The invention concerns the process for the preparation of 4-(4-methylpiperazin-l- ylmethyl)-N- {4-methyl-3-[4-(pyridin-3 -yl)pyrimidin-2-ylamino]phenyl } benzamide of the Formula 1, known under the international non-proprietary name (INN) of Imatinib.

Imatinib is a selective tyrosine kinase inhibitor, used first of all in the treatment of tumours, mainly chronic myeloid leukaemia.

Imatinib has been first disclosed in the patent document EP 0 564 409. Two methods for the preparation of Imatinib have been indicated in this document. The first synthetic route, named the Method (a), consists in reacting the compound defined by the Formula III in this document with the compound defined by the Formula IV in this document, whereas at least one carbon atom in the benzene ring has to be substituted with nitro group or lower alkoxy group that is. in turn, substituted with fluorine atom or a bulky group defined by the Formula (II) in the discussed document. The other carbon atoms of the ring may be substituted with halogen atoms. The functional groups of both substrates react to form a 6-membered heterocyclic ring containing two nitrogen atoms. In the second route disclosed in the patent EP 0 564 409, described as the Method (b), one of the substrates already contains the heterocyclic ring including two nitrogen atoms, and the substituents of the benzene ring are defined otherwise - necessarily one of the substituents bears an amino group. Also in this case, at least one of the remaining carbon atoms of the benzene ring may be substituted with a halogen atom.

The European Patent No. EP 0 564 409 presents the synthesis of Imatinib following the Method (b). According to this example, in the first step, 2-methyl-5-nitroaniline is converted into 2-methyl-5-nitrophenylguanidine nitrate which, in the second step, is condensed with 3-dimethylamino-l-(pyridin-3-yl)prop-2-en-l-one to yield N-(2-methyl-5- nitrophenyl)-4-(pyridin-3-yl)-pyrimidin-2-ylamine. As a result of a catalytic reduction of nitro group in this latter compound, N-(5-amino-2-methylphenyl)-4-(pyridin-3-yl)-pyrimidin-2- ylamine is obtained which, in turn, is acylated with 4-(4-methylpiperazin-l-ylmethyl)-benzoyl chloride.

The process for the preparation of Imatinib known from the International Patent Application No. WO03066613 employs 3-bromo-4-methylaniline. 3-Bromo-4-methylaniline is reacted with methyl 4-(4-methylpiperazin-l-ylmethyl)-benzoate, prepared previously by the reductive alkylation of N-methylpiperazine with methyl 4-formylbenzoate. As a result of this reaction, N-(3-bromo-4-methylphenyl)-4-(4-methylpiperazin- 1 -ylmethyl)benzamide is obtained, which is then condensed with 4-(pyridin-3-yl)-pyrimidin-2-ylamine to prepare Imatinib.

The synthesis known from the International Patent Application No. WO2004/ 108699 starts from 2-methyl-5-nitroaniline, similarly to the synthesis according to the patent No. EP 0 564409. The obtained amine was acylated with 4-(chloromethyl)benzoyl chloride to yield 4-(chloromethyl)-N-{4-methyl-3-[(4-(pyridin-3-yl)-pyrimidin- 2-ylamino]phenyl}benzamide which, as a result of the condensation reaction with N-methylpiperazine, gave Imatinib.

All the above-mentioned methods of the synthesis of Imatinib employ the reaction of the amino and halogen functional groups. In the case, when the reaction substrate is a nitro- substituted compound, e.g., 2-methyl-5-nitroaniline, a previous step of reduction of nitro group into amino group is necessary.

However, no method of the synthesis is known in which 2-methyl-5-halogenoani)ine of the Formula 2 would be used as a starting compound.

The process for the preparation of Imatinib according to the invention is characterised in that the 2-methyl-5-halogenoaniline of the Formula 2 is converted into the salt of the 2- methyl-5-halogenophenylguanidine of the Formula 3, which is then condensed with the 3- dialkylamino-l-(pyridin-3-yl)prop-2-en-l-one of the Formula 4 to yield the N-(2-methyl-5- halogenophenyl)-4-(pyridin-3-yl)-pyrimidin-2-ylamine of the Formula 5. In the next step, the compound of the Formula 5 is reacted with 4-(4-methylpiperazin-l-ylmethyl)benzamide of the Formula 6 to yield the resulting Imatinib. Then Imatinib can be converted into the addition salt, preferably the mesylate, in the reaction with methanesulphonic acid.

