Use of a mechanical force in the process of preparation of osimertinib

Abstract

The invention relates to the use of a mechanical force to generate a mechanochemical reaction in the implementation of a process of preparation, of N-(2- { [2(dimethylamino)ethyl] (methyl)amino } -4-methoxy-5- { [4-( 1 -methyl- lH-indol-3 -yl)pyrimidin-2- yl]amino}phenyl)prop-2-enamide (osimertinib) or a pharmaceutically acceptable salt thereof, comprising n steps, n being 5 or 6, from 1-methylindole, wherein at least one step is mechanochemical, and said process comprising a reduction step of N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l- methylindol-3-yl)pyrimidin-2-yl] -5 -nitrobenzene- 1,4-diamine into N'-(2- dimethylaminoethyl)-5 -methoxy-N1 -methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2- yl]benzene-l,2,4-triamine, said triamine being possibly under the form of a salt, said reduction step being mechanochemical, wherein said reduction step does not involve the use of cobalt and / or comprising an amidation step of the above mentioned N1-(2-dimethylaminoethyl)-5-methoxy- N1 -methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2-yl]benzene- 1,2,4-triamine into osimertinib or osimertinib salt of mesylate, said amidation step being mechanochemical.

Description

[0001] USE OF A MECHANICAL FORCE IN THE PROCESS OF PREPARATION OF AN ACTIVE PHARMACEUTICAL INGREDIENT

[0002] The present invention refers to the use of a mechanical force to generate a mechanochemical reaction in the implementation of a process of preparation of N-(2-{ [2(dimethylamino)ethyl ](methyl)amino}-4- methoxy-5 - { [4-( 1 -methyl- I / / -indol -3 -yl)pyrimidin-2-yl]amino }phenyl)prop-2-enamide (osimertinib) and their process of preparation.

[0003] Background of the Invention

[0004] Osimertinib, a third-generation Epidermal growth factor receptor (EGFR) inhibitor, is highly effective against specific mutated forms of the epidermal growth factor receptor, including L858R, Exonl9 deletion, and T790M mutations. Developed by AstraZeneca, it gained accelerated Food and Drug Administration (FDA) approval in 2015 for treating non-small cell lung carcinoma. The drug covalently binds to EGFR, targeting the T790M mutation while sparing the wild-type form. Sold under the brand name Tagrisso® (Osimertinib mesylate), it is available in 40 mg and 80 mg tablets, taken daily with or without food, until disease progression or intolerable side effects occur. Tagrisso® ranked among the top 25 best-selling pharmaceuticals of 2023, with nearly $5.8 billion in sales.

[0005] The current manufacturing route of Tagrisso®, developed by AstraZeneca, is based on classical solution chemistry. In this route, inherent drawbacks of solution-based processes are present, such as: (1) the use of large amounts of solvents, which generate toxic waste, (2) the use of hazardous chemicals, such as acyl chlorides, organic amines as bases or metal-catalyzed processes, (3) the use of energy-intensive methods for heating / cooling reaction mixtures, or (4) the use of laborious purification methods, which often generate large amounts of toxic waste.

[0006] Over the past century, intensified human activities involving chemistry have led to significant environmental issues, including ozone layer depletion, global warming, air pollution, and overexploitation of natural resources. In response, several various measures have been implemented over the last 50 years to mitigate the negative environmental impacts of chemical production.

[0007] Acknowledging the necessity to lessen the environmental damage caused by the chemical industry has spurred the growth of mechanochemistry.

[0008] This approach seeks to safeguard future generations by advancing more sustainable chemical processes. Mechanochemistry allows reactions to occur without solvents or with minimal liquid media, in a process named Liquid Assisted Grinding (LAG) making it a viable alternative for green and more sustainable chemical synthesis. Its advantages include the absence of bulk solvents, precise stoichiometric control (using reagents in exact amounts rather than excess), and more selective reactions, which simplify workup procedures, thus reducing the amount of total waste generated. These features highlight the superiority of mechanochemical processes compared to traditional solution-based chemistry.

[0009] One of the issues to address is to find new mechanochemical reactions intended to be used in the process of preparation of active pharmaceutical ingredients.

[0010] One of the aims of the invention is to provide new use of a mechanical force to conduct a mechanochemical total synthesis to provide osimertinib or a pharmaceutically acceptable salt thereof.

[0011] Another aim of the invention is to provide a mechanochemical process of preparation of osimertinib.

[0012] Another aim of the invention is to provide a mechanochemical process of salification of osimertinib by using methanesulfonic acid.

[0013] Additional aims of the invention, in comparison with the manufacturing method in solution concern: a) shorter reaction times for each step by using BM and / or RAM and / or TSE b) reduced waste for each step by using BM and / or RAM and / or TSE c) reduced energetic costs (in principle) for both synthesis and / or work-up by BM and / or by RAM and / or TSE, by providing milder operational reaction conditions at room temperature, which avoids the use of heating / cooling procedures (used in solution) for both synthesis and / or workup. d) Reduce the amount of raw materials needed for the syntheses (for each step by BM and / or by RAM and / or TSE) using no excess of chemicals (and also no-solvents), which turns in a more economic process in terms of raw materials use. This also translate in e) Less waste generated by BM / RAM / TSE for each step (and when they are generated, they remain less harmful as well compared to those generated by the manufacturing route in solution) f) Simplified work-up procedures (operationally simple - no chromatography needed) and generating less waste

[0014] Brief summary of the invention

[0015] The Applicant has surprisingly found that a mechanical force to generate a mechanochemical reaction in the implementation of a process of preparation of osimertinib can be used. Inventors were able to carry out a mechanochemical total synthesis of osimertinib mesylate or osimertinib dimesylate in 6 steps, by implementing mechanochemical processes for its preparation in 6 steps, which is 1 step shorter than the solution-based manufacturing method that is being used in the industry.

[0016] Detailed description of the invention

[0017] More particularly, one of the objects of the present invention is the use of a mechanical force to generate a mechanochemical reaction in the implementation of a process of preparation, of N-(2- { [2(dimethylamino)ethyl] (methyl)amino } -4-methoxy-5- { [4-( 1 -methyl- lH-indol-3 -yl)pyrimidin-2- yl]amino}phenyl)prop-2-enamide (osimertinib) or a pharmaceutically acceptable salt thereof, comprising n steps, n being 5 or 6, from 1-methylindole, wherein at least one step is mechanochemical.

[0018] Another object of the present invention is the use of a mechanical force to generate a mechanochemical reaction in the implementation of a process of preparation, of N-(2- { [2(dimethylamino)ethyl] (methyl)amino } -4-methoxy-5- { [4-( 1 -methyl- lH-indol-3 -yl)pyrimidin-2- yl]amino}phenyl)prop-2-enamide (osimertinib) or a pharmaceutically acceptable salt thereof, comprising n steps, n being 5 or 6, from 1-methylindole, wherein at least one step is mechanochemical, and said process comprising a reduction step of N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l- methylindol-3 -yl)pyrimidin-2-yl] -5 -nitrobenzene- 1 ,4-diamine into N1-(2- dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2- yl]benzene-l,2,4-triamine, said triamine being possibly under the form of a salt, said reduction step being mechanochemical, wherein said reduction step does not involve the use of cobalt and / or comprising an amidation step of the above mentioned N1-(2-dimethylaminoethyl)-5- methoxy-N1-methyl -N4-[4-( 1 -methylindol-3-yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine into osimertinib or osimertinib salt of mesylate, said amidation step being mechanochemical .

[0019] As used herein the expression “mechanochemical force” refers to mechanochemical activation or mechanochemistry, that is a technology and a research field in which solid chemical reactants, i.e in the form of granules or powders (pulverulent) or in the pasty state, are milled or ground together or ground together under mechanical activation and chemical reaction are induced by the direct absorption of mechanical energy, (McNaught, A.D.; Wilkinson, A. IUPAC Compendium of Chemical Terminology (“The Gold Booldy, 2nd edition; Blackwell Scientific publications, Oxford, 1997) without solvents (neat grinding) or with minimum / small amounts of solvent in a process named liquid-assisted grinding (LAG) in comparison with solution-based methods. The mechanochemical reaction allows to perform chemical reactions without solvents or with minimum / small amounts of solvent. The mechanochemical reaction occurs because of the mechanochemical activation by the mechanochemical force.

[0020] N-(2- { [2(dimethylamino)ethyl] (methyl)amino } -4-methoxy-5 - { [4-( 1 -methyl- lH-indol-3 -yl)pyrimidin- 2-yl]amino}phenyl)prop-2-enamide (osimertinib, CAS number : 1421373-65-0) has the following structure :

[0021] The expression “pharmaceutically acceptable salt” means all pharmaceutically or physiologically acceptable salt forms of the compounds of osimertinib which may be formed, by protonation of a nitrogen an amino function, with an inorganic or organic acid. Examples acid addition salts comprise, mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), phosphate salts (such as hexafluorophosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogenocarbonate salts, borate salts, organic acid salts such as oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate salts; sulfonate salts such as methanesulfonate (monomesylate or dimesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), p-toluenesulfonate (tosylate), or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. Preferred pharmaceutically / physiologically acceptable salt of osimertinib include methanesulfonate (monomesylate or dimesylate).

[0022] “wherein at least one step is mechanochemical” refers to the fact that in the process of preparation of osimertinib, the minimum number of step that is performed thanks to mechanical activation is 1.

[0023] The starting product in the preparation of osimertinib is 1-methylindole (CAS number: 603-76-9) is an alkylated bicyclic aromatic compound containing a nitrogen. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring, in which the nitrogen is alkylated by a methyl group.

[0024] According to a particular embodiment of the use of the invention, said process does not involve the use of cobalt.

[0025] In the context of the invention, the reduction step and the amidation step does not involve the use of cobalt under any form.

[0026] According to a particular embodiment of the use of the invention, said process does not involve the use of a metal either under its toxic form or under toxic quantities, said metal being in particular chosen from: arsenic, barium, cadmium, chromium, cobalt, lithium, nickel, palladium, osmium, rhodium, thallium, tin, antimony, gold, silver, platinum. According to a particular embodiment of the use of the invention, said process does not involve the use of metal.

[0027] According to a particular embodiment of the use of the invention, in said process, the reduction step does not involve the use of halogen.

[0028] According to a particular embodiment of the use of the invention, the number of steps n is 5.

[0029] According to a particular embodiment of the use of the invention, the process of preparation comprises an arylation step, two subsequent nucleophilic aromatic substitution steps, a reduction step and an amidation step.

[0030] According to a particular embodiment of the use of the invention, the number of steps n is 6.

[0031] According to a particular embodiment of the use of the invention, the process of preparation comprises an arylation step, two subsequent nucleophilic aromatic substitution steps, a reduction step, an amidation step and a salification step.

[0032] According to another embodiment, the use of the invention consists in the use of a mechanical force to generate a mechanochemical reaction in the implementation of a process of preparation, of A-(2- { [2(dimethylamino)ethyl] (methyl)amino } -4-methoxy-5- { [4-( 1 -methyl- lH-indol-3 -yl)pyrimidin-2- yl]amino}phenyl)prop-2-enamide (osimertinib) or a pharmaceutically acceptable salt thereof, comprising n steps, n being 6 or 7, from indole, wherein at least one step is mechanochemical.

[0033] According to a particular embodiment of the use of the invention, the process of preparation comprises an alkylation step, an arylation step, two subsequent nucleophilic aromatic substitution steps, a reduction step and an amidation step.

[0034] According to a particular embodiment of the use of the invention, the mechanical forces are generated by a method chosen among: ball-milling (BM) or resonant acoustic mixing (RAM).

[0035] According to a particular embodiment of the use of the invention, the mechanical forces are generated by a method chosen among: ball-milling (BM), bead milling, resonant acoustic mixing (RAM) and screw extrusion (single, twin or multi).

[0036] Ball-milling comprises the following devices in a non-limiting manner: vibrating ball-mill, planetary ball-mill, drum mill, bead mill in particular dyno-mill, or vibrating eccentric mill.

[0037] Examples of the reaction vessel and the balls as an agitation medium used in the milling devices include ones formed of such materials as stainless steel, agate, alumina, tungsten carbide, chrome steel, zirconia oxide, silicon nitride and the like. Among these materials, zirconia oxide, is preferred. The size of the vessel used in the planetary ball mill is not particularly limited and may be approximately 1 cm3to 5000 L. The size of the balls is also not particularly limited and may be approximately from 2 to 50 mm in diameter. Particularly preferred specific examples of the vibrating and / or planetary ball mill include stainless steel and zirconia oxide as reaction vessel material.

[0038] Resonant acoustic mixing (RAM) involves applying a vibration to a container to induce reciprocating up and down motions on the contents of the container. The vibration may be applied with a relatively high (up to 100 g) acceleration (g) and a relatively low amplitude. The frequency of the vibration is typically around 60 Hz. The container can be cylindrical shaped with a circumferential side wall and disc-shaped top and bottom walls. The force is applied along the longitudinal axis of the container.

[0039] In resonant acoustic mixing, acoustic energy is delivered to the components to be mixed. An oscillating mechanical driver creates motion in a mechanical system comprising engineered plates, eccentric weights and springs. This energy is then acoustically transferred to the material to be mixed. The underlying technology principle is that the system operates at resonance. In this mode, there is a nearly complete exchange of energy between the mass elements and the elements in the mechanical system.

[0040] In a resonant acoustic mixing, the only element that absorbs energy (apart from some negligible friction losses) is the reactant composition. Thus, the resonant acoustic mixing provides a highly efficient way of transferring mechanical energy directly into the starting materials. The resonant frequency can be from about 15 Hertz to about 2000 Hertz, or from about 20 Hertz to about 1800 Hertz, or from about 20 Hertz to about 1700 Hertz. The g force applied by the acoustic mixer to the reactant composition can be from about 2 g force to about 100 g force.

[0041] Resonant acoustic mixers are available from Resodyn™ Acoustic Mixers and can be chosen from LabRAM I and LabRAM II and like.

[0042] Screw extrusion may be performed at various speeds (Ss), barrel temperatures (ST) and residence times (TR), as described herein. A single pass through the extruder may be sufficient to form the product of a mechanochemical reaction. Alternatively, when step a) is conducted in a twin-screw extruder, step a) may comprise collecting the product emerging from the twin screw extruder and subjecting it to one or more additional passes through the simple or twin-screw extruder.

[0043] Multi-screw extruders for use herein are not particularly limited. Any multi-screw extruder comprising a reaction chamber commonly known in the art may be used in the context of the present disclosure. Suitable multi-screw extruders for use herein will be easily identified by those skilled in the art, in the light of the present description.

[0044] In a particular aspect of the present application, the screw extruder for use herein is selected from the group of Single Screw Extruders (Helibar Transfer Mix, Co-Kneader), Twin Screw Extruders : 1. Intermeshing Screws: Co-rotating Parallel Screws, Counter-rotating Parallel Screws), 2: Non- intermeshing Screws (Co-rotating Parallel Screws, Co-rotating Conical Screws, Counter-rotating Screws), 3 : Multiple Screw Extruders (Rotating Center Shaft: Planetary Roller Extruder), Static Center Shaft (Ring Extruder, Multiple Screw Extruder)

[0045] In one preferred aspect, the multi-screw extruder for use in the process according to the disclosure is a twin-screw extruder, in particular a co-rotating twin-screw extruder.

[0046] In an alternative execution, the multi-screw extruder for use herein is a planetary roller extruder comprising in particular a center spindle and multiple planetary gear spindles with center spindle and planetary gear spindles featuring a screw like geometry.

[0047] Selecting and fine-tuning the various operating parameters of the multi-screw extruder to the specifics of the targeted chemical reaction, is well within the capabilities of those skilled in the art. These operating parameters will be typically adapted in particular to the nature of the chemical reactants.

[0048] In one exemplary aspect, the multi-screw extruder is operated at a screw speed in a range from 1 to 2000 rpm (revolutions per minute), from 20 to 1800 rpm, from 30 to 1600 rpm, from 50 to 1500 rpm, from 50 to 1300 rpm, from 80 to 1000 rpm, from 100 to 1000 rpm, from 150 to 800 rpm, from 180 to 700 rpm, from 180 to 500 rpm, or even from 200 to 350 rpm.

[0049] In an exemplary aspect, the multi-screw extruder further comprises at least a first addition port, a second addition port, and optionally a third addition port, and the first addition stream is incorporated into the reaction chamber of the multi-screw extruder through the first addition port, the second addition stream is incorporated through the second addition port, and the optional third addition stream is incorporated through the optional third addition port.

[0050] According to a typical aspect of the process of the present disclosure, the chemical reactants, and in particular the first addition stream, the second addition stream, and the optional third addition stream are incorporated simultaneously, optionally at a different flow speed, into the reaction chamber of the multi-screw extruder. Alternatively, the chemical reactants, and in particular the first addition stream, the second addition stream, and the optional third addition stream are incorporated into the reaction chamber of the multi-screw extruder in successive steps.

[0051] In an advantageous aspect of the process, the chemical reactants, and in particular the first addition stream, the second addition stream and the optional third addition stream are such that the chemical reactants, and in particular the first, second and optionally third addition stream are liquid prior to incorporation into the reaction chamber of the multi-screw extruder.

[0052] In an advantageous aspect of the process, the chemical reactants, and in particular the first addition stream, the second addition stream and the optional third addition stream are such that the chemical reactants, and in particular the first, second and optionally third addition stream are solid prior to incorporation into the reaction chamber of the multi-screw extruder.

[0053] In an alternative aspect, the chemical reactants, and in particular the first addition stream, the second addition stream and the optional third addition stream are such that the chemical reactants, and in particular the first addition stream, the second addition stream and the optional third addition stream are at least flowable / pumpable through conventional multi-screw extruders addition pumps prior to incorporation into the reaction chamber of the multi-screw extruder.

[0054] According to a typical aspect of the process of the present disclosure, the temperature of the chemical reactants, and in particular the first addition stream, the second addition stream and the optional third addition stream is in a range from 0°C to 120°C, from 0°C to 100°C, from 0°C to 80°C, from 0°C to 70°C, from 5°C to 60°C, from 10°C to 55°C, from 15°C to 45°C, from 20°C to 35°C, or even from 20°C to 25 °C, prior to incorporation into the reaction chamber of the multi-screw extruder.

[0055] In an advantageous aspect of the process, the chemical reactants, and in particular the first addition stream, the second addition stream and the optional third addition stream are incorporated into the reaction chamber of the multi-screw extruder each at a flow speed in a range from 0.01 ml / min to 500 ml / min, 0.3 ml / min to 300 ml / min, 0.5 ml / min to 200 ml / min, 0.5 ml / min to 100 ml / min, from 1 ml / min to 80 ml / min, from 2 ml / min to 60 ml / min, or even from 2 ml / min to 50 ml / min.

[0056] In another advantageous aspect, the first addition stream and / or the optional third addition stream is incorporated into the reaction chamber of the multi-screw extruder at a flow speed in a range from 1 ml / min to 30 ml / min, from 2 ml / min to 25 ml / min, from 5 ml / min to 25 ml / min, from 5 ml / min to 20 ml / min, from 8 ml / min to 20 ml / min, or even from 10 ml / min to 20 ml / min, or for an extruder that is adapted to a laboratory: from 0.1 g / min to 10 g / min, or for larger extruders in the industry: from 1 kg / min to 50 kg / min.

