A process for making osimertinib

Abstract

The invention relates to a process for preparation of compounds of formula (6) and (7), key intermediates for preparation of Osimetrtinib, compound of formula (1).

Description

A process for MAKING OsimertinibA process for MAKING Osimertinib

[0001] The present invention relates to an improved process for preparation of Osimertinib or a salt thereof or a solvate thereof.BACKGROUND OF THE INVENTION

[0002] Osimertinib, chemically N-(2-[[2-(Dimethylamino)ethyl](methyl)amino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino]phenyl)acrylamide of formula (1): ,is EGFR inhibitor, which is used for the treatment of advanced non-small cell lung cancer (NSCLC). Osimertinib is marketed as methanesuflonate salt under trade name Tagrisso by AstraZeneca. Osimertinib was first disclosed in WO2013014448. Several processes for preparation of Osimertinib are described in the prior art for example in WO2013 / 014448 or WO2017134051 or CN109134435 applications. The process described in WO2013 / 014448 is depicted in following scheme:

[0003] The solubility of reagents and reaction products in STEP 1 and STEP 2 in the solvents described in pror art documents is low that results in a need for high volumes of used solvents. Also the number of reaction step is high.

[0004] The process described in WO2013 / 014448 application uses iron in conjunction with NH4Cl for reduction of compound of formula (6) into compound of formula (7). This reduction is not suitable for large scale production since purification of the product requires ion exchange chromatography. WO2017 / 134051 application describes a process for preparing compound of formula (7) by reduction of compound of formula (6) by using gaseous H2in pressure equipment (autoclave) in a presence of an acid. Then the stoichiometric amount of the acid needs to be neutralized by NaOH and removed thereby generating additional waste. Additionally to that using of gaseous H2at high pressure can represent a safety hazard.

[0005] Thus, there is still a need to find an improved process for preparation of Osimertinib, a salt or a solvate thereof.

[0006] There is still also a need to find an improved process for preparation of Osimertinib and its key intermediate, compound of formula (7), which is suitable for high scale production and does not use hazardous gaseous H2.

[0007] BRIEF DESCRIPTION OF THE PRESENT INVENTION

[0008] The presented invention relates to a process for preparing compound of formula (1) or a salt or a solvate thereof: ,comprising:a. Reacting compound of formula (2) with compound of formula (3) in in a presence of an acid in N-methyl-2-pyrrolidone to provide compound of formula (4): ;b. Transforming compound of formula (4) into Osimertinib, a salt or a solvate thereof.

[0009] The presented invention also relates to a process for preparing compound of formula (1) or a salt or a solvate thereof comprising:a. Reacting compound of formula (2) with compound of formula (3) in a presence of ac acid in N-methyl-2-pyrrolidone to provide compound of formula (4): ;b. Reacting compound of formula (4) with compound of formula (5) in N-methyl-2-pyrrolidone to provide compound of formula (6): ;c. Transforming compound of formula (6) into Osimertinib, a salt or a solvate thereof.

[0010] The presented invention further relates to a process for preparing compound of formula (1) or a salt or a solvate thereof comprisingReacting compound of formula (2) with compound of formula (3) in a presence of an acid in N-methyl-2-pyrrolidone to provide compound of formula (4);Reacting compound of formula (4) with compound of formula (5) in N-methyl-2-pyrrolidone to provide compound of formula (6),wherein the steps a. and b. are performed as one-pot process;Transforming compound of formula (6) into Osimertinib, a salt or a solvate thereof.

[0011] The presented invention further relates to a process for preparing compound of formula (1) or a salt thereof: ;comprising:a. Reacting compound of formula (6) with hydrazine or ammonium formate in a presence of a Pt catalyst in 2-propanol to obtain compound of formula (7): ;b. Transforming compound of formula (7) into compound of formula (1) or a salt thereof.

[0012] The presented invention also relates to a process for preparing compound of formula (3) comprising:a. Reacting compound of formula (6) with hydrazine or ammonium formate in a presence of a Pt catalyst in 2-propanol to obtain compound of formula (7): .

[0013] The advantage of the presented processes when comparing to processes described in the prior art are improved yields and purity of prepared compounds of formula (4), (6), (7) and / or formula (1).

