Adagrasib oxalate of crystalline form a and process for its preparation

Abstract

The present invention relates to Adagrasib Oxalate of Formula I la in Crystalline Form A: (IIa) The present invention further relates to a process for the preparation of Adagrasib dicarboxylate salt in Crystalline Form, in particular a process for the preparation of Adagrasib Oxalate in Crystalline Form A.

Description

[0001] ADAGRASIB OXALATE OF CRYSTALLINE FORM A AND PROCESS FOR ITS PREPARATION

[0002] FIELD OF APPLICATION

[0003] The present invention refers to the technical field of pharmaceutical active ingredients . Specifically, the present invention relates to a new crystalline form of Adagrasib Oxalate, in particular Adagrasib oxalate in crystalline Form A. The present invention further relates to a process for the preparation of Adagrasib dicarboxylate salt in crystalline Form, in particular a process for the preparation of Adagrasib oxalate in crystalline Form A.

[0004] BACKGROUND

[0005] Adagrasib is a pharmaceutical active ingredient of Formula I :

[0006]

[0007] Formula I Adagrasib is a covalent and highly selective inhibitor of KRAS (Kirsten rat sarcoma viral oncogene homolog) , which has been recently approved as a monotherapy drug and is currently under evaluation for combination therapy in patients with advanced-stage KRAS mutation solid tumours .

[0008] In particular, Adagrasib was first described by Mirati Therapeutics as MRTX849, and its synthesis is described in US10689377, US10647715, W0202303920, and WO202325074 .

[0009] However, Adagrasib base of Formula I is practically insoluble in water, effectively making the intravenous administration impossible .

[0010] Currently, to the best of our knowledge, pharmaceutically acceptable salts of Adagrasib, which could provide improved solubility to the product, have not been widely explored in the prior art .

[0011] Only a few pharmaceutically acceptable salts of Adagrasib are reported in patent application CN115521312A, in particular, salts with fumaric acid, maleic acid, tartaric acid, and citric acid have been described in detail . However, these salts have several drawbacks, including a low melting point or being eutectic salts . The procedure for the preparation of these salts is not reproducible and therefore cannot be used industrially. The salts further have a poorly crystalline solid form, which is difficult to filter, thus making it hard to remove impurities . Therefore, these salts have a low purity.

[0012] The Applicant has therefore addressed the problem of finding a pharmacologically acceptable salt of the compound of Formula I in a crystalline form that can be readily prepared at an industrial scale and that allows to overcome the drawbacks of the prior art, particularly in terms of stability, solubility, and purity of the final product .

[0013] SUMMARY OF THE INVENTION

[0014] The Applicant has now found a new crystalline form of Adagrasib oxalate, in particular Adagrasib oxalate of Formula Ila in crystalline Form A, which meets the above-mentioned needs .

[0015] Therefore, in accordance with a first aspect, the present invention relates to Adagrasib oxalate of Formula Ila in crystalline Form A

[0016]

[0017] Formula I la

[0018] having a characteristic X-ray powder di f f ractogram (XRPD) comprising at least two characteristic peaks expressed as 2-Theta ( 20 ) values selected from 10 . 67 ° ± 0 . 2 ° , 11 . 43 ° ± 0 . 2 ° , 13 . 67 ° ± 0 . 2 ° , 14 . 14 ° ± 0 . 2 ° , 15 . 58 ° ± 0 . 2 ° , 16 . 73 ° ± 0 . 2 ° , 16 . 99 ° ± 0 . 2 ° , 17 . 22 ° ± 0 . 2 ° , 17 . 97 ° ± 0 . 2 ° , 17 . 97 ° ± 0 . 2 ° , 18 . 20 ° ± 0 . 2 ° , 20 . 28 ° ± 0 . 2 ° , 20 . 89 ° ± 0 . 2 ° , 21 . 08 ° ± 0 . 2 ° , 21 . 64 ° ± 0 . 2 ° , 22 . 01 ° ± 0 . 2 ° , 23 . 29 ° ± 0 . 2 ° , 23 . 94 ° ± 0 . 2 ° .

[0019] Advantageously, crystalline Form A of Adagrasib oxalate of Formula I la is characteri zed by high purity and stability, as well as high solubility, particularly in water .

[0020] In accordance with a second aspect , the present invention relates to a process for obtaining Adagrasib dicarboxylate salt of Formula I I in crystalline Form,

[0021]

[0022] said process comprising the steps of :

[0023] a) dissolving Adagrasib base of Formula I

[0024]

[0025] Formula I

[0026] in a solvent;

[0027] b) adding a dicarboxylic acid of formula HOOC- (CH2)n_COOH, wherein n is comprised between 0 and 6, to obtain a solution of Adagrasib base of Formula I and dicarboxylic acid;

[0028] c) heating the solution obtained in step b) to obtain a suspension of Adagrasib dicarboxylate salt of Formula II in crystalline Form;

[0029] d) cooling the suspension of Adagrasib dicarboxylate salt of Formula II in crystalline Form obtained in step c) ;

[0030] e) isolating Adagrasib dicarboxylate salt of Formula II in crystalline Form.

[0031] In particular, said process allows to obtain Adagrasib oxalate (n=0) of Formula Ila in crystalline Form A, and allows an advantageous control of the impurity profile on the final product .

[0032] Furthermore, advantageously, the process of the invention is adapted to be implemented on an industrial scale .

[0033] Further aspects, features, and advantages of the invention will become apparent from the following detailed description.

[0034] BRIEF DESCRIPTION OF THE FIGURES

[0035] Figure 1 . X-ray diffraction spectrum (XRPD) of the compound of Formula Ila in Form B .

[0036] Figure 2 . Differential scanning calorimetry (DSC) of the compound of Formula Ila in Form B .

[0037] Figure 3. Thermogravimetric analysis (TGA) of the compound of Formula Ila in Form B .

[0038] Figure 4 . Hydrogen nuclear magnetic resonance (1H-NMR) spectrum of the compound of Formula Ila in Form B . Figure 5. X-ray diffraction spectrum (XRPD) of the compound of Formula Ila in Form A.

[0039] Figure 6. Differential scanning calorimetry (DSC) of the compound of Formula Ila in Form A.

[0040] Figure 7 . Thermogravimetric analysis (TGA) of the compound of Formula Ila in Form A.

[0041] Figure 8 . Hydrogen nuclear magnetic resonance (1H-NMR) spectrum of the compound of Formula Ila in Form A.

[0042] DETAILED DESCRIPTION OF THE INVENTION

[0043] For the purposes of the present invention, in the following description and claims, numerical range definitions comprise the single values within the range itself and the corresponding endpoints, unless otherwise specified.

[0044] For the purposes of the present invention, in the following description and claims, the term "comprising" further includes the terms "consisting of" or "consisting essentially of" .

[0045] A first aspect of the invention therefore relates to Adagrasib oxalate of Formula Ila in crystalline Form A:

[0046]

[0047] Formula I la having a characteristic XRPD di f f ractogram comprising at least two characteristic peaks expressed as 2-Theta ( 20 ) values selected from 10 . 67 ° ± 0 . 2 ° , 11 . 43 ° ± 0 . 2 ° , 13 . 67 ° ± 0 . 2 ° , 14 . 14 ° ± 0 . 2 ° , 15 . 58 ° ± 0 . 2 ° , 16 . 73 ° ± 0 . 2 ° , 16 . 99 ° ± 0 . 2 ° , 17 . 22 ° ± 0 . 2 ° , 17 . 97 ° ± 0 . 2 ° , 17 . 97 ° ± 0 . 2 ° , 18 . 20 ° ± 0 . 2 ° , 20 . 28 ° ± 0 . 2 ° , 20 . 89 ° ± 0 . 2 ° , 21 . 08 ° ± 0 . 2 ° , 21 . 64 ° ± 0 . 2 ° , 22 . 01 ° ± 0 . 2 ° , 23 . 29 ° ± 0 . 2 ° , 23 . 94 ° ± 0 . 2 ° .

[0048] Preferably, Adagrasib oxalate of Formula I la in crystalline Form A has a characteristic XRPD di f f ractogram comprising at least three characteristic peaks expressed as 2-Theta ( 20 ) values selected from 10 . 67 ° ± 0 . 2 ° , 11 . 43 ° ± 0 . 2 ° , 13 . 67 ° ± 0 . 2 ° , 14 . 14 ° ± 0 . 2 ° , 15 . 58 ° ± 0 . 2 ° , 16 . 73 ° ± 0 . 2 ° , 16 . 99 ° ± 0 . 2 ° , 17 . 22 ° ± 0 . 2 ° , 17 . 97 ° ± 0 . 2 ° , 17 . 97 ° ± 0 . 2 ° , 18 . 20 ° ± 0 . 2 ° , 20 . 28 ° ± 0 . 2 ° , 20 . 89 ° ± 0 . 2 ° , 21 . 08 ° ± 0 . 2 ° , 21 . 64 ° ± 0 . 2 ° , 22 . 01 ° ± 0 . 2 ° , 23 . 29 ° ± 0 . 2 ° , 23 . 94 ° ± 0 . 2 Preferably, Adagrasib oxalate of Formula I la in crystalline Form A has a characteristic XRPD di f f ractogram comprising at least four characteristic peaks expressed as 2-Theta ( 20 ) values selected from 10 . 67 ° ± 0 . 2 ° , 11 . 43 ° ± 0 . 2 ° , 13 . 67 ° ± 0 . 2 ° , 14 . 14 ° ± 0 . 2 ° , 15 . 58 ° ± 0 . 2 ° , 16 . 73 ° ± 0 . 2 ° , 16 . 99 ° ± 0 . 2 ° , 17 . 22 ° ± 0 . 2 ° , 17 . 97 ° ± 0 . 2 ° , 17 . 97 ° ± 0 . 2 ° , 18 . 20 ° ± 0 . 2 ° , 20 . 28 ° ± 0 . 2 ° , 20 . 89 ° ± 0 . 2 ° , 21 . 08 ° ± 0 . 2 ° , 21 . 64 ° ± 0 . 2 ° , 22 . 01 ° ± 0 . 2 ° , 23 . 29 ° ± 0 . 2 ° , 23 . 94 ° ± 0 . 2 ° .

[0049] According to a preferred aspect , Adagrasib oxalate of Formula I la in crystalline Form A has a characteristic XRPD di f f ractogram comprising the following characteristic peaks , expressed as 2 -Theta ( 20 ) values : 10 . 67 ° ± 0 . 2 ° , 11 . 43 ° ± 0 . 2 ° , 13 . 67 ° ± 0 . 2 ° , 14 . 14 ° ± 0 . 2 ° , 15 . 58 ° ± 0 . 2 ° , 16 . 73 ° ± 0 . 2 ° , 16 . 99 ° ± 0 . 2 ° , 17 . 22 ° ± 0 . 2 ° , 17 . 97 ° ± 0 . 2 ° , 17 . 97 ° ± 0 . 2 ° , 18 . 20 ° ± 0 . 2 ° , 20 . 28 ° ± 0 . 2 ° , 20 . 89 ° ± 0 . 2 ° , 21 . 08 ° ± 0 . 2 ° , 21 . 64 ° ± 0 . 2 ° , 22 . 01 ° ± 0 . 2 ° , 23 . 29 ° ± 0 . 2 ° , 23 . 94 ° ± 0 . 2 ° .

[0050] According to a preferred aspect , Adagrasib oxalate of Formula I la in crystalline Form A has a molar ratio between the compound of Formula I and oxalic acid of 1 : 1 . Preferably, Adagrasib oxalate of Formula Ila in crystalline Form A has characteristic endothermic peaks at 175. 9°C and 190.99°C in the differential scanning calorimetry (DSC) analysis (Figure 6) .

[0051] A second aspect of the invention relates to a process for obtaining Adagrasib dicarboxylate salt of Formula II in crystalline form

[0052]

[0053] Formula II,

[0054] said process comprising the steps of :

[0055] a) dissolving Adagrasib base of Formula I in a solvent ;

[0056] b) adding a dicarboxylic acid of formula HOOC- (CH2)n_COOH, wherein n is comprised between 0 and 6, to obtain a solution of Adagrasib base of Formula I and dicarboxylic acid;

[0057] c) heating the solution obtained in step b) to obtain a suspension of Adagrasib dicarboxylate salt of Formula II in crystalline form; d) cooling the suspension of Adagrasib dicarboxylate salt of Formula II in crystalline form obtained in step c) ;

[0058] e) isolating Adagrasib dicarboxylate salt of Formula II in crystalline form.

[0059] With reference to step a) of the process according to the invention, such step refers to the preparation of a solution of Adagrasib base of Formula I .

[0060] According to a preferred aspect, in step a) , Adagrasib base of Formula I is selected from any amorphous or crystalline form. Adagrasib base of Formula I can be prepared as known in the art, for example as described in US10689377, US10647715, W0202303920, and WO202325074 .

[0061] Preferably, in step a) , the solvent is selected from alcohols, more preferably methanol, ethanol, propanol, butanol, isopropanol ; esters, more preferably ethyl acetate; ethers, preferably methyl tert-butyl ether (MTBE) , 2-methyl tetrahydrofuran, tetrahydrofuran (THF) ; water, or mixtures thereof .

[0062] Preferably, in step a) , the ratio of the solvent and the compound of Formula I, calculated as volume to weight (v / w) , is comprised between 2 and 20 / vi, more preferably between 3 and 15 v / w.

[0063] Preferably, step a) is carried out at a temperature comprised between 5°C and 30°C, preferably between 15°C and 28 °C .

[0064] With reference to step b) of the process according to the invention, such step refers to the addition of a dicarboxylic acid to the solution obtained in step a) .

[0065] According to a preferred aspect of the invention, the dicarboxylic acid of formula H00C- (CH2)n_C00H used in step b) has a number n comprised between 0 and 4, more preferably n=0.

[0066] According to a further preferred aspect of the invention, the dicarboxylic acid in step b) is oxalic acid, with n=0.

[0067] Preferably, in step b) , when the dicarboxylic acid is oxalic acid (n=0) , it is selected from anhydrous oxalic acid, oxalic acid monohydrate, oxalic acid dihydrate, or mixtures thereof .

[0068] In step b) , the molar ratio between the dicarboxylic acid and the compound of Formula I is preferably comprised between 0.5 and 2.0, preferably between 0.8 and 1.5.

[0069] According to a preferred aspect of the invention, in step b) , the dicarboxylic acid is added either in solid form or dissolved in a solvent selected from alcohols, preferably methanol, ethanol, propanol, butanol, isopropanol, esters, preferably ethyl acetate, ethers, preferably methyl tert-butyl ether (MTBE) , 2-methyl tetrahydrofuran, tetrahydrofuran (THE) , water, or mixtures thereof . The ratio of the solvent and the dicarboxylic acid, calculated as volume to weight (v / w) , is preferably comprised between 2 and 20 v / w, more preferably between 3 and 15 v / w.

[0070] With reference to step c) of the process according to the invention, such step refers to the heating of the solution obtained in step b) to obtain a suspension of Adagrasib dicarboxylate salt of Formula II in crystalline form.

[0071] According to a preferred aspect of the invention, step c) is carried out at a temperature comprised between 30°C and 80°C, preferably between 40°C and 70°C .

[0072] Preferably, step c) is carried out under stirring, more preferably stirring is maintained for at least 30 minutes .

[0073] Step c) of the present invention allows, by heating, to obtain Adagrasib dicarboxylate salt of Formula II in crystalline form, which precipitates into the reaction environment .

[0074] The Adagrasib salts thus obtained have an excellent filterability, and the impurities contained in the suspension are easily removed during product filtration .

[0075] When the dicarboxylic acid used is oxalic acid (n=0) , the heating provided in step c) of the present invention is essential to obtain Adagrasib oxalate of Formula Ila in crystalline Form A, which precipitates from the reaction environment . Form A thus obtained is easily filterable and efficiently removes both solvent and impurities; for this reason, the final product has high crystallinity and purity, and is suitable, in accordance with ICH guidelines, to be used in pharmaceutical formulations . Furthermore, crystalline Form A, which is the subj ect of the present invention, has high stability under standard storage temperature and humidity conditions .

[0076] In Example 1, it was experimentally demonstrated that if the reaction between Adagrasib base of Formula I and oxalic acid is carried out following the process described in CN115521312A, therefore at a temperature below 30°C, i . e . , if step c) of the process of the invention is carried out at a temperature lower than 30°C, Adagrasib oxalate in crystalline Form B is obtained. Said Crystalline Form B is characterized by endothermic peaks at 119.47 °C and 184. 67 °C in the differential scanning calorimetry (DSC) analysis (Figure 2 ) , and by an X-ray diffraction spectrum (XRPD) that comprises characteristic peaks expressed as 2-Theta (20) values at 6.8 °±0.2 ° , 8.5°±0.2 ° , 10.23°±0.2 ° , 12.89°±0.2 ° , 16.45°±0.2 ° , 17.06°±0.2 ° (Figure 1 ) . Form B of Adagrasib oxalate of Formula Ila is metastable under standard ambient temperature and humidity conditions and can be readily transformed into Form A, as reported in Example 5.

[0077] With reference to step d) of the process according to the invention, said step refers to the cooling of the suspension of Adagrasib dicarboxylate salt of Formula II in crystalline Form.

[0078] Step d) is carried out at a temperature preferably comprised between 0°C and 30°C, more preferably between 15 °C and 28 °C .

[0079] Preferably, step d) is carried out under stirring, more preferably stirring is maintained for at least 30 minutes . With reference to step e) of the process according to the invention, such step refers to the isolation of Adagrasib dicarboxylate salt of Formula II in crystalline Form.

[0080] According to a preferred aspect of the invention, in step e) , the isolation of Adagrasib dicarboxylate salt of Formula II in crystalline Form is obtained through a process comprising the following steps :

[0081] e' ) filtering the suspended solid;

[0082] e' ' ) drying Adagrasib dicarboxylate salt of Formula II in crystalline Form obtained in step e' ) .

[0083] Preferably, in step e ' ) , the solid is filtered under vacuum.

[0084] Preferably, in step e ' ' ) , Adagrasib dicarboxylate salt of Formula II in crystalline Form is dried under vacuum.

[0085] In step e ' ' ) , Adagrasib dicarboxylate salt of Formula II in crystalline Form is preferably dried at a temperature of 30°-60°C, more preferably 40°-50°C .

[0086] Preferably, in step e ' ' ) , Adagrasib dicarboxylate salt of Formula II in crystalline Form is dried for at least 5 hours .

[0087] According to a preferred aspect of the invention, in step e ' ' ) , Adagrasib dicarboxylate salt of Formula II in crystalline Form is dried under vacuum at a temperature of 30°-60°C for at least 5 hours .

[0088] According to a preferred aspect of the invention, step e) can be followed by a step f ) of purifying Adagrasib dicarboxylate salt of Formula II in crystalline Form.

[0089] Preferably, in step f ) , Adagrasib dicarboxylate salt of Formula Ila in crystalline Form is suspended in a polar solvent, more preferably the solvent is selected from alcohols, water, or mixtures thereof . The suspension is preferably heated to a temperature above 40°C to obtain a solution; subsequently, the temperature of the solution is lowered to obtain the precipitation of Adagrasib dicarboxylate salt of Formula II in crystalline Form. According to a preferred aspect of the invention, the suspended solid is isolated by filtration. Preferably, the wet product is dried. Drying is preferably carried out under vacuum. The drying temperature is preferably comprised between 30°C and 60°C, more preferably between 40°C and 50°C . The drying time is preferably comprised between 5 and 48 hours, more preferably between 10 and 24 hours . According to a preferred aspect of the invention, the process according to the invention is to obtain Adagrasib oxalate of Formula Ila in crystalline Form A

[0090]

[0091] Formula Ila,

[0092] said process comprising the steps of :

[0093] a) dissolving Adagrasib base of Formula I in a solvent ;

[0094] b) adding oxalic acid to obtain a solution of Adagrasib base of Formula I and oxalic acid;

[0095] c) heating the solution obtained in step b) to obtain a suspension of Adagrasib oxalate of Formula Ila in crystalline form A;

[0096] d) cooling the suspension of Adagrasib oxalate of Formula Ila in crystalline Form A obtained in step c) ;

[0097] e) isolating Adagrasib oxalate of Formula Ila in crystalline Form A.

[0098] LIST OF ABBREVIATIONS MTBE : methyl tert-butyl ether

[0099] DMSO: dimethyl sulfoxide

[0100] MHz : megahertz

[0101] 1H-NMR: hydrogen nuclear magnetic resonance spectroscopy

[0102] s : singlet

[0103] d: doublet

[0104] t : triplet

[0105] m: multiplet

[0106] td: overlapping triplet and doublet

[0107] dd: doublet of doublets

[0108] EXAMPLES

[0109] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.

[0110] Example 1. Preparation of Adagrasib Oxalate of Formula Ila in Crystalline Form B (comparative example) .

[0111] Adagrasib Oxalate of Formula Ila was prepared following the procedure described in CN115521312A. 1.0 g of the compound of Formula I was dissolved in 10 mL of ethanol and stirring was maintained at 25°C until dissolution. 0.18 g of oxalic acid were added to the solution, and stirring was maintained for additional 2 hours . During this time, precipitation of the product was observed. The solid was filtered, and the panel was washed with 20 mL of MTBE . The wet product was dried at 30°C under vacuum for 16 hours, obtaining Adagrasib Oxalate of Formula Ila in crystalline Form B with a yield of 90% .

[0112] Characterization of Adagrasib Oxalate of Formula Ila in crystalline Form B :1H-NMR (500 MHz, DMSO) : 7.93 (d, 1H) , 7.75 (q, 1H) , 7.56 (td, 2H) , 7.45 (t, 1H) , 7.35 (dd, 1H) , 5.40 (dd, 1H) , 5.28 (d, 1H) , 4.75 (d, 2H) , 4.45 (m, 3H) 4.08 (m, 4H) , 3.77 (t, 2H) , 3.51 (m, 3H) , 3.27 (dd, 1H) , 3. 11 (m, 4H) , 2.95 (m, 2H) , 2.83 (d, 3H) , 2.71 (d, 1H) , 2.19 (td, 1H) , 1.95 (m, 1H) , 1.84 (td, 2H) ( Figure 4 ) .

[0113] Example 2. Preparation of Adagrasib Oxalate of Formula Ila in Crystalline Form A.

[0114] 8.0 g ( 0.013 mol) of the compound of Formula I was dissolved in 40 mL of ethanol, and stirring was maintained at 25°C until dissolution. A solution of 1.44 g ( 0.016 mol) of oxalic acid dissolved in 40 mL of ethanol was then added. The temperature was increased to 50°C, and stirring was maintained for additional 2 hours . During this time, precipitation of the product was observed. The temperature was then lowered to 25°C, and stirring was maintained for 1 hour . The solid was then filtered, and the panel washed with 40 mL of ethanol . The wet product was dried at 45°C under vacuum for 16 hours, obtaining Adagrasib Oxalate of Formula Ila in Crystalline Form A with a yield of 90% .

[0115] Characterization of Adagrasib Oxalate of Formula Ila in Crystalline Form A:1H-NMR (500 MHz, DMSO) : 7.93 (d, 1H) , 7.75 (q, 1H) , 7.56 (td, 2H) , 7.45 (t, 1H) , 7.35 (dd, 1H) , 5.40 (dd, 1H) , 5.28 (d, 1H) , 4.75 (d, 2H) , 4.45 (m, 3H) 4.08 (m, 4H) , 3.77 (t, 2H) , 3.51 (m, 3H) , 3.27 (dd, 1H) , 3. 11 (m, 4H) , 2.95 (m, 2H) , 2.83 (d, 3H) , 2.71 (d, 1H) , 2.19 (td, 1H) , 1.95 (m, 1H) , 1.84 (td, 2H) ( Figure 8 ) .

[0116] XRPD Analysis of Adagrasib Oxalate of Formula Ila in crystalline Form A (Figure 5) :

[0117] Table 1

[0118] Index Angle ( 20 ) Spacing D (A) Relative Intensity

[0119] 2 10 . 67 8 . 32 2 .73 3 11.43 7.76 5.78 4 13 . 67 6.48 23 . 13

[0120]

[0121] 14 . 14 6.25 48 . 01 15.03 5.89 7 . 64 15.58 5. 68 20 . 61 16.73 5.30 27 . 08 16.99 5.22 73 . 97 17.22 5.15 69.42 17 . 97 4 . 93 41 . 60 18.20 4 . 87 10.29 19.35 4 . 59 2 .44 20 . 05 4 .43 5.79 20.28 4 .38 14 . 02 20.89 4.25 24 . 85 21 . 08 4.21 28.40 21 . 64 4 .11 22 .30 22 . 01 4 . 04 16.37 23.29 3 . 82 19.20 23 . 94 3 . 72 12 . 32 24 .47 3 . 64 0 . 91 24 . 96 3 . 57 4 . 96 25.85 3 .45 8 .31 26.38 3 .38 11 . 01 27.20 3.28 1 .48

[0122]

[0123] 27 28 . 00 3 .19 16.20 28 28 . 50 3 . 13 3 . 50 29 29.02 3 . 08 5.00 30 29.37 3 . 04 4 .19 31 29. 69 3 . 01 5. 63 32 30.27 2 . 95 5.98 33 32 .30 2 .77 3 .70 34 33 . 83 2 . 65 2 . 50 35 34 . 67 2 . 59 2.26 36 36.43 2 .47 3 . 69 37 37 . 15 2 . 42 1 .36 38 37 . 84 2 .38 1 . 09 39 38 . 63 2 . 33 0 .36 40 39.31 2.29 1.76

[0124]

[0125] Example 3. Preparation of Adagrasib Oxalate of Formula Ila in Crystalline Form A.

[0126] 8.0 g ( 0.013 mol) of the compound of Formula I was dissolved in 80 mL of ethanol, and stirring was maintained at 25°C until dissolution. 1.44 g ( 0.016 mol) of oxalic acid were then added. The temperature was increased to 50°C and stirring was maintained for additional 2 hours . During this time, precipitation of the product was observed. The temperature was then lowered to 25°C and stirring was maintained for 1 hour . The solid was then filtered and the panel washed with 40 mL of ethanol . The wet product was dried at 45°C under vacuum for 16 hours, obtaining Adagrasib Oxalate of Formula Ila in Crystalline Form A, with a yield of 90% .

[0127] Example 4. Preparation of Adagrasib Oxalate of Formula Ila in Crystalline Form A.

[0128] 1.0 g of the compound of Formula I was dissolved in 5 mL of methanol, and stirring was maintained at 25°C until dissolution. A solution of 0.18 g of oxalic acid dissolved in 5 mL of methanol was then added. The temperature was increased to 50°C and stirring was maintained for additional 2 hours . During this time, precipitation of the product was observed. The temperature was then lowered to 25°C, and stirring was maintained for 1-2 hours . The solid was then filtered and the panel washed with 5 mL of methanol . The wet product was dried at 45°C under vacuum for 16 hours, obtaining Adagrasib Oxalate of Formula Ila in Crystalline Form A, with a yield of 90% . Example 5. Preparation of Adagrasib Oxalate of Formula Ila in Crystalline Form A from Adagrasib Oxalate of Formula Ila in Crystalline Form B .

[0129] 500 mg of Adagrasib Oxalