 1 and 1: 1, preferably it is 0.6: 1. Obtained mixture was cooled ot a temperature between 0°C and 10°C and stirred at this temperature for between 30 and 300 minutes to obtain a suspension. Obtained solid is filtered off and optionally washed with methanol to provide solid compound of formula (6).

[0024] A solid form of compound of formula (6) can be also prepared by a process comprising: a. Dissolving compound of formula (6) with a mixture of N-methyl-2- pyrrolidone and dimethylformamide ; b. Distilling off approx. 'A of original volume of the mixture of N-methyl-2- pyrrolidone and dimethylformamide ; c. Adding a mixture of n-butyl acetate and n-heptane; d. Isolating solid form of compound of formula (6). Compound of formula (6) is dissolved in a mixture of N-methyl-2- pyrrolidone and dimethyl formamide. The concentration of compound of formula (6) in the mixture of N-methyl-2- pyrrolidone and dimethyl formamide can be between 0.06 g / g and 0.11 g / g. The weight ratio between N-methyl-2 - pyrrolidone and dimethyl formamide can be between 1:3 and 1:3.5. The compound of formula (6) is dissolved in a mixture of N-methyl-2- pyrrolidone and dimethyl formamide preferably at a temperature between 100°C and 135°C. The solution can be optionally treated with cellite and filtered off. From the mixture approximately i of the original volume of N-methyl-2- pyrrolidone and dimethyl formamide is disstiled off. The mixture is heated to a temperature between 90°C and 110°C, to the filtrate a mixture of n-butyl acetate and n-heptane is added. The weight ratio between n-butyl acetate and n-heptane can be between 1 : 1 and 1: 1.2. The weight ratio between the mixture of between n-butyl acetate and n-heptane and the mixture of of N-methyl-2- pyrrolidone and dimethyl formamide in the beginning of the process can be between 1 : 1 and 1: 1.2. The mixture is cooled to a temperature between 0°C and 30°C and stirred at this tempereature for between 1 and 10 hours to obtain a suspension. The suspension is filtered off and obtained solid can be optionally washed for example with methanol and dried.

[0025] In a preferred embodiment compound of formula (4) is not isolated from the reaction mixture after reacting compounds of formula (2) and formula (3) and is reacted with compound of formula (5) (one-pot process). The presented invention therefore also relates to the process comprising: a. Reacting compound of formula (2) with compound of formula (3) to provide compound of formula (4); b. Reacting compound (4) with compound of formula (5) to provide compound of formula (6) wherein the step a. and b. is performed as one-pot process; c. Transforming compound of formula (6) into Trametinib, a salt or a solvate thereof.

[0026] The reaction conditions such as reagents concentrations, reaction temperatures and times are described above.

[0027] Compound of formula (1) can be prepared from compound of formula (6) by a process described in the prior art, for example in W02005121142 application. The presented invention also relates to a process for preparation of Trametinib, compound of formula (1) or a salt or a solvate thereof, the process comprising: a. Reacting compound of formula (2) with compound of formula (3 a) to provide compound of formula (6): wherein the reaction is performed in N-methyl-2 -pyrrolidone and the molar ratio between compound of formula (2) and compound of formula (3a) is higher than 1:3; b. Transforming compound of formula (6) into Trametinib, a salt or a solvate thereof.

[0028] The solvate of compound of formula (1) is preferably dimethyl sulfoxide solvate.

[0029] LG, leaving group, can be selected from a halogen such as Cl or Br or I or a substituted or unsubstituted alkyl Ci-Cio alkyl sulfonate or Ce-Cio aryl sulfonate. Substituted or unsubstituted alkyl Ci-Cio alkyl sulfonate or Ce-Cio aryl sulfonate can be selected for example from methanesulfonate or ethane sulfonate or benzenesulfonate or 4-methyl benzene sulfonate or perfluoroalkylsulfonate such as triflate.