[0014] The salt of Osimertinib is preferably methanesulfonate salt.

[0015] BRIEF DESCRIPTION OF THE DRAWINGS

[0016] : XRPD pattern of solid form of compound of formula (7) prepared according to the Example 2.

[0017] DETAILED DESCRIPTION OF THE INVENTION

[0018] The presented invention relates to a process for preparing compound of formula (1) or a salt or a solvate thereof: ,comprising:a. Reacting compound of formula (2) with compound of formula (3) in a presence of an acid in N-methyl-2-pyrrolidone to provide compound of formula (4): ;b. Transforming compound of formula (4) into Osimertinib, a salt or a solvate thereof.

[0019] The presented invention also relates to a process for preparing compound of formula (1) or a salt or a solvate thereof comprisinga. Reacting compound of formula (2) with compound of formula (3) in N-methyl-2-pyrrolidone to provide compound of formula (4): ;b. Reacting compound of formula (4) with compound of formula (5) in N-methyl-2-pyrrolidone to provide compound of formula (6): ;c.Transforming compound of formula (6) into Osimertinib, a salt or a solvate thereof.

[0020] The presented invention further relates to a process for preparing compound of formula (1) or a salt or a solvate thereof comprising:Reacting compound of formula (2) with compound of formula (3) in a presence of an acid in N-methyl-2-pyrrolidone to provide compound of formula (4);Reacting compound of formula (4) with compound of formula (5) in N-methyl-2-pyrrolidone to provide compound of formula (6),wherein the steps a. and b. are performed as one-pot process;Transforming compound of formula (6) into Osimertinib, a salt or a solvate thereof.

[0021] The presented invention relates to a process for preparing compound of formula (1) or a salt or a solvate thereof: ,comprising:a. Reacting compound of formula (2) with compound of formula (3) in a presence of an acid in N-methyl-2-pyrrolidone to provide compound of formula (4): ;b. Transforming compound of formula (4) into Osimertinib, a salt or a solvate thereof.

[0022] The acid in step a. can be selected from a mineral acid such as HCl or HBr or sulfuric acid or phosphoric acid or a carboxylic acid such as formic acid or acetic acid or a sulfonic acid such as 4-methylbenzene sulfonic acid or methanesulfonic acid or ethanesulfonic acid or benzenesulfonic acid or toluenesulfonic acid. In a preferred embodiment a sulfonic acid such as 4-methylbenzene sulfonic acid, methanesulfonic acid or ethanesulfonic acid or benzenesulfonic acid or toluenesulfonic acid is used.

[0023] The concentration of compound of formula (2) in N-methyl-2-pyrroline can be between 0.1 g / ml and 0.3 g / ml, preferably it is between 0.15 g / ml and 0.25 g / ml. The concentration of compound (3) in N-methyl-2-pyrrolidone can be between 0.1 g / ml and 0.2 g / ml, preferably between 0.12 g / ml and 0.17 g / ml. The molar ratio between compound of formula (2) and the compound of formula (3) can be between 1:1.02 and 1:1.1, preferably it is between 1:1.04 and 1:1.07. The molar ratio between the compound of formula (2) and the acid can be between 1:1.01 and 1:1.05, preferably it is between 1:1.02 and 1:1.04.

[0024] Compound of formula (2) is mixed with N-methyl-2-pyrrolidone. To the mixture the acid and compound of formula (3) are added. The mixture is stirred for at a temperature between 90°C and 120°C for between 2 and 6 hours to provide compound of formula (4). Compound of formula (4) can be optionally isolated from the reaction mixture for example by distilling off the solvent or precipitation by use of a suitable antisolvent (solvent in which compound of formula (4) is poorly soluble). In a preferred embodiment, compound of formula (4) is not isolated.

[0025] In a subsequent step, compound of formula (4) reacts with compound of formula (5) in N-methyl-2-pyrrolidone to provide compound of formula (6): .

[0026] Concentration of compound (4) in N-methyl-2-pyrrolidone can be between 0.2 g / ml and 0.5 g / ml, preferably between 0.25 and 0.35 g / ml. Concentration of compound (5) in N-methyl-2-pyrrolidone can be between 0.06 g / ml and 0.15 g / ml. The molar ratio between compound (5) and compound (4) can be between 1:1.1 and 1:1.5, preferably it is between 1:1.2 and 1:1.4. The reaction is performed in a presence of an organic or an inorganic base. The inorganic base can be selected from an carbonate such as sodium carbonate or potassium carbonate or lithium carbonate or a hydroxide such as sodium hydroxide or potassium hydroxide. The organic base can be selected for example from an amine or an amidine base or a guanidine base. As a base a carbonate such as sodium carbonate or potassium carbonate or lithium carbonate is preferably used. The concentration of the base in N-methyl-2-pyrroline can be between 0.1 g / ml and 0.9 g / ml. The molar ratio between the base and the compound of formula (4) can be betweeen 1:2 and 1:3, preferably it is between 1:2 and 1:2.5. Compound of formula (4) is mixed with N-methyl-2-pyrrolidone. To the mixture the base is added. The base can be added in several portions, for example in 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 portions. The base can be added as solid or as a solution in N-methyl-2-pyrrolidone. To the mixture compound of formula (5) is added. Compound of formula (5) can be added in several portions, for example in 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 portions. Preferably, compound of formula (5) is added in the course of between 5 and 60 minutes. The mixture is then heated to a temperature between 70°C and 90°C and stirred at this temperature for between 45 and 180 minutes. The reaction progress can be monitored by a suitable analytical technique, e.g. by HPLC or GC. After the reaction is finished, a mixture of water and acetone is added to the mixture at a temperature between 80°C and 90°C. The volume ratio between water and acetone can be between 5:1 and 7:1, preferably it is 6:1. The volume ratio between the mixture water and acetone and N-methyl-2-pyrrolidone can be between 1.2:1 and 1.6:1, preferably it is between 1.3:1 and 1.5:1. The mixture of water and acetone is added preferably in the course of between 5 to 60 minutes. After water and acetone mixture addition obtained mixture is stirred at a temperature between 80°C and 90°C for between 15 and 60 minutes. The mixture is then cooled to a temperature beween 30°C and 40°C and stirred at this temperature for between 1 and 4 hours. Obtained suspension was filtered off to provide solid compound of formula (4).

[0027] The advantage of use of N-methyl-2-pyrroline as a solvent in reaction between compound of formulas (2) and (3) and subsequent reaction between compound of formula (4) and formula (5) is that the solubility of compounds of formulas (2) and (3) and (4) and (5) is relativelly high so the volume of used N-methyl-2-pyrrolidone can be lower in comparison with solvents described in the prior art. That is a big advantage of process of presented invention especially at high scale productions. The second advantage of use of N-methyl-2-pyrrolidone in comparison with solvents described in the prior art is that the reaction steps between compounds of formulas (2) and (3) and subsequent reaction between compound of formula (4) and (5) can be joined and performed without isolating of compound of formula (4). This is called one-pot process. It highly contributes to the economy of the process and decreased the time needed for preparation of compound of formula (6). Another advantage of the process of presented invention and use of N-methyl-2-pyrrolidone as a reaction solvent, is that in the reaction step between compounds (4) and (5) a carbonate, preferably as sodium carbonate or potassium carbonate or lithium carbonate, can be used as a base. In comparison with bases described in the prior art, a carbonate, preferably potassium carbonate, is a solid compound that can be easily processed in high scale production, with low toxicity and processability.

[0028] The presented invetion therefore also relates to a process for preparation of Osimetrinib, compound of formula (1), a salt or a solvate thereof, the process comprising:Reacting compound of formula (2) with compound of formula (3) in a presence of an acid in N-methylpyrrolidone to provide compound of formula (4);Reacting compound of formula (4) with compound of formula (5) in N-methylpyrrolidone to provide compound of formula (6),wherein the steps a. and b. are performed as one-pot process;Transforming compound of formula (6) into Osimertinib, a salt or a solvate thereof.

[0029] The concentrations and molar ratios of compounds of formulas (2), (3), (4) and (5) as same as reaction contidions for performing the one-pot process are the same as described above.

[0030] The presented invention also relates to a process for preparing compound of formula (3) comprising:Reacting compound of formula (6) with hydrazine or ammonium formate in a presence of a Pt catalyst in 2-propanol to obtain compound of formula (7):

[0031] .