[0057] The main extruder parameters to consider are:

[0058] • feed rate of chemical reactants forming the starting material mixture: from 0. 1 g / min to 10 g / min for an extruder that is adapted to a laboratory (as a matter of example and in a non-limiting manner, with 9 mm, (length / diameter ratio) 25: 1 TSE; from 0.1 to 1.5 g / min) and for larger extruders in the industry, from 1 kg / min to 50 kg / min)

[0059] • Number of the liquid inlet ports and their position (as a matter of example and in a non-limiting manner with ZE9 Three-Tec extruder (LD 25: 1) of Three Tec company, 2 liquid ports are available: one close to the beginning of the barrel and one close to the end) used for the addition of LAG (the flow rate of LAG depends on the eta value and the feed rate of solid chemical reactants)

[0060] • Presence or not of a die and the type of die (The dies are defined and manufactured according to process requirements. Die diameters are possible from 0.1 mm. The empty volume in the die is negligible, as the screws extend into the die until just before the opening. Due to the simple design and low mass, separate die heating can be dispensed with in most cases. If heating of the die is nevertheless necessary, the same heating elements as for the barrel can be used for this purpose. The following die geometries are possible: Single and double dies, Sieve dies, Film dies (fixed or adjustable), Hose dies, Cooling dies for meat substitutes).

[0061] • Screw speed (from 1 to 1000 RPM) (as a matter of example and in a non-limiting manner Hybrid ZE9 / ZE12 Three-Tec extruder of Three Tec company can rotate from 1 to 200 RPM).

[0062] • Barrel temperature (as a matter of example and in a non-limiting manner, the hybrid ZE 9 / 12 Three-Tec TSE extruder of Three Tec company is able to heat from 25°C to 400°C, more preferably from 25°C to 230 °C.

[0063] • Screw profile: Modular allow infinite configuration of screw profiles by replacing some screw elements by others. Screw elements can be: conveying element (reverse or not), mixing elements (reverse or not) and kneading elements.

[0064] According to a particular embodiment of the use of the invention at least two steps, three steps, four steps, five steps or all the steps are mechanochemical.

[0065] The expression “all the steps” means, as a matter of example and in a non-limiting manner, that six steps are mechanochemical.

[0066] According to a particular embodiment of the use of the invention, at least two steps are mechanochemical .

[0067] According to a particular embodiment of the use of the invention, the at least two steps that are mechanochemical are chosen among the following one : the arylation step and one of the nucleophilic aromatic substitution step, the arylation step and the reduction step, the arylation step and the amidation step, the arylation step and the salification step, the two subsequent nucleophilic aromatic substitution steps, a nucleophilic aromatic substitution step and the reduction step, one of the nucleophilic aromatic substitution step and the amidation step, one of the nucleophilic aromatic substitution step and the salification step, the reduction step and the amidation step, the reduction step and the salification step and the amidation step and the salification step.

[0068] According to a particular embodiment of the use of the invention, wherein at least three steps are mechanochemical .

[0069] According to a particular embodiment of the use of the invention, the at least three steps that are mechanochemical are chosen among the following one: the arylation step and the two subsequent nucleophilic aromatic substitution steps, the arylation step, one of the nucleophilic aromatic substitution steps and the reduction step, the arylation step, one of the nucleophilic aromatic substitution steps and the amidation step, the arylation step, one of the nucleophilic aromatic substitution steps and the salification step, the arylation step, the reduction step and the amidation step, the arylation step, the reduction step and the salification step, the arylation step, the amidation step and the salification step, the two subsequent nucleophilic aromatic substitution steps and the reduction step, the two subsequent nucleophilic aromatic substitution steps and the amidation step, the two subsequent nucleophilic aromatic substitution steps and the salification step, one of the nucleophilic aromatic substitution steps, the reduction step and the amidation step, one of the nucleophilic aromatic substitution steps, the reduction step and the salification step, one of the nucleophilic aromatic substitution steps, the amidation step and the salification step, the reduction step, the amidation step and the salification step.

[0070] According to a particular embodiment of the use of the invention, wherein at least four steps are mechanochemical .

[0071] According to a particular embodiment of the use of the invention, the at least four steps that are mechanochemical are chosen among the following one: the arylation step, one of the nucleophilic aromatic substitution steps, the nucleophilic aromatic substitution step and the reduction step, the arylation step, the nucleophilic aromatic substitution step, one of the nucleophilic aromatic substitution steps and the amidation step, the arylation step, the two subsequent nucleophilic aromatic substitution steps and the salification step, the arylation step, one of the nucleophilic aromatic substitution steps, the reduction step and the amidation step, the arylation step, one of the nucleophilic aromatic substitution steps, the reduction step and the salification step, the arylation step, one of the nucleophilic aromatic substitution steps, the amidation step and the salification step, the arylation step, the reduction step, the amidation step and the salification step, the two subsequent nucleophilic aromatic substitution steps, the reduction step and the amidation step, the two subsequent nucleophilic aromatic substitution steps, the reduction step and the salification step, the two subsequent nucleophilic aromatic substitution steps, the amidation step and the salification step, the nucleophilic aromatic substitution step, the reduction step, the amidation step and the salification step.

[0072] According to a particular embodiment of the use of the invention, wherein at least five steps are mechanochemical .

[0073] According to a particular embodiment of the use of the invention, the at least five steps that are mechanochemical are chosen among the following one: the arylation step, the two subsequent nucleophilic aromatic substitution steps, the reduction step and the amidation step, the arylation step, the two subsequent nucleophilic aromatic substitution steps, the reduction step and the salification step, the arylation step, the two subsequent nucleophilic aromatic substitution steps, the amidation step and the salification step, the arylation step, one of the nucleophilic aromatic substitution steps, the reduction step, the amidation step and the salification step, the two subsequent nucleophilic aromatic substitution steps, the reduction step, the amidation step and the salification step

[0074] According to a particular embodiment of the use of the invention, wherein at least six steps are mechanochemical .

[0075] According to a particular embodiment of the use of the invention, wherein an arylation step, two subsequent nucleophilic aromatic substitution steps, a reduction step, an amidation step and a salification step are mechanochemical.

[0076] According to a particular embodiment of the use of the invention, said process of preparation can provide from 0.1 g to 1 kg of osimertinib or of a pharmaceutically acceptable salt thereof.

[0077] As used herein the expression “scalable” means the ability to be changed in size or scale to industrial equipment.

[0078] According to a particular embodiment of the use of the invention, said process of preparation can provide from 0.1 g to 500 g of osimertinib or of a pharmaceutically acceptable salt thereof.

[0079] According to a particular embodiment of the use of the invention, said process of preparation can provide from 500 g to 1 kg of osimertinib or of a pharmaceutically acceptable salt thereof.

[0080] According to a particular embodiment of the use of the invention, said osimertinib or of a pharmaceutically acceptable salt thereof being produced in an amount greater than 10 g. According to a particular embodiment of the use of the invention, said pharmaceutically acceptable salt of osimertinib is either osimertinib monomesylate or osimertinib dimesylate.

[0081] Osimertinib mesylate or osimertinib monomesylate (2-Propenamide, N-(2-((2- (dimethylamino)ethyl)methylamino)-4-methoxy-5-((4-(l-methyl-lH-indol-3-yl)-2- pyrimidinyl)amino)phenyl)-, methanesulfonate (1: 1); CAS number: 1421373-66-1 has the following structure :

[0082] Osimertinib dimesylate (N-(2- { [2-(Dimethylamino)ethyl] (methyl)amino } -4-methoxy-5 - { [4-( 1 -methyl - lH-indol-3-yl)-2-pyrimidinyl]amino}phenyl)acrylamide methanesulfonate (1:2) ; CAS number : 2070014-82-1 has the following structure :

[0083] According to a particular embodiment of the use of the invention, the reduction step involves the reduction of N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2- yl] -5 -nitrobenzene- 1 ,4-diamine into N1-(2-dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 - methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine and into N-(2-{[2-

[0084] (dimethylamino)ethyl] (methyl)amino } -4-methoxy-5 - { [4-( 1 -methyl- lH-indol-3 -yl)pyrimidin-2- yl] amino (phenyl) sulfamic acid.

[0085] N-(2- { [2-(dimethylamino)ethyl] (methyl)amino } -4-methoxy-5 - { [4-( 1 -methyl- lH-indol-3 - yl)pyrimidin-2-yl]amino}phenyl)sulfamic acid has the following structure :

[0086] In the context of the invention, N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(l- methyl-lH-indol-3-yl)pyrimidin-2-yl]amino}phenyl)sulfamic acid is subsequently transformed into N1- (2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l-methylindol-3-yl)pyrimidin-2-yl]benzene- 1,2,4-triamine in acidic conditions during the post-reactional treatment, and N1-(2-dimethylaminoethyl)- 5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine can be retrieved under the form of a hydrochloric salt.

[0087] According to a preferred embodiment of the use of the invention, comprising a reduction step of N'-(2- dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene- 1,4-diamine into Nl-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l-methylindol-3- yl)pyrimidin-2-yl]benzene-l,2,4-triamine, said reduction step is mechanochemical, and / or comprising an amidation step of the above mentioned N1-(2-dimethylaminoethyl)-5-methoxy-Nl- methyl-N4-[4-(l-methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine into osimertinib, said amidation step is mechanochemical.

[0088] The expression “N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l-methylindol-3- yl)pyrimidin-2-yl]-5-nitrobenzene-l,4-diamine” refers to the following compound :

[0089] The expression “N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l-methylindol-3- yl)pyrimidin-2-yl]benzene-l,2,4-triamine” refers to the following compound :

[0090] The reduction step is this embodiment consists in a reduction of the nitro group into an amine.

[0091] Additional advantages of the invention are : a) the reduction reaction in solution occurs in the presence of metals and generate halogenated (chlorinated) waste (reduction system : Fc / NHA’I). while the reduction method by BM or RAM occurs without metals and without halogens (and it does not generate halogenated / chlorinated waste). b) The reaction time for the reduction reaction in solution for the commercial route is not specified. The reaction time in solution is 2h. The reaction by BM occurs in 3h, while the reaction by RAM occurs in 30 min.

[0092] The amidation step in this embodiment consists in the introduction of a group, linked through an amide bond to the NH2 function of the phenyle ring. The amidation step is referred to the introduction of an acrylamide group directly, which is not the way osimertinib is prepared is solution in the prior art, being the acrylamide group generated only at the end of the process of preparation of osimertinib by an elimination reaction. Indeed, acrylamide is sensitive to nucleophiles, which makes its handling difficult in the conventional synthetic steps in solution. Herein, it is introduced directly, which make the synthesis by mechanochemistry 1 step shorter.

[0093] An additional advantage of the invention concerns the amidation reaction in solution that occurs in 90 minutes. The reaction by BM last for the same time, however, by RAM, the amidation method is 60 min (thus shorter than the method in solution).

[0094] According to a particular embodiment of the use of the invention, comprising a reduction step of N'-(2- dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene- 1 ,4-diamine into N1-(2-dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 - yl)pyrimidin-2-yl]benzene-l,2,4-triamine, said reduction step is mechanochemical.

[0095] According to a particular embodiment of the use of the invention, comprising an amidation step of the above mentioned N1-(2-dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 - yl)pyrimidin-2-yl]benzene-l,2,4-triamine into osimertinib, said amidation step is mechanochemical.

[0096] Another object of the present invention is a mechanochemical process of preparation of osimertinib.

[0097] A mechanochemical process of preparation of osimertinib, which comprises the step of : d) a mechanochemical reduction step of N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N- [4-(l -methylindol-3 -yl)pyrimidin-2-yl] -5 -nitrobenzene- 1,4-diamine with sodium dithionite or thiourea dioxide, under neat grinding or in liquid-assisted grinding (LAG) conditions, using BM or RAM, to obtain a crude product containing Nl-(2-dimethylaminoethyl)-5- methoxy-N1-methyl -N4-[4-( 1 -methylindol-3-yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine, followed by a purification of said crude product, to obtain N1-(2-dimethylaminoethyl)-5- methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine .

[0098] The invention relates to a mechanochemical process of preparation of osimertinib, which comprises the step of : d) a mechanochemical reduction step of N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N- [4-(l-methylindol-3-yl)pyrimidin-2-yl] -5 -nitrobenzene- 1,4-diamine with sodium dithionite, thiourea dioxide or rongalite, under neat grinding or in liquid-assisted grinding (LAG) conditions, using BM, RAM or twin screw extrusion (TSE), to obtain a crude product containing N1-(2 -dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2- yl]benzene-l,2,4-triamine, said triamine being in the neutral form or possibly under the form of a salt, followed by a post-reactional treatment, in particular a purification of said crude product, to obtain N1-(2-dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 - yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine, and wherein said process does not involve the use of cobalt.

[0099] In the context of step d), a post-reactional treatment can be a hydrolysis using an acid medium. The expression “neat grinding” corresponds to the mechanical force that takes place in absence of solvent.

[0100] As used herein, the term “liquid-assisted grinding (LAG)” refers to minimum or limited amounts of a liquid, the role of which is to increase ease of mixing and / or to participate to the reaction occurring in a mechanochemical system. Under conventionally defined LAG conditions; the liquid solvent has also been described as functioning essentially as a catalyst or lubrificant.

[0101] LAG uses a small amount of a liquid to accelerate reactions, as well as to enable transformations that do not take place by neat grinding. The empirical definition of LAG is based on the way mechanochemical reactivity is affected by the ratio of the liquid solvent to the weight of chemical reactants (q, eta).

[0102] A value of q = 0 pL / mg of reactants corresponds to neat grinding, q > 2 pL / mg of rectants corresponds to a typical solution reaction, while LAG lies in the range of ~ 0-1 pL / mg of rectants. In that range, reactivity appears independent of reactant solubility, distinguishing LAG from slurry reactions (1 pL / mg < q < 2 pL / mg of reactants) in which low solubility does hinder reactivity. (Friscic et al., ACS Cent. Set. 2017, 3(1), 13-19).

[0103] As used herein, the terms “minimum or limited amounts of a liquid” or “minimum / small amount of solvent” refers to an eta value ( / ;) up to 1, compared to the same reaction without mechanochemical conditions”.

[0104] “a crude product containing” means that during one of the step a), b), c), d), e) or f), a crude product containing various traces of unwanted reagents is obtained, and this crude product must go through a purification to give the desired product.

[0105] As a matter of example and in a non-limiting manner, the step d) can be carried out at 25 °C, with a mixture of water and ethanol under LAG conditions.

[0106] According to a particular embodiment, the process of the invention comprises the steps of : d) a mechanochemical reduction step of N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l- methylindol-3-yl)pyrimidin-2-yl] -5 -nitrobenzene- 1,4-diamine with sodium dithionite or thiourea dioxide, under neat grinding or in liquid-assisted grinding (LAG) conditions, using BM or RAM, to obtain a crude product containing N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l- methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine, followed by a purification of said crude product, to obtain N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l-methylindol-3- yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine, e) a mechanochemical amidation step of the above mentioned N1-(2-dimethylaminoethyl)-5- methoxy-N1-methyl -N4-[4-( 1 -methylindol-3-yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine with acrylic acid, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH), and tripotassium phosphate or potassium hydrogenophosphate, in liquid-assisted grinding (LAG) conditions, using BM to obtain a crude product containing osimertinib, followed by a purification of said crude product, to obtain osimertinib, or e) a mechanochemical amidation step of the above mentioned N1-(2-dimethylaminoethyl)-5- methoxy-N1-methyl -N4-[4-( 1 -methylindol-3-yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine with potassium acrylate and (3 -dimethylamino-propyl)-ethyl -carbodiimide hydrochloride (EDC.HC1), in liquid-assisted grinding (LAG) conditions, using RAM to obtain a crude product containing osimertinib, followed by a purification of said crude product, to obtain osimertinib,

[0107] As a matter of example and in a non-limiting manner, the step e) can be carried out at 25°C, with ethyl acetate under LAG conditions.

[0108] According to a particular embodiment, the process of the invention comprises the steps of : d) a mechanochemical reduction step of N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N- [4-(l-methylindol-3-yl)pyrimidin-2-yl] -5 -nitrobenzene- 1,4-diamine with sodium dithionite or thiourea dioxide, under neat grinding or in liquid-assisted grinding (LAG) conditions, using BM, to obtain a crude product containing N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl - N4-[4-(l-methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine, followed by a purification of said crude product, to obtain N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l- methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine, e) a mechanochemical amidation step of the above mentioned N1-(2-dimethylaminoethyl)-5- methoxy-N1-methyl -N4-[4-( 1 -methylindol-3-yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine with acrylic acid, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH), and tripotassium phosphate or potassium hydrogenophosphate, in liquid-assisted grinding (LAG) conditions, using BM to obtain a crude product containing osimertinib, followed by a purification of said crude product, to obtain osimertinib

[0109] According to a particular embodiment, the process of the invention comprises the steps of : d) a mechanochemical reduction step of N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N- [4-(l-methylindol-3-yl)pyrimidin-2-yl] -5 -nitrobenzene- 1,4-diamine with sodium dithionite or thiourea dioxide, under neat grinding or in liquid-assisted grinding (LAG) conditions, using RAM, to obtain a crude product containing N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl - N4-[4-(l-methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine, followed by a purification of said crude product, to obtain N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l- methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine, and, e) a mechanochemical amidation step of the above mentioned N1-(2-dimethylaminoethyl)-5- methoxy-N1-methyl -N4-[4-( 1 -methylindol-3-yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine with potassium acrylate and (3 -dimethylamino-propyl)-ethyl -carbodiimide hydrochloride (ECD.HC1), in liquid-assisted grinding (LAG) conditions, using RAM to obtain a crude product containing osimertinib, followed by a purification of said crude product, to obtain osimertinib

[0110] According to a particular embodiment of the process of the invention, said process does not involve the use of a metal either under its toxic form or under toxic quantities, said metal being chosen from: arsenic, barium, cadmium, chromium, cobalt, lithium, nickel, palladium, osmium, rhodium, thallium, tin, antimony, gold, silver, platinum.

[0111] According to a particular embodiment of the process of the invention, said process does not involve the use of metal.

[0112] According to a particular embodiment of the process of the invention, the reduction step d) involves the reduction of N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2- yl] -5 -nitrobenzene- 1 ,4-diamine into N1-(2-dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 - methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine and into N-(2-{[2-

[0113] (dimethylamino)ethyl] (methyl)amino } -4-methoxy-5 - { [4-( 1 -methyl- lH-indol-3 -yl)pyrimidin-2- yl] amino} phenyl) sulfamic acid.

[0114] In the context of the invention, N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(l- methyl-lH-indol-3-yl)pyrimidin-2-yl]amino}phenyl)sulfamic acid is subsequently transformed into N1- (2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l-methylindol-3-yl)pyrimidin-2-yl]benzene- 1,2,4-triamine in acidic conditions during the post-reactional treatment, and N1-(2-dimethylaminoethyl)- 5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine can be retrieved under the form of a hydrochloric salt.