[0030] The concentration of compound of formula (2) in N-methyl-2 -pyrrolidone can be between 0.8 g / g and 1.2 g / g, preferably it is between 0.9 g / g and 1.1 g / g. The concentration of compound of formula (3a) in N-methyl-2 -pyrrolidone 0.6 g / g and 1 g / g, preferably between 0.7 g / g and 0.9 g / g. The molar ration between compounds of formula (2) and formula (3a) is higher than 1:3, preferably it is 1:3.5. The reaction is preferably performed in a presence of a base. The base can be selected form an organic or an inorganic base, for example diisopropylethyl amine or 2,6-lutidine. The base is preferably 2,6-lutidine. The concentration of the base in the solvent can be between 0.4 g / g and 0.7 g / g, preferably it is between 0.5 g / g and 0.6 g / g. The molar ratio between the base and the compound of formula (2) can be between 2.5: 1 and 5: 1, preferably it is between 2.9: 1 and 3.5: 1. Compound of formula (2) is mixed with compound of formula (3a), the base and the solvent. The mixture is stirred at a temperature between 100°C and 140°C for between 3 and 6 hours, preferably between 3.5 and 4 hours, to provide the compound of formula (6). 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 60°C and 80°C. To the mixture N-methyl-2- pyrrolidone can be optionally added. The volume ratio between added N-methyl-2- pyrrolidone and N-methyl-2- pyrrolidone added in the beginning of the reaction can be between 1 : 1 and 1 : 1.3. To the mixture methanol or n-butyl - acetate or a mixture thereof is added. When methanol is used as a sole solvent, the weight ratio between methanol and N-methyl-2 -pyrrolidone added in the beginning of the reaction can be between 8: 1 and 12: 1. When a mixture of methanol and n-butyl acetate is used, the weight ratio between methanol and N-methyl-2 -pyrrolidone added in the beginning of the reaction can be between 2: 1 and 2.3: 1 and the weight ratio between n-butyl acetate and N-methyl-2 -pyrrolidone added in the beginning of the reaction can be between 6: 1 and 6.5: 1. The weight ratio between methanol and n-butyl acetate can be between 1:3 and 1:3.2. The mixture is cooled to a temperatire between 0°C and 30°C and stirred at this temperature for between 1 and 5 hours to obtain a suspension. The suspension was fdtered off to provide solid compound of formula (6) that can be optionally washed with methanol and dried.

[0031] Compound of formula (1) or a solvate thereof can be prepared from compound of formula (6) by a process described in the prior art, for example in W02005121142 application or by a process comprising:

[0032] 1. Mixing compound of formula (6) with a base in a solvent;

[0033] 2. Addition of 2-propanol to the mixture; 3. Addition of an acid to the mixture;

[0034] 4. Isolation of 2-propanol solvate of compound of formula (1).

[0035] The solvent used in step a. is preferably dimethylacetamide. The concentration of compound of formula (6) in the solvent can be between 0.15 g / g and 0.25 g / g. The base used in step a. can be preferably an alcoholate for example an methanolate such as sodium or pottasium methanolate. The molar ratio between the base and compound of formula (6) can be between 1.35: 1 and 1.45: 1, preferably it is 1.4: 1. Compound of formula (6) is mixed with the solvent and the base and the mixture is stirred at a temperature between 10°C and 30°C for between 1.5 and 5 hours. To the mixture 2- propanol is added. The weight ratio between added 2-propanol and the solvent used in step a. can be between 2.5: 1 and 3.5: 1. The mixture can be optionally fdtered over for example cellite or active carbon. To the mixture an acid, preferably acetic acid is added. The molar ratio between the acid and the base can be between 1.1: 1 na 1.5: 1. 2-propanol solvate of the compound of formula (1) is isolated form the mixture for example by addition of an antisolvent (solvent that poorly dissolves the solvate of compound of formula (1)), for example by addition of water. The weight ratio between the antisolvent and 2-propanol can be between 0.1: 1 and 0.3: 1. After antisovent addition, the mixture is stirred at a temperature between 10°C and 30°C for between 30 and 180 minutes to obtain a suspension. The suspension can be optionally warmed to a temperature between 45°C and 55°C, stirred at this temperature for between 1 and 5 hours and cooled to a temperature between -10°C and 10°C. The suspension is fdtered off to provide a solid form of 2-propanol solvate of compound of formula (1).

[0036] A solid form of 2-propanol solvate can be also prepared by a process comprising:

[0037] 1. Mixing a solvate of compound of formula (1), preferably 2-propanol solvate, with a base and 2-propanol;

[0038] 2. Stirring the mixture at a temperature between 10°C and 30°C for between 1 and 5 hours;

[0039] 3. Addition of an acid in an antisolvent;

[0040] 4. Isolating the solid form of 2-propanol solvate of compound of formula (1).

[0041] The concentration of a solvate of compound of formula (1) in 2-propanol can be between 0.2 g / g and 0.3 g / g. The molar ration between the base and the solvate of compound of formula (1) can be between 1.3: 1 and 1.5: 1. The base used in step a. can be preferably an alcoholate for example an methanolate such as sodium or pottasium methanolate. The base is dissolved in 2-propanol and the solvate of compound of formula (1), preferably 2-propanol solvate is added. The mixture is stirred at a temperature between 10°C and 30°C for between 1 and 5 hours and cooled to a temperature beween - 15°C and 0°C. To the mixture an acid, preferably acetic acid in an antisolvent, preferably an alkane such as heptane or pentane or hexane is added. The molar ratio between added acid and base can be between 1: 1 and 1.2: 1. The concentration of the acid in the antisolvent can be between 0.007 g / g and 0.012 g / g. The mixture is stirred at the temperature between -15°C and 0°C for between 15 and 120 minutes to obtain suspension. The suspension is filtered off, obtained solid can be optionally washed for example with 2-propanol or water or a mixture thereof.

[0042] The solvate of compounf of formula (1), preferably 2-propanol solvate of compound of formula (1), can be trannsformed into dimethyl sufloxide solvate of compound of formula (1) by a process comprising:

[0043] 1. Dissolving of the solvate, preferably 2-propanol solvate, in dimethyl sulfoxide, preferably at a temperarure between 75°C and 90°C;

[0044] 2. Isolating dimethyl sulfoxide solvate of the compound of formula (1).

[0045] The concentration of the solvate, preferably 2-propanol solvate, of compound of formula (1) can be between 0. 1 g / g and 0.3 g / g. The solvate is dissolved preferably at a temperarure between 75°C and 90°C. The mixture is preferably stirred at this temperature for between 4 and 10 hours. The mixture is then cooled to a temperature between 30°C and 50°C and preferably stirred at this temperature for between 30 and 180 minutes. The mixture is then cooled to a temperature between 10°C and 25 °C and preferably stirred at this temperature for between 1 and 5 hours. Obtained suspension is fdtered off and solid dimethyl sulfoxide of compound of formula (1) can be optionally washed with dimethyl sulfoxide or water or a mixture thereof. The advantage of the process for prepartion of dimethyl sulfoxide of compound of formula (1) is high yield and purity of obtained dimethyl sulfoxide of compound of formula (1) in comparison with the processes described in prior art.

[0046] The solvate of compound of formula (1) is preferably dimethyl sulfoxide solvate. The invention will be further described with reference to the following examples.

[0047] EXAMPLES

[0048] Example 1: Preparation of N-(3-((3-cyclopropyl-l-(2-fluoro-4-iodophenyl)-6,8-dimethyl- 2,4,7-trioxo-l,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)acetamide

[0049] (compound of formula (6))

[0050] 2.50 g of compound of formula (2) was mixed with 1.95 g oc compound of formula (3), 1.4 ml of 2,6-Lutidine and 7.5 g of dimethylacetamide. The mixture was stirred at 130 °C for 1.5 hours. To the mixture 3.7 g compound of formula (5) was added to the reaction mixture. The mixture was stirred for 5 minutes. The mixture was cooled down to 70°C and to the mixture 50 g of mixture MeOH / water (vol:vol 1: 1) was added to obtain a suspension.

[0051] Suspension was cooled down to 5 °C and the product was isolated and washed with 30 g of MeOH in 90% yield with 98% purity (HPLC). When the process for preparation of compound of formula (6) described in W02005121142 was repeated, compound of formula (6) was prepared in 77% yield and 89% purity (HPLC). It can be concluded that both yield and purity of obtained compound of formula (6) are improved and the reaction time is decreased when process according to presented invention is used. Example 2: Recrystallization of compound of formula (6)

[0052] 2 g of compound of formula (6) were dissolved in 14 g of N-methyl -2 -pyrrolidone at 125 °C. The solution was filtered via cellite and washed with 2 g of N-methyl -2 -pyrrolidone. To the filtrate a mixture of 12 g n-butyl-acetate and 12 g of n-heptane was added. The mixture was cooled down to 5°C, stirred for 60 minutes and isolated. Product was washed with 30 g of MeOH.

[0053] Example 3: Preparation of N-(3-((3-cyclopropyl-l-(2-fluoro-4-iodophenyl)-6,8-dimethyl-

[0054] 2,4,7-trioxo-l,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)acetamide

[0055] (compound of formula (6))

[0056] 140 g of compound of formula (2) and 118 g of compound of formula (3a) were mixed with

[0057] 140 g on N-methyl-2 -pyrrolidone and 72.1 of 2,6-Lutidine at 20-25°C. The mixture was then heated to 125 °C. The mixture was stirred at 125°C for 4 hours. Then, the mixture was allowed to cool down to 70 °C and 1500 g of methanol was added at once with stirring.

