WO2024209392A1

WO2024209392A1 - Process for preparing pralsetinib in amorphous form

Info

Publication number: WO2024209392A1
Application number: PCT/IB2024/053302
Authority: WO
Inventors: Balasaheb Jadhav; Madhu SADASHIVAIAH; Vijay KUMBHAR; Makarand Gore; Sachin DEVADHE
Original assignee: Olon SpA
Current assignee: Olon SpA
Priority date: 2023-04-06
Filing date: 2024-04-04
Publication date: 2024-10-10
Anticipated expiration: 2025-10-06
Also published as: WO2024209391A1; IT202300006819A1

Abstract

Process for preparing Pralsetinib in amorphous form, which allows to obtain a product free of solvents, so as to comply with the requirements provided by the ICH regulation. Furthermore, the process requires reduced volumes of solvents and low processing temperatures, thereby allows to obtain high purity and yields. Finally, the process can be readily performed on an industrial scale.

Description

PROCESS FOR PREPARING PRALSETINIB IN AMORPHOUS FORM

Field of the invention

The present invention relates to a process for preparing Pralsetinib in amorphous form. Background of the invention

The Food and Drug Administration (FDA) granted accelerated approval for Pralsetinib on September 4th, 2020 for non-small cell lung cancer (NSCLC) and on December 1st, 2020 for thyroid cancer, for: (i) adult patients with metastatic RET fusion-positive NSCLC, (ii) adult and paediatric patients >12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy, and (iii) adult and paediatric patients >12 years of age with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine refractory (if radioactive iodine is appropriate) .

The synthesis of Pralsetinib and its intermediates is disclosed in WO 2017/079140 Al and WO 2022/120136 Al by Blueprint Medicines Corporation.

Moreover, polymorphs and salts of Pralsetinib have been studied. For example, WO 2021/243192 Al describes crystalline forms A, B, C, F, G, J, K, L, M, N, P, 5-A, 5-B, and 5-C of Pralsetinib.

WO 2022/086899 Al describes Pralsetinib crystalline Forms I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII. Forms CM-I, CM-II, CM-III, CM-IV, CM- V, CM-VI, CM-VII and CM-VIII are described in CN111777595A. In WO 2022/117448 Al, crystalline Form-II and HyB of Pralsetinib are mentioned. WO 2021 /243192 Al describes also di f ferent Pralsetinib salts with other acids , such as benzene sul fonic acid, methane sul fonic acid, hydrochloric acid, hydrobromic acid, nitric acid, pyruvic acid, citric acid, fumaric acid, maleic acid, salicylic acid, glutaric acid, sulphuric acid, tartaric acid, phosphoric acid and succinic acid .

Moreover, Pralsetinib co-crystals are disclosed in WO 2021 /243192 Al . In particular, co-crystals are reported with 4-amino benzoic acid, 4-hydroxy benzoic acid, benzoic acid, vani llic acid, quercetin dihydrate , gentisic acid, saccharin and urea .

Finally, Pralsetinib solvates are known . For example , solvates with tetrahydrofuran ( THF) , chloroform, cyclohexane , methanol are described in WO 2021 /243192 Al and a solvate with dimethyl sul foxide ( DMSO) is described in WO2022117448A1 .

However, processes for the preparation o f pralsetinib salts as described in the prior art have many disadvantages , for example : high volumes of solvents are used, and reactions are performed at elevated temperature . The yield and quality of the salts , whose formation generally takes a long time , are not clearly described in the prior art . For these reasons , the process and the salts described in the prior art are not industrially feasible .

As regards the amorphous form of Pralsetinib, its preparation process by chloroform distillation is described in WO 2021 /243192 Al . This process results in the formation of the amorphous form of Pralsetinib, however a substantial amount of chloroform remains trapped in the isolated solid . For this reason, controlling residual chloroform within 60 ppm as per ICH limit could be challenging . Moreover, the process according to WO 2021 /243192 Al is not an industrially feasible process .

For all the reasons above , there is a strong need to develop an industrially feasible and easier process for producing Pralsetinib in amorphous form . Summary of the invention

The Applicant has found that the problems of the prior art can be solved by a process as defined hereinbelow .

The present invention relates to a proces s for the preparation of a compound of Formula I :

Formula I in amorphous form, said process comprising : a ) preparing a solution of the compound of Formula I in a mixture of organic solvents comprising a polar aprotic solvent and a polar protic solvent ; b ) treating the solution of the compound of Formula I obtained in step a ) so as to remove the mixture of solvents and obtain a solid residue of the compound of Formula I ; c ) adding an apolar organic solvent to the sol id residue obtained in step b ) to obtain a suspension of the compound of Formula I ; d) isolating the compound of Formula I from the suspension obtained in step c ) to obtain the compound of Formula I in amorphous form .