[0115] According to a preferred embodiment, the process of the invention comprises the steps of : a) a mechanochemical Friedel-Craft arylation step of 1-methylindole with 2,4- dichloropyrimidine and a Lewis acid, using BM or RAM under neat grinding or in liquid- assisted grinding (LAG) conditions, to obtain a crude product containing 3-(2- chloropyrimidin-4-yl)-l -methyl- IH-indole, followed by a purification of said crude product, to obtain 3-(2-chloropyrimidin-4-yl)-l-methyl-lH-indole, b) a mechanochemical nucleophilic aromatic substitution step of the above mentioned 3-(2- chloropyrimidin-4-yl)-l -methyl- IH-indole with 4-fluoro-2-methoxy-5-nitroaniline and a sulfonic acid, under neat grinding or in liquid-assisted grinding (LAG) conditions, using BM or RAM to obtain a crude product containing N-(4-fluoro-2-methoxy-5-nitrophenyl)- 4-(l-methyl-lH-indol-3-yl)pyrimidin-2-amine, followed by a purification of said crude product, to obtain N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3- yl)pyrimidin-2 -amine, c) a mechanochemical nucleophilic aromatic substitution step of the above mentioned N-(4- fluoro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3-yl)pyrimidin-2 -amine with

[0116] N,N,N'-trimethylethylenediamine and a base, in particular K2CO3, in liquid-assisted grinding (LAG) conditions, using BM or RAM, to obtain a crude product containing N'-(2- dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5- nitrobenzene-l,4-diamine, followed by a purification of said crude product, to obtain N'-(2- dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5- nitrobenzene- 1 ,4-diamine,

[0117] It can be noted that the reaction by BM and / or by RAM occurs at room temperature, while the reaction in solution (manufacturing route) occurs at 85°C. The present procedure is milder (no heating) than the manufacturing one in solution. d) a mechanochemical reduction step of the above mentioned N'-(2-dimethylaminoethyl)-2- methoxy-N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-l,4-diamine with sodium dithionite or thiourea dioxide, under neat grinding or liquid-assisted grinding (LAG) conditions, using BM or RAM, to obtain a crude product containing N’-(2- dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2- yl]benzene-l,2,4-triamine, followed by a purification of said crude product, to obtain N’-(2- dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2- yl]benzene- 1 ,2,4-triamine, e) a mechanochemical amidation step of the above mentioned N’-(2- dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2- yl]benzene-l,2,4-triamine with acrylic acid, chloro-N,N,N',N'- tetramethylformamidinium hexafluorophosphate (TCFH), and tripotassium phosphate or potassium hydrogenophosphate, in liquid-assisted grinding (LAG) conditions, using BM to obtain a crude product containing osimertinib, followed by a purification of said crude product, to obtain osimertinib, or e) a mechanochemical amidation step of the above mentioned N’-(2- dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2- yl]benzene-l,2,4-triamine with potassium acrylate and (3-dimethylamino-propyl)- ethyl -carbodiimide hydrochloride (EDC.HC1), in liquid-assisted grinding (LAG) conditions, using RAM to obtain a crude product containing osimertinib, followed by a purification of said crude product, to obtain osimertinib,

[0118] According to a preferred embodiment, the process of the invention comprises the steps of: a) a mechanochemical Friedel-Craft arylation step of 1-methylindole with 2,4- dichloropyrimidine and a Lewis acid, using BM in particular vibrating ball-milling or planetary ball-milling, or RAM under neat grinding or in liquid-assisted grinding (LAG) conditions, to obtain a crude product containing 3-(2-chloropyrimidin-4-yl)-l-methyl-lH-indole, followed by a purification of said crude product, to obtain 3-(2-chloropyrimidin-4-yl)-l-methyl-lH-indole, Lewis acid Mechanochemical force b) a mechanochemical nucleophilic aromatic substitution step of the above mentioned 3-(2- chloropyrimidin-4-yl)-l -methyl- IH-indole with 4-fluoro-2-methoxy-5-nitroaniline and a sulfonic acid, under neat grinding or in liquid-assisted grinding (LAG) conditions, using BM, in particular planetary ball-milling or vibrating ball-milling to obtain a crude product containing N-(4-fhioro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3-yl)pyrimidin-2 -amine, followed by a purification of said crude product, to obtain N-(4-fluoro-2-methoxy-5- nitrophenyl)-4-( 1 -methyl- lH-indol-3 -yl)pyrimidin-2 -amine, fluoro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3-yl)pyrimidin-2 -amine with N,N,N'- trimethylethylenediamine and a base, in particular K2CO3 or K3PO4, in liquid-assisted grinding (LAG) conditions, using BM, in particular vibrating ball-milling, or RAM, to obtain a crude product containing N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l-methylindol-3- yl)pyrimidin-2-yl]-5-nitrobenzene-l,4-diamine, followed by a purification of said crude product, to obtain N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l-methylindol-3- yl)pyrimidin-2-yl] -5 -nitrobenzene- 1 ,4-diamine, d) a mechanochemical reduction step of the above mentioned N'-(2-dimethylaminoethyl)-2- methoxy-N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-l,4-diamine with sodium dithionite, thiourea dioxide or rongalite, under neat grinding or in liquid-assisted grinding (LAG) conditions, using BM, in particular planetary ball-milling, RAM or TSE, to obtain a crude product containing N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l- methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine, said triamine being in the neutral form or possibly under the form of a salt, followed by a post-reactional treatment, in particular a purification of said crude product, to obtain N1-(2-dimethylaminoethyl)-5-methoxy-N1- methyl-N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine, and, e) a mechanochemical amidation step of the above mentioned N1-(2-dimethylaminoethyl)- 5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine with potassium acrylate and (3 -dimethylamino-propyl)-ethyl -carbodiimide hydrochloride (EDC.HC1), in liquid-assisted grinding (LAG) conditions, using BM, in particular vibrating ball-milling or planetary ball-milling, RAM or TSE, to obtain a crude product containing osimertinib, followed by a post-reactional treatment, in particular a purification of said crude product, to obtain osimertinib or osimertinib mesylate,

[0119] Said 2,4-dichloropyrimidine (CAS Number : 3934-20-1) involved in the step a) has the following structure :

[0120] As a matter of example and in a non-limiting manner, the step a) can be carried out at 25 °C under neat grinding without additional or external heating.

[0121] Said 3-(2-chloropyrimidin-4-yl)-l-methyl-lH-indole (CAS Number: 1032452-86-0) involved in step b) has the following structure:

[0122] Said 4-fluoro-2-methoxy-5 -nitroaniline (CAS Number: 1075705-01-9) involved in step b) has the following structure:

[0123] As a matter of example and in a non-limiting manner, the step b) can be carried out at 90°C during 3 hours under neat grinding or in LAG conditions.

[0124] In the context of step a) and / or b), an auxiliary grinding such as SiC>2 can be introduced under neat grinding.

[0125] Said N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3-yl)pyrimidin-2 -amine (CAS

[0126] Number: 1421372-94-2) involved in step c) has the following structure:

[0127] During the mechanochemical nucleophilic aromatic substitution step with 4-fluoro-2-methoxy-5- nitroaniline, a formation of a nitrogen-carbon bond between the chlorine atom of the pyrimidine moiety of 3-(2-chloropyrimidin-4-yl)-l-methyl-lH-indole and the NH2 function of the 4-fluoro-2-methoxy-5- nitroaniline leads to the formation of the desired product.

[0128] Said N,N,N'-trimethylethylenediamine (CAS number : 142-25-6) involved in step c) has the following structure :

[0129] During the mechanochemical nucleophilic aromatic substitution step with N,N,N'- trimethylethylenediamine, a nitrogen-carbon bond is created between the amino function of N,N,N'- trimethylethylenediamine bearing a hydrogen and the carbon bearing the fluorine of N-(4-fluoro-2- methoxy-5 -nitrophenyl)-4-( 1 -methyl- lH-indol-3 -yl)pyrimidin-2 -amine .

[0130] As a matter of example and in a non-limiting manner, the step c) can be carried out at 25 °C with dimethylsulfoxide under LAG conditions without additional or external heating.

[0131] As a matter of example and in a non-limiting manner, the step c) can be carried out at 70°C during 2 hours in LAG conditions.

[0132] In the context of step d), a post-reactional treatment can be a hydrolysis using an acid medium.

[0133] In the context of step e), a post-reactional treatment can be the formation of the mesylate compound (osimertinib mesylate). According to a particular embodiment, the process of the invention comprises the steps of : a) a mechanochemical Friedel-Craft arylation step of 1-methylindole with 2,4- dichloropyrimidine and a Lewis acid, using BM under neat grinding or in liquid-assisted grinding (LAG) conditions, to obtain a crude product containing 3-(2-chloropyrimidin-4-yl)-l- methyl-lH-indole, followed by a purification of said crude product, to obtain 3-(2- chloropyrimidin-4-yl)- 1 -methyl- IH-indole, b) a mechanochemical nucleophilic aromatic substitution step of the above mentioned 3-(2- chloropyrimidin-4-yl)-l -methyl- IH-indole with 4-fluoro-2-methoxy-5-nitroaniline and a sulfonic acid, under neat grinding or in liquid-assisted grinding (LAG) conditions, using BM to obtain a crude product containing N-(4-fhioro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH- indol-3-yl)pyrimidin-2 -amine, followed by a purification of said crude product, to obtain N-(4- fluoro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3-yl)pyrimidin-2 -amine, c) a mechanochemical nucleophilic aromatic substitution step of the above mentioned N-(4- fluoro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3-yl)pyrimidin-2 -amine with N,N,N'- trimethylethylenediamine and a base, in particular K2CO3, in liquid-assisted grinding (LAG) conditions, using BM, to obtain a crude product containing N'-(2-dimethylaminoethyl)-2- methoxy-N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-l,4-diamine, followed by a purification of said crude product, to obtain N'-(2-dimethylaminoethyl)-2- methoxy-N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-l,4-diamine,

[0134] It can be noted that the reaction by BM and / or by RAM occurs at room temperature, while the reaction in solution (manufacturing route) occurs at 85°C. The present procedure is milder (no heating) than the manufacturing one in solution d) a mechanochemical reduction step of the above mentioned N'-(2-dimethylaminoethyl)-2- methoxy-N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-l,4-diamine with sodium dithionite or thiourea dioxide, under neat grinding or in liquid-assisted grinding (LAG) conditions, using BM, to obtain a crude product containing N1-(2-dimethylaminoethyl)- 5-methoxy-N1-methyl -N4-[4-( 1 -methylindol-3-yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine, followed by a purification of said crude product, to obtain N1-(2-dimethylaminoethyl)-5- methoxy-N1-methyl -N4-[4-( 1 -methylindol-3-yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine, and, e) a mechanochemical amidation step of the above mentioned N1-(2-dimethylaminoethyl)-5- methoxy-N1-methyl -N4-[4-( 1 -methylindol-3-yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine with acrylic acid, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH), and tripotassium phosphate or potassium hydrogenophosphate, in liquid-assisted grinding (LAG) conditions, using BM to obtain a crude product containing osimertinib, followed by a purification of said crude product, to obtain osimertinib,

[0135] In this embodiment, the ball-milling is carried out in at least one device or a combination of devices chosen among: planetary ball-mill, drum mill, bead mill in particular dyno-mill, or vibrating eccentric mill.

[0136] According to a particular embodiment, the process of the invention comprises the steps of : a) a mechanochemical Friedel-Craft arylation step of 1-methylindole with 2,4- dichloropyrimidine and a Lewis acid, using RAM under neat grinding or in liquid-assisted grinding (LAG) conditions, to obtain a crude product containing 3-(2-chloropyrimidin-4-yl)-l- methyl-lH-indole, followed by a purification of said crude product, to obtain 3-(2- chloropyrimidin-4-yl)- 1 -methyl- IH-indole, b) a mechanochemical nucleophilic aromatic substitution step of the above mentioned 3-(2- chloropyrimidin-4-yl)-l -methyl- IH-indole with 4-fluoro-2-methoxy-5-nitroaniline and a sulfonic acid, under neat grinding or in liquid-assisted grinding (LAG) conditions, using RAM to obtain a crude product containing N-(4-fhioro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH- indol-3-yl)pyrimidin-2 -amine, followed by a purification of said crude product, to obtain N-(4- fluoro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3-yl)pyrimidin-2 -amine, fluoro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3-yl)pyrimidin-2 -amine with N,N,N'-trimethylethylenediamine and a base, in particular K2CO3, in liquid-assisted grinding (LAG) conditions, using RAM, to obtain a crude product containing N'-(2- dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5- nitrobenzene-l,4-diamine, followed by a purification of said crude product, to obtain N'-(2- dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5- nitrobenzene- 1 ,4-diamine,

[0137] It can be noted that the reaction by BM and / or by RAM occurs at room temperature, while the reaction in solution (manufacturing route) occurs at 85°C. The process according to the present invention is milder (no heating) than the manufacturing one in solution. d) a mechanochemical reduction step of the above mentioned N'-(2-dimethylaminoethyl)-2- methoxy-N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-l,4-diamine with sodium dithionite or thiourea dioxide, under neat grinding or in liquid-assisted grinding (LAG) conditions, using RAM, to obtain a crude product containing N’-(2- dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2- yl]benzene-l,2,4-triamine, followed by a purification of said crude product, to obtain N’-(2- dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2- yl]benzene- 1 ,2,4-triamine, and, e) a mechanochemical amidation step of the above mentioned N1-(2-dimethylaminoethyl)-5- methoxy-N1-methyl -N4-[4-( 1 -methylindol-3-yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine with potassium acrylate and (3 -dimethylamino-propyl)-ethyl -carbodiimide hydrochloride (EDC.HC1), in liquid-assisted grinding (LAG) conditions, using RAM to obtain a crude product containing osimertinib, followed by a purification of said crude product, to obtain osimertinib,

[0138] According to a preferred embodiment, in the process of the invention, in the step a), the Lewis acid used is AlCh, and / or, in the step b), the sulfonic acid used is camphorsulfonic acid.

[0139] According to a particular embodiment, in the process of the invention, in the step a), the Lewis acid used is AICI3.

[0140] According to a particular embodiment, in the process of the invention, in the step b), the sulfonic acid used is camphorsulfonic acid.

[0141] According to a particular embodiment of the process of the invention, in the step a), the Lewis acid is FcCL and / or in step a), the BM is a planetary ball-milling, and / or in step b), the BM is a vibrating ball-milling, and / or, in the step b), the sulfonic acid is camphorsulfonic acid.

[0142] In a preferred embodiment, in step a) or in step b), silica is introduced. It acts as a solid additive / grinding auxiliary.

[0143] According to a particular embodiment of the process of the invention, in the step c), a polar solvent is added, preferably dimethylsulfoxide (DMSO), and / or in the step d), a mixture of ethanol and water is added, and / or in the step e), the solvent used under LAG conditions is chosen among ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, dimethyl sulfoxide, ethanol, glycerol, methyl-tert-butyl ether (MTBE), is added, preferably ethyl acetate or isopropyl acetate.

[0144] According to a preferred embodiment, in the process of the invention, in the step c), a polar solvent is added, preferably dimethylsulfoxide (DMSO), and / or in the step d), a mixture of ethanol and water is added, and / or in the step e), a solvent chosen among ethyl acetate, 2-methyltetrahydrofuran, dimethyl sulfoxide, ethanol, glycerol, methyl-tert-butyl ether (MTBE), is added, preferably ethyl acetate.

[0145] According to a particular embodiment of the process of the invention, in the step c), a polar solvent is added, preferably dimethylsulfoxide (DMSO), and / or in step b), the BM is a vibrating ball-milling and / or in the step e), the solvent used under LAG conditions is chosen among triethyl phosphate, isopropyl tetradecanoate, dipropylene glycol dibenzoate, dibutyl carbonate, ethylene carbonate, 4-methyl-l,3-dioxolan-2-one, preferably isopropyl tetradecanoate or triethyl phosphate.

[0146] In a preferred embodiment, DMSO is introduced and acts in liquid-assisted grinding (LAG) conditions.

[0147] According to a particular embodiment, in the process of the invention, in the step c), a polar solvent is added, preferably dimethylsulfoxide (DMSO).

[0148] According to a particular embodiment, in the process of the invention, the polar solvent is polyethylene glycol (PEG).

[0149] According to a particular embodiment, in the process of the invention, in the step d), a mixture of ethanol and water is added.

[0150] According to a particular embodiment, in the process of the invention, the volumetric ratio of the mixture of ethanol and water is from 5 : 1 to 1: 1, preferably is 3 : 1.

[0151] According to a particular embodiment, in the process of the invention, in the step e), a solvent chosen among ethyl acetate, 2-methyltetrahydrofuran, dimethyl sulfoxide, ethanol, glycerol, methyl-tert-butyl ether (MTBE), is added, preferably ethyl acetate.

[0152] According to a preferred embodiment, in the process of the invention, in the step d), the N’-(2- dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2-yl]benzene- 1,2,4- triamine is recovered from the crude product containing it, by a washing with ethanol, a fdtration and an evaporation of said ethanol, or, in the step d), the N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l-methylindol-3- yl)pyrimidin-2-yl]benzene-l,2,4-triamine is recovered from the crude product containing it, by an adjustment of the pH to 10 by using a 10% solution of K2CO3 (w / w), an extraction using ethyl acetate and an evaporation of said ethyl acetate.

[0153] According to a particular embodiment, in the process of the invention, in the step d), the N’-(2- dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2-yl]benzene- 1,2,4- 1 triamine is recovered from the crude product containing it, by a washing with ethanol, a fdtration and an evaporation of said ethanol.

[0154] This embodiment is preferred when the step d) resorts to BM.

[0155] According to a particular embodiment, in the process of the invention, the N1-(2-dimethylaminoethyl)- 5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine is recovered from the crude product containing it, by an adjustment of the pH to 10 by using a 10% solution of K2CO3 (w / w), an extraction using ethyl acetate and an evaporation of said ethyl acetate.

[0156] This embodiment is preferred when the step d) resorts to RAM.

[0157] According to a preferred embodiment, in the process of the invention, the osimertinib is recovered from the crude product containing it, by a precipitation in water.

[0158] This embodiment concerns the step e) when resorts to BM or RAM.

[0159] This work-up also concerns step d (reduction) by both ball-mill and by RAM and this work-up is better than that one used in the manufacturing route in solution for step d (reduction), where a purification by column chromatography is required.

[0160] According to a preferred embodiment, in the process of the invention, in step a), the mechanical forces are generated under neat grinding, and / or in step b), the mechanical forces are generated under neat grinding.

[0161] According to a particular embodiment of the process of the invention, in the step d), the N’-(2- dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2-yl]benzene- 1 ,2,4- triamine is recovered under the form of a hydrochloric salt from the crude product containing it, by an adjustment of the pH to 10 by using a 10% solution of K2CO3 (w / w) in presence of ethanol, then a filtration, then an adjustment of the pH to 1 by using a dropwise solution of hydrochloric acid at IM, then an evaporation of said ethanol and said solution of hydrochloric acid, or in the step d), the N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l-methylindol-3- yl)pyrimidin-2-yl]benzene-l,2,4-triamine is recovered from the crude product containing it by using an acid, optionally neutralized with a base, said acid and said base been independently selected from solid, liquid, or gaseous forms, and being introduced into a milling vessel after the reaction, in successive steps, then additional milling is performed and precipitation of the N1-(2-dimethylaminoethyl)-5- methoxy-N1-methyl-N4-[4-(l-methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine in a solvent occurs, preferably water, or in the step d), the N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l-methylindol-3- yl)pyrimidin-2-yl]benzene-l,2,4-triamine is recovered from the crude product containing it by suspending said crude product in an aqueous solution of hydrochloric acid at a concentration ranging from 0.8 to 1.2 M to obtain a suspension, the suspension is heated under reflux conditions, then adjusting the pH of the suspension to a basic value of a range from 11-12 using a base, then inducing the precipitation of said N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l-methylindol-3- yl)pyrimidin-2-yl]benzene-l,2,4-triamine, followed by extraction with an organic solvent and an evaporation of the solvent to obtain the purified N1-(2 -dimethylaminoethyl)-5 -methoxy-N1-methyl -N4- [4-( 1 -methylindol-3 -yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine . or in the step d), the N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l-methylindol-3- yl)pyrimidin-2-yl]benzene-l,2,4-triamine is recovered from the crude product containing it by suspending the crude in methanol to obtain a filtrate, then hydrochloric acid is added to the filtrate to obtain a suspension, the suspension is heated under reflux conditions, optionally the methanol is removed, then the pH is adjusted to a value of from 11 to 12, using a base to obtain a basic suspension, then the basic suspension is heated under reflux conditions to obtain a precipitate of N'-(2- dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2-yl]benzene- 1 ,2,4- triamine, which is subsequently filtered. or in the step d), the N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l-methylindol-3- yl)pyrimidin-2-yl]benzene-l,2,4-triamine is recovered from the crude product containing it by suspending the crude product in a methanolic solution of hydrochloric acid to obtain a suspension, the suspension is heated under reflux conditions, optionally the methanol is removed, then the pH of the suspension is adjusted to a value from 11 to 12, using abase to obtain a basic precipitate, then a filtration of the basic precipitate is performed and recrystallisation step is carried out using an alcohol.

[0162] In the context of the invention, the milling vessel is a part of the mechanochemical device.

[0163] According to a particular embodiment, in the process of the invention, in step a), the mechanical forces are generated under neat grinding.

[0164] According to a particular embodiment, in the process of the invention, in step b), the mechanical forces are generated under neat grinding.

[0165] According to a particular embodiment of the process of the invention, in step a) and / or in step b), the mechanical forces are generated in presence of a solid additive, in particular silica.

[0166] According to a preferred embodiment, in the process of the invention, in the step c), the LAG conditions are defined by the parameter p that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably is comprised from about 0.1 pL / mg to 0.5 pL / mg of reactants, more preferably 0.5 pL / mg of reactants, and / or in the step d), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably is comprised from about 0. 1 pL / mg to 0.5 pL / mg of reactants, more preferably 0.5 pL / mg of reactants, and / or, in the step d), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg and less than or equal to 1 pL / mg of reactants, more preferably is comprised from about 0.5 pL / mg to 1 pL / mg of reactants, more preferably 0.75 pL / mg of reactants, and / or in the step e), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less or equal to 1 pL / mg of reactants, more preferably is comprised from about 0.1 pL / mg to 0.5 pL / mg of reactants, more preferably 0.4 pL / mg of reactants, even more preferably 0.2 pL / mg of reactants.

[0167] According to a particular embodiment, in the process of the invention, in the step c), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably is comprised from about 0.1 pL / mg to 0.5 pL / mg of reactants, more preferably 0.5 pL / mg of reactants.

[0168] According to a particular embodiment, in the process of the invention, in the step d), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably is comprised from about 0.1 pL / mg to 0.5 pL / mg of reactants, more preferably 0.5 pL / mg of reactants.

[0169] According to a particular embodiment, in the process of the invention, in the step d), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg and less than or equal to 1 pL / mg of reactants, more preferably is comprised from about 0.5 pL / mg to 1 pL / mg of reactants, more preferably 0.75 pL / mg of reactants.

[0170] According to a particular embodiment, in the process of the invention, in the step e), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg and less or equal to 1 pL / mg of reactants, more preferably is comprised from about 0.1 pL / mg to 0.5 pL / mg of reactants, more preferably 0.4 pL / mg of reactants, even more preferably 0.2 pL / mg of reactants.

[0171] According to a particular embodiment of the process of the invention, in the step c), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably the parameter q is comprised from about 0.1 pL / mg of reactants to 0.9 pL / mg of reactants, more preferably 0.5 pL / mg of reactants, and / or in the step c), the LAG conditions are defined by the parameter p that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably the parameter q is comprised from about 0.05 pL / mg of reactants to 0.25 pL / mg of reactants, and more preferably is of 0.1 pL / mg of reactants or 0.2 pL / mg of reactants, and / or in the step d), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably the parameter q is comprised from about 0.1 pL / mg of reactants to 0.5 pL / mg of reactants, more preferably 0.5 pL / mg of reactants, and / or, in the step d), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably the parameter q is comprised from about 0.5 pL / mg of reactants to 1 pL / mg of reactants, more preferably 0.75 pL / mg of reactants, and / or in the step e), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less or equal to 1 pL / mg of reactants, more preferably the parameter q is comprised from about 0.1 pL / mg of reactants to 0.5 pL / mg of reactants, more preferably 0.4 pL / mg of reactants, even more preferably 0.2 pL / mg of reactants and / or in the step e), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less or equal to 1 pL / mg of reactants, more preferably the parameter q is comprised from about 0.25 pL / mg of reactants to 0.75 pL / mg of reactants, more preferably 0.5 pL / mg of reactants.

[0172] In the context of the present invention, the reactants do not comprise the minimum or limited amounts of a liquid the role of which is to increase ease of mixing and / or that participate to the reaction occurring in a mechanochemical system. In other words, the reactants do not comprise the above defined LAG.

[0173] In a preferred embodiment, in step d), in liquid-assisted grinding (LAG) conditions, using BM, in particular planetary ball-milling, the parameter q is 0.5 pL / mg of reactants.

[0174] In a preferred embodiment, in step d), in liquid-assisted grinding (LAG) conditions, using RAM, the parameter q is 0.5 pL / mg of reactants.

[0175] In a preferred embodiment, in step d), in liquid-assisted grinding (LAG) conditions, using TSE, the parameter q is 0.5 pL / mg of reactants.

[0176] In a preferred embodiment, in step e), in liquid-assisted grinding (LAG) conditions, using BM, the parameter q is 0.2 pL / mg of reactants and ethyl acetate is added.

[0177] In a preferred embodiment, in step e), in liquid-assisted grinding (LAG) conditions, using RAM, the parameter q is 0.5 pL / mg of reactants and i-propyl acetate is added.

[0178] In a preferred embodiment, in step e), in liquid-assisted grinding (LAG) conditions, using TSE, the parameter q is 0.2 pL / mg of reactants and i-propyl acetate is added.

[0179] According to a particular embodiment of the process of the invention, the LAG conditions are defined by the parameter q that is greater than 0 pL / mg and less than or equal to 1 pL / mg of reactants, more preferably is comprised from about 0.5 pL / mg to 1 pL / mg of reactants, more preferably 0.75 pL / mg of reactants, and in which the volumetric ratio of the mixture of ethanol and water is from 5: 1 to 1: 1, preferably is 3 : 1.

[0180] According to a preferred embodiment, in the process of the invention, comprises the step of: f) a salification step of the above mentioned osimertinib, in particular a mechanochemical salification with methane sulfonic acid using BM or RAM, to obtain osimertinib mesylate in particular in the step f), the mechanical forces are generated under neat grinding.

[0181] It can be noted that there is no work-up by ball-milling for this step (alternatively, a filtration by 2-Me- THF is conducted), while for the commercial route in solution, the work-up consists in a filtration by acetone. If the two work-up methods are compared for BM vs solution based methods, one can say the following: a) no work-up needed (when the synthesis is done by ball-milling) is beter than filtration in acetone, which is used when the synthesis is done in solution. b) The filtration by 2-MeTHF (used after BM synthesis), is beter that filtration is acetone, (used when the synthesis is done in solution). Indeed, 2-Me-THF is a biomass derivative solvent, which is a green alternative to ether solvents (e.g. THF, diethyl ether) and other organic volatile solvents. Therefore, 2.-Me-THF is in any case preferable to acetone (which is not green and more flammable and volatile than 2-Me-THF).

[0182] As a mater of example and in a non-limiting manner, the step f) can be carried out at 25°C.

[0183] According to a particular embodiment, the process of the invention comprises the steps of: f) a salification step of the above mentioned osimertinib, in particular a mechanochemical salification with methanesulfonic acid using RAM, to obtain a crude product containing osimertinib mesylate, followed by a post-reactional treatment, in particular a purification of said crude product, to obtain osimertinib mesylate

[0184] In the context of the invention, in the step f), the purification step can be a rinsing step using a solvent, in particular acetone.

[0185] According to a particular embodiment, the process of the invention comprises the steps of: f) a salification step of the above mentioned osimertinib, in particular a mechanochemical salification with methanesulfonic acid using BM, RAM or TSE, to obtain a crude product containing osimertinib dimesylate, followed by a post-reactional treatment, in particular a purification of said crude product, to obtain osimertinib dimesylate,

[0186] In the context of the invention, in the step f), the purification step can be a rinsing step using a solvent, in particular acetone.

[0187] According to a particular embodiment, the process of the invention comprises the steps of: f) a salification step of the above mentioned osimertinib, in particular a mechanochemical salification with methanesulfonic acid using TSE, to obtain a crude product containing osimertinib mesylate, followed by a post-reactional treatment, in particular a purification of said crude product, to obtain osimertinib mesylate

[0188] According to a particular embodiment, the process of the invention comprises the steps of : a) a mechanochemical Friedel-Craft arylation step of 1-methylindole with 2,4-dichloropyrimidine and a Lewis acid, using BM or RAM under neat grinding or in liquid-assisted grinding (LAG) conditions, to obtain a crude product containing 3-(2-chloropyrimidin-4-yl)-l-methyl-lH-indole, followed by a purification of said crude product, to obtain 3-(2-chloropyrimidin-4-yl)-l-methyl-lH-indole, b)a mechanochemical nucleophilic aromatic substitution step of the above mentioned 3-(2- chloropyrimidin-4-yl)-l -methyl- IH-indole with 4-fluoro-2-methoxy-5-nitroaniline and a sulfonic acid, under neat grinding or in liquid-assisted grinding (LAG) conditions, using BM or RAM to obtain a crude product containing N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3-yl)pyrimidin-2- amine, followed by a purification of said crude product, to obtain N-(4-fluoro-2-methoxy-5- nitrophenyl)-4-( 1 -methyl- lH-indol-3 -yl)pyrimidin-2 -amine, c) a mechanochemical nucleophilic aromatic substitution step of the above mentioned N-(4-fluoro-2- methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3-yl)pyrimidin-2 -amine with N,N,N'- trimethylethylenediamine and a base, in particular K2CO3, in liquid-assisted grinding (LAG) conditions, using BM or RAM, to obtain a crude product containing N'-(2-dimethylaminoethyl)-2-methoxy-N'- methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-l,4-diamine, followed by a purification of said crude product, to obtain N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l- methylindol-3 -yl)pyrimidin-2-yl] -5 -nitrobenzene- 1 ,4-diamine,

[0189] It can be noted that the reaction by BM and / or by RAM occurs at room temperature, while the reaction in solution (manufacturing route) occurs at 85°C. The present procedure is milder (no heating) than the manufacturing in solution. d) a mechanochemical reduction step of the above mentioned N'-(2-dimethylaminoethyl)-2- methoxy-N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-l,4-diamine with sodium dithionite or thiourea dioxide, under neat grinding or in liquid-assisted grinding (LAG) conditions, using BM or RAM, to obtain a crude product containing N’-(2- dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2- yl]benzene-l,2,4-triamine, followed by a purification of said crude product, to obtain N’-(2- dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2- yl]benzene- 1 ,2,4-triamine, e) a mechanochemical amidation step of the above mentioned N1-(2-dimethylaminoethyl)-5- methoxy-N1-methyl -N4-[4-( 1 -methylindol-3-yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine with acrylic acid, chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH), and tripotassium phosphate or potassium hydrogenophosphate, in liquid-assisted grinding (LAG) conditions, using BM to obtain a crude product containing osimertinib, followed by a purification of said crude product, to obtain osimertinib, or e) a mechanochemical amidation step of the above mentioned N1-(2-dimethylaminoethyl)-5- methoxy-N1-methyl -N4-[4-( 1 -methylindol-3-yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine with potassium acrylate and (3 -dimethylamino-propyl)-ethyl -carbodiimide hydrochloride

[0190] (EDC.HC1), in liquid-assisted grinding (LAG) conditions, using RAM to obtain a crude product containing osimertinib, followed by a purification of said crude product, to obtain osimertinib, and, f) a salification step of the above mentioned osimertinib, in particular a mechanochemical salification with methanesulfonic acid using BM, to obtain osimertinib mesylate in particular in the step f), the mechanical forces are generated under neat grinding.

[0191] It can be noted that the mesylation reaction by BM occurs in 15 min, while the manufacturing route in solution required 90 min reaction.

[0192] According to a preferred embodiment, the process of the invention comprises the step of: f) a salification step of the above mentioned osimertinib, in particular a mechanochemical salification with methanesulfonic acid using RAM, to obtain a crude product containing osimertinib mesylate, followed by a purification of said crude product, to obtain osimertinib mesylate

[0193] As a matter of example and in a non-limiting manner, the step f) can be carried out at 25°C with a mixture of isopropanol and water in LAG conditions.

[0194] It can be noted that the mesylation reaction by RAM occurs in 5 min, while the manufacturing route in solution required 90 min reaction.

[0195] It can be noted that the work up is done by precipitation in water (as the commercial manufacturing route).

[0196] According to a particular embodiment, the process of the invention comprises the steps of : a) a mechanochemical Friedel-Craft arylation step of 1-methylindole with 2,4-dichloropyrimidine and a Lewis acid, using BM or RAM under neat grinding or in liquid-assisted grinding (LAG) conditions, to obtain a crude product containing 3-(2-chloropyrimidin-4-yl)-l-methyl-lH-indole, followed by a purification of said crude product, to obtain 3-(2-chloropyrimidin-4-yl)-l-methyl-lH-indole,

[0197] Lewis acid Mechanochemical force b) a mechanochemical nucleophilic aromatic substitution step of the above mentioned 3-(2- chloropyrimidin-4-yl)-l -methyl- IH-indole with 4-fluoro-2-methoxy-5-nitroaniline and a sulfonic acid, under neat grinding or in liquid-assisted grinding (LAG) conditions, using BM or RAM to obtain a crude product containing N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3-yl)pyrimidin-2- amine, followed by a purification of said crude product, to obtain N-(4-fluoro-2-methoxy-5- nitrophenyl)-4-( 1 -methyl- lH-indol-3 -yl)pyrimidin-2 -amine, c) a mechanochemical nucleophilic aromatic substitution step of the above mentioned N-(4-fluoro-2- methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3-yl)pyrimidin-2 -amine with N,N,N'- trimethylethylenediamine and a base, in particular K2CO3, in liquid-assisted grinding (LAG) conditions, using BM or RAM, to obtain a crude product containing N'-(2-dimethylaminoethyl)-2-methoxy-N'- methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-l,4-diamine, followed by a purification of said crude product, to obtain N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l- methylindol-3 -yl)pyrimidin-2-yl] -5 -nitrobenzene- 1 ,4-diamine,

[0198] It can be noted that the reaction by BM and / or by RAM occurs at room temperature, while the reaction in solution (manufacturing route) occurs at 85°C. The present procedure is milder (no heating) than the manufacturing one in solution. d) a mechanochemical reduction step of the above mentioned N'-(2-dimethylaminoethyl)-2-methoxy- N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-l,4-diamine with sodium dithionite or thiourea dioxide, under neat grinding or in liquid-assisted grinding (LAG) conditions, using BM or RAM, to obtain a crude product containing N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl - N4-[4-(l-methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine, followed by a purification of said crude product, to obtain N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l-methylindol-3- yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine, e) a mechanochemical amidation step of the above mentioned N1-(2-dimethylaminoethyl)-5-methoxy- N1-methyl-N4-[4-(l-methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine with acrylic acid, chloro- N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH), and tripotassium phosphate or potassium hydrogenophosphate, in liquid-assisted grinding (LAG) conditions, using BM to obtain a crude product containing osimertinib, followed by a purification of said crude product, to obtain osimertinib, or e) a mechanochemical amidation step of the above mentioned N1-(2-dimethylaminoethyl)-5-methoxy- N1-methyl-N4-[4-(l-methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine with potassium acrylate and (3 -dimethylamino-propyl)-ethyl -carbodiimide hydrochloride (EDC.HC1), in liquid-assisted grinding (LAG) conditions, using RAM to obtain a crude product containing osimertinib, followed by a purification of said crude product, to obtain osimertinib, and, f) a salification step of the above mentioned osimertinib, in particular a mechanochemical salification with methanesulfonic acid using RAM, to obtain a crude product containing osimertinib mesylate, followed by a purification of said crude product, to obtain osimertinib mesylate

[0199] According to a preferred embodiment, in the process of the invention, in the step f), 2-methyltetrahydrofuran is added and / or, in the step f), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg and less than or equal to 1 pL / mg of reactants, more preferably is comprised from about 0.1 pL / mg to 0.5 pL / mg of reactants, more preferably 0.4 pL / mg of reactants, or, in the step f), a mixture of an alcohol chosen among methanol, ethanol, isopropanol, polyol, glycerol or polyethylene glycol (PEGs), preferably isopropanol, and H2O is added, and / or, in the step f), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg and less than or equal to 1 pL / mg of reactants, more preferably is comprised from about 0.1 pL / mg to 0.5 pL / mg of reactants, more preferably 0.3 pL / mg of reactants.

[0200] According to a particular embodiment, the process of the invention comprises the steps of: the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably the parameter q is comprised from about 0.25 pL / mg of reactants to 0.5 pL / mg of reactants, more preferably 0.75 pL / mg of reactants, or, in the step f), 2-methyltetrahydrofuran or a mixture of acetone and water at a volumetric ratio of 10: 1, is added and / or, in the step f), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably the parameter q is comprised from about 0.1 pL / mg of reactants to 0.6 pL / mg, more preferably 0.3 pL / mg of reactants. or, in the step f), acetone is added. The expression “polyol” refers to compounds containing at least two alcohol functions that can be liquid under mechanochemical stress.

[0201] As a matter of example and in a non-limiting manner, PEG can be PEG-400, 600, 800, 1000, 2000, 3400, 5000, 20 000 etc. and also end-chain can be selected from HO-PEG-OH, MeO-PEG-OMe, or HO- PEG-OMe or chosen among HO-PEG-OR, RO-PEG-OR and RO-PEG-OR’, R and R’ being identical or different and chosen independently from an alkyl from 1 to 10 carbon atoms and / or an aryl chain.

[0202] According to a particular embodiment, in the process of the invention, in the step f), 2- methyltetrahydrofuran is added.

[0203] According to a particular embodiment, in the process of the invention, in the step f), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably is comprised from about 0.1 pL / mg to 0.5 pL / mg of reactants, more preferably 0.4 pL / mg of reactants.

[0204] According to a particular embodiment, in the process of the invention, in the step f), a mixture of an alcohol chosen among methanol, ethanol, isopropanol, polyol, glycerol or PEGs, preferably isopropanol, and H2O is added.

[0205] According to a particular embodiment, in the process of the invention, in the step f), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably is comprised from about 0.1 pL / mg to 0.5 pL / mg of reactants, more preferably 0.3 pL / mg of reactants.

[0206] In a preferred embodiment, in step f) in order to obtain osimertinib monomesylate, using BM, the mechanical forces are generated under neat grinding.

[0207] In a preferred embodiment, in step f) in order to obtain osimertinib monomesylate, using RAM, the LAG conditions are defined by the parameter q that is 0.75 pL / mg of reactants and a mixture of isopropanol and water at a volumetric ratio of 1 : 1 is added.

[0208] In a preferred embodiment, in step f) in order to obtain osimertinib monomesylate, using TSE, the mechanical forces are generated under neat grinding.

[0209] In a preferred embodiment, in step f) in order to obtain osimertinib monomesylate, using TSE, the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants.

[0210] In a preferred embodiment, in step f) in order to obtain osimertinib dimesylate, using RAM, the LAG conditions are defined by the parameter q that is 0.75pL / mg of reactants and a mixture of acetone and water at a volumetric ratio of 1 : 1 is added.

[0211] In a preferred embodiment, in step f) in order to obtain osimertinib dimesylate, using RAM, the LAG conditions are defined by the parameter q that is 0.3 pL / mg of reactants and 2-Me-THF is added.

[0212] According to a preferred embodiment, in the process of the invention, the osimertinib mesylate is recovered from the crude product containing it, by a filtration and a wash using a solvent, in particular acetone.

[0213] According to a particular embodiment of the process of the invention, in at least one step chosen among: step a), step b), step c), step d), step e) and step f), the milling speed range value is chosen from 1 to 6000 rpm for BM, or m x g force is applied, m being a positive number chosen from 1 to 100, for RAM.

[0214] The expression “from 1 to 6000 rpm” means: from 1 to 1000 rpm ; from 1000 to 2000 rpm ; from 2000 to 3000 rpm ; from 3000 to 4000 rpm ; from 4000 to 5000 rpm ; from 5000 to 6000 rpm. In the context of the process according to the invention, 1 g (acceleration) is defined as the standard acceleration due to Earth gravity, so in units of the International System: I g = 9.80665 m s2.

[0215] According to a particular embodiment, in the process of the invention, m is a positive number chosen from 50 g to 100 g, and in particular 80 g or 90 g.

[0216] LIST OF FIGURES

[0217] Figure 1. 'H NMR spectrum of Example 8, the chemical shift is in the ordinate (in ppm)

[0218] Figure 2.13C Attached-Proton-Test (APT) NMR spectrum of Example 8, the chemical shift is in the ordinate (in ppm)

[0219] Figure 3. 'H NMR spectrum of Example 9, the chemical shift is in the ordinate (in ppm)

[0220] Figure 4. 'HNMR spectrum of Example 10, the chemical shift is in the ordinate (in ppm)

[0221] Figure 5.13C Attached-Proton-Test (APT) NMR spectrum of Example 10, the chemical shift is in the ordinate (in ppm)

[0222] Figure 6. 'HNMR spectrum of A1-(2-(Dimethylamino)ethyl)-5-methoxy-A!-methyl-A4-(4-(l -methyl- 177-indol-3-yl)pyrimidin-2-yl)benzene-l,2,4-triamine under the form of a hydrochloric salt in Example 11, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in PPm)

[0223] Figure 7. 'H NMR spectrum of A1-(2-(Dimethylamino)ethyl)-5-methoxy-A1-methyl-A4-(4-(l -methyl- 177-indol-3-yl)pyrimidin-2-yl)benzene-l,2,4-triamine in Example 11, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0224] Figure 8.13C Attached-Proton-Test (APT) NMR spectrum of A1-(2-(Dimethylamino)ethyl)-5- methoxy-A'1-methyl -A4-(4-( 1 -methyl - 1 H-m dol -3 -yl)pyrimidin-2-yl)benzene- 1 ,2,4-triamine in Example 11, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0225] Figure 9. 'H NMR spectrum of Example 12, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0226] Figure 10. 'H NMR spectrum of Example 12, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0227] Figure 11. 'H NMR spectrum of Example 14, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0228] Figure 12. 'H NMR spectrum of Example 14, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0229] Figure 13. 'H NMR spectrum of Example 15, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0230] Figure 14. 'H NMR spectrum of Example 16, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0231] Figure 15.13C NMR spectrum of Example 16, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0232] Figure 16. 'H NMR spectrum of Example 17, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0233] Figure 17.13C NMR spectrum of Example 17, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm) Figure 18. ’H NMR spectrum of Example 18, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0234] Figure 19.13C NMR spectrum of Example 18, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0235] Figure 20. ’H NMR spectrum of Example 19, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0236] Figure 21.13C NMR spectrum of Example 19, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0237] Figure 22. ’H NMR spectrum of Example 20, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0238] Figure 23.13C NMR spectrum of Example 20, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0239] Figure 24. 'HNMR spectrum of osimertinib dimesylate (method with 2-MeTHF) in Example 21, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0240] Figure 25.13C NMR spectrum of osimertinib dimesylate (method with 2-MeTHF) in Example 21, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0241] Figure 26. ’H NMR spectrum of osimertinib dimesylate (method with Acetone / H2O) in Example 21, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0242] Figure 27.13C NMR spectrum of osimertinib dimesylate (method with Acetone / H2O) in Example 21, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0243] Figure 28. ’H NMR spectrum of Example 22, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0244] Figure 29 corresponds to the detailed configuration of a ZE9 twin-screw extruder of Example 22 and Example 23, the numbers displayed are millimeters, as follows:

[0245] 1. LD 25:1 twin screw ((A) ; OrderNr: C04094): A primary twin screw element with a length of 78.5 mm and a pitch of 13.5 mm, ensuring efficient conveying of materials.

[0246] 2. Concave screw elements ((B), (E), (G), (S) ; OrderNr: C03930): Multiple concave elements with a length of 13.5 mm and a pitch of 9 mm, placed at various intervals to aid in consistent material transport and initial mixing.

[0247] 3. Kneading blocks: o OrderNr: ((C) ; C03935): A kneading block with a length of 13.5 mm, 60° phase angle, and 4 kneading segments, positioned to provide initial intensive shear. o OrderNr: ((F) ; C09042): Another kneading block with a length of 13.5 mm, 90° phase angle, and 5 kneading segments, enhancing the mixing and kneading process. o OrderNr: ((H), (I), (J), (L), (M), (N), (P, (Q), (R); C03291 and C03292: Several shorter kneading elements with lengths of 3 mm, phase angles of 0° and 90°, respectively, strategically placed to continue the shearing and kneading process.

[0248] 4. Mixing screw elements: o OrderNr: ((D) ; C04871): A mixing element with a length of 9 mm and a pitch of 9 mm, designed to ensure thorough mixing of the reactants. o OrderNr: ((K) ; C08930): An inverted mixing element with a length of 9 mm and a pitch of 9 mm, creating backflow to enhance mixing efficiency.

[0249] 5. Additional concave elements ((O) ; OrderNr: C03278 and C03930 : Further concave elements with the same dimensions as previously mentioned, placed to aid in the consistent conveyance and mixing of the materials towards the end of the process.

[0250] 6. End screws and segments: o OrderNr: C03938: End screw elements with no pitch, ensuring complete discharge of the material from the extruder. o OrderNr: ((T) ; C04872:) End segment with a concave shape, positioned at the final stage to ensure thorough processing and discharge of the extrudate.

[0251] Figure 30. ’H NMR spectrum of Example 23, signal intensity (arbitrary unit) in abscissae as a function of the chemical shift in the ordinate (in ppm)

[0252] The present invention will be described in more detail with reference to examples below.

[0253] Example 1 - Step d) by BM

[0254] The starting material A'- l -(2-(Dimcthylamino)cthyl)-5-mcthoxy-A'- l -mcthyl-A'-4-(4-( l -mcthyl- l / / - indol-3-yl)pyrimidin-2-yl)-2 -nitrobenzene- 1,4-diamine was obtained by mechanochemical synthesis but, it can be provided commercially.

[0255] A' I -(2-(Dimethylamino)ethyl)-5 -mcthoxy-A'- 1 -methyl -A'-4-(4-( 1 -methyl- 1 H-indol -3 -yl)pyrimidin-2- yl)-2 -nitrobenzene- 1,4-diamine (300.0 mg, 0.63 mmol) and Na2S2O4 (439.6 mg, 2.52 mmol, 4 eq) were placed in a 12 mb ZrO2 jar charged with 25x5 mm ZrO2 ball. Then, LAG additive was added (EtOH, 277 zL; H2O, 92 zL, r] = 0.5 pL / mg) and milled at 450 rpm for 180 min.

[0256] To the resulting reaction crude, EtOH (15 mb) was added and the mixture filtered. The solid residue was washed with additional EtOH (3 x 5 mb). The filtrate was collected, evaporated and dried to obtain N 1 -(2-dimethylaminoethyl)-5 -mcthoxy-A'- 1 -methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2- yl]benzene-l,2,4-triamine as an orange solid (245.1 mg, 87% yield).

[0257] ’H NMR (400 MHz, DMSO-zA) 5 (ppm): 9.88 (s, 1H), 8.92 (s, 1H), 8.51 (s, 1H), 8.43 (d, J = 8.0 Hz, 2H), 8.34-8.29 (m, 4H), 8.27 (d, J = 5 Hz, 2H), 8.16 (d, J = 8.0 Hz, 2H), 7.79 (sbrOad, 2H), 7.75 (sbrOad, 2H), 7.55-7.49 (d, J = 10.0 Hz, 6H), 7.28-7.13 (m, 13H), 6.89 (s, 2H), 6.79 (s, 2H), 3.92 (s, 6H), 3.88 (s, 6H), 3.82 (s, 6H), 3.75 (s, 7H), 3.14-3.03 (m, 12H), 2.88-2.77 (m, 9H), 2.61-2.57 (m, 12H).

[0258] Example 2 - Step e) using TCFH and tripotassium phosphate by BM

[0259]

[0260] Al -(2-(Dimethylamino)ethyl)-5 -mcthoxy-A I -methyl -A-4-(4-( 1 -methyl- I H-indol -3 -yl)pyrimidin-2- yl)benzene-l,2,4-triamine (2000.2 mg, 4.49 mmol), acrylic acid (323 pL, 4.71 mmol, 1.05 eq), TCFH (1385.5 mg, 4.94 mmol, 1.1 eq) and K3PO4 (2858.8 mg, 13.47 mmol, 3 eq) were placed in a 45 mL ZrCL jar charged with 100x5 mm ZrCL balls. Then, LAG additive was added (EtOAc, 1316 pL, r| = 0.2 pL / mg) and milled at 450 rpm for 120 min.

[0261] To the resulting reaction crude, water (50 mL) was added, and the precipitate was isolated by fdtration. The solid was washed with water (5x30 mL) and dried in vacuo in the presence of P2O5, to give osimertinib as a brown solid (2122.6 mg, 94% yield). ’H NMR (400 MHz, DMSO- e) 5 (ppm): 10.21 (s, 1 H), 9.16 (s, 1H), 8.69 (s, 1H), 8.34 (d, J = 5.3 Hz, 1H), 8.26 (d, J = 8.2 Hz, 1H), 7.92 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.28-7.23 (m, 2H), 7.21-7.13 (m, 2H), 7.05 (s, 1H), 6.46 (dd,3Jtrans = 16.7 Hz,3JC1S= 9.9 Hz, 1H), 6.29 (dd,3Jtrans = 16.7 Hz,2Jgem= 2.0 Hz, 1 H), 5.79 (dd,3JC1S= 9.9 Hz,2Jgem= 2.0 Hz, 1 H), 3.93 (s, 3H), 3.87 (s, 3H), 2.96-2.88 (m, 2H), 2.72 (s, 3H), 2.37-2.32 (m, 2H), 2.24 (s, 6H).

[0262] Example 3 - Step e) using TCFH and potassium hydrogenophosphate by BM Acrylic acid (72 pL, 1.05 mmol, 1.05 eq), TCFH (308.6 mg, 1.1 mmol, 1.1 eq) and K2HPO4 (522.6 mg, 3.0 mmol, 3 eq) were placed in a 10 mL ZrCL jar charged with 1x10 mm ZrCL ball and milled at 30 Hz for 60 min. Then, A- l-(2-(dimethylamino)ethyl)-5-methoxy-A-l -methyl -JV4-(4-( 1 -methyl- lH-indol-3- yl)pyrimidin-2-yl)benzene-l,2,4-triamine (2000.2 mg, 4.49 mmol) and LAG additive (EtOAc, 270 pL, q = 0.2 pL / mg) were added and milled at 30 Hz for 90 min. To the resulting reaction crude, water (30 mL) was added, and the precipitate was isolated by filtration. The solid was washed with water (6x20 mL) and dried in vacuo in the presence of P2O5, to give osimertinib as a brown solid (493.2 mg, 99% yield).

[0263] The NMR data are the same than Example 2.

[0264] Example 4 - Step f) under neat grinding by BM

[0265] Osimertinib (350.0 mg, 0.70 mmol) and methane sulfonic acid (45 pL, 0.70 mmol, 1.0 eq) were placed in a 10 mL Teflon™ jar charged with 1x10 mm ZrCL ball and milled at 30 Hz for 15 min. The resulting solid was recovered without further workup to give osimertinib mesylate as a brown solid (387.7 mg, 93% yield).

[0266] Optionally, if a sticky solid was obtained as the reaction crude (due to the presence of humidity in the atmosphere and in the starting material), 15 mL 2 -methyltetrahydrofuran (2-MeTHF) were added and the precipitate was recovered by filtration. The solid was washed with 2-MeTHF (5x5 mL) and dried in the air to yield osimertinib mesylate.

[0267] ’H NMR (400 MHz, DMSO-tL) 5 (ppm): 9.50 (s, 1 H), 9.30 (sbroad, 1H), 8.76 (s, 1H), 8.34 (sbroad, 2H), 7.58 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 6.4 Hz, 1H), 7.34-7.25 (m, 2H), 7.22-7.13 (m, 2H), 7.08 (s, 1H), 6.74 (dd,3Jtrans = 16.8 Hz,3JC1S= 10.5 Hz, 1H), 6.29 (d,3Jtrans = 16.7 Hz, 1 H), 5.79 (d,3JC1S= 10.5 Hz, 1 H), 3.92 (s, 3H), 3.86 (s, 3H), 2.98-2.92 (s, 2H), 2.85 (s, 6H), 2.707-2.62 (m, 2H), 2.39 (s, 6H).

[0268] Example 5 - Step d) by RAM

[0269] The starting material Al -(2-(Dimethylamino)ethyl)-5-methoxy-Al-methyl-N4-(4-(l -methyl- IH-indol-

[0270] 3 -yl)pyrimidin-2-yl)-2 -nitrobenzene- 1,4-diamine was obtained by mechanochemical synthesis but, it can be provided commercially.

[0271] 700mg (1.47mmol, leq) of the A1-(2-(Dimethylamino)ethyl)-5-methoxy-A1-methyl -N4-(4-(l -methyl - IH-indol-3-yl)pyrimidin-2-yl)-2 -nitrobenzene- 1,4-diamine and 1.03 g of sodium dithionite (5.89 mmol,

[0272] 4 eq) were added in a 5 mL PTEE jar. Then EtOH (970 pL) and water (324 pL) were added in a ratio of 3: 1 and of a total q value of 0.75 pL / mg. Then the vessel was stirred in a LabRAM II Resodyn mixer of the company Resodyn™ at 100 g for 30 minutes. The crude reaction mixture was dissolved in water and the pH was adjusted at 10 with a 10% (w / w) solution of K2CO3. Then the dissolved crude reaction mixture was extracted with EtOAc and the organic phase was washed with brine, isolated and dried over MgSO4. Then it was evaporated under reduced pressure to give N1-(2-dimethylaminoethyl)-5-methoxy- N1-methyl-N4-[4-(l-methylindol-3-yl)pyrimidin-2-yl]benzene-l, 2, 4-triamine as a grey powder (368.9mg, 55%).

[0273] ’H NMR (400 MHz, DMSO-6) 5 (ppm) : 8.42 (d, J = 7.8 Hz, 1H), 8.30 (s, 1H), 8.27 (d, J = 5.4 Hz, 1H), 7.78 (s, 1H), 7.54 - 7.47 (m, 2H), 7.24 (t, J= 7.6 Hz, 1H), 7.16 (dd, J= 11.4, 6.4 Hz, 2H), 6.76 (s, 1H), 3.88 (s, 3H), 3.74 (s, 3H), 2.88 (t, J= 6.7 Hz, 2H), 2.63 (s, 3H), 2.35 (t, J= 6.7 Hz, 2H), 2.17 (s, 6H).

[0274] 13C NMR (101 MHz, DMSO-d6) 5 (ppm) : 162.66, 160.98, 157.55, 142.38, 138.17, 137.27, 133.89, 133.38, 126.12, 125.73, 122.78, 122.62, 121.39, 112.97, 110.8, 109.57, 107.29, 105.77, 66.88, 57.89, 56.96, 54.53, 46.24, 42.19, 33.49.

[0275] HRMS ESI (+) m / z: Calcd. For C25H32N7O [M+ H]+, 446.2668; found, 446.2663.

[0276] Example 6 - Step e) using N-Ethyl-N'-(3-dim ethylaminopropyl) carbodiimide hydrochloride by RAM

[0277] Nl-(2-(Dimethylamino) ethyl) -5-methoxy-Nl-methyl-N4-(4-(l-methyl-lH-indol-3-yl) pyrimidineyl) benzene- 1, 2, 4-triamine (1g, 2.24 mmol), potassium acrylate (271.9mg, 2.47 mmol, 1.1 eq) and N- Ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHC1) (516.3 mg, 2.69 mmol, 1.2 eq) and EtOAc (715 pl, r|=0.4 pL / mg) were added in a 10 mL glass vial and the vial was stirred in a LabRAM II Resodyn mixer of the company Resodyn™ at 90 g for 60 minutes. After the end of the mixing, the resulting crude was transferred to a 100 mL beaker and distilled water (50 mL) was added and a brown precipitate was formed. Then it was filtered under vacuum and the resulting precipitate was washed further with 100 mL of distilled water, and the water was dried in vacuo in the presence of P2O5, to give osimertinib as a brown solid (1.08 g, 97% yield).

[0278] ’H NMR (400 MHz, DMSO-zL) 5 (ppm) 10.21 (s, 1 H), 9.16 (s, 1H), 8.69 (s, 1H), 8.34 (d, J = 5.3 Hz, 1H), 8.26 (d, J = 8.2 Hz, 1H), 7.92 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.28-7.23 (m, 2H), 7.21-7.13 (m, 2H), 7.05 (s, 1H), 6.46 (dd, J = 16.7 Hz, J = 9.9 Hz, 1H), 6.29 (dd, J = 16.7 Hz, J = 2.0 Hz, 1 H), 5.79 (dd, J = 9.9 Hz, J= 2.0 Hz, 1 H), 3.93 (s, 3H), 3.87 (s, 3H), 2.96-2.88 (m, 2H), 2.72 (s, 3H), 2.37-2.32 (m, 2H), 2.24 (s, 6H).

[0279] Example 7 - Step f) with Z-PrOH / HzO by RAM

[0280] In a 4 mL polypropylene vial, osimertinib (338.1 mg, 0.68 mmol) and methanesulfonic acid (71.5 mg, 0.74 mmol, 48.3 / d) and i-PrOH / H2O (1: 1) (123 / zL, rf = 0.3 zL / mg) were added and mixed at 80 g for 5 minutes in a LabRAM II Resodyn mixer of the company Resodyn ™. After the end of the mixing, the resulting crude was washed with 20 mL acetone and a yellow precipitate was formed. Then it was filtered under vacuum and the resulting precipitate was washed further with 30 mL of acetone and dried in vacuo to give osimertinib mesylate as a yellow solid (396.7 mg, 98% yield).

