WO2017041771A1

WO2017041771A1 - Process for the preparation of ceritinib using "in situ" prepared 5-methyl-2-(1 -methylethoxy)-4-(4-piperidinyl)-benzenamine monohydrochloride (1 :1 ) as an intermediate

Info

Publication number: WO2017041771A1
Application number: PCT/CZ2016/000098
Authority: WO
Inventors: Katerina Kaminska; Igor CERNA
Original assignee: Zentiva, K.S.
Priority date: 2015-09-09
Filing date: 2016-09-02
Publication date: 2017-03-16
Also published as: CZ2015613A3

Abstract

The object of the invention is a preparation method of Ceritinib of formula (I) and its salts wherein 2-isopropylthioaniline is used in the first step. Even under mild conditions, it provides an intermediate, which is further oxidized to a sulfone in a high yield. The sulfone is subsequently transferred by means of a one-step reaction to Ceritinib of formula I in the form of a salt either through a reaction with the intermediate of formula (V) catalyzed by an acid, or in neutral conditions with its unprotected analog of formula (IX), which is in the form of the in-situ generated monohydrochloride. The product is easily isolated from the reaction as crystalline Ceritinib of formula (I) in the form of the salt with hydrochloric acid.

Description

PROCESS FOR THE PREPARATION OF CERITINIB USING "IN SITU" PREPARED 5-METHYL-2-(1 -METHYLETHOXY)-4-(4-PIPERIDINYL)-BENZENAMINE MONOHYDROCHLORIDE

(1 :1 ) AS AN INTERMEDIATE

Field of the Invention

The invention relates to a preparation method of 5-chloro-N²-(2-isopropoxy-5-methyl-4- (piperidin-4-yl)phenyl)-A^-(2-isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine of formula I, known under the generic name Ceritinib, and its salts.

Ceritinib (CAS no. 1032900-25-6) belongs to the group of anaplastic lymphoma kinase (ALK) inhibitors and is designed for the treatment of lung cancer, incl. non-small cell lung carcinoma. Ceritinib free base was approved under the trade name Zykadia by the European Medicines Agency (EMA) for the treatment of adult patients with non-small cell lung carcinoma (NSCLC) positive for anaplastic lymphoma kinase (ALK), formerly treated with crizotinib.

Background Art

A preparation method of Ceritinib was first published in the patent application WO2008073687. The last three steps of the synthesis (shown in Scheme 1) comprise nucleophilic substitution of chlorine of 2,4,5 -trichloropyrimidine of formula III in position 4 with relatively poorly reactive 2-(isopropylsulfonyl)aniline of formula II. For this reason, a strong base must also be used, in this case NaH namely, in a high surplus (2.4 equivalents). The use of such a strong base also results in the necessity to use a high surplus of 2,4,5- trichloropyrimidine of formula III (at least 2 equivalents), which consequently impairs the economic aspect of the selected method and leads to contamination of the product with side products of degradation of 2,4,5-trichloropyrimidine of formula III in strongly basic conditions.

This reaction, conducted in dimethylformamide with a small addition of dimethyl sulfoxide (in the ratio of 9:1), involves a considerable safety risk. Information has been published that a combination of dimethylformamide with sodium hydroxide represents a great risk of a reaction with uncontrolled exothermal course, especially if the reaction is conducted in a larger scale or if the reaction is heated (Buckley, J Chem Eng News 1982, 60(28), 5; De Wall, G. Chem. Eng. News, 1982, 60(37), 5).

Scheme 1: A preparation method of Ceritinib according to the basic patent WO2008073687

III IV

A more advantageous two-step synthesis shown in Scheme 2 was described with the use of examples of structurally close intermediates, e.g. in the patent application WO2006021454 or WO2010138578, and recently also in the context of preparation of deuterated diaminopyrimidine compounds in the patent application WO2014173291.

Scheme 2: Examples of execution of a two-step synthesis of amino dihalogen derivatives of pyrimidine

The next step of synthesis of Ceritinib according to WO2008073687 (Scheme 1) is the Buchwald-Hartwig animation to possition 2 of the intermediate of formula IV with the protected aniline V (tert-Butyl-4-(4-amino-5-isopropoxy-2-methylphenyl)piperidine-l- carboxylate), which is catalyzed by a transition metal, in particular palladium (II) acetate, in the presence of the ligand Xantphos and the base Cs₂C0₃ in tetrahydrofuran by the action of microwave radiation at a high temperature (150 °C). In addition, the product of formula VI is isolated from the reaction mixture by means of column chromatography, which represents a considerable obstacle in industrial preparation. Also, the use of the catalytic system is associated with increased financial costs and especially the risk of residues of the transition metal in the reaction product, possibly also in the final active substance.