[0032] The presented invention further relates to a process for preparing compound of formula (1) or a salt thereof: ;comprising:a. Reacting compound of formula (6) with hydrazine or ammonium formate in a presence of a Pt catalyst in 2-propanol to obtain compound of formula (7): ;b. Transforming compound of formula (7) into compound of formula (1) or a salt thereof.

[0033] The Pt catalyst in reaction step between compound of formula (6) and hydrazine can be selected Pt / C (Pt on carbon), preferably the amount of Pt on carbon can be between 5-10 % (wt / wt), more preferably 5% Pt / C. The reaction step is performed in 2-propanol (propan-2-ol or isopropanol) The concentration of compound of formula (6) in the solvent can be between 0.1 g / ml and 0.5 g / ml, preferably it is between 0.15 g / ml and 0.4 g / ml. The molar ratio between the compound of formula (6) and hydrazine can be between 1:3 and 1:20, preferably it is between 1:5 and 1:10, more preferably it is between 1:5 and 1:8. The molar ratio between the compound of formula (6) and the catalyst can be between 10:1 and 2000:1, preferably it is between 10:1 and 100:1, more preferably it is between 10:1 and 20:1. Hydrazine is preferably used as hydrazine hydrate.

[0034] The reaction steps are preferably performed under a protective atmosphere, for example under nitrogen or argon.

[0035] Compound of formula (6) is mixed with 2-propanol. To the mixture the catalyst is added. The mixture is heated to a temperature between 60°C and 100°C. To the mixture hydrazine, preferably hydrazine hydrate is added in the course of between 10 and 60 minutes. The mixture is stirred at between 60°C - 100°C temperature for between 1 and 25 hours, preferably for between 2 and 5 hours. The reaction progress can be monitored by any suitable analytical method for example by HPLC or GC.

[0036] When the reaction is finished, optionally to the mixture activated charcoal is added. The weight ratio between compound of formula (6) and the charcoal can be between 1 and 10% (wt / wt). The mixture is stirred for between 0.5 and 5 hours and filtered. The filtrate or the reaction mixture (in case activated carbon was not added) is cooled to a temperature between 50°C and 60°C, preferably to 55°C. The mixture can be optionally seeded with a solid form of compound of formula (7). The weight ratio between added solid of compound of formula (7) and the compound of formula (6) can be between 0.4 and 2%. The mixture is then stirred for between 15 and 60 minutes. The mixture is cooled to a temperature between 0 and 30°C, preferably between 15°C and 25°C. The mixture is then stirred at this temperature for between 15 and 120 minutes. The mixture was filtered off and the filtration cake can be optionally washed with a solvent for example with 2- propanol. Obtained solid can be optionally dried.

[0037] The solid form of compound of formula (7) can be characterized by XRPD pattern having 2θ values 8.1°, 15.5°, 18.6°, 24.9° and 25.7° 2θ (+0.2 degrees 2θ) when measured with CuKα1 radiation (λ = 1.5406 Å). The solid form of compound of formula (3) can be also characterized by XRPD pattern having 2θ values 8.1°, 12.3°, 15.5°, 18.6°, 24.9°, 25.7° and 26.5° 2θ (+0.2 degrees 2θ) when measured with CuKα1 radiation (λ = 1.5406 Å). The solid form can be also characterized by XRPD pattern described in following table:

[0038] Angle / 2-Theta °Intensity / %Angle / 2-Theta °Intensity / %Angle / 2-Theta °Intensity / %Angle / 2-Theta °Intensity / %6.11.615.915.522.94.828.82.67.40.916.317.923.21.530.03.98.150.016.711.123.51.430.41.18.92.417.21.823.93.530.70.911.32.417.811.224.54.131.31.212.324.618.26.024.930.431.81.512.87.818.623.825.24.032.41.713.315.118.811.725.7100.032.91.313.86.419.65.826.517.933.81.614.214.521.21.326.913.034.70.914.91.122.01.327.83.515.556.622.58.728.55.1

[0039]

[0040] The solid form can be also characterized by XRPD pattern depicted in.

[0041] Compound of formula (7) can be transformed into compound of formula (1) or a salt thereof by a process known in the prior art for example by a process comprising reacting compound of formula (7) with compound of formula (9) in a solvent or solvent mixture, preferably a mixture comprising tetrahydrofurane and water, preferably in a presence of a base: LG, leaving group, means a suitable leaving group such as an halogen (such as Cl or Br or I) or C1-C10alkyl or aryl sulfonate (such as methane sulfonate or ethane sulfonate or benzenesulfonate) or a perfluoroalkylsulfonate (for example triflate).

[0042] The LG is preferably halogen, more preferably Cl or Br.

[0043] Compound of formula (7) can be also transformed into compound of formula (1) or a salt thereof by a process comprising reacting compound of formula (7) with 3-halopropanoyl halide (compound of formula (8)) in a solvent or solvent mixture, preferably a mixture comprising tetrahydrofurane and water, in a presence of a base:

[0044] and optionally converting compound of formula (1) into a salt thereof.

[0045] LG, leaving group, means a suitable leaving group such as an halogen (such as Cl or Br or I) or C1-C10alkyl or aryl sulfonate (such as methane sulfonate or ethane sulfonate or benzenesulfonate) or a perfluoroalkylsulfonate (for example triflate).

[0046] The LG is preferably halogen, more preferably Cl or Br.

[0047] In a preferred embodiment the volume ratio between tetrahydrofurane and water can be between 2:1 and 4:1, preferably it is between 2.5:1 and 3.5:1, most preferably it is between 2.9:1 and 3.1:1. The concentration of compound of formula (7) in the solvent mixture tetrahydrofurane and water can be between 0.2 and 0.5 g / ml, preferably it is between 0.2 g / ml and 0.3 g / ml. The molar ratio between compound of formula (7) and 3-halopropanoyl halide can be between 1:1 and 1:3, preferably it is between 1:2 and 1:2.7. As base for example an inorganic base such as a carbonate such as sodium carbonate or potassium carbonate or a hydrogen carbonate such as sodium hydrogen carbonate or potassium hydrogen carbonate or a hydroxide such as sodium hydroxide or potassium hydroxide or an organic base such as triethylamine can be used. The base is preferably an hydroxide, more preferably sodium hydroxide. The molar ratio between the base and the compound of formula (7) can be between 1:1 and 110:1, preferably between 95:1 and 105:1. The reaction is preferably performed in a presence of a phase transfer catalyst such as for example tetrabutylammonium chloride or tetrabutylammonium bromide or tetrabutylammonium iodide or tetrabutyl ammonium hydrogen sulphate or benzyltrimethylammonium chloride ammonium or benzyl triethyl ammonium chloride or trioctyl methyl ammonium chloride or l8-crown-6 or dipheny1-18- crown-6, preferably tetrabutylammonium chloride. The molar ratio between compound of formula (7) and the phase transfer catalyst can be between 1:0.3 and 1:1, preferably between 1:0.4 and 1:0.6. Compound of formula (7) is mixed with the solvent. To the mixture compound of formula (8) is added preferably in 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 portions, more preferably dropwise. The mixture is stirred at a temperature between 0°C and 25°C for between 5 and 60 minutes. To the mixture the phase transfer catalyst can be optionally added. To the mixture the base is added. The base can be optionally used as a solid or in a form of a solution in a solvent, for example as water solution. The mixture is stirred at temperature between 10°C and 35°C for between 1 and 10 hours, more preferably for between 2 and 5 hours. The reaction progress can be monitored by any suitable analytical method for example by HPLC or GC. After the reaction is completed the layers are separated and the organic phase is washed for example with water or a solution of NaCl in water such as brine or 20% solution of NaCl in water. The washing step can be optionally repeated for example 2x or 3x or 4x or 5x.

[0048] After the washing step to the mixture, the mixture can be optionally warmed to a temperature between 35°C and 50°C and to the mixture a mixture of acetone and water can be optionally added. The volume ration between acetone and water can be between 1:2 and 1:4, preferably it is between 1:2 and 1:3. The mixture can be optionally seeded with a solid form of compound of formula (1) and stirred for between 15 and 120 minutes. The mixture is then cooled to a temperature between -5°C and 5°C and stirred at this temperature for between 20 and 120 minutes to obtain a suspension. The suspension was filtered off and obtained solid can be optionally washed for example with a mixture of acetone and water and dried.

[0049] The presented invention relates to a process for purification of compound of formula (1) comprising:Dissolving compound of formula (1) in a mixture of 2-methyl tetrahydrofurane and toluene and water;Isolating the solid form of compound of formula (1).

[0050] The volume ratio between 2-methyl tetrahydrofurane and toluene can be between 1:5.5 and 1:8. The volume ratio between and toluene and water can be between 1:7 and 1:9. The concentration of compound of formula (1) in the mixture of 2-methyl tetrahydrofurane and toluene and water can be between 0.15 g / ml and 0.4 g / ml, preferably it is between 0.15 g / ml and 0.25 g / ml. Compound of formula (1) is dissolved in the solvent mixture 2-methyl tetrahydrofurane and toluene and water preferably at a temperature between 50°C and 80°C. The mixture can be optionally mixed with active carbon, the weight ratio between active carbon and compound of formula (1) can be between 1% and 10%, the mixture is stirred for between 15 and 60 minutes and filtrated. To the filtrate a solid form of compound of formula (1) can be optionally added. Solid form of compound of formula (1) can be isolated in step b. for example by cooling the mixture the mixture to a temperature between -10°C and 10°C and stirring the mixture for between 15 and 120 minutes to obtain a suspension. The suspension is filtered off and obtained solid compound of formula (1) can be optionally dried.

[0051] The presented invention relates to a process for preparation of a solid form of formula (1), preferably used for purification of compound of formula (1), the process comprising:Dissolving compound of formula (1) with a mixture of 2-methyl tetrahydrofurane and toluene;Adding water to the mixture;Cooling the mixture;Isolating the solid form of compound of formula (1).

[0052] The volume ratio between 2-methyl tetrahydrofurane and toluene can be between 5.5:1 and 7:1. The concentration of compound of formula (1) in the mixture of 2-methyl tetrahydrofurane and toluene can be between 0.2 g / ml and 0.5 g / ml, preferably it is between 0.25 g / ml and 0.35 g / ml. Compound of formula (1) is dissolved in the mixture of 2-methyl tetrahydrofurane and toluene preferably at higher temperature, for example between 65°C and 80°C. To the mixture active carbon can be optionally added, the mixture can be stirred for between 15 and 60 minutes and filtrated. The weight ratio between activated carbon and compound of formula (1) can be between 1-10% (wt. %). To the mixture or the filtrate (in case the mixture is treated by active carbon) water is added, preferably at a temperature between 50°C and 60°C. The volume ratio between the water and the mixture of 2-methyl tetrahydrofurane and toluene can be between 0.1:1 and 0.3:1. The mixture is then cooled, preferably to a temperature between -10°C and 20°C, more preferably between -10°C and 10°C and stirred at this temperature preferably for between 15 and 130 minutes to obtain a suspension. The suspension is filtered off to obtain solid form of compound of formula (1).

[0053] Compound of formula (1) can be transformed into a salt thereof by reacting with a suitable acid, for example hydrochloric acid or hydrobromic acid or sulphuric acid or phosphoric acid or formic acid or acetic acid or trifluoroacetic acid or citric acid or maleic acid or oxalic acid or benzoic acid or fumaric acid or succinic acid or tartaric acid or lactic acid or pyruvic acid or methane sulfonic acid or ethane sulfonic acid or benzene sulfonic acid or p-toluene sulfonic acid, preferably with methane sulfonic acid, in a suitable solvent, for example acetone or acetonitrile or dimethylformamide or a chlorinated solvent such as dichloromethane or trichloromethane or tetrachloromethane or an ether such as dioxane or 2-methyl tetrahydrofuran or tetrahydrofuran, preferably in acetone.

[0054] Osimertinib is preferably transformed into methane sulfonate salt.

[0055] The invention will be further described with reference to the following examples.

[0056] EXAMPLES

[0057] Example 1: Preparation of N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-nitrobenzene-1,4-diamine (compound of formula (6))

[0058] 70 g of compound of formula (2) wasmixed with 55.61g of compound of formula (3), 56.28 g of 4-methylbenzenesulfonic acid hydrate and 385 ml of N-Methyl-2-pyrrolidinone. The mixture was heated at 110 °C for 3 hours. The mixture was cooled down to 45 °C. 83.37 g of K2CO3was added in 4 portions followed by addition of 44.8 ml of compound of formula (5) in the course of 20 minutes. The mixture was heated up to 85 °C and stirred for 1 hour. Then a mixture of 420 ml of water and 70 ml of acetone was added at temperature range between 80 - 85°C in the course of 20 minutes. The mixture was stirred at 80 °C for 20 minutes, then cooled down to 35 °C, stirred for additional 1hour at 35 °C and filtered. The filtration cake was washed with 210 ml of mixture of acetone / water (volume ratio acetone:water is 1:1) and dried overnight at 80 °C to provide 111 g of compound of formula (6) (81% of theory) in HPLC purity 99.4%.

[0059]

[0060] Example 2: Preparation of N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)benzene-1,2,4-triamine (compound of formula (3))

[0061] Raction was done under argon atmosphere.

[0062] 545 g of compound of formula (6) was mixed with 16 g of 5% Pt / C and 2450 ml of isopropanol.The mixture was heated to 80 °C. To the mixture 316 g of hydrazine hydrate was slowly added during 20 minutes at temperature between 75 – 80 °C. The mixture was stirred at this temperature for 2.5 hour. To the mixture 10.9 g of activated charcoal was added. The mixture was stirred for 0.5 hour. Reaction mixture was filtered, filtrated mass was washed with 545 ml of isopropanol. The filtrate was cooled to 55 °C then seeded with 3 g of compound of formula (7) and stirred at 55°C for 20 minutes. The mixture was cooled to 20 °C, stirred for additional 0.5 hour and filtered. The filtration cake was washed with 400 ml of isopropanol. Obtained mass was vacuum dried for 8 hours at 60 °C to give 465 g of compound of formula (7) (yield 91% of theoretical yield, purity 99.0%, HPLC IN). XRPD pattern of obtained solid corresponds to XRPD pattern depicted in.

[0063]

[0064] Example 3: Preparation of compound of formula (1) and methane sulfonate salt thereof

[0065] To 444 g of compound of formula (3) 152 g of 3-chloropropanoyl chloride in 220 ml of tetrahydrofuran was added dropwise. To the mixture a mixture of 1007 ml of tetrahydrofuran and 440 ml of water was added. The mixture was cooled to 5 °C and stirred at this temperature for 15 minutes. To the mixture 14 g of Tetrabutylammonium chloride was added. A mixture of 399 g of sodium hydroxide in 670 ml of water was slowly added during 20 minutes to the mixture while maintaining the temperature of the mixture under 20 °C. The mixture was heated to 25 °C and stirred for 3 hours at this temperature. Reaction mixture was separated and organic phase was washed with 350 ml of 20% sodium chloride water solution. The phases were separated and the organic phase was heated to 40 °C. To the organic phase a solution of 890 ml of acetone in 2170 ml of water was added. To the mixture 2 g of solid form of compound of formula (1) was added and the mixture was stirred for 0.5 hour. The mixture was cooled to 0 °C and stirred for additional 30 minutes to obtain a suspension. The suspension was filtered. The filtration cake was washed with 1500 ml of acetone in water (volume ratio 1:1). Obtained solid was dried on filter for 10 hours to provide 421 g of compound of formula (1) in purity 99.1% (HPLC IN).

[0066]

[0067] Example 4: Purification of solid compound of formula (1)

[0068] 421 g or compound of formula (1) was mixed with a mixture of 1110 ml of toluene and 170 ml of 2-methyl tetrahydrofuran. Mixture was heated to 70 °C and 8.4 g of activated charcoal was charged and the mixture stirred for 0.5 hour. Reaction mixture was filtered, filter cake was washed with mixture of 580 ml of toluene and 80 ml of 2-methyltetrahydrofuran. The filtrate was cooled to 60 °C and 210 ml of water was added. Mixture was cooled down to 45 °C and then seed with 2 g of compound of formula (1). The mixture was stirred at same temperature for 15 minutes. The mixture was then cooled to 5 °C and stirred for additional 0.5 hour to obtain a suspension. The suspension was filtered, filtration cake was washed with 1500 ml of acetone in water (volume ratio 1:1 ) and vacuum dried for 8 hours at 60 °C to give 320 g of compound of formula (1) (yield 64%, HPLC purity 99.8%).