[0281] ’H NMR (400 MHz, DMSO-zL) 5 (ppm) 9.50 (s, 1 H), 9.30 ( 1H), 8.76 (s, 1H), 8.34 (2H), 7.58 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 6.4 Hz, 1H), 7.34-7.25 (m, 2H), 7.22-7.13 (m, 2H), 7.08 (s, 1H), 6.74 (dd, J= 16.8 Hz, J = 10.5 Hz, 1H), 6.29 (d, J= 16.7 Hz, 1 H), 5.79 (d, J= 10.5 Hz, 1 H), 3.92 (s, 3H), 3.86 (s, 3H), 2.98-2.92 (s, 2H), 2.85 (s, 6H), 2.707-2.62 (m, 2H), 2.39 (s, 6H).

[0282] Example 8 - Step a) by BM (planetary ball-milling)

[0283] 2,4-Dichloropyrimidine (2.20 g, 14.8 mmol, 1.0 equiv), silica (7.11 g, 40-63 micron), 1-methylindole (2.04 g, 14.8 mmol, 1.0 equiv), and anhydrous iron(III) trichloride (2.87 g, 17.7 mmol, 1.2 equiv) were added to a 80 mL zirconium oxide jar filled with 25 x 10 mm balls. The content of the jar was milled at 750 rpm for 3 h in a Fritsch P7 premium mill. The crude powder was removed from the jar, added to an Erlenmeyer filled with water (50 mL) and stirred for 20 min. The remaining solid was filtered and washed with water (3 x 30 mL), said water forming an aqueous filtrate. After discarding the aqueous filtrate, the remaining solid was washed with acetone (3 x 50 mL) to obtain filtrate. The volume of the collected filtrate was reduced in vacuo and the product was collected after crystallization in acetone as a yellow solid (2.25 g ,63%).

[0284] TLC (EtOAc / w-heptane, 50 / 50 v / v): RF= 0.37; 'H NMR in Figure 1 (500 MHz, DMSO-de) 5 (ppm) : 8.53 (d, J= 5.4 Hz, 1H), 8.50 (s, 1H), 8.44 - 8.39 (m, 1H), 7.82 (d, J= 5.4 Hz, 1H), 7.58 (d, J= 8.1 Hz, 1H), 7.35 - 7.25 (m, 2H), 3.90 (s, 3H).13C NMR in Figure 2 (126 MHz, DMSO-de) 5 164.5, 160.3, 158.7, 137.8, 134.7, 125.3, 122.8, 121.7, 121.6, 114.3, 110.8, 110.7, 33.3. ESI-MS (m / z): [M + H]+calcd for C13H10CIN3 : 244,07; found: 244.33

[0285] Example 9 - Step b) by BM (vibrating ball-milling)

[0286] 3 -(2-Chloropyrimidin-4-yl)-l -methyl- IH-indole (1.00 g, 4.10 mmol, 1.0 equiv), 4-fluoro-2-methoxy-5- nitroaniline (916 mg, 4.92 mmol, 1.2 equiv), silica (2.4 g, 40 - 63 micron), and camphorsulfonic acid (763 mg, 3.28 mmol, 0.8 equiv) were added to a 50 mL zirconium oxide jar fdled with 11 x 10 mm zirconium oxide balls. Hie jar was placed into a preheated (90 °C) milling platform and milled at 30 Hz at 90 °C for 3 h using a Retsch 500 MM control to obtain a solid. The solid was collected, washed with ethanol (200 mL), and subsequently washed with acetonitrile (100 mL) to obtain a remaining bright yellow solid. The remaining yellow solid was identified as mixture of silica and A-(4-Fluoro-2-methoxy- 5 -nitrophenyl)-4-(l -methyl- lH-indole-3-yl)pyrimidin-2-amine (1.1 g, 68%). The yield determined by subtracting the silica mass (2.4 g) from the mass of the received bright yellow solid (3.50 g).

[0287] TLC (DCM): RF= 0.35; 'H NMR in Figure 3 (400 MHz, DMSO-de) 5 (ppm): 9.88 (bs, 1H), 8.77 (d, J = 8.3 Hz, 1H), 8.70 (s, 1H), 8.34 (d, J = 6.5 Hz, 1H), 8.25 - 8.18 (m, 1H), 7.61 (d, J= 8.1 Hz, 1H), 7.51 (d, J= 13.4 Hz, 1H), 7.47 (d, J= 6.5 Hz, 1H), 7.36 - 7.28 (m, 1H), 7.18 - 7.10 (m, 1H), 4.00 (s, 3H), 3.93 (s, 3H). ESI-MS (m / z): [M + H]+calcd for C20H16FN5O3 : 394.13; found: 394.12

[0288] Example 10 - Step c) by BM (vibrating ball-milling)

[0289] A-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(l -methyl- I A-indolc-3-yl)pyrimidin-2 -amine (400 mg, 1.02 mmol, 1.0 equiv), A, A, N' -trimethylethylenediamine (125 mg, 1.23 mmol, 1.2 equiv), tripotassium phosphate (432 mg, 2.03 mmol, 2.0 equiv), and dimethyl sulfoxide (95 pL, q = 0.1 pL / mg) were added to a 10 mL inox jar filled with 20 x 5 mm inox balls. The jar was placed intro a preheated (70 °C) milling platform and milled at 30 Hz at 70 °C for 2 h using a Retsch 500 MM control to obtain a crude mixture. The crude mixture was precipitated in water (20 mL), filtered, and washed with water (2 x 10 mL) to obtain a residue. After removing the aqueous filtrate, the residue was washed with acetone (3 x 10 mL) to obtain a filtrate. Al-(2-(Dimcthylamino)cthyl)-5-mcthoxy-Al-mcthyl-N4-(4-( l -mcthyl- IA-indol-3- yl)pyrimidin-2-yl)-2 -nitrobenzene- 1,4-diamine was collected by concentrating the filtrate in vacuo as an orange solid (472 mg, 98%).

[0290] TLC (MeOH / DCM, 5 / 95, v / v): RF= 0.23; 'H NMR in Figure 4 (600 MHz, DMSO-de) 5(ppm): 8.64 (s, 1H), 8.36 (d, J= 7.9 Hz, 1H), 8.34 - 8.31 (m, 2H), 8.10 (s, 1H), 7.52 (d, J= 8.2 Hz, 1H), 7.28 - 7.23 (m, 1H), 7.22 (d, J= 5.4 Hz, 1H), 7.16 - 7.09 (m, 1H), 6.85 (s, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 3.27 (t, J = 6.9 Hz, 2H), 2.86 (s, 3H), 2.48 (t, J= 6.9 Hz, 2H), 2.16 (s, 6H).13C NMR in Figure 5 (151 MHz, DMSO-de) 5(ppm) : 162.1, 160.1, 157.2, 154.9, 143.8, 137.6, 133.0, 132.1, 125.5, 122.2, 122.1, 121.3, 120.9, 119.4, 112.3, 110.4, 107.4, 102.0, 56.5, 56.3, 52.9, 45.5, 40.5, 33.1. ESI-MS (m / z): [M + H]+calcd for C25H29N7O3: 476.24; found: 476.28

[0291] Example 11 - Step d) by BM (planetary ball-milling)

[0292] T -NO2TAG-HH2T G-NHJ

[0293] A1-(2-(Dimethylamino)ethyl)-5 -methoxy-A1-methyl -N4-(4-( 1 -methyl- 1 A-indol -3 -yl)pyrimidin-2-yl)- 2-nitrobenzene-l,4-diamine (950.5 mg, 2.0 mmol) and Na2S2O4 (1.393 g, 8.0 mmol, 4 eq) were placed in a 20 mL stainless steel jar charged with 40x5 mm stainless steel balls. Then, (EtOH, 878 pL; H2O, 293 pL, r| = 0.5 pL / mg) was added as LAG additive and milled at 450 rpm for 180 min to obtain a reaction crude.

[0294] Work-up 1: To the resulting reaction crude, EtOH (15 mL) and K2CO3 was added (until pH 9-10) and the mixture was filtered to obtain a resulting filtrate. To the resulting filtrate, HC1 1 M was added dropwise until pH 1 was reached and the solvent was evaporated at reduced pressure to obtain A'-(2- (Dimethylamino)ethyl)-5 -methoxy -N}-methyl - -(4-( 1 -methyl- IH-indol -3 -yl)pyrimidin-2-yl)benzene- 1 ,2,4-triamine under the form of a hydrochloric salt as a yellow solid (724.0 mg, 75% yield).

[0295] Work-up 2: To the resulting reaction crude, methanol (30 mL) was added and the suspension filtered to obtain a filtrate. Concentrated HC1 (10 mL) was added to the filtrate, and heated to reflux temperature for 60 min. After cooling down to 25°C, methanol was removed under reduced pressure and the resulting aqueous solution was neutralized with a 10% (w / w) K2CO3 solution until pH 11 (85 mL) to obtain a suspension. The suspension was heated at reflux temperature for 60 min to obtain a resulting solid, and then the resulting solid in suspension was filtered, washed with water (3x 5 mL) and dried under reduced pressure to obtain A1-(2-(Dimethylamino)ethyl)-5 -methoxy- A1-methyl -A4-(4-( 1 -methyl- lA-indol-3 - yl)pyrimidin-2-yl)benzene-l,2,4-triamine as a brown solid (816.0 mg, 85% yield).

[0296] 'H NMR (400 MHz, DMSO- e) 5 (ppm) A1-(2-(Dimethylamino)ethyl)-5-methoxy-A1-methyl-A4-(4-(l- methyl-lH-indol-3-yl)pyrimidin-2-yl)benzene-l,2,4-triamine under the form of a hydrochloric salt in figure 6: 10.33 (sbroad, 3H), 8.31 - 8.23 (m, 1H), 8.21 - 8.02 (m, 1H), 7.81 - 7.68 (m, 1H), 7.6 (d,3J = 8.2 Hz, 1H), 7.45 (d,3J = 6.7 Hz, 1H), 7.35 - 7.30 (m, 1H), 7.26 - 7.19 (m, 2H), 3.95 (s, 3H), 3.85 (s, 3H), 3.81 - 3.66 (m, 2H), 3.44 - 3.38 (m, 4H), 2.78 (s, 6H), 2.75 (s, 3H). ’H NMR (400 MHz, DMSO- dd) 5 (ppm) Nx-(2-(Dimethylamino)ethyl)-5 -methoxy-#1-methyl -JV4-(4-( 1 -methyl- 177-indol -3 - yl)pyrimidin-2-yl)benzene-l,2,4-triamine in Figure 7: 8.42 (d,3J= 7.9 Hz, 1 H), 8.30 (s, 1H), 8.27 (d, V= 5.4 Hz, 1H), 7.78 (s, 1H), 7.51 (d,3J= 7.9 Hz, 1H), 7.48 (s, 1H), 7.25 (t,3. / = 7.1 Hz, 1H), 7.19 - 7.13 (m, 2H), 6.76 (s, 1H), 4.57 (s, 2H), 3.88 (s, 3H), 3.74 (s, 3H), 2.88 (t,3J = 6.6 Hz, 2H), 2.63 (s, 3H), 2.36 (t,3. / = 6.6 Hz, 2H), 2.17 (s, 6H).

[0297] 13C APTNMR (101 MHz, DMSO-t / 6) 5 (ppm) #1-(2-(Dimethylamino)ethyl)-5-methoxy-A1-methyl-A4- (4-(l -methyl- l / / -indol -3 -yl)pyrimidin-2-yl)benzene-l, 2, 4-triamine in Figure 8: 162.06 (-C-), 160.40 (- C-), 156.93 (-CH-), 141.70 (-C-), 137.58 (-C-), 136.74 (-C-), 133.36 (-C-), 132.82 (-CH-), 125.55 (-C- ), 125.19 (-C-), 122.26 (-CH-), 122.11 (-CH-), 120.86 (-CH-), 112.44 (-C-), 110.29 (-CH-), 109.03 (- CH-), 106.76 (-CH-), 105.27 (-CH-), 57.41 (-CH2-), 56.46 (-CH3), 54.01 (-CH2-), 45.71 (-CH3), 41.62 (-CH3), 32.99 (-CH3). HRMS (ESI): m / z calculated for C25H32N7O [M+H]+446.2668, found 446.2659.

[0298] Example 12 - Step e) by BM (vibrating ball-mill)

[0299] A'1-(2-(Dimethylamino)ethyl)-5 -mcthoxy-A'1-methyl -A'4-(4-( 1 -methyl- 177-indol -3 -yl)pyrimidin-2- yl)benzene- 1,2, 4-triamine (623.8 mg, 1.40 mmol), potassium acrylate (185.1 mg, 1.68 mmol, 1.2 eq), and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HC1) (375.7 mg, 1.96 mmol, 1.4 eq) were placed in a 10 mb ZrO2jar charged with 1x10 mm ZrO2ball. Then, EtOAc, 237 pL, (q = 0.2 pL / mg) was added as LAG additive and milled at 30 Hz for 120 min to obtain a reaction crude. Water (50 mL) was added to the resulting reaction crude, and the precipitate was isolated by filtration to obtain a solid. The solid was washed with water (4x15 mL) and dried overnight in vacuo in the presence of P2O3, to obtain a brown solid (667.8 mg). Then, the solid was dissolved in the minimum amount of EtOAc / EtOH (80:20) and filtered through a thin layer of silica gel (660 mg, 2 cm 0, 3 mm thickness) and eluted with further 35 mL of EtOAc / EtOH (80:20). The EtOAc / EtOH was evaporated at reduced pressure to obtain Osimertinib as a beige solid (722.8 mg, 52%).

[0300] ’H NMR in Figure 9 (400 MHz, DMSO-#,) 5(ppm): 10.22 (s, 1 H), 9.14 (s, 1H), 8.68 (s, 1H), 8.34 (d, J = 5.3 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.27-7.21 (m, 2H), 7.17- 7.12 (m, 1H), 7.04 (s, 1H), 6.42 (dd,3Jtrans = 16.9 Hz,3JC1S= 10.1 Hz, 1H), 6.27 (dd,3Jtrans = 16.9 Hz,2Jgem= 2.0 Hz, 1 H), 5.79 (dd,3JC1S= 10.1 Hz,2Jgem= 2.0 Hz, 1 H), 3.92 (s, 3H), 3.87 (s, 3H), 2.89 (t, J = 5.4 Hz, 2H), 2.72 (s, 3H), 2.29 (t, J = 5.8 Hz, 2H), 2.21 (s, 6H).13C NMR in Figure 10 (101 MHz, DMSO-tA) 5(ppm): 162.4, 161.6, 159.8, 157.7, 145.9, 137.7, 137.4, 133.8, 132.4, 127.7, 126.0, 125.5, 125.3, 121.9, 121.3, 120.8, 113.3, 112.5, 110.5, 107.1, 105.3, 56.9, 55.9, 55.8, 45.2, 42.7, 32.9. HRMS (ESI): m / z calculated for C28H34N7O2[M+H]+500.2771, found 500.2772. qNMR purity: 91±3% (number of qNMR replicates : 3).

[0301] Example 13 - Step e) by BM (planetary ball-mill)

[0302] Owmtrtimb

[0303] A'1-(2-(Dimethylamino)ethyl)-5 -methoxy-A1-methyl -A'4-(4-( 1 -methyl- I H-indol -3 -yl)pyrimidin-2- yl)benzene-l,2,4-triamine (1.337g, 3.0 mmol), potassium acrylate (396.5 mg, 3.60 mmol, 1.2 eq), and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HC1) (805.1 mg, 4.20 mmol, 1.4 eq) were placed in a 20 mL ZrCh jar charged with 30x5 mm ZrCh balls. Then, EtOAc (508 pL, q = 0.2 pL / mg) as LAG additive was added and milled at 450 rpm for 180 min to obtain a resulting crude. Water (75 mL) was added to the resulting reaction crude and a precipitate was isolated by fdtration. The precipitate was washed with water (3x20 mL) and dried overnight in vacuo in the presence of P2O5, to obtain a brown solid. Then, the precipitate and the brown solid was dissolved in the minimum amount of EtOAc / EtOH (80:20) and fdtered through a thin layer of silica gel (660 mg, 0 = 2 cm, 3 mm thickness) and eluted with further 50 mL of EtOAc / EtOH (80:20). The EtOAc / EtOH was evaporated at reduced pressure to obtain osimertinib as a beige solid (1.102 g, 73%)

[0304] 'H NMR (400 MHz, DMSO-tA) 5(ppm): 10.22 (s, 1 H), 9.14 (s, 1H), 8.68 (s, 1H), 8.34 (d, J = 5.3 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.27-7.21 (m, 2H), 7.17-7.12 (m, 1H), 7.04 (s, 1H), 6.42 (dd,3Jtrans = 16.9 Hz,3JC1S= 10.1 Hz, 1H), 6.27 (dd,3Jtrans = 16.9 Hz,2Jgem= 2.0 Hz, 1 H), 5.79 (dd,3JC1S= 10.1 Hz,2Jgem= 2.0 Hz, 1 H), 3.92 (s, 3H), 3.87 (s, 3H), 2.89 (t, J = 5.4 Hz, 2H), 2.72 (s, 3H), 2.29 (t, J = 5.8 Hz, 2H), 2.21 (s, 6H).13C NMR (101 MHz, DMSO-tA) 5(ppm): 162.4, 161.6, 159.8, 157.7, 145.9, 137.7, 137.4, 133.8, 132.4, 127.8, 126.05, 125.5, 125.3, 121.9, 121.3, 120.8, 113.3, 112.5, 110.5, 107.1, 105.3, 56.9, 55.9, 55.8, 45.2, 42.7, 32.9. HRMS (ESI): m / z calculated for C28H34N7O2 [M+H]+500.2771, found 500.2772. qNMR purity: 85±0% (number of qNMR replicates : 2).

[0305] Example 14 - Step f) by BM (vibrating ball-mill ; osimertinib monomesylate) Osimertinib (350.0 mg, 0.70 mmol) and methane sulfonic acid (48 pL, 0.73 mmol, 1.05 eq) were placed in a 10 mL teflon jar charged with 1x10 mm ZrO2ball and milled at 30 Hz for 15 min. 15 mL acetone were added to the resulting reaction crude to form a precipitate, and the precipitate was recovered by filtration. The precipitate was washed with acetone (3x10 mL) and dried overnight in vacuo to obtain Osimertinib monomesylate salt as a brown solid (342 mg, 82%)

[0306] 'H NMR in Figure 11 (400 MHz, DMSO-dA) 5(ppm) 9.54 (s, 1 H), 9.24 (sbroad, 1H), 8.80 (s, 1H), 8.54 (s, 1H), 8.39-8.25 (m, 2H), 7.95 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.29-7.20 (m, 2H), 7.19-7.12 (m, 1H), 7.01 (s, 1H), 6.71 (dd,3Jtrans = 16.7 Hz,3JC1S= 10.4 Hz, 1H), 6.33 (d,3Jtrans = 16.7 Hz, 1H), 5.81 (d,3JC1S= 10.4 Hz, 1 H), 3.91 (s, 3H), 3.90 (s, 3H), 3.37 - 3.32 (m, 2H), 2.82 (s, 6H), 2.63 (s, 3H), 2.35 (s, 3H), 2.10-2.05 (m, 2H).13C NMR in Figure 12 (101 MHz, DMSO-de) 5(ppm) 163.6, 161.9, 159.8, 157.4, 147.0, 138.4, 137.7, 133.6, 131.9, 126.9, 125.5, 125.4, 125.3, 122.1, 121.6, 120.9, 116.2, 112.4, 110.5, 107.3, 104.7, 56.2, 53.8, 49.02, 43.3, 42.4, 33.01, 30.7. HRMS (ESI): m / z calculated for C28H34N7O2[M+H]+500.2771, found 500.2769. qNMR purity: 93±4% (number of qNMR replicates : 2).

[0307] Example 15 - Step c) by RAM

[0308] N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3-yl)pyrimidin-2 -amine (500 mg, 1.27 mmol), N,N,N'-Trimethylethylenediamine (155.9 mg, 1.5 mmol, 198.3 pL), K3PO4 (404.6 mg, 1.9 mmol) and DMSO (530 pL, >7 = 0.5 pL / mg) were added in a 7 mL glass vial. The reaction mixture was mixed at 90 g for 240 minutes to form an orange crude. The orange crude was suspended in 100 mL distilled water and filtered under vacuum to obtain a precipitate. The resulting precipitate was further washed with 200 mL acetonitrile to obtain a filtrate and the filtrate was collected and evaporated under reduced pressure to obtain an orange-red powder. The orange-red powder was collected and dried over P2O5 in a desiccator under vacuum to give 543 mg (90%) of A1-(2-(Dimethylamino)ethyl)-5-methoxy- '1-methyl -N4-(4-( 1 -methyl- 177-indol -3 -yl)pyrimidin-2-yl)-2 -nitrobenzene- 1 ,4-diamine .

[0309] 'H NMR in Figure 13 (400 MHz, DMSO-dA) 5(ppm): 8.62 (s, 1H), 8.35 (d, J= 6.9 Hz, 1H), 8.31 (d, J = 5.2 Hz, 2H), 8.09 (s, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.21 (d, J = 5.4 Hz, 1H), 7.11 (t, J= 7.5 Hz, 1H), 6.84 (s, 1H), 3.96 (d, J= 6.1 Hz, 3H), 3.88 (d, J= 5.0 Hz, 3H), 3.26 (t, J= 6.9 Hz, 2H), 2.86 (s, 3H), 2.52 - 2.43 (m, 2H), 2.15 (s, 6H).

[0310] Example 16 - Step d) by RAM (protocol 1)

[0311] 700 mg (1.47mmol, 1.0 eq) of A'l-(2-(Dimcthylamino)cthyl)-5-mcthoxy-A'l-mcthyl-N4-(4-( l -mcthyl- lH-indol-3-yl)pyrimidin-2-yl)-2 -nitrobenzene- 1,4-diamine and 1.03 g of sodium dithionite (5.89 mmol, 4.0 eq) were added in a 5 ml PTFE vessel, Then EtOH (970 pL) and water (324 pL) were added in a ratio of 3: 1 v / v (total >7 = 0.75 pL / mg). Then the reaction mixture was mixed in a LabRAM II Resodyn mixer at 90 g for 30 minutes to obtain a crude reaction mixture. The crude reaction mixture was dissolved in a methanolic solution 3M HC1 and refluxed for Ih. MeOH was evaporated under reduced pressure and a 10% (w / w) solution of K2CO3 was added until the pH was adjusted at 11 to obtain a sticky solid. The sticky solid was refluxed for Ih. Then, it was fdtered and dried under vacuum to obtain N’-(2- (dimethylamino)ethyl)-5-methoxy-A1-methyl-JV4-(4-(l-methyl-17 -indol-3-yl)pyrimidin-2-yl)benzene- 1,2,4-triamine as a brown shiny powder (486.2 mg, 74%).

[0312] 'H NMR in Figure 14 (400 MHz, DMSO-6) 5(ppm): 8.45 (d, J= 7.8 Hz, IH), 8.28 (d, J= 3.7 Hz, 2H), 7.81 (s, IH), 7.55 (s, IH), 7.50 (d, J= 8.1 Hz, IH), 7.25 (t, J= 1.3 Hz, IH), 7.21 - 7.12 (m, 2H), 6.77 (s, IH), 4.61 (s, 2H), 3.86 (s, 3H), 3.75 (s, 3H), 2.89 (t, J= 6.6 Hz, 2H), 2.63 (s, 3H), 2.36 (t, J= 6.5 Hz, 2H), 2.17 (s, 6H).

[0313] 13C NMR in Figure 15 (101 MHz, DMSO-6) 5(ppm): 162.1, 160.4, 156.9, 141.6, 137.6, 136.8, 133.3, 132.8, 125.6, 125.3, 122.2, 122.1, 120.9, 112.5, 110.3, 108.9, 106.8, 105.2, 57.3, 56.4, 53.9, 45.6, 41.6, 32.9.

[0314] Example 17 - Step d) by RAM (protocol 2)

[0315] 10 g (21.03 mmol, 1.0 eq) of / V1-(2-(dimethylamino)ethyl)-5-methoxy-A1-methyl -N4-(4-(l -methyl- 1H- indol-3-yl)pyrimidin-2-yl)-2 -nitrobenzene- 1,4-diamine and 14.65 g of sodium dithionite (84.11 mmol, 4.0 eq) were added in a 100 mL PTFE vessel. Then EtOH and water were added, (18.5 mL, in a ratio of 3: 1 v / v, total = 0.75 pL / mg). The reaction mixture was mixed in a LabRAM II Resodyn mixer at 90 g for 30 minutes to obtain a crude reaction mixture. The crude reaction mixture was dissolved in a methanolic solution 3M HC1 and refluxed for Ih. Then MeOH was evaporated under reduced pressure and a 10% (w / w) solution of K2CO3 was added until the pH was adjusted at 11 to form a sticky solid. The sticky solid was formed, and water was filtered to obtain a resulting crude. The resulting crude was recrystallized from EtOH. Then the crystals were washed with cold EtOH, filtered and dried under vacuum to obtain N1-(2-(dimethylamino)ethyl)-5 -methoxy- V1-methyl -A4-(4-( 1 -methyl - lH-indol-3 - yl)pyrirnidin-2-yl)benzene-l,2,4-triarnine as a grey crystal (6.54 g, 70%).

[0316] 'H NMR in Figure 16 (400 MHz, DMSO-d6) 5(ppm): 8.42 (d, J = 7.8 Hz, IH), 8.32 - 8.25 (m, 2H), 7.79 (s, IH), 7.50 (m, 2H), 7.24 (t, J = 7.3 Hz, IH), 7.14 (m, 2H), 6.76 (s, IH), 4.59 (s, ArNH2, 2H), 3.87 (s, 3H), 3.74 (s, 3H), 2.89 (t, J= 6.7 Hz, 2H), 2.63 (s, 3H), 2.36 (dd, J= 12.1, 5.6 Hz, 2H), 2.18 (d, J= 6.3 Hz, 6H).

[0317] 13C NMR in Figure 17 (101 MHz, DMSO-de) 5(ppm): 162.1, 160.4, 156.9, 141.7, 137.6, 136.8, 133.3, 132.8, 125.6, 125.3, 122.2, 122.1, 120.9, 112.5, 110.3, 109.04, 106.8, 105.2, 57.3, 56.4, 53.9, 45.6, 41.6, 33.0.

[0318] Example 18 - Step e) by RAM (protocol 1) N1-(2-(dimethylamino) ethyl) -5 -methoxy-N1-methyl -N4-(4-( 1 -methyl- lH-indol-3 -yl) pyrimidin-2-yl) benzene- 1, 2, 4-triamine (1.0 g, 2.24 mmol), potassium acrylate (271.9 mg, 2.47 mmol, 1.1 eq) and N- ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HC1) (516.3 mg, 2.69 mmol, 1.2 eq) and z-PrOAc (894 pL, = 0.5 pL / mg) were added in a 10 mL PTFE vessel, and the content of the vial was mixed in a LabRAM II Resodyn mixer at 90 g for 60 minutes to obtain a resulting crude. After the end of the mixing, the resulting crude was transferred to a 200 mL beaker and distilled water (100 mL) was added and a brown precipitate was formed and sonicated for 10 minutes. Then the brown precipitate was filtered under vacuum to obtain a resulting precipitate and the resulting precipitate was washed further with 100 mL of distilled water and the water was dried in vacuo in the presence of P2O5 to form a solid. Then the solid was dissolved to 100 mL of EtOAc and filtered through a thin layer of silica gel (4cm tall) and was further wash with 200 mL of EtOAc. Then the EtOAc was evaporated to obtain osimertinib as an off-white solid (859.8mg, 77% yield).

[0319] ’H NMR in Figure 18 (400 MHz, DMSO-de) 5(ppm): 10.21 (s, 1H), 9.14 (s, 1H), 8.68 (s, 1H), 8.33 (d, J = 5.3 Hz, 1H), 8.24 (d, J= 8.0 Hz, 1H), 7.90 (s, 1H), 7.52 (d, J= 8.2 Hz, 1H), 7.30 - 7.19 (m, 2H), 7.19 - 7.09 (m, 1H), 7.04 (s, 1H), 6.44 (dd, J= 16.9, 10.1 Hz, 1H), 6.27 (dd, J= 16.9, 2.1 Hz, 1H), 5.77 (dd, J= 10.0, 2.1 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 2.89 (t, J= 5.8 Hz, 2H), 2.72 (s, 3H), 2.30 (t, J = 5.6 Hz, 2H), 2.22 (s, 6H).

[0320] 13C NMR in Figure 19 (101 MHz, DMSO-de) 5(ppm) 162.4, 161.6, 159.8, 157.9, 157.7, 146.04, 137.7, 137.5, 133.8, 132.4, 127.6, 126.1, 125.4, 125.3, 121.9, 121.6, 121.3, 120.9, 120.8, 112.4, 110.5, 57.6, 56.9, 56.01, 55.7, 45.2, 42.7, 32.9.

[0321] Example 19 - Step e) by RAM (protocol 2)

[0322] N1-(2-(dimethylamino) ethyl)-5 -methoxy-N1-methyl -N4-(4-( 1 -methyl- lH-indol-3 -yl) pyrimidin-2-yl) benzene- 1,2, 4-triamine (20.0 g, 44.87 mmol), potassium acrylate (5.44 g, 49.36 mmol, 1.1 eq) and N- ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HC1) (10.32 g, 53.84 mmol, 1.2 eq) and z-PrOAc (17.9 mL, r / = 0.5 pL / mg) in a 120 mL PTFE vessel, were added, and the reaction mixture was mixed in a LabRAM II Resodyn mixer at 90 g for 60 minutes to obtain a resulting crude. After the end of the mixing, the resulting crude was transferred to a 200 mL flask to evaporate z-PrOAc. Then, distilled water (300 mL) was added, and a brown precipitate was formed and sonicated for 10 minutes. Then the brown precipitate was filtered under vacuum to obtain a resulting precipitate and the resulting precipitate was washed further with 300 mL of distilled water, then dried in vacuo in the presence of P2O5 to obtain a solid. The solid was recrystallized from EtOAc. The crystals were filtered and washed with EtOAc, to obtain osimertinib as beige powder (18.64 g, 83% yield).

[0323] ’H NMR in Figure 20 (400 MHz, DMSO-t / e) 5(ppm): 10.22 (s, 1H), 9.17 (s, 1H), 8.69 (s, 1H), 8.33 (d, J= 5.2 Hz, 1H), 8.24 (d, J= 7.9 Hz, 1H), 7.91 (s, 1H), 7.52 (d, J= 8.2 Hz, 1H), 7.24 (t, J= 6.7 Hz, 2H), 7.15 (t, J= 7.5 Hz, 1H), 7.04 (s, 1H), 6.43 (dd, J= 16.8, 10.1 Hz, 1H), 6.28 (d, J= 16.8 Hz, 1H), 5.78 (d, J= 10.1 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 2.88 (t, J= 5.8 Hz, 2H), 2.72 (s, 3H), 2.29 (t, J= 5.6 Hz, 2H), 2.21 (s, 6H).

[0324] 13C NMR in Figure 21 (101 MHz, DMSO-t / e) 5(ppm): 162.4, 161.6, 159.8, 157.8, 145.8, 137.7, 137.3, 133.9, 132.4, 127.8, 126.06, 125.5, 125.4, 121.9, 121.3, 120.9, 113.3, 112.5, 110.5, 107.2, 105.3, 56.90, 56.00, 55.8, 45.1, 42.7, 32.9.

[0325] Example 20 - Step f) by RAM (osimertinib monomesylate)

[0326] Osimertinib (500 mg, 1.0 mmol), methanesulfonic acid (96.2 mg, 1.0 mmol, 65 pL) and 447 pL i- PrOFLTLO (1: 1 v / v, = 0.75 pL / mg) were added in a 5 mL glass vial, and mixed at 90 g for 20 minutes in a LabRAM II Resodyn mixer. After the end of the mixing, z-PrOFLTLO was evaporated to obtain a resulting crude, and the resulting crude was washed with 50 mL acetone to form a beige precipitate. Then the beige precipitate was filtered under vacuum to form a precipitate and the precipitate was washed further with 50 mL of acetone and dried in vacuo to obtain osimertinib monomesylate salt (490.3 mg, 82%).

[0327] 'H NMR in Figure 22 (400 MHz, DMSO L) 5(ppm): 9.52 (s, 1H), 9.26 (s, 1H), 8.73 (s, 1H), 8.57 (s, 1H), 8.31 (d, J= 5.4 Hz, 2H), 7.54 (d, J= 8.2 Hz, 2H), 7.25 (t, J= 7.3 Hz, 1H), 7.16 (t, J= 7.4 Hz, 1H), 7.02 (s, 1H), 6.72 (dd, J= 16.9, 10.2 Hz, 1H), 6.32 (d, J= 16.7 Hz, 1H), 5.80 (d, J= 11.3 Hz, 1H), 3.90 (s, 6H), 3.30 (s, 5H), 2.82 (s, 6H), 2.63 (s, 3H), 2.36 (s, 3H).

[0328] 13C NMR in Figure 23 (101 MHz, DMSO L) 5(ppm): 163.6, 147.4, 146.6, 137.7, 134.3, 131.9, 126.9, 125.4, 125.3, 122.2, 121.7, 121.1, 112.3, 110.6, 107.2, 104.8, 56.2, 53.8, 48.9, 43.2, 42.4, 33.1.

[0329] Example 21 - Step f) by RAM (osimertinib dimesylate)

[0330] Osimertinib (350 mg, 0.7 mmol), methanesulfonic acid (134 mg, 1.4 mmol, 91 pL) and 145 pL (rj = 0.3 pL / mg) of a mixture of acetone / H2O (10: 1 v / v) or 2-methyl tetrahydrofuran (2-MeTHF) were added In a 2.7 mL polypropylene vial, and mixed at 80 g for 5 minutes in a LabRAM II Resodyn mixer to obtain a resulting crude. After the end of the mixing, the resulting crude was washed with 50 mL of acetone or 50 mL of 2-MeTHF and a yellow precipitate was formed. Then, the yellow precipitate was filtered under vacuum to obtain a resulting precipitate, and the resulting precipitate was washed further with 50 mL of acetone and dried in vacuo to obtain 420 mg (87%) of osimertinib dimesylate.

[0331] Spectral data (method with 2-MeTHF): 'H NMR in Figure 24 (400 MHz, DMSO-de) 5(ppm): 10.15 (s, 1H), 9.49 (s, 1H), 9.36 (s, 1H), 8.83 (s, 1H), 8.23 (s, 3H), 7.59 (d, J= 8.0 Hz, 1H), 7.44 (d, J= 6.8 Hz, 1H), 7.31 (s, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 6.78 (dd, J= 16.8, 10.2 Hz, 1H), 6.28 (s, 1H), 5.77 (d, J= 10.3 Hz, 1H), 3.88 (m, 11H), 2.85 (d, J = 4.3 Hz, 6H), 2.69 (s, 3H), 2.42 (s, 6H).

[0332] 13C NMR in Figure 25 (101 MHz, DMSO-de) 5(ppm): 167.1, 163.7, 152.8, 138.9, 138.2, 131.8, 127.1, 125.5, 125.4, 123.5, 122.6, 111.6, 111.3, 111.2, 105.9, 105.8, 56.1, 53.7, 49.0, 42.6, 42.4, 33.7.

[0333] Spectral data (method with Acetone / H2O):

[0334] 'H NMR in Figure 26 (400 MHz, DMSO-de) 5(ppm): 10.06 (s, 1H), 9.49 (s, 1H), 9.36 (s, 1H), 8.82 (s, 1H), 8.29 (s, 1H), 8.23 (s, 2H), 7.59 (d, J= 8.3 Hz, 1H), 7.43 (d, J= 6.8 Hz, 1H), 7.31 (s, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 6.78 (dd, J= 16.9, 10.2 Hz, 1H), 6.27 (d, J= 16.9 Hz, 1H), 5.77 (d, J= 11.6 Hz, 1H), 3.88 (m, 11H), 2.85 (d, J= 4.6 Hz, 6H), 2.69 (s, 3H), 2.41 (s, 6H).

[0335] 13C NMR in Figure 27 (101 MHz, DMSO-de) 5(ppm): 166.9, 163.7, 153.1, 138.8, 138.2, 131.8, 131.2, 127.0, 125.4, 123.4, 122.5, 111.6, 111.2, 105.9, 105.7, 56.1, 53.7, 49.0, 42.6, 42.4, 33.7.

[0336] Example 22 - Step d) by twin screw extrusion

[0337] 0 Stj'min

[0338] Solid N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(l-methyl-lH-indol-3-yl)pyrimidin-2- yl)-2 -nitrobenzene- 1,4-diamine (95 wt% purity) and sodium dithionite (85 wt% purity, 4.00 equivalents) were first homogenized using a mortar and pestle to obtain a solid mixture. The solid mixture (total mass: 9.8637 g) was transferred into a gravimetric feeder.

[0339] The four segments of the ZE9 barrel (Three-Tec, diameter: 9 mm, L / D = 25: 1) were preheated to 35 °C. Once temperature equilibrium was reached, extrusion began at 60 RPM. The solid mixture was introduced at approximately 0.50 g / min, while an EtOH / H2O (3: 1 v / v) solution was co-fed at 0.375 mL / min (q = 0.75 mL / g). The solution was added through an inlet located 34.5 mm downstream from the solid entry port (73 mm from the screw start).

[0340] Upon completion of solid addition, NELCl was used to flush the remaining material from the barrel.

[0341] The collected extrudate was suspended in 80 mL of 1 M HC1 and heated at reflux overnight (pH ~ 1). After cooling to 25°C, 20 mL of 28 wt% aqueous NH3 was added under stirring to adjust the pH to 11- 12, prompting the oily precipitation of A1-(2-(Dimethylamino)ethyl)-5-methoxy-A1-methyl- ^-(4-(l- niethyl-lH-indol-3-yl)pyriniidin-2-yl)benzene-l,2,4-trianiine and forming a mixture. The mixture was extracted with 60 mL of organic solvent, and the organic phase was separated. Organic solvent was removed by rotary evaporation to obtain A1-(2-(Dimethylamino)ethyl)-5-methoxy-Arl-methyl-A4-(4-(l- methyl-lH-indol-3-yl)pyrimidin-2-yl)benzene-l,2,4-trianiine (2.8601 g, 80% yield).

[0342] 'H NMR in Figure 28 (400 MHz, DMSO-de) 5(ppm): 8.42 (d, J= 7.8 Hz, 1H), 8.30 (s, 1H), 8.27 (d, J = 5.4 Hz, 1H), 7.78 (s, 1H), 7.51 (dt, J= 8.1, 0.8 Hz, 1H), 7.49 (s, 1H), 7.24 (ddd, J= 8.2, 7.1, 1.2 Hz, 1H), 7.16 (ddd, J= 8.0, 7.1, 1.1 Hz, 1H), 7.14 (d, J= 5.4 Hz, 1H), 6.76 (s, 1H), 4.59 (s, 2H), 3.87 (s, 3H), 3.74 (s, 3H), 2.89 (t, J= 6.7 Hz, 2H), 2.63 (s, 3H), 2.36 (t, J= 6.7 Hz, 2H), 2.17 (s, 6H).