Preferably the salt of the 2-methyl-5-halogenophenylguanidine used is the nitrate.

Preferably the alkyl substituent in the 3-dialkylamino-l-(pyridin-3-yl)prop-2-en-l -one of the Formula 4 is a straight-chained or branched C1-C4 aliphatic group, an aliphatic- aromatic group or an aromatic group. Preferably the 3-dialkylamino-l-(pyridin-3-yl)prop-2-en-l-one used is 3-dimethyl- amino-l-(pyridin-3-yl)prop-2-en-l-one of the Formula 4.

Preferably, in the first reaction step, the 2-methyl-5-halogenoaniline is reacted with cyanamide in an organic solvent.

Preferably the 2-methyl-5-halogenoaniline used is 2-methyl-5-bromoaniline or 2- methyl-5-iodoaniline.

Preferably the 2-methyl-5-halogenoaniline is used in an inorganic salt form, most preferably in a hydrochloride form.

Preferably the solvent used is an alcohol, preferably a C 1 -C4 alcohol, most preferably tert-butanol.

Preferably the 2-methyl-5-halogenophenylguanidine of the Formula 3, obtained in the first step, is isolated by extraction with an organic solvent, preferably selected from esters, ethers, halogenated solvents, aromatic hydrocarbons, most preferably with ter/-butyl-ethyl ether or toluene.

Preferably the condensation of the 2-methyl-5-halogenophenylguanidine nitrate of the Formula 3 with the 3-dialkylamino-l-(pyridin-3-yl)prop-2-en-l-one of the Formula 4 is carried out under alkaline conditions, in an organic solvent.

Preferably the condensation is carried out in the presence of a base, most preferably selected from the group comprising metal hydrogen carbonates, metal alkoxylates, metal hydroxides, metal carbonates, most preferably sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, caesium carbonate.

Preferably C1-C4 alcohols, ketones, DMSO, DMF, or aromatic hydrocarbons, most preferably w-butanol, are used as a solvent.

Preferably the reaction of the N-(2-methyl-5-halogenophenyl)-4-(pyridin-3-y])- pyrimidin-2-ylamine of the Formula 5 with 4-(4-methylpiperazin-l-ylmethyl)benzamide of the Formula 6 is carried out in an organic solvent, in the presence of a copper catalyst.

Preferably the reaction of the N-(2-methyl-5-halogenophenyl)-4-(pyridin-3-yl)- pyrimidin-2-ylamine of the Formula 5 with 4-(4-methylpiperazin-l-ylmethyl)benzamide of the Formula 6 is carried out in an organic solvent, in the presence of an amine ligand. Preferably the reaction of the N-(2-methyl-5-halogenophenyl)-4-(pyridin-3-yl)- pyrimidin-2-ylamine of the Formula 5 with 4-(4-methylpiperazin- 1 -ylmethyl)benzamide of the Formula 6 is carried out in an organic solvent, in the presence of a copper catalyst and an amine ligand.

Preferably the product of the reaction of the N-(2-methyl-5-halogenophenyl)-4- (pyridin-3-yl)-pyrimidin-2-ylamine of the Formula 5 with 4-(4-methylpiperazin-l- ylmethyl)benzamide of the Formula 6 is isolated by extraction in an organic solvent/water system, optionally with addition of a copper-complexing agent.

Preferably DMF, DMSO, ethers, aromatic hydrocarbons, acetonitrile, or N- methylimidazole, most preferably dioxane, are used as a solvent.

Preferably the amine catalyst used is a primary or secondary amine, a diamine, especially a 1 ,2-diamine, or an aliphatic derivative of a 1,2-diamine, most preferably trans- N,N'-cyclohexyl-l,2-diamine as well as N,N'-dimethylethylenediamine.

Preferably the copper catalyst used is a copper halide, most preferably copper(I) iodide.

Preferably the extraction is carried out in the methylene chloride/water system.

Preferably the copper-complexing compounds, most preferably edetic acid (EDTA) or ammonia, are used in order to remove copper.