[0069]

[0070] Example 5: Prepration of methane sulfonate salt of compound of formula (1)

[0071] 315 g of compound of formula (1) were mixed with 1310 ml of acetone. Mixture was heated to 45 °C and activated charcoal was added and the mixture was stirred for 0.5 hour. Mixture was filtered, the filter cake was washed with 940 ml of acetone. To the filtrate 56 g of methane sulfonic acid in 315 ml of water was added during 0.5 hour. The mixture was stirred for 3 hours at 30°C, cooled to 5 °C, stirred for additional 0.5 hour to obtain a suspension. The suspension was filtered. The filtration cake was washed with 1500 ml of acetone and vacuum dried for 5 hour at 50 °C and 5 hours at 85 °C to provide 321 g of methane sulfonate salt of compound of formula (1) (yield 85 %, HPLC purity 99.9%).

Claims

A process for preparation of Osimertinib, 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) in a presence of an acid in N-methyl-2-pyrrolidone to provide compound of formula (4):;b. Transforming compound of formula (4) into Osimertinib or a salt or a solvate thereof.The process according to claim 1 wherein the step b. comprises:a. Reacting compound of formula (4) with compound of formula (5) in N-methyl-2-pyrrolidone to provide compound of formula (6):;b. Transforming compound of formula (6) into Osimertinib or a salt or a solvate thereof.The process according to claim 2 wherein step a. is performed in a presence of a base.A process for preparation of Osimertinib, 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) in a presence of an acid in N-methyl-2-pyrrolidone to provide compound of formula (4);b. Reacting compound of formula (4) with compound of formula (5) in N-methyl-2-pyrrolidone to provide compound of formula (6),wherein the steps a. and b. are performed as one-pot process;c. Transforming compound of formula (6) into Osimertinib, a salt or a solvate thereof.The process according to claim 4 wherein step b. is performed in a presence of a base.The process according to any one of claims 1 to 5 wherein the transformation from compound (6) into Osimertinib, or a salt or a solvate thereof comprises:a. Reduction of compound of formula (6) to provide compound of formula (7):;b. Reacting compound of formula (7) with compound of formula (8) or compound of formula (9) to provide compound of formula (1) or compoud of formula (10):;c. Transforming compound of formula (10) into compound of formula (1).A process for preparing compound of formula (1) or a salt or a solvate thereof:;comprising:a. Reacting compound of formula (6) with hydrazine or ammonium formate in a presence of a Pt catalyst in 2-propanol to obtain compound of formula (7):;b. Transforming compound of formula (7) into compound of formula (1).The process according to claim 7 wherein the catalyst is Pt / C.The process according o claim 7 or 8 wherein the catalyst is 5% Pt / C.The process according to any one claims 7 to 9 wherein hydrazine is hydrazine hydrate.The process according to any one of claims 7 to 10 wherein the compound of formula (7) is transformed into compound of formula (1) by:a. Reacting compound of formula (7) with compound of formula (9) in a solvent or a solvent mixture<img src='' class="img-anchor img-center" img-id="WO-DOC-FIGURE-11A" / >or;b. Reacting compound of formula (7) with compound of formula (8) in a solvent or a solvent mixture.The process according to claim 11 wherein the solvent mixture is a mixture of tetrahydrofurane and water.The process according to claim 1 or 4 or 7 wherein the salt of compound of formula (1) is methane sulfonate salt.A process for preparation of a solid form of compound of formula (1), the process comprising:a. Dissolving compound of formula (1) in a mixture of 2-methyl tetrahydrofurane and toluene and water;b. Isolating the solid form of compound of formula (1).A solid form of compound of formula (7) characterized by XRPD pattern having 2θ values 8.1°, 15.5°, 18.6°, 24.9° and 25.7° 2θ (+0.2 degrees 2θ) when measured with CuKα1 radiation (λ = 1.5406 Å):.

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