[0343] The screw profile is represented on Figure 29. Example 23 - Step e) by twin screw extrusion to obtain osimertinib mesylate

[0344] Solid N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(l-methyl-lH-indol-3-yl)pyrimidin-2- yl)benzene-l,2,4-triamine (99.56 wt% purity), potassium acrylate (97 wt% purity, 1.20 equivalents), and EDC HC1 (99 wt% purity, 1.40 equivalents) were homogenized using a mortar and pestle to obtain a solid mixture. The resulting solid mixture (total mass: 9.23 g) was transferred into a gravimetric feeder.

[0345] The four heating zones of the ZE9 barrel (Three-Tec, diameter: 9 mm, L / D = 25: 1) were preheated to 70 °C. Once the temperature stabilized, extrusion was initiated at 60 RPM. The solid mixture was introduced at 0.24 g / min, and isopropyl acetate (i-PrOAc) was co-fed at 0.048 mL / min (q = 0.20 mL / g). The liquid inlet was positioned 34.5 mm downstream from the solid entry port (73 mm from the screw start).

[0346] The extrudate was collected in 40 mb of distilled water under stirring. Upon completion of solid feeding, NaCl was used to flush the remaining material from the barrel. A resulting beige / brown suspension is obtained.

[0347] 60 mb of Me-THF was added to the resulting beige / brown suspension under stirring to dissolve the crude product. The organic phase was washed five times with 6.5 wt% aqueous NaCl solution, followed by one wash with 20 mb of brine. The aqueous phase was clear (pH ~ 7). The organic layer was concentrated under reduced pressure to obtain 4.95 g of crude osimertinib.

[0348] Crude osimertinib was dissolved in 49 mb of acetone and heated to 55 °C for 30 minutes. Activated carbon (165 mg, 3.33 wt% relative to crude) was added, and stirring was maintained at 55 °C for an additional 20 minutes to obtain a supension. The suspension was hot-filtered through a Celite pad, which was rinsed with 6 mb of acetone at room temperature.

[0349] The combined filtrate was cooled to 35 °C, then 1.65 mb of distilled water was added to obtain a solution. The solution was reheated to 55 °C and stirred for 30 minutes. Subsequently, methanesulfonic acid (951.7 mg, 1 equivalent) was added dropwise over 10 minutes. Stirring was kept at 50-55 °C for 3 hours. The crystallization of osimertinib mesylate began approximately 6 minutes after the end of the methane sulfonic acid addition.

[0350] The mixture was cooled to 20-25 °C to form a precipitate, and the precipitate was collected by filtration on a glass frit (porosity 3) and suction-dried using a vacuum pump (no further drying step) to obtain osimertinib mesylate as a white to slightly beige solid (4.43 g, 68.5% overall yield).

[0351] 'H NMR in Figure 30 (400 MHz, DMSO-de) 5(ppm): 9.54 (s, 1H), 9.26 (sbroad, 1H), 8.80 (s, 1H), 8.53 (s, 1H), 8.35 - 8.29 (m, 2H), 7.94 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.27 - 7.21 (m, 2H), 7.19 - 7.13 (m, 1H), 7.01 (s, 1H), 6.71 (dd, J= 16.9, 10.2 Hz, 1H), 6.33 (dd, J= 17.0, 1.8 Hz, 1H), 5.81 (dd, J= 10.2, 1.7 Hz, 1H), 3.90 (d, J= 3.8 Hz, 6H), 3.31 - 3.24 (m, 4H), 2.82 (s, 6H), 2.63 (s, 3H), 2.35 (s, 3H).

Claims

CLAIMS1. Use of a mechanical force to generate a mechanochemical reaction in the implementation of a process of preparation, of A-(2-{[2(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-( 1 -methyl- lH-indol-3-yl)pyrimidin-2-yl ]amino}phenyl)prop-2-enamide (osimertinib) or a pharmaceutically acceptable salt thereof, comprising n steps, n being 5 or 6, from 1- methylindole, wherein at least one step is mechanochemical, and said process comprising a reduction step of N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N- [4-( 1 -methylindol-3 -yl)pyrimidin-2-yl] -5 -nitrobenzene- 1 ,4-diamine into N1-(2- dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2- yl]benzene-l,2,4-triamine, said triamine being possibly under the form of a salt, said reduction step being mechanochemical, wherein said reduction step does not involve the use of cobalt and / or comprising an amidation step of the above mentioned N1-(2 -dimethylaminoethyl)-5- methoxy-N1-methyl -N4-[4-( 1 -methylindol-3-yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine into osimertinib or osimertinib salt of mesylate, said amidation step being mechanochemical .

2. The use according to claim 1, wherein said process does not involve the use of a metal either under its toxic form or under toxic quantities, said metal being chosen from: arsenic, barium, cadmium, chromium, cobalt, lithium, nickel, palladium, osmium, rhodium, thallium, tin, antimony, gold, silver, platinum.

3. The use according to claim 1, wherein said process does not involve the use of metal.

4. The use according to any one of claim 1 to 3, wherein the mechanical forces are generated by a method chosen among: ball-milling (BM), bead milling, resonant acoustic mixing (RAM) and screw extrusion (single, twin or multi).

5. The use according to any one of claims 1 to 4, wherein at least two steps, three steps, four steps, five steps or all the steps are mechanochemical.

6. The use according to any one of claims 1 to 5, wherein said pharmaceutically acceptable salt of osimertinib is either osimertinib monomesylate or osimertinib dimesylate.

7. The use according to any one of claim 1 to 6, wherein the reduction step involves the reduction of N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l-methylindol-3- yl)pyrimidin-2-yl] -5 -nitrobenzene- 1,4-diamine into N1-(2-dimethylaminoethyl)-5-methoxy- N1-methyl-N4-[4-(l-methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine and into N-(2- { [2-(dimethylamino)ethyl] (methyl)amino } -4-methoxy-5 - { [4-( 1 -methyl- lH-indol-3 - yl)pyrimidin-2-yl] amino } phenyl)sulfamic acid .

8. A mechanochemical process of preparation of osimertinib, which comprises the step of : d) a mechanochemical reduction step of N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N- [4-(l -methylindol-3 -yl)pyrimidin-2-yl] -5 -nitrobenzene- 1,4-diamine with sodium dithionite, thiourea dioxide or rongalite, under neat grinding or in liquid-assisted grinding (LAG) conditions, using BM, RAM ortwin screw extrusion (TSE), to obtain a crude product containing N1-(2 -dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2- yl]benzene-l,2,4-triamine, said triamine being in the neutral form or possibly under the form of a salt, followed by a post-reactional treatment, in particular a purification of said crude product, to obtain N1-(2-dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 - yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine,CH4N2O2S orNa2S2O4Mechanochemical forceand wherein said process does not involve the use of cobalt.

9. The process according to claim 8, wherein said process does not involve the use of a metal either under its toxic form or under toxic quantities, said metal being chosen from: arsenic, barium, cadmium, chromium, cobalt, lithium, nickel, palladium, osmium, rhodium, thallium, tin, antimony, gold, silver, platinum.

10. The process according to claim 9, wherein said process does not involve the use of metal.

11. The process according to any one of claim 8 to 10, wherein the reduction step d) involves the reduction of N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l-methylindol-3- yl)pyrimidin-2-yl] -5 -nitrobenzene- 1,4-diamine into N1-(2-dimethylaminoethyl)-5-methoxy- N1-methyl-N4-[4-(l-methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine and into N-(2- { [2-(dimethylamino)ethyl] (methyl)amino } -4-methoxy-5 - { [4-( 1 -methyl- lH-indol-3 - yl)pyrimidin-2-yl] amino } phenyl) sulfamic acid .

12. The mechanochemical process according to any one of claim 6 to 9 or 11, comprises the steps of : a) a mechanochemical Friedel-Craft arylation step of 1-methylindole with 2,4- dichloropyrimidine and a Lewis acid, using BM in particular planetary ball-milling or vibrating ball-milling, or RAM under neat grinding or in liquid-assisted grinding (LAG) conditions, to obtain a crude product containing 3-(2-chloropyrimidin-4-yl)-l-methyl-lH-indole, followed by a purification of said crude product, to obtain 3-(2-chloropyrimidin-4-yl)-l-methyl-lH-indole,Lewis acidMechanochemical forceb) a mechanochemical nucleophilic aromatic substitution step of the above mentioned 3-(2- chloropyrimidin-4-yl)-l -methyl- IH-indole with 4-fluoro-2-methoxy-5-nitroaniline and a sulfonic acid, under neat grinding or in liquid-assisted grinding (LAG) conditions, using BM, in particular planetary ball -milling or vibrating ball -milling to obtain a crude product containingN-(4-fhioro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3-yl)pyrimidin-2 -amine, followed by a purification of said crude product, to obtain N-(4-fluoro-2-methoxy-5- nitrophenyl)-4-( 1 -methyl- lH-indol-3 -yl)pyrimidin-2 -amine,c) a mechanochemical nucleophilic aromatic substitution step of the above mentioned N-(4- fluoro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3-yl)pyrimidin-2 -amine with N,N,N'- trimethylethylenediamine and a base, in particular K2CO3 or K3PO4, in liquid-assisted grinding (LAG) conditions, using BM, in particular vibrating ball-milling, or RAM, to obtain a crude product containing N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l-methylindol-3- yl)pyrimidin-2-yl]-5-nitrobenzene-l,4-diamine, followed by a purification of said crude product, to obtain N'-(2-dimethylaminoethyl)-2-methoxy-N'-methyl-N-[4-(l-methylindol-3- yl)pyrimidin-2-yl] -5 -nitrobenzene- 1 ,4-diamine,d) a mechanochemical reduction step of the above mentioned N'-(2-dimethylaminoethyl)-2- methoxy-N'-methyl-N-[4-(l-methylindol-3-yl)pyrimidin-2-yl]-5-nitrobenzene-l,4-diamine with sodium dithionite, thiourea dioxide or rongalite, under neat grinding or in liquid-assisted grinding (LAG) conditions, using BM, in particular planetary ball-milling, RAM or TSE, to obtain a crude product containing N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l- methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine, said triamine being in the neutral form or possibly under the form of a salt, followed by a post-reactional treatment, in particular a purification of said crude product, to obtain N1-(2-dimethylaminoethyl)-5-methoxy-N1- methyl-N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine,and, e) a mechanochemical amidation step of the above mentioned N’-(2- Dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2- yl]benzene-l,2,4-triamine with potassium acrylate and (3-dimethylamino-propyl)- ethyl-carbodiimide hydrochloride (EDC.HC1), in liquid-assisted grinding (LAG) conditions, using BM, in particular vibrating ball-milling or planetary ball-milling, RAM or TSE, to obtain a crude product containing osimertinib, followed by a post- reactional treatment, in particular a purification of said crude product, to obtain osimertinib or osimertinib mesylate,13. The mechanochemical process according to one of claim 6 to 9 or 11 to 12, wherein in the step a), the Lewis acid is FcCT and / or wherein in step a), the BM is a planetary ball-milling, and / or wherein in step b), the BM is a vibrating ball-milling, and / or, wherein in the step b), the sulfonic acid is camphorsulfonic acid.

14. The mechanochemical process according to any one of claims 6 to 9 or 11 to 13, wherein in the step c), a polar solvent is added, preferably dimethylsulfoxide (DMSO), and / orwherein in the step d), a mixture of ethanol and water is added, and / or wherein in the step e), the solvent used under LAG conditions is chosen among ethyl acetate, isopropyl acetate, 2 -methyltetrahydrofuran, dimethyl sulfoxide, ethanol, glycerol, methyl-tert- butyl ether (MTBE), is added, preferably ethyl acetate or isopropyl acetate.

15. The mechanochemical process according to any one of claims 6 to 9 or 11 to 14, wherein in the step c), a polar solvent is added, preferably dimethylsulfoxide (DMSO), and / or wherein in step b), the BM is a vibrating ball-milling and / or wherein in the step e), the solvent used under LAG conditions is chosen among triethyl phosphate, isopropyl tetradecanoate, dipropylene glycol dibenzoate, dibutyl carbonate, ethylene carbonate, 4-methyl-l,3-dioxolan-2-one, preferably isopropyl tetradecanoate or triethyl phosphate.

16. The mechanochemical process according to any one of claims 6 to 9 or 11 to 15, wherein in the step d), the N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l- methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine is recovered under the form of a hydrochloric salt from the crude product containing it, by an adjustment of the pH to 10 by using a 10% solution of K2CO3 (w / w) in presence of ethanol, then a fdtration, then an adjustment of the pH to 1 by using a dropwise solution of hydrochloric acid at IM, then an evaporation of said ethanol and said solution of hydrochloric acid, or wherein in the step d), the N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l- methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine is recovered from the crude product containing it by using an acid, optionally neutralized with a base, said acid and said base been independently selected from solid, liquid, or gaseous forms, and being introduced into a milling vessel after the reaction, in successive steps, then additional milling is performed and precipitation of the N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l-methylindol-3- yl)pyrimidin-2-yl]benzene-l,2,4-triamine in a solvent occurs, preferably water, or wherein in the step d), the N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l- methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine is recovered from the crude product containing it by suspending said crude product in an aqueous solution of hydrochloric acid at a concentration ranging from 0.8 to 1.2 M to obtain a suspension, the suspension is heated under reflux conditions, then adjusting the pH of the suspension to a basic value of a range from 11- 12 using a base, then inducing the precipitation of said N1-(2-dimethylaminoethyl)-5-methoxy- N1-methyl -N4-[4-( 1 -methylindol-3-yl)pyrimidin-2-yl]benzene- 1 ,2,4-triamine, followed by extraction with an organic solvent and an evaporation of the solvent to obtain the purified N1- (2 -dimethylaminoethyl)-5 -methoxy-N1-methyl -N4-[4-( 1 -methylindol-3 -yl)pyrimidin-2- yl]benzene- 1 ,2,4-triamine . or wherein in the step d), the N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l- methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine is recovered from the crude product containing it by suspending the crude in methanol to obtain a filtrate, then hydrochloric acid is added to the filtrate to obtain a suspension, the suspension is heated under reflux conditions, optionally the methanol is removed, then the pH is adjusted to a value of from 11 to 12, using a base to obtain a basic suspension, then the basic suspension is heated under reflux conditions to obtain a precipitate of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l- methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine, which is subsequently filtered. or wherein in the step d), the N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(l- methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine is recovered from the crude product containing it by suspending the crude product in a methanolic solution of hydrochloric acid toobtain a suspension, the suspension is heated under reflux conditions, optionally the methanol is removed, then the pH of the suspension is adjusted to a value from 11 to 12, using a base to obtain a basic precipitate, then a filtration of the basic precipitate is performed and recrystallisation step is carried out using an alcohol.

17. The mechanochemical process according to any one of claims 6 to 9 or 11 to 16, wherein in step a), the mechanical forces are generated under neat grinding, and / or wherein in step b), the mechanical forces are generated under neat grinding.

18. The mechanochemical process according to claim 6 to 9 or 11 to 17, wherein in step a) and / or in step b), the mechanical forces are generated in presence of a solid additive, in particular silica.

19. The mechanochemical process according to any one of claims 6 to 9 or 11 to 18, wherein in the step c), the LAG conditions are defined by the parameter p that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably the parameter q is comprised from about 0.1 pL / mg of reactants to 0.9 pL / mg of reactants, more preferably 0.5 pL / mg of reactants, and / or wherein in the step c), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably the parameter r| is comprised from about 0.05 pL / mg of reactants to 0.25 pL / mg of reactants, and more preferably is of 0.1 pL / mg of reactants or 0.2 pL / mg of reactants, and / or wherein in the step d), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably the parameter r| is comprised from about 0.1 pL / mg of reactants to 0.5 pL / mg of reactants, more preferably 0.5 pL / mg of reactants, and / or, wherein in the step d), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably the parameter r| is comprised from about 0.5 pL / mg of reactants to 1 pL / mg of reactants, more preferably 0.75 pL / mg of reactants, and / or wherein in the step e), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less or equal to 1 pL / mg of reactants, more preferably the parameter q is comprised from about 0.1 pL / mg of reactants to 0.5 pL / mg of reactants, more preferably 0.4 pL / mg of reactants, even more preferably 0.2 pL / mg of reactants and / or wherein in the step e), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less or equal to 1 pL / mg of reactants, more preferably the parameter r| is comprised from about 0.25 pL / mg of reactants to 0.75 pL / mg of reactants, more preferably 0.5 pL / mg of reactants.

20. The mechanochemical process according to any one of claims 6 to 9 or 11 to 19, comprises the step of : f) a salification step of the above mentioned osimertinib, in particular a mechanochemical salification with methanesulfonic acid using BM, in particular vibrating ball-mill, or RAM, to obtain osimertinib mesylatein particular in the step f), the mechanical forces are generated under neat grinding.

21. The mechanochemical process according to any one of claims 6 to 9 or 11 to 20, comprises the step of : f) a salification step of the above mentioned osimertinib, in particular a mechanochemical salification with methanesulfonic acid using RAM, to obtain a crude product containing osimertinib mesylate, followed by a post-reactional treatment, in particular a purification of said crude product, to obtain osimertinib mesylate22. The mechanochemical process according to any one of claims 6 to 9 or 11 to 21, comprises the step of : f) a salification step of the above mentioned osimertinib, in particular a mechanochemical salification with methanesulfonic acid using BM, RAM or TSE, to obtain a crude product containing osimertinib dimesylate, followed by a post-reactional treatment, in particular a purification of said crude product, to obtain osimertinib dimesylate,23. The mechanochemical process according to any one of claims 6 to 9 or 11 to 22, comprising the step of: f) a salification step of the above mentioned osimertinib, in particular a mechanochemical salification with methanesulfonic acid using TSE, to obtain a crude product containing osimertinib mesylate, followed by a post-reactional treatment, in particular a purification of said crude product, to obtain osimertinib mesylate24. The mechanochemical process according to any one of claims 21 to 23, wherein the LAG conditions are defined by the parameter p that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably the parameter r| is comprised from about 0.25 pL / mg of reactants to 0.5 pL / mg of reactants, more preferably 0.75 pL / mg of reactants, or, wherein in the step f), 2 -methyltetrahydrofuran or a mixture of acetone and water at a volumetric ratio of 10: 1, is added and / or, wherein in the step f), the LAG conditions are defined by the parameter q that is greater than 0 pL / mg of reactants and less than or equal to 1 pL / mg of reactants, more preferably the parameter q is comprised from about 0.1 pL / mg of reactants to 0.6 pL / mg, more preferably 0.3 pL / mg of reactants. or, wherein in the step f), acetone is added.

25. The mechanochemical process according to any one of claims 21 to 24, the osimertinib mesylate is recovered from the crude product containing it, by a fdtration using a solvent, in particular acetone.

26. The mechanochemical process according to any one of claims 6 to 9 or 11 to 25, wherein in at least one step chosen among: step a), step b), step c), step d), step e) and step f), the milling speed range value is chosen from 1 to 6000 rpm for BM, or m x g force is applied, m being a positive number chosen from 1 to 100, for RAM.

27. The mechanochemical process according to claim 26, wherein m is a positive number chosen from 50 g to 100 g, and in particular 80 g or 90 g.

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