The whole sequence is concluded by deprotection of nitrogen of piperidine of the adduct of formula VI in strongly acidic conditions of trifluoroacetic acid in dichloromethane. Subsequently, a solution of HC1 in an ether is added to the concentrated reaction mixture and the final product of formula I is isolated as a salt with hydrochloric acid.

The above mentioned patent application WO2014173291 for the preparation of deuterated diaminopyrimidine compounds and also the publication IP.com Journal 2014, vol. 14, 12B, 1-3; describe synthesis of ceritinib base and its deuterated analogs through a reaction of the intermediate of formula IV with the intermediate of formula IX in the dihydrochloride form (Scheme 3) in iPrOH under reflux of the solvent, the product of which is ceritinib hydrochloride, which however must be recrystallized due to low purity and the total yield of the dihydrochloride is then only approx. 60 %. cheme 3: Procedure described in IP.com Journal, 2014, vo.l 14, 12B, 1-3

Disclosure of the Invention

The object of the invention is the preparation method of Ceritinib of formula I and its salts where in the first step 2-isopropylthioaniline of formula VII is used instead of the poorly reactive aniline of formula II. Even under mild conditions, it provides the intermediate of formula VIII, which is further oxidized to the sulfone of formula IV in a high yield. The sulfone of formula IV is subsequently transferred by means of a one-step reaction to Ceritinib of formula I in the form of a salt either through a reaction with the intermediate of formula V catalyzed by an acid, or in neutral conditions with its unprotected analogue of formula IX, which is in the form of the in-situ generated monohydrochloride (Scheme 4). The product is easily isolated from the reaction as crystalline Ceritinib of formula I in the form of the salt with hydrochloric acid.

Scheme 4 Preferred method of preparing of Ceritinib (I)

l*2HCI Detailed description of the Invention

The object of the invention is a preparation method of Ceritinib of formula I and its salts using the method illustrated in Scheme 4. For the reaction of the aniline of formula VII with trichloropyrimidine of formula III as the base a trialkylamine is used, e.g. triethylamine or ethyl-diisopropylamine (DIPEA), or an inorganic base as Na₂C0₃, K₂C0₃, CS2CO3 etc. The reaction is conducted in an inert solvent as alcohols, acetonitrile, tetrahydrofuran etc. Preferably, a solvent from the EtOH, z^'PrOH, n-BuOH or t-BuOH group can be used. In an especially preferred embodiment /PrOH is used, from which after cooling and reduction of the solvent volume the product of formula VIII can be obtained as a crystalline compound without further processing.

The oxidation of the sulphide of formula VIII can be carried out with the use of common oxidizing agents as peroxy acids, preferably m-chloroperbenzoic acid (mCPBA), sodium perborate, hydrogen peroxide and more. When mCPBA is used, the reaction is carried out in an inert solvent, preferably in dichloromethane, which is also used for processing of the reaction by aqueous extraction, and subsequently, as a low-boiling solvent, it is replaced in a technologically easy manner with another solvent suitable for crystallization of the sulfone of formula IV as alcohols, acetonitrile and others, MeOH can be preferably used.

The oxidation reaction with the use of hydrogen peroxide can be conducted in the presence of a suitable agent as Na₂W0₄, Na₂Mo0₄ etc. in a suitable inert solvent, from which after the end of the reaction after addition of another solvent as a co-solvent the sulfone of formula IV can be obtained by crystallization.

The two-step synthesis designed this way represents a great advantage as compared to the original synthesis published inter alia in the patent application WO2008073687, namely thanks to the use of mild conditions and achievement of high yields and purity of the final product of formula IV.

Another advantage of the method according to the present invention is the possibility to avoid using a combination of a surplus of a strong base, usually NaH and the polar aprotic solvent DMF and/or DMSO, which is necessary for the preparation of the adduct of formula IV from the intermediate of formula II and which represents a great risk of a reaction with an uncontrolled course from the safety point of view, especially if the reaction is conducted in a larger scale or under heating (Buckley, J. Chem. Eng. News 1982, 60(28), 5; De Wall, G. Chem. Eng. News, 1982, 60(37), 5). Subsequent substitution of aminodichloropyrimidine of formula IV to position 2 can be conducted both with the intermediate of formula V where nitrogen of the piperidine is protected by a butyloxycarbonyl group (Boc), and with the intermediate of formula IX with unprotected nitrogen of the piperidine.