[0058] The mixture was re-heated to 60 °C and allowed to cool down to 5 °C. Then, the solid was collected by filtration, washed twice with 300 g of methanol and suction dried overnight to provide 120 g (87% of theory) of compound of formula (6) in 98.3% purity (HPLC).

[0059] When the process for preparation of compound of formula (6) described in W02005121142 was repeated, compound of formula (6) was prepared in 77% yield and 89% purity (HPLC). It can be concluded that both yield and purity of obtained compound of formula (6) are improved when process according to presented invention is used. Example 4: Preparation of N-(3-((3-cyclopropyl-l-(2-fluoro-4-iodophenyl)-6,8-dimethyl-

[0060] 2,4,7-trioxo-l,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)acetamide

[0061] (compound of formula (6))

[0062] 140 g of compound of formula (2) and 118 g of compound of formula (3a) were mixed with

[0063] 140 g of N-methyl -2 -pyrrolidone (NMP) and 72.1 g of 2,6-Lutidine. The mixture was then heated to

[0064] 125 °C. Then, the mixture was allowed to cool down to 100 °C and 140 g of N-methyl-2-pyrrolidone was added. Mixture of 840 g n-butyl acetate and 280 g of methanol were added during 25 minutes.

[0065] The mixture was cooled down to 20 °C and it was stirred for 2 hours to obtain a suspension. The suspension was filtered off and obtained solid was washed with 560 g of methanol in three portions to provide 120 m of compound of formula (6) in 87% yield and 98.3% purity (HPLC).

[0066] Example 5: Recrystallization of compound of formula (6)

[0067] 2 g of compound of formula (6) crude was dissolved in 6 g of N-methyl -2 -pyrrolidone (NMP)and 18 g of dimethylformamide (DMF) at 125 °C. The solution was filtered via cellite and washed with 2 g of dimethylformamide. The solution was heated up to 100 °C and was i of original volume was distilated off from the solution. Mixture of 12 g n-butyl acetate and 12 g of n-heptane was added to the solution at 100°C. The mixture was cooled down to 20°C and stirred for 2 hours to obtain a suspension. The suspension was filteref off, obtained solid was washed with 30 g of methanol to provide compound of formula (6) in 90 % yield. Example 6: Preparation of 2-propanol solvate of N-[3-[3-Cyclopropyl-5-(2-fluoro-4- iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-l,2,3,4,6,7-hexahydropyrido[4,3-d]pyrimidin-l- yljphenyl] acetamide dimethyl, compound of formula (1).

[0068] 150 g of compound of formula (6) was suspended in 750 g of dimethylacetamide (DMA) at 23 °C. To the mixture a solution of 57 g of 30 % sodium methanolate was added. The mixture was stirred for 2 hours. To the mixture 1100 g of 2-propanol was added and solution was filtered through kiesselghur. To the mixture 1100 g of 2-propanol was added. To the mixture 23.4 g of acetic acid was added. To the mixture 300 ml of water was added, the mixture was stirred for 1 hour at a temperature between 20°C and 25°C. The mixture was warmed up to 50°C and stirred at this temperature for 2 hours. The mixture was cooled down to 5 °C, stirred for 2 hours and filtrated. Obtained solid 2- propanol solvate of compound of formula (1) was washed with mixture of 960 g of 2-propanol and 240 g of water in yield to provide 140 g of 2-propanol solvate of compound of formula (1), 85% yield, 99.85% purity (HPLC IN).

[0069] Example 7: Preparation of a solid form of 2-propanol solvate of N-[3-[3-Cyclopropyl-5-(2- fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-l,2,3,4,6,7-hexahydropyrido[4,3- d]pyrimidin-l-yl]phenyl]acetamide dimethyl, compound of formula (1).