When compared to processes for obtaining Pralsetinib in amorphous form known in the art , the process according to the present invention is advantageous under various aspects .

In particular, the process of the invention allows to obtain a product free of solvents , therefore being in compliance with ICH regulation will be easy .

Furthermore , the process of the present invention requires reduced volumes of solvents and low processing temperatures , thereby allows to obtain high purity and yields .

Finally, the process of the present invention can be readily performed on an industrial scale .

Brief description of the drawings :

Figure 1 : XRPD pattern of Pral setinib of Formula I in amorphous form .

Detailed description of the invention

In the following description and claims , definitions of numerical ranges comprise the single values within the range itsel f and the corresponding endpoints , unless otherwise speci fied .

In the following description and claims , the term "comprising" also includes the terms "consisting of" or "consisting essentially of" .

Preferably, the compound of Formula I used in step a ) is in crystalline form .

Preferably, in step a ) the polar aprotic solvent is a chlorinated solvent , more preferably methylene chloride .

Preferably, in step a ) the polar protic solvent is an alcohol with general formula R-OH, where R is a linear or branched Ci-Cg alkyl, preferably linear, more preferably the alcohol is ethanol.

Preferably, in step a) the ratio of the volume of the polar protic solvent and the volume of the polar aprotic solvent (v/v) is between 0.5/99.5 v/v and 80/20 v/v, preferably between 5/95 v/v and 70/30 v/v, more preferably between 10/90 v/v and 50/50 v/v.

Preferably, in step a) the ratio of the volume of the mixture of organic solvents and the weight of the compound of Formula I is between 2 and 20 v/w, more preferably between 5 and 15 v/w, still more preferably between 8 and 12 v/w.

Preferably, the solution of the compound of Formula I obtained in step a) is filtered to eliminate possible suspended particles.

Preferably, in step b) the solution of the compound of Formula I obtained in step a) is treated by distillation or by spray-drying. More preferably, the solution of the compound of Formula I obtained in step a) is treated by distillation, in particular distillation under vacuum. Preferably, the distillation temperature is not higher than 100°C, more preferably not higher than 90°C.

Preferably, in step b) the distillation temperature is gradually increased to 80°C, more preferably from 25°C to 80°C.

According to a preferred aspect of the invention, in step b) the distillation is carried out under vacuum gradually increasing the temperature to 80°C, more preferably the temperature is increased from 25°C to 80°C. The Applicant considers that the use of a mixture of solvents for preparing the solution of the compound of Formula I in step a) allows to easily remove both the solvents without any degradation of Pralsetinib, in particular when using the distillation with a distillation temperature not higher than 100°C, preferably not higher than 90°C. Thereby, the compound of Formula I in amorphous form free of solvents is obtained; in particular the analyses show that all the used solvents fall within the specifications of the ICH guidelines .

Preferably, in step c) the apolar organic solvent is selected from: alkanes, preferably hexane or heptane; cycloalkanes, preferably cyclohexane; ethers, preferably methyl-tert-butyl ether (MTBE) ; or mixtures thereof .

Preferably, in step c) the apolar organic solvent is added in a temperature range between 15°C and 40°C, preferably between 20°C and 35°C.

Preferably, in step c) the ratio of the volume of the apolar organic solvent and the weight of the compound of Formula I is between 2 and 20 v/w, more preferably between 5 and 15 v/w, still more preferably between 8 and 12 v/w.

Preferably, in step c) the suspension of the compound of Formula I is maintained under stirring for a time between 0.5 hours and 24 hours, more preferably between 1 hour and 18 hours.

Preferably, in step d) the compound of Formula I is isolated by filtering.

Preferably, in step d) the compound of Formula I, after filtering, is dried at a temperature lower than 80°C, preferably lower than 75°C.

Preferably, in step d) the compound of Formula I, after filtering, is dried for a time between 2 hours and 48 hours, preferably between 8 hours and 30 hours.

According to an alternative embodiment of the invention, step b) , wherein the solution of the compound of Formula I obtained in step a) is treated so as to remove the mixture of solvents and obtain a solid residue of the compound of Formula I, is carried out by spray-drying. Spray drying can be carried out in a spray dryer according to known techniques, by spraying the solution in a chamber, where the nebulized solution is dried almost instantaneously.

Preferably, the temperature entering the spray dryer chamber is between 160°C and 240°C, more preferably between 180°C and 230°C.

Preferably, the temperature exiting the spraydryer chamber is between 80°C and 200°C, more preferably between 100°C and 120°C.

According to a preferred aspect, the feeding rate of the solution to the spray-dryer chamber is between 5% and 50%, preferably between 5% and 15%.

Preferably, the treatment by spray-drying is carried out under inert atmosphere, in particular under nitrogen atmosphere. Preferably, the nitrogen pressure in the spray-dryer chamber is between 2.5 bar and 6.5 bar, more preferably between 3.5 and 5.5 bar.

According to a preferred aspect of the invention, the compound of Formula I used in step a) is obtained according to the following steps: i) dissolving the compound of Formula I in the form of salt in an organic solvent immiscible with water obtaining a solution; ii) adding to the solution of step i) an aqueous solution of an inorganic base; iii) separating the organic phase from the aqueous phase ; iv) concentrating the organic phase obtained in step iii) until obtaining a solid residue of the compound of Formula I.

Preferably, the organic solvent immiscible with water of step i) is a chlorinated solvent, more preferably methylene chloride.

Preferably, the inorganic base of step ii) is selected from: sodium hydroxide (NaOH) , lithium hydroxide (LiOH) and potassium hydroxide (KOH) , or mixtures thereof; preferably, the aqueous solution of the inorganic base has a concentration between 1% and 30%, more preferably between 5% and 15%.

Preferably, the concentration of step iii) is carried out by distillation under vacuum. Preferably, the distillation temperature is gradually increased to 80°C, more preferably is increased from 25°C to 80°C.

The compound of Formula I in the form of salt is preferably in the form of hydrochloride, or in the form of salt with an organic acid, selected from those known in the art. In a preferred embodiment, the organic acid is selected from: ( IS ) - (+ ) -1 O-camphorsulphonic acid (CSA) , trifluoroacetic acid (TFA) and pyroglutamic acid (PGA) .

In more detail, according to a preferred aspect of the invention, the compound of Formula I in the form of salt used in step i) is obtained according to the following steps: 1) reacting a compound of Formula II

Formula II with a base in a solvent to obtain a compound of

Formula III

Formula III, wherein the solvent is selected from an organic solvent, water or a combination thereof;

2) isolating the compound of Formula III at a pH ranging from 2 to 9; 3) reacting the isolated compound of Formula III with a compound of Formula IV

Formula IV in the presence of a coupling agent, a base and a polar aprotic solvent to obtain Pralsetinib in the form of a solution;

4) isolating a crystalline compound containing

Pralsetinib by reacting Pralsetinib in the form of a solution obtained in step c) with an acid selected from: ( IS ) - (+ ) -1 O-camphorsulphonic acid (CSA) , trifluoroacetic acid (TFA) and pyroglutamic acid (PGA) .

With reference to step 1) , the base is preferably selected from: sodium hydroxide (NaOH) , lithium hydroxide (LiOH) and potassium hydroxide (KOH) . The solvent used in step 1) is preferably selected from: alcohols; ethers; water; or mixtures thereof. Preferably, when the solvent is an alcohol, it is selected from: methyl alcohol (MeOH) , ethyl alcohol (EtOH) . Preferably, when the solvent is an ether, it is tetrahydrofuran (THE) . Mixtures of solvent are preferably selected from: THF/water, THF/EtOH/water , EtOH/water and MeOH/water. Preferably, the mixture of solvents is THF/EtOH/water.

According to a preferred aspect, in step 1) the solvent is selected from: alcohols, preferably methyl alcohol (MeOH) or ethyl alcohol (EtOH) ; ethers, preferably tetrahydrofuran (THE) ; and water, or mixtures thereof.

According to a preferred embodiment, the compound of Formula IT is reacted in step 1) with a base at a temperature from 25°C to 70°C, preferably from 50°C to 60°C.

With reference to step 2) , the pH is preferably from 2 to 5. As known by the skilled person, the pH value can be obtained by adding an acid, preferably hydrochloric acid (HC1) .

As regards step 2) , isolation of the compound of Formula ITT is preferably carried out by crystallization or precipitation. Preferably, to that purpose, a solvent selected from alcohols and ketones is added. Preferably, when the solvent is an alcohol, it is selected from MeOH, EtOH, or isopropyl alcohol (IPA) , when the solvent is a ketone, it is preferably acetone. Preferably, the solvent is MeOH.

According to a preferred aspect, in step 2) the isolation is carried out by crystallization or precipitation, by adding a solvent selected from: alcohols, preferably MeOH, EtOH, or isopropyl alcohol (IPA) ; ketones, preferably acetone; or mixtures thereof .