Compared to the reactions known from EP 0 564409 and WO2004/108699, the use of 2-methyl-5-bromoaniline instead of 2-methyl-5-nitroaniline as a starting compound leads to preparation of the compound of the Formula 5, in which the halogen atom replaces the nitro group. This avoids the step of the catalytic reduction of a nitro group to an amino group, which then reacts with a halogen atom to introduce the fragment containing the benzene and piperazine rings. Moreover, the reduction of a nitro group always poses a risk of leaving traces of the starting compound possessing the nitro group as well as the intermediate compound possessing the nitroso group in the reaction environment. One should keep in mind that compounds possessing nitroso groups are carcinogens, and compounds possessing nitro groups belong to mutagens. According to the CHMP guidelines, Guideline on the limits of genotoxic impurities (CPMP/SWP/5199/02, EMEA/CHMP/QWP/251344/2006). level of presence of such compounds in the pharmaceutical products must be extremely low. Moreover, the final product possessing an amino group is sensitive to the oxidation reactions characteristic for all aromatic amines. In turn, in the process disclosed in the International Patent Application No. WO 03/066613, in which 3-bromo-4-methylaniline is the starting compound, that after conversion into N-(3-bromo-4-methylphenyl)-4-(4-methyl-piperazin-l-ylmethyl) benzamide is reacted with 4-(3-pyridyl)-2-pyrimidineamine, the reaction of an amino group and a bromine atom served to join the part comprising heterocyclic rings with the fragment comprising benzene rings and a piperazine ring. There was no necessity to reduce the nitro group here, but the reaction known from the state of the art allows for obtaining a secondary amine from a primary amine. The synthesis according to the invention consists in obtaining a secondary amide from a primary amide. These reactions are completely different in their chemical nature, and the successful carrying out the process according to the invention was possible due to use of a copper catalyst and an amine ligand. The synthetic process disclosed in the patent application WO 03/066613 requires use of highly expensive catalysts, and the resulting product is prepared in 72% yield along with 10% of isomeric impurities, that may be removed by liquid chromatography using the reversed phase technique. The above-mentioned factors make the commercial preparation of Imatinib according to that patent application hardly feasible.

The process according to the invention has been presented in more detail in the preparation examples. An example of the synthesis according to the invention is shown in the synthetic scheme.

Example 1.

Preparation of 2-methyl-5-bromophenylguanidine nitrate of the Formula 3

Preparation of 5-bromo-2-methylaniline hydrochloride

A 5-L reactor has been charged with 812.3 g of 5-bromo-2-methylaniline (4.36 mol. 1.0 eq), and 3.7 kg of methylene chloride. After cooling the obtained clear solution to 1O ⁰ C, 190.7 g of dry hydrogen chloride gas was added from a bottle over a period of 2.5 h. The resulting mixture was stirred for ca. 30 minutes, whereafter the obtained crystalline product was filtered off on a filter funnel. The precipitate was washed on a filter funnel with two portions of methylene chloride (200 g each). The product was dried at room temperature for 3 days to yield 976.4 g of 5-bromo-2-methylaniline hydrochloride (100%) having an HPLC purity of 99.6%. Preparation of 5-bromo-2-methylphenylguanidine nitrate

A 500-mL reactor was charged with 10.2 g of cyanamide (242.6 mmol, 1.2 eq), 44.6 g of 5-bromo-2-methylaniline hydrochloride (200 mmol, 1.0 eq). and 200 g of tert-butanol. The reaction mixture was heated to reflux (temperature 85°C) and stirred at reflux for 4 h. 200 g of toluene was added to the reactor, and distillation was carried out to remove tørt-butanol from the reaction medium. 200 g of the distillate was stripped off what resulted in an increase of temperature to 96°C. After cooling the reaction mixture to 25°C , 200 g of TBME were added, followed by 12O g of 7% aqueous NaOH solution. The mixture was stirred vigorously for 1 h. After separation of the layers, 200 g of water were added to the organic layer remaining in the reactor, and stirring was continued for 15 minutes. After removing water, the contents of the reactor was cooled to 12°C, and then 16.0 g of 65% nitric acid were added. The mixture was cooled to 7°C and, after one hour of stirring, the product was filtered off and washed with 80 g of TBME. The product was dried at 60°C for 12 h to yield 49.09 g of 5- bromo-2-methylphenylguanidine nitrate (84% yield) having an HPLC purity of 98.1%.

Example 2.

Preparation of N-(5-bromo-2-methylphenyl)-4-(pyridin-3-yl)-pyrimidin-2-ylam ine of the Formula 5

Preparation of N-(5-bromo-2-methylphenyl)-4-(pyridin-3-yl)-pyrimidin-2-ylam ine

A 1 L-reactor is charged with 52.5 g of 5-bromo-2-methylphenylguanidine nitrate (171.7 mmol, 1.0 eq), 30.2 g of 3-dimethylamino-l-(pyridin-3-yl)prop-2-en-l-one (171.3 mmol, 1.0 mmol), 28.0 g of sodium hydrogen carbonate (333.3 mmol, 1.9 mmol) and 300 g of M-butanol. The reaction mixture was heated to reflux (temperature of 120°C) and stirred at reflux under nitrogen for 16 h. After that time, the reaction mixture was cooled down to 80°C and 150 g of TBME ether was added. When temperature reached 60°C, cooling was started until reaching -10°C, and then the reaction mixture was stirred at that temperature for 2 h. The product was filtered off under reduced pressure. The crude product was stirred in the reactor with 180 g of water for 30 minutes. The product was filtered off again, and the precipitate was washed with 80 g of water on a filter funnel. The product was dried at 60°C for 15 h to yield 47.98 g (82.0%) of (5-bromo-2-methylphenyl)-4-(pyridin-3-yl)-pyrimidin-2-ylamin e having an HPLC purity of 99.0%.

Example 3 Preparation of Imatinib Preparation of 4-(4-methyl-l-piperazinyl)methyl)-N-[4-methyl-3-[(4-pyridin- 3- ylρyrimidin-2-yl)amino])phenyl]benzamide

A flask was charged with 7.11 g of (5-bromo-2-methylphenyl)-4-(pyridin-3-yl)- pyrimidin-2-ylamine (20.8 mmol), 7.29 g of 4-(4-methylpiperazin-l-ylmethyl)benzamide (31.2 mmol), 5.74 g of potassium carbonate (41.6 mmol), 177 mg of N ₅ N- dimethylethylenediamine (2.0 mmol, 10 mole %), 380 mg of copper(I) iodide (2.0 mmol, 10 mole %) and 50 g of dioxane. The reaction mixture was heated to reflux (temperature of 85°C) under the nitrogen atmosphere and stirred at reflux for 18 h. The reaction mixture was cooled down to 30°C, and then 200 g of methanol were added. The contents of the reactor was filtered off, and the precipitate was washed with 50 g methanol on a filter funnel. The filtrate and the washings were combined and concentrated using a vacuum evaporator at a temperature of 40°C and a pressure p=20 mmHg.

In order to isolate possible residues of the product, the precipitate from the filter was returned to the reactor, and 200 g of water and 300 g of methylene chloride were added subsequently. The solution prepared in that manner was combined with the first crop of the product obtained after evaporating of the solvents. The whole product was stirred in the reactor for 30 minutes, and then the layers were separated. The aqueous layer was extracted with 100 g of methylene chloride. The organic phases were combined, and then washed consecutively with 100 g of water, 100 g of 1.2% aqueous EDTA solution, 100 g of water, and finally dried over MgSO ₄ . After filtering the drying agent off, the filtrate was evaporated using an evaporator, and the precipitate obtained in this manner was dried in vacuo at a temperature of 40°C and a pressure p=20 mmHg. To yield 8.78 g of 4-(4-methyl-l- piperazinyl)methyl)-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin- 2-yl)amino])phenyl]benzamide (85.4% yield) having an HPLC purity of 95%.

Example 4

Preparation of Imatinib mesylate

Preparation of the α form of the methanesulphonic acid addition salt of 4-(4-methyl-l- piperazinyl)methyl)-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin- 2-yl)amino])phenyl]benzamide

A suspension of 7.14 g of 4-(4-methyl-l-piperazinyl)methyl)-N-[4-methyl-3-[(4- pyridin-3-ylpyrimidin-2-yl)amino])phenyl]benzamide (14.4 mmol) in 45 g of ethanol was heated to reflux, and then a solution of methanesulphonic acid in 10 g of ethanol was added dropwise to the thus-obtained mixture, the contents of the flask was stirred at reflux for 15 minutes and then filtered while hot. The resulting filtrate was seeded with the crystals of the α form, followed by start of cooling. After cooling to 30°C, a spontaneous crystallisation of the product was observed. Following 1.5 h of stirring at room temperature, the product was filtered off and washed with 5 g of ethanol. The isolated product was dried at 60°C for 13 h. 6.37 g (74.1% yield) of the α form of methanesulphonic acid addition salt of 4-(4-methyl-l— piperazinyl)methyl)-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin- 2-yl)amino])phenyl]benzamide was obtained, having an HPLC purity of 98.8%.