If the substitution is conducted with the intermediate of formula IX, it can be used in the form of monohydrochloride or dihydrochloride. However, if it is conducted directly with the dihydrochloride of formula IX (as described in the patent application WO2014173291 and also in the publication IP.com Journal, 2014, vol. 14, 12B, 1-3), the yield of the reaction is reduced by approx. 10% of the intermediate of formula IV being hydrolyzed to the impurity IMP1 under these conditions (Figure 1). In addition, it also remains in the quantity of approx. 5% in the crystalline product, which must be re-purified by recrystallization, which leads to further weight losses and the final Ceritinib of formula I dihydrochloride is thus obtained in a low yield of approx. 60% (Example 11).

Figure 1. Structure of the impurity

One of the objects of the invention is a more advantageous execution of the reaction with monohydrochloride of the intermediate of formula IX. It is prepared in situ in such a way that to a suspension of a mixture of the compounds of formula IV and formula IX*2HC1 in a suitable solvent (e.g. alcohols, acetonitrile etc.) 0.5 - 1 equivalent of an organic base (e.g. triethylamine) is added and the reaction mixture is heated up. Another option of in situ preparation of the monohydrochloride of the intermediate of formula IX is the method where to a solution of the free base of the compound of formula IX in a suitable solvent 1 equivalent of HC1 is added in the form of concentrated aqueous hydrochloric acid, subsequently the intermediate of formula IV is added and the reaction is heated. In both the cases, the product of the reaction is crystalline Ceritinib of formula I in the form of a salt with hydrochloric acid in the yield of over 90% and with the purity of > 97% where individual impurities do not exceed 0.5%.

Another preferred embodiment of this reaction consists in the use of the intermediate of formula V instead of the intermediate of formula IX*2HC1 when the reaction is carried out with an addition of hydrochloric acid in the quantity of 0.3 - 3 equivalents, namely in parts, at the boiling temperature of a suitable solvent. Solvents suitable for the reaction are e.g. alcohols, preferably PrOH, «-BuOH or t-BuOH. These conditions are sufficient both for the initiation of the substitution reaction and for the hydrolysis of the protecting group of the piperidine. Under the conditions selected this way the final crystalline Ceritinib of formula I can be directly obtained from the reaction in the form of the salt with hydrochloric acid, which can be further converted to Ceritinib free base of formula I through a reaction with at least 2 equivalents of a base (e.g. a diluted aqueous solution of NaOH, or a solution of Na₂C0₃ or another base is used).

An advantage of this procedure as compared to the procedure published in the patent application WO2008073687 is a reduction of the number of reaction steps from three (coupling of the compounds of formula IV and V, hydrolysis of the protecting group with TFA, conversion to the salt with HC1) to one and especially replacement of the palladium catalyzed reaction (Buchwald-Hartwig animation). Thus, the use of a costly catalyst and the required ligands can be eliminated and possible problems associated with the removal of palladium residues in the final product can be avoided. An advantage of the use of the protected intermediate V and intermediate of formula IX in the monohydrochloride form, as compared to the procedure published in the patent application WO2014173291 as well as in the publication IP.com Journal, 2014, vol. 14, 12B, 1-3, is prevention of occurence of the impurity IMP1, i.e. increase of the yield and purity of the final product, in addition without further losses caused by the necessity of recrystallization.

Examples

HPLC measurement conditions

Sample preparation: 10.0 mg of the sample is dissolved in 10.0 ml of the water/acetonitrile 20/80 v/v solution

Column:

- size: 1 = 0.010 m, 0 = 4.6 mm, 2.7 μιη particles

- stationary phase: Ascentic Express CI 8

- temperature: 40°C

Mobile phase:

For the analysis of the reaction mixtures and product of reaction steps 1 and 2:

- A: water B: acetonitrile Elution gradient:

For the analysis of the reaction mixtures and product of reaction step 3 (preparation of Ceritinib dihydrochloride of formula P2HC1):

- A: 0.01 KH₂P0₄ in water (pH adjustment with the use of phosphoric acid to 2.80 ± 0,05); B: acetonitrile

- elution gradient:

Detection: spectrophotometer at 210 nm

Injected quantity: 5 μΐ

Sample temperature: 20°C

1H NMR

measured with Bruker Avance 500, probe Prodigy 5 mm devices

Mass spectrometry

High-performance liquid chromatography with a weight spectrometer (HPLC - MS/MS) HPLC pump Flux instrument AG, Rheos Allerro 22110 model

Column thermostat: Jetstream 2 Plus 170807

Mass spectrometer: Thermofisher Scientific, LTQ Orbitrap 0132 IB Column

Phenomenex, Kinetex C18 100A, 150 x 3.0 mm; 2.6μ Chemicals

Acetonitrile for chromatography R

Water for chromatography R

Ammonium formate R

Separation conditions

Mobile phase: constituent A in a mixture with B in accordance with the gradient program

Constituent A: 0,63 g of ammonium formate in 1000 ml of water

Constituent B: Acetonitrile

Flow: 0.6 ml/min

Injected quantity: 10.0 μ1 - 50 μ1

Column temperature: 30°C

Sample preparation: 1 - 5 mg vzorku is dissolved in 1 ml of a suitable solvent

(acetonitrile, methanol)

Gradient program

Time (min) A [%] B [%]

0 70 30

4 70 30

18 0 100

23 0 100

25 70 30

30 70 30

Mass spectrometer

Ion sources: ESI, APCI

Polarity: positive

Scanning range m/z 50 Preparation of the intermediate of formula VIII:

Example 1

The aniline VII (30.11 g, 0.18 mol) was dissolved in propan-2-ol (300 ml), trichloropyrimidine of formula III (36.32 g, 1.1 eq.) and diisopropylethylamine (40.7 ml; 1.3 eq) were added and the mixture was heated up to reflux for 30 h. The course of the reaction was monitored by means of HPLC. Subsequently, 150 ml of the solvent was removed from the reaction by distillation, the mixture was cooled down to 10°C and was left to crystallize for 8 h under stirring. The separated crystals were aspirated, washed with 2 x 100 ml of propan-2-ol and dried until constant weight was achieved. The amount of 48.76 g (86 %) of the sulphide of formula VIII with the HPLC purity of > 99 % was obtained.

1H NMR (500 MHz, CDC13), σ (ppm): 9.29 (bs, 1H), 8.66 (d, J=7.8 Hz, 1H), 8.23 (s, 1H), 7.59 (dd, J=7.7, 1.4 Hz), 7.46 (m, 1H), 7.1 (m, 1H), 3.15 (sp, J=6.7), 1.27 (d, 1H). 13C NMR (500 MHz, CDC13): 158.0, 155.9, 154.5, 139.7, 137.1, 130.4, 124.0, 122.9, 119.7, 114.8, 40.7, 23.2.

Example 2

The aniline of formula VII (84 g, 0.5 mol) was dissolved in n-butanol (1 ml), trichloropyrimidine of formula III (120 mg, 1.3 eq.) and diisopropylethylamine (0.11 ml; 1.3 eq) were added and the mixture was heated up to 100°C for 24 h. The course of the reaction was monitored by means of HPLC. The mixture was cooled down to the laboratory temperature and left to crystallize for 4 h under stirring. The separated crystals were aspirated, washed with 2 x 0.5 ml of propan-2-ol and dried until constant weight was achieved. The amount of 82 mg (52 %) of the sulphide of formula VIII with the HPLC purity of > 99% was obtained.

Example 3

The aniline of formula VII (167 g, 1 mol) was dissolved in propan-2-ol (1 ml), trichloropyrimidine of formula III (238 mg, 1.3 eq.) and triethylamine (0.18 ml; 1.3 eq) were added and the mixture was heated up to 80 °C for 24 h. The course of the reaction was monitored by means of HPLC. The mixture was cooled down to the laboratory temperature and left to crystallize for 4 h under stirring. The separated crystals were aspirated, washed with 2 x 0.5 ml of propan-2-ol and dried until constant weight was achieved. The amount of 172 mg (60%) of the sulphide of formula VIII with the HPLC purity of > 98% was obtained.

Example 4

The aniline of formula VII (84 g, 0.5 mol) was dissolved in propan-2-ol (1 ml), trichloropyrimidine of formula III (120 mg, 1.3 eq.) and K₂C0₃ (138 mg, 2 eq) were added and the mixture was heated up to 80 °C for 24 h. The course of the reaction was monitored by means of HPLC. The mixture was cooled down to the laboratory temperature, 2 ml of dichloromethane was added, the mixture was washed with 2x2 ml of water and 1x2 ml of salt brine, dried with MgS0₄ and filtered. The filtrate was concentrated to the volume of 1 ml and left to crystallize overnight. The separated crystals were aspirated, washed with 2 x 0.5 ml of propan-2-ol and dried until constant weight was achieved. The amount of 51 mg (32%) of the sulphide of formula VIII with the HPLC purity of > 95% was obtained. Example 5

The aniline of formula VII (84 g, 0.5 mol) was dissolved in acetonitrile (1 ml), trichloropyrimidine of formula III (120 mg, 1.3 eq.) and K₂C0₃ (138 mg, 2 eq) were added and the mixture was heated up to 80 °C for 24 h. The course of the reaction was monitored by means of HPLC. The mixture was cooled down to the laboratory temperature, 2 ml of dichloromethane was added, the mixture was washed with 2x2 ml of water and 1x2 ml of salt brine, dried with MgS0₄ and filtered. The filtrate was concentrated to the volume of 1 ml and left to crystallize overnight. The separated crystals were aspirated, washed with 2 x 0.5 ml of propan-2-ol and dried until constant weight was achieved. The amount of 85 mg (54 %) of the sulphide of formula VIII with the HPLC purity of > 98 % was obtained.

Oxidation of the sulphide of formula VIII to the sulfone of formula IV

Example 6

To a solution of the intermediate of formula VIII (1.885 g; 6 mmol) in dichloromethane (10 ml) a solution of 3-chloroperbenzoic acid (2.5 eq) in CH₂C1₂ (30 ml) was added by dripping under moderate cooling (exothermal reaction) during 10 min and the reaction was stirred at the laboratory temperature for another 45 min. Then, it was terminated by addition of 25 ml of a 2M solution of Na₂C0₃. The phases were separated, the organic phase was washed with water (2 x 20 ml) and salt brine (20 ml) and dried over MgS0₄. Subsequently, at a reduced pressure a greater part of CH₂C1₂ was removed by crystallization, 7 ml MeOH was added and the mixture was left to crystallize. The amount of 1.710 (82%) of the sulfone of formula IV was obtained with an HPLC purity of over 99 %.

1H NMR (CDC13, 500 MHz), σ (ppm): 10.08 (bs) NH, 8.65 (d, J= Hz, 1H), 8.32 (s, 1H), 7.94 (dd, J= , Hz, 1H), 7.75 (m, 1H), 7.34 (m, 1H), 3.24 (sp, J = 6.7 Hz, 1H), 1.33 (d, J= Hz, 6H). 13C NMR (CDC13, 500 MHz), σ (ppm): , 157.8, 156.3, 155.6, 137.3, 135.2, 131.4, 124.5, 124.2, 122.6, 115.2, 56.0, 15.3. HRMS (M+H+)=346.0178.

Example 7

To a solution of the intermediate of formula VII (3.14 g, 10 mmol) in 1,2-dichlorobenzene (20 ml) Na₂W0₄-2H₂0 (0.015 eq), Aliquat 336 (0.02 eq) were added and a 30% solution of hydrogen peroxide (2.55 ml; 2.5 eq) was added by dripping. The mixture was heated up to 45 °C and stirred for 1 h. The surplus of the oxidation agent was reduced by an addition of a 20% solution of NaHS0₃. Hexane was added to the two-phase mixture before the start of the crystallization. The separated crystals were aspirated, washed with 2 x 10 ml of propan-2-ol and dried until constant weight was achieved. The amount of 2.76 g (79 %) of glossy white crystals of the sulfone of formula IV was obtained with a purity of over 99 %.

Preparation of ceritinib dihydrochloride of formula I*2HC1:

Example 8

To a suspension of the sulfone of formula IV (0.693 g, 2 mmol) and aniline of formula V (0.697 g; 1 eq) in propan-2-ol (4 ml) hydrochloric acid (35% aq., 177 μΐ, 1 eq) was added by dripping under stirring and the mixture was heated up to 80 °C for 8 h. Then, it was cooled down to 50 °C, 2 more eq (354 μΐ) of 35% HC1 were added and the mixture was stirred for another 4 h. The mixture was then cooled down to the laboratory temperature and left to crystallize for 2 h under stirring. The separated crystals were aspirated, washed with 3 x 3 ml of propan-2-ol and dried until constant weight was achieved. The amount of 1.163 g (92%) of ceritinib dihydrochloride of formula I*2HC1 was obtained with the HPLC purity of > 98%. 1H NMR (DMSO, 500 MHz), σ (ppm): 9.96 (bs,lH), 9.06-8.92 (m, 3H), 8.45 (s, 1H), 8.18 (bs, 1H), 7.91 (d, 1H), 7.73-7.70 (m, 1H), 7.52-7.49 (m, 1H), 7.37 (s, 1H), 6.80 (s, 1H), 4.53 (sp, 1H), 4.44 (bs, 1H), 3.77 (sp, 1H), 3.34-3.32 (m, 2H), 3.04-2.94 (m, 3H), 2.04 (s, 3H), 1.91-1.84 (m, 2H), 1.79-1.76 (m, 2H), 1.25 (d, 6H), 1.13 (d, 6H). HRMS (M+H+)=558.2296. Example 9

To a suspension of the sulfone of formula IV (1.038 g, 3 mmol, 1.0 eq) and aniline of formula IX dihydrochloride (0.964 g; 3 mmol) in propan-2-ol (6 ml) 0.25 ml (0.6 eq) of triethylamine was added under stirring and the mixture was heated up to 80 °C for 24 h. Then it was cooled down to the laboratory temperature and left to crystallize for 2 h under stirring. The separated crystals were aspirated, washed with 3 x 5 ml of propan-2-ol and dried until constant weight was achieved. The amount of 1.72 g (84%) of ceritinib dihydrochloride of formula I*2HC1 was obtained with the HPLC purity of > 97%. Example 10

To a solution of the aniline base of formula IX in isopropanol (1 ml) 0.044 ml (1 eq) of 35% HC1 was added and the mixture was stirred at the laboratory temperature for 10 min. The intermediate of formula IV (1 eq) was added to the solution and the reaction was heated up to reflux for 18 h. Then it was cooled down to the laboratory temperature and left to crystallize for 2 h. The amount of 0.264 g (84%) of ceritinib dihydrochloride of formula I*2HC1 was obtained with the HPLC purity of > 97%.

Reproduction of the procedure published in IP.com Journal, 2014, vol 14, 12B, 1-3:

Example 11

Step A: Preparation of crude ceritinib dihydrochloride of formula P2HCI

0.5 g of the aniline of formula IX dihydrochloride (1.56 mmol) and 0.56 g of the sulfone of formula IV (1.62 mmol, 1.04 eq) were dosed into a flask. The amount of 5 ml of propan-2-ol was added and the reaction mixture was heated up to the boiling point of the solvent and at this temperature it was further stirred for 17 h. Subsequently, the reaction mixture was cooled down to the room temperature and stirred for another 2 h. The separated crystals were aspirated, washed with 3 x 1,5 ml of propan-2-ol and dried in a vacuum drier at 50 °C for 3 h. The amount of 0.897 g (in the yield of 91%) of ceritinib dihydrochloride of formula I*2HC1 was obtained with the HPLC purity of 87%) (IMP1 impurity content of 5%).

Step B: Recrystallization of ceritinib dihydrochloride of formula I*2HC1

0.7 g of ceritinib dihydrochloride of formula I*2HC1 from the previous step was dosed into a flask and 5 ml of a mixture of the solvents acetone and water in the ratio of 10:1 was added. The suspension was brought to boiling under stirring and the obtained clear solution was left at the boiling point of the mixture for 30 minutes. The reaction mixture was cooled down to the room temperature and stirred for 1 h at this temperature and for another 1 h in an ice bath. The separated crystals were aspirated, washed with a minimal quantity of cooled acetone and dried in a vacuum drier at 50°C for 3 h. The amount of 0.485 g (in the yield of 69%) of ceritinib dihydrochloride of formula I*2HC1 was obtained with the HPLC purity of > 98%.

Claims

1. A method for preparing the 5-chloro-N -(2-isopropoxy-5-methyl-4-(piperidin-4- yl)phenyl)-iV^-(2-isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine of formula I and its salts, characterized in that it comprises:

a) a reaction of 2-isopropylthioaniline with 2,4,5-trichloropyrimidine in the presence of a base, producing 2,5-dicWoro-N-(2-isopropylthio)phenyl)pyrimidine-4-amine, b) oxidation of 2,5-dichloro-N-(2-isopropylthio)phenyl)pyrimidine-4-amine to 2,5- dichloro-N-(2-isopropylsulfonyl)phenyl)pyrimidine-4-amine,

c) a reaction of 2,5-dicUoro-N-(2-isopropylsulfonyl)phenyl)pyrimidme-4-amine with the in situ prepared monohydrochloride of formula IX,

d) and optionally conversion of the obtained salt of 5-chloro-N -(2-isopropoxy-5- methyl-4-(piperidin-4-yl)phenyl)-A^-(2-isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine to its free base.

2. The method for preparing in accordance with claim 1, characterized in that the monohydrochloride of the compound of formula IX is prepared in situ by addition of 0.5 - 1 equivalent of an organic base to a suspension of 2,5-dichloro-N-(2- isopropylsulfonyl)phenyl)pyrimidine-4-amine and the dihydrochloride of the compound of formula IX and heating of the reaction mixture.

3. The method for preparing in accordance with claim 2, characterized in that the organic base is triethylamine.

4. The method for preparing in accordance with claim 1, characterized in that the monohydrochloride of the compound of formula IX is prepared in situ by addition of 1 equivalent of hydrochloric acid to a solution of the free base of the intermediate of formula IX.

5. A method for preparing the 5-chloro-N²-(2-isopropoxy-5-methyl-4-(piperidin-4- yl)phenyl)-N^¥-(2-isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine and its salts, characterized in that it comprises: a) a reaction of 2-isopropylthioaniline with 2,4,5-tricUoropyrhriidine in the presence of a base, producing 2,5-dicMoro-N-(2-isopropyltWo)phenyl)pyrimidine-4-arnine, b) oxidation of 2,5-dicUoro-N-(2-isopropylthio)phenyl)pyrimidine-4-amine to 2,5- dichloro-N-(2-isopropylsulfonyl)phenyl)pyrimidine-4-amine,

c) a reaction of 2,5-dichloro-N-(2-isopropylsulfonyl)phenyl)pyrimidine-4-amine with the compound of formula V

wherein Boc is butyloxycarbonyl,

the reaction being carried out with an addition of hydrochloric acid in the quantity of 0.3 - 3 equivalents,

d) and optionally conversion of the obtained salt of 5-chloro-N²-(2-isopropoxy-5- methyl-4-(piperidin-4-yl)phenyl)-A^-(2-isopropylsulfonyl)phenyl)pyrimidine-2,4- diamine to its free base.

6. The method for preparing in accordance with claim 5, characterized in that hydrochloric acid is added to the suspension of 2,5-dichloro-N-(2- isopropylsulfonyl)phenyl)pyrimidine-4-amine and the compound of formula V in parts.

7. The method for preparing in accordance with claim 6, characterized in that 1 equivalent of hydrochloric acid is first added to the suspension and at least after 8 h of the reaction 2 more equivalents of hydrochloric acid are added.

8. The method for preparing in accordance with any of claims 1 to 10, characterized in that as the base in step a) a trialkylamine or an inorganic base is used.

9. The method for preparing in accordance with claim 8, characterized in that the trialkylamine is triethylamine or ethyl-diisopropylamine.

10. The method for preparing in accordance with claim 8, characterized in that the inorganic base is selected from the group of Na₂C0₃, K₂C0₃ and Cs₂C0₃.

11. The method for preparing in accordance with any of claims 1 to 10, characterized in that the reactions in steps a) and c) are carried out in the presence of a solvent selected from the group consisting of C1-C4 alcohols, acetonitrile and tetrahydrofuran.

12. The method for preparing in accordance with claim 11, characterized in that the alcohol is selected from the group of ethanol, isopropyl alcohol, n-butanol and tert- butanol.

13. The method for preparing in accordance with any of claims 1 to 12, characterized in that the oxidation of 2,5-dichloro-N-(2-isopropylthio)phenyl)pyrimidine-4-amine is performed with an oxidation agent selected from the group of peroxy acids, sodium perborate and hydrogen peroxide.

14. The method for preparing in accordance with claim 13, characterized in that the peroxy acid is m-chloroperbenzoic acid.

15. The method for preparing in accordance with claim 14, characterized in that the oxidation is carried out in a solvent, which is dichloromethane.