[0070] 37 g of Potassium tert-butoxide was dissolved in 600 g of 2-propanol. To the solution 150 g of 2-propanol solvate of compound of formula (1) was added and the mixture was stirred at 20°C-25°C for 2 hours. The mixture cooled down to -10°C. To the mixture a pre-cooled mixture (-10 °C) of 2250 g of n-heptane and 22 g of acetic acid was added. The mixture was stirred for 30 minutes at -10 °C to obtain a suspension. The suspension was filtered, obtained solid was washed with 300 g of 2-propanol and a mixture of 1400 of 2-propanol and 360 g of water to provide 135 g of 150 g of 2-propanol solvate of compound of formula (1), 90% yield, 100% purity (HPLC IN). Example 8: Preparation of a solid form of dimethyl sulfoxide solvate of N-[3-[3-Cyclo- propyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-l,2,3,4,6,7-hexahydro- pyrido[4,3-d]pyrimidin-l-yl]phenyl]acetamide dimethyl, compound of formula (1).

[0071] 150 g of 2-propanol solvate of compound of formula (1) was dissolved in 800 g of dimethyl sulfoxide at 85 °C. The mixture was stirred at this temperature for 5 hours. The mixture was cooled down to 40 °C and stirred for 1 hour at this temperature. The mixture was cooled down to 20 °C and sirred at this temperature for 2 hours. Obtained suspension was filtered off od solid dimethyl sulfoxide solvate of compound of formula (1) was washed with 300 g od dimethyl sulfoxide and a mixture of

[0072] 1000 g of dimethyl sulfoxide and 1000 g of water to provide 135 g of dimethyl sulfoxide solvate of compound of formula (1), 87% yield, 99.9% purity (HPLC IN).

Claims

CLAIMS1. A process for preparation of Trametinib, compound of formula (1) or a salt or a solvate thereof, the process comprising:a. Reacting compound of formula (2) with compound of formula (3) to provide compound of formula (4):b. Transforming compound of formula (4) into Trametinib, a salt or a solvate thereof.

2. The process according to claim 1 wherein the step b. comprises: a. Reacting compound of formula (4) with compound of formula (5) to provide compound of formula (6):b. Transforming compound of formula (6) into Trametinib or a salt or a solvate thereof.

3. A process for preparation of Trametinib, compound of formula (1) or a salt or a solvate thereof, the process comprising: a. Reacting compound of formula (2) with compound of formula (3) to provide compound of formula (4); b. Reacting compound of formula (4) with compound of formula (5) to provide compound of formula (6) wherein the step a. and b. is performed as one-pot process; c. Transforming compound of formula (6) into Trametinib or a salt or a solvate thereof.

4. A process for preparation of a solid form of compound of formula (6) comprising: a. Dissolving compound of formula (6) in N-methyl-2 -pyrrolidone or dimethylformamide; b. Adding a mixture of butyl acetate and heptane; c. Isolating the solid form of compound of formula (6).

5. A process for preparation of Trametinib, compound of formula (1) or a salt or a solvate thereof, the process comprising:a. Reacting compound of formula (2) with compound of formula (3a) to provide compound of formula (6):wherein the reaction is performed in N-methyl-2 -pyrrolidone and the molar ratio between compound of formula (2) and compound of formula (3a) is higher than 1:3; b. Transforming compound of formula (6) into Trametinib or a salt or a solvate thereof.

6. The process according to claim 6 wherein the molar ratio between compound of formula (2) and compound of formula (3a) is 1:3.5.

7. The process according to any one of claims 1 or 6 wherein the solvate of compound of formula (1) is dimethyl sulfoxide solvate.

8. A process for preparation of 2-propanol solvate of compound of formula (1), the process comprising: a. Mixing compound of formula (6) with a base in a solvent; b. Addition of 2-propanol to the mixture; c. Addition of an acid to the mixture; d. Isolation of 2-propanol solvate of compound of formula (1).

9. A process for preparation of solid form of 2-propanol solvate od compound of formula ( 1), the process comprising: a. Mixing a solvate of compound of formula (1) with a base and 2-propanol; b. Stirring the mixture at a temperature between 10°C and 30°C for between 1 and 5 hours; c. Addition of an acid in an antisolventd. Isolating the solid form of 2-propanol solvate of compound of formula (1).

10. A process for preparation of dimethyl sulfoxide solvate of compound of formula (1), the process comprising transformation of a solvate of compound of formula (1) into dimethyl sulfoxide solvate of compound of formula (1).

11. The process according to claim 10 wherein the solvate of compound of formula (1) is 2- propanol solvate.

12. The process according to claims 10 or 11 comprising: a. Dissolving the solvate in dimethyl sulfoxide; b. Isolating dimethyl sulfoxide solvate of the compound of formula (1).

13. The process according to claim 12 wherein the step b. comprises cooling the mixture to a temperature between 30°C and 50°C and subsequent cooling to a temperature between 10°C and 25 °C.

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