With reference to step 3) , the coupling agent is preferably selected from: benzotriazole-l-yl-oxy-tris- pyrrolidine phosphonium hexafluorophosphate (PyBOP) , N, N, N ' , N ' -tetramet hy 1-0- ( IH-benzotriazole-l-yl ) uronium hexafluorophosphate (HBTU) , 2- ( IH-benzotriazole-l-yl ) - 1 , 1 , 3 , 3-tetramethylaminium tetrafluoroborate (TBTU) , N- ethyl-N'- ( 3-dimethylaminopropyl ) carbodiimide hydrochloride (EDC.HC1) and 1-

[bis (dimethyl amino) methylene] -1H-1, 2, 3-triazolo [4, 5- b] pyridinium 3-oxid hexafluorophosphate (HATU) .

Preferably, the coupling agent is PyBOP.

With reference to the base of step 3) , it is preferably selected from N, N-diisopropylethylamine (DIPEA) or triethylamine (TEA) . Preferably, the base is DIPEA.

With reference to the polar aprotic solvent of step 3) , it is preferably selected from: N,N-dimethyl acetamide (DMAc) , dimethyl sulfoxide (DMSO) , N,N- dimethyl formamide (DMF) or mixtures thereof. Preferably, the polar aprotic solvent is DMAc.

More preferably, the compound of Formula III is reacted with the compound of Formula IV in step 3) by using PyBOP as the coupling agent , DMAc as the polar aprotic solvent and DIPEA as the base .

The crystalline compound containing Pralsetinib o f step 4 ) , which can be used as raw material of the process to obtain the compound of Formula I in amorphous form according to the present invention, can be represented by one of the following formulas :

wherein the compound of Formula V is Pralset inib/CSA salt , the compound of Formula VI is Pralsetinib/TFA salt and the compound of Formula VI I is Pralsetinib/PGA co-crystal . With reference to step 4 ) , the used acid is preferably tri fluoroacetic acid ( TFA) to obtain the crystalline compound containing Pralsetinib of Formula

VI . Preferably, as regards step 4) , when the crystalline compound containing Pralsetinib is of Formula V, the isolation is obtained by adding a solvent selected from alcohols, esters, nitriles, and water, or mixtures thereof. Preferably, when the solvent is an alcohol, it is selected from MeOH and EtOH, more preferably is MeOH. Preferably, when the solvent is a nitrile, it is acetonitrile (AON) . Preferably, when the solvent is an ester, it is ethyl acetate (EtOAc) . Preferably, the mixture of solvents is selected from MeOH/water and ACN/water.

Preferably, when the crystalline compound containing Pralsetinib is of Formula VI, the isolation according to step 4) is obtained by adding a solvent selected from: esters, nitriles, ethers, chlorinated solvents, and water, or mixtures thereof. Preferably, when the solvent is an ester, it is ethyl acetate (EtOAc) . Preferably, when the solvent is a nitrile, it is AON. Preferably, when the solvent is a chlorinated solvent, it is dichloromethane (DOM) . Preferably, when the solvent is an ether, it is methyl-tert-butyl ether (MTBE) . Preferably, the mixture of solvents is EtOAc/MTBE or DCM/MTBE .

Preferably, when the crystalline compound containing Pralsetinib is of Formula VII, the isolation according to step 4) is obtained by adding a solvent selected from: esters, nitriles, chlorinated solvents, and water, or mixtures thereof. Preferably, when the solvent is an ester, it is EtOAc. Preferably, when the solvent is a nitrile, it is AON. Preferably, when the solvent is a chlorinated solvent, it is dichloromethane (DCM) . Preferably, the mixture of solvents is ACN/water .

Preferably, the compounds of Formula V, VI and VII are isolated according to step 4) at a temperature from 25°C to 70°C, more preferably from 25°C to 30°C. List of abbreviations

1. CSA: ( IS ) - (+ ) -1 O-camphorsulphonic acid

2. TFA: Trifluoroacetic acid

3. XRPD: X-Ray Powder Diffraction

4. DSC: Differential Scanning Calorimetry

5. TGA: Thermo Gravimetric Analysis

6. LiOH: Lithium Hydroxide

7. NaOH: Sodium Hydroxide

8. KOH: Potassium Hydroxide

9. MeOH: Methanol

10. EtOH: Ethanol

11. t-BuOH: tert-Butyl alcohol

12. THE: Tetrahydrofuran

13. MTBE : Methyl- tert-butyl ether

14. DCM: Dichloromethane

15. ACN : Acetonitrile

16. PyBOP: Benzotriazole-l-yl-oxy-tris-pyrrolidine phosphonium hexafluorophosphate

17. TEA: Triethylamine

18. DIPEA: N, N-Diisopropylethylamine

19. DMAc : Dimethyl Acetamide

20. EtOAc: Ethyl Acetate

Examples

Example 1: Synthesis of the compound of Formula III (cyclohexanecarboxylic acid, l-metoxy-4- [ 4-methyl- 6- [ ( 5-methyl-lH-pyrazol-3-yl ) amino] -2-pyrimidinyl ] ) .

L1OH.H2O (186.78 g, 4.5 mol) at room temperature was added to a solution of the compound of Formula II (cyclohexanecarboxylic acid, l-metoxy-4- [ 4-methyl- 6- [ ( 5-methyl-lH-pyrazol-3-yl ) amino] -2-pyrimidinyl ] methyl ester) (800.0 g, 2.2 mol) in a mixture of THF/EtOH/JbO (20.0 L) . The reaction mixture was stirred for 16 hours. The end of the reaction was monitored by TLC or HPLC . The solvent was distilled under vacuum and the residue was suspended in a mixture of THF/EtOH (8.0 L) . The product was filtered and the wet cake was suspended in MeOH (8.0 L) . The pH was then adjusted to 5.0 using diluted HC1, the product was filtered and dried in Vacuum Tray Dryer to get pure compound of Formula ITT (cyclohexanecarboxylic acid, l-metoxy-4- [ 4- methyl-6- [ ( 5-methyl-lH-pyrazol-3-yl ) amino] -2- pyrimidinyl) (640 g, yield 83.3%) .

Example 2: Synthesis of the compound of Formula ITT (cyclohexanecarboxylic acid, l-metoxy-4- [ 4-methyl- 6- [ ( 5-methyl-lH-pyrazol-3-yl ) amino] -2-pyrimidinyl] ) .

L1OH.H2O (1.17 g, 0.03 mol) was added to a solution of the compound of Formula IT (cyclohexanecarboxylic acid, l-metoxy-4- [ 4-methyl- 6- [ ( 5-methyl-lH-pyrazol-3-yl ) amino] -2-pyrimidinyl] -, methyl ester) (5.0 g, 0.01 mol) in a mixture of THF/H2O (67.5 mL) . The reaction mixture was heated to 50-60°C for 12 hours. The end of the reaction was monitored by HPLC. The solvent was distilled under vacuum, the residue was suspended in MeOH (50 mL) and the pH was adjusted to 5.0. The product was filtered and dried in Vacuum Tray Dryer to get pure compound of Formula ITT (cyclohexanecarboxylic acid, l-metoxy-4- [ 4-methyl- 6- [ ( 5-methyl-lH-pyrazol-3-yl ) amino] -2-pyrimidinyl] ) (4.3 g, yield 90.0%) . Example 3: Synthesis of the compound of Formula ITT (cyclohexanecarboxylic acid, l-metoxy-4- [ 4-methyl- 6- [ ( 5-methyl-lH-pyrazol-3-yl ) amino] -2-pyrimidinyl] ) .

NaOH (1.11 g, 0.03 mol) was added to a solution of the compound of Formula II (cyclohexanecarboxylic acid, l-metoxy-4- [4-methyl-6- [ ( 5-methyl-lH-pyrazol-3- yl ) amino ] -2-pyrimidinyl ]- , methyl ester) (5.0 g, 0.01 mol) in a mixture of THF/H2O (67.5 mL) . The reaction mixture was heated to 50-60°C for 12 hours. The end of the reaction was monitored by HPLC. The solvent was distilled under vacuum, the residue was suspended in MeOH (50 mL) and the pH was adjusted to 5.0. The product was filtered and dried in Vacuum Tray Dryer to get pure compound of Formula III (cyclohexanecarboxylic acid, l-metoxy-4- [4-methyl-6- [ (5-methyl-lH-pyrazol-3- yl ) amino ] -2-pyrimidinyl ] ) (4.5 g, yield 93.75 %) . Example 4: Synthesis of Pralsetinib/CSA salt of Formula V.

DIPEA (20.17 mL, 115 mmol) and the compound of Formula IV ( ( S ) -1- ( 6- ( 4-f luoro-lH-pyrazol-l-yl ) pyridin- 3-yl ) ethanamine hydrochloride) (4.85 g, 17.37 mmol) were added to a suspension of the compound of Formula III (cyclohexanecarboxylic acid, l-metoxy-4- [ 4-methyl- 6- [ ( 5-methyl-lH-pyrazol-3-yl ) amino] -2-pyrimidinyl] ) (5 g, 14.47 mmol) in DMAc (100 mL) . The suspension was stirred for 30 minutes, then PyBOP (11.30 g, 21.71 mmol) was added. The reaction mixture was stirred for 2 hours, then PyBOP (1.51 g, 2.89 mmol) was added and the stirring was maintained for 1 hour. PyBOP (1.51 g, 2.89 mmol) was added again and the stirring was maintained for another hour. The end of the reaction was monitored by HPLC. The reaction mixture was diluted with H2O (200 mL) and the product was extracted with EtOAc (200 mL) . The organic layer was washed with 9.0% aqueous NaHCCh followed by a 15% NaCl solution. The organic phase was distilled to get oily residue to which MeOH (40 mL) and H2O (10 mL) and CSA (2.7 g, 11.58 mmol) were added. The reaction mixture was stirred for 24 hours and the solvent was distilled. Then, an ACN/H2O mixture (150 ml) was added to the residue and the stirring was maintained for 18 hours obtaining a suspension. Finally, the product was filtered obtaining the Pralsetinib/CSA salt compound (Formula V) with yield >90.0% and purity >95%. The XPRD pattern is shown in table 1.

Example 5: Synthesis of Pralsetinib/TFA salt of Formula VI .

DIPEA (20.17 mL, 115 mmol) and the compound of Formula IV (S) -1- ( 6- ( 4-f luoro-lH-pyrazol-l-yl ) pyridin- 3-yl ) ethanamine hydrochloride) (4.85 g, 17.37 mmol) were added to a suspension of the compound of Formula III (cyclohexanecarboxylic acid, l-metoxy-4- [ 4-methyl- 6- [ ( 5-methyl-lH-pyrazol-3-yl ) amino] -2-pyrimidinyl ] ) (5.0 g, 14.47 mmol) in DMAc (100 mL) . The suspension was stirred for 30 minutes, then PyBOP (11.30 g, 21.71 mmol) was added. The reaction mixture was stirred for 2 hours and the end of the reaction was monitored by HPLC . The reaction mixture was diluted with H2O (200 mL) and the product was extracted with EtOAc (200 mL) . The organic layer was washed with 9.0% aqueous NaHCCL followed by a 15.0% NaCl solution. The organic layer was distilled to get an oily residue to which EtOAc (50 mL) was added and the stirring was maintained to get clear solution. TEA (2.14 g, 18.79 mmol) was added to the solution and the stirring was maintained for 3 hours, during this time the precipitation of the product was observed. Then, MTBE (50 mL) was added and the suspension was further stirred for 2-3 hours. The product was filtered and dried to get Pralsetinib/TFA salt (Formula VI) with yield >90.0% and HPLC purity >96.00%. XPRD pattern is shown in Table 2.

Example 6: Synthesis of Pralsetinib/TFA salt of Formula VI .

DIPEA (20.17 mL, 115 mmol) and the compound of Formula IV (S) -1- ( 6- ( 4-f luoro-lH-pyrazol-l-yl ) pyridin- 3-yl ) ethanamine hydrochloride (4.85 g, 17.37 mmol) were added to a suspension of the compound of Formula III (cyclohexanecarboxylic acid, l-metoxy-4- [ 4-methyl- 6- [ ( 5-methyl-lH-pyrazol-3-yl ) amino] -2-pyrimidinyl ] ) (5.0 g, 14.47 mmol) in DMAc (100 mL) . The suspension was stirred for 30 minutes, then PyBOP (11.30 g, 21.71 mmol) was added. The reaction mixture was stirred for 2 hours and the end of the reaction was monitored by HPLC. The reaction mixture was diluted with H2O (200 mL) and the product was extracted with EtOAc (200 mL) . The organic layer was washed with 9.0% NaHCO3 and with a 15.0% NaCl solution. The organic layer was distilled to get an oily residue, DCM (25 mL) was then added and was distilled again to oily residue. DCM (100 mL) was therefore added and the stirring was maintained to get clear solution. TFA (2.14 g, 18.79 mmol) was added to the solution, the stirring was maintained for 3 hours obtaining the precipitation of the product. Therefore, MTBE (100 mL) was added to the suspension, the stirring was maintained for further 3 hours. The product was filtered and dried to get Pralsetinib/TFA salt (Formula VI) with yield >90.0% and HPLC purity >98.00%. Example 7: Synthesis of Pralsetinib/PGA co-crystal of Formula VI I .

DIPEA (8.0 mL, 46.32 mmol) and the compound of Formula IV (S) -1- ( 6- ( -f luoro-lH-pyrazol-l-yl ) pyridin- 3-yl ) ethanamine hydrochloride) (1.97 g, 8.10 mmol) were added to a suspension of the compound of Formula III (cyclohexanecarboxylic acid, l-metoxy-4- [ 4-methyl- 6- [ ( 5-methyl-lH-pyrazol-3-yl ) amino] -2-pyrimidinyl ] ) (2.0 g, 5.79 mmol) in DMAc (40 mL) . The suspension was stirred for 30 minutes and PyBOP (4.52 g, 8.68 mmol) was added. The reaction mixture was stirred for 2 hours and the end of the reaction was monitored by HPLC . The reaction mixture was diluted with H2O (80 mL) and the product extracted with ethyl acetate (80 mL) . The organic layer was washed with 9.0% aqueous NaHCCh followed by 15.0% NaCl solution. The organic layer was distilled to get an oily residue to which EtOAc (20 mL) was added and the stirring was maintained to get clear solution. Pyroglutamic acid (0.97 g, 7.5 mmol) was added and the reaction mixture was stirred for 12 hours. The product was filtered and dried to get Pralsetinib/PGA co-crystal (Formula VII) with yield >90.0% and HPLC purity >96.0%. XPRD pattern is shown in Table 3.

Example 8: Preparation of Pralsetinib in amorphous form from Pralsetinib/CSA salt (Formula V) .

Pralsetinib/CSA salt 5.0 gr (Formula V) was dissolved in 50 ml of DCM. The obtained solution was washed with 10% aqueous NaOH solution (50 ml) . The aqueous phase was separated and sent to disposal. The organic phase was distilled under vacuum gradually increasing the temperature in a range between 25 and 80°C to get foamy solid residue which was dissolved in 35 ml of DCM and 15 ml of EtOH were added. The solution was filtered to remove possible suspended particles and the solvent was distilled under vacuum gradually increasing the temperature in a range between 25 and 80°C to remove the solvents completely. The residue was cooled to 25-30°C and 50 ml of cyclohexane were added to obtain a suspension of the compound of Formula I, the stirring was maintained for 2 hours. The product was filtered and dried under vacuum at the temperature of 70°C for 24 hours to obtain the compound of Formula I in amorphous form with molar yield of 95%.

Example 9: Preparation of Pralsetinib in amorphous form from Pralsetinib/TFA salt (Formula VI) .

Pralsetinib/TFA salt (Formula VI) (5.0 g, 7.73 mmol) was dissolved in DCM (50 ml) . The obtained solution was washed with 10% aqueous NaOH solution (50 ml) . The aqueous phase was separated and sent to disposal. The solvent of the organic phase was distilled under vacuum gradually increasing the temperature in a range between 25 and 80°C to get foamy and amorphous solid residue which was dissolved in 35 ml of DCM and 15 ml of EtOH were added. The solution was filtered to remove possible suspended particles and distilled under vacuum gradually increasing the temperature in a range between 25 and 80°C to remove the solvents completely. The residue was cooled to 25- 30°C and 50 ml of cyclohexane were added to obtain a suspension of the compound of Formula I, the stirring was maintained for 2 hours. The product was filtered and dried under vacuum at the temperature of 70 °C for 24 hours to obtain the compound of Formula I in amorphous form with molar yield of 96%.

Example 10: Preparation of Pralsetinib in amorphous form from Pralsetinib/PGA co-crystal (Formula VII) .

Pralsetinib/PGA co-crystal (5.0 g, Formula VII) was dissolved in 50 ml of DCM. The obtained solution was washed with 50 ml of 10% aqueous NaOH solution. The aqueous phase was separated and sent to disposal. The solvent of the organic phase was distilled under vacuum gradually increasing the temperature in a range between 25 and 80°C to get foamy and amorphous solid residue which was dissolved in 35 ml of DCM and 15 ml of EtOH were added. The solution was filtered to remove possible suspended particles and distilled under vacuum gradually increasing the temperature in a range between 25 and 80°C to remove the solvents completely. The residue was cooled to 25-30°C and 50 ml of cyclohexane were added to obtain a suspension of the compound of Formula I, the stirring was maintained for 2 hours. The product was filtered and dried under vacuum at the temperature of 70 °C for 24 hours to obtain the compound of Formula I in amorphous form with molar yield of 93%. Example 11: Preparation of Pralsetinib in amorphous form from the crystalline form A of Pralsetinib (free base) .

The compound of Formula I of crystalline form A (5.0 g) was dissolved in 35 ml of DCM and 15 ml of EtOH were added. The solution was filtered to remove possible suspended particles and distilled under vacuum gradually increasing the temperature in a range between 25 and 80°C to remove the solvents completely. The residue was cooled to 25-30°C and 50 ml of cyclohexane were added to obtain a suspension of the compound of Formula I , the stirring was maintained for 2 hours . The product was filtered and dried under vacuum at the temperature of 70 ° C for 24 hours to obtain the compound of Formula I in amorphous form with molar yield of 96% . Example 12 : Preparation of Pralsetinib in amorphous form from the compound of Formula I in the form of hydrochloride .

The compound of Formula I in the form of hydrochloride ( 5 . 0 g) was di ssolved in 50 ml of DCM . The obtained solution was washed with 10% aqueous NaOH solution ( 50 ml ) . The aqueous phase was separated and sent to disposal . The solvent of the organic phase was distilled under vacuum gradually increasing the temperature in a range between 25 and 80 ° C to get foamy and amorphous solid residue which was dissolved in 35 ml of DCM and 15 ml of EtOH were added . The solution was filtered to remove possible suspended particles and distilled under vacuum gradually increasing the temperature in a range between 25 and 80 ° C to remove the solvents completely . The residue was cooled to 25- 30 ° C and 50 ml of cyclohexane were added to obtain a suspension of the compound of Formula I , the stirring was maintained for 2 hours . The product was filtered and dried under vacuum at the temperature of 70 ° C for 24 hours to obtain the compound of Formula I in amorphous form with molar yield of 96% .

Claims

1. A process for preparing a compound of Formula I

Formula I, in amorphous form, said process comprising: a) preparing a solution of the compound of Formula I in a mixture of organic solvents comprising a polar aprotic solvent and a polar protic solvent; b) treating the solution of the compound of Formula I obtained in step a) so as to remove the mixture of solvents and obtain a solid residue of the compound of Formula I; c) adding an apolar organic solvent to the solid residue obtained in step b) to obtain a suspension of the compound of Formula I; d) isolating the compound of Formula I from the suspension obtained in step c) to obtain the compound of Formula I in amorphous form.

2. Process according to claim 1, wherein the compound of Formula I used in step a) is in crystalline form.

3. Process according to any one of the previous claims, wherein in step a) the aprotic polar solvent is a chlorinated solvent, preferably methylene chloride.

4. Process according to any one of the previous claims, wherein in step a) the polar protic solvent is an alcohol with general formula R-OH, where R is a linear or branched Ci-Cg alkyl, preferably linear; preferably the alcohol is ethanol.

5. Process according to any one of the previous claims, wherein in step a) the ratio of the volume of the polar protic solvent and the volume of the polar aprotic solvent (v/v) is between 0.5/99.5 v/v and 80/20 v/v, preferably between 5/95 v/v and 70/30 v/v, more preferably between 10/90 v/v and 50/50 v/v.

6. Process according to any one of the previous claims, wherein in step a) the ratio of the volume of the mixture of organic solvents and the weight of the compound of Formula I is between 2 and 20 v/w, preferably between 5 and 15 v/w, more preferably between 8 and 12 v/w.

7. Process according to any one of the previous claims, wherein in step b) the solution of the compound of Formula I obtained in step a) is treated by distillation or by spray-drying.

8. Process according to claim 7, wherein in step b) the solution of the compound of Formula I obtained in step a) is treated by distillation, preferably distillation under vacuum, with a distillation temperature not higher than 100°C, preferably not higher than 90°C.

9. Process according to claim 8, wherein the distillation temperature is gradually increased to 80°C, more preferably from 25°C to 80°C.

10. Process according to any one of the previous claims, wherein in step c) the apolar organic solvent is selected from: alkanes, preferably hexane or heptane; cycloalkanes, preferably cyclohexane; ethers, preferably methyl-tert-butyl ether (MTBE) ; or mixtures thereof .

11. Process according to any one of the previous claims, wherein in step c) the suspension of the compound of Formula I is maintained under stirring for a time between 0.5 hours and 24 hours, preferably between 1 hour and 18 hours.

12. Process according to any one of the previous claims, wherein in step d) the compound of Formula I is isolated by filtering.

13. Process according to any one of the previous claims, wherein the compound of Formula I used in step a) is obtained according to the following steps: i) dissolving the compound of Formula I in the form of salt in an organic solvent immiscible with water obtaining a solution; ii) adding to the solution of step i) an aqueous solution of an inorganic base; iii) separating the organic phase from the aqueous phase ; iv) concentrating the organic phase obtained in step iii) to get a solid residue of the compound of Formula I .

14. Process according to claim 13, wherein the compound of Formula I in the form of salt is in the form of hydrochloride, or in the form of salt with an organic acid.

15. Process according to claim 14, wherein the organic acid is selected from: (IS) — ( + ) — 10 — camphorsulphonic acid (CSA) , trifluoroacetic acid (TFA) and pyroglutamic acid (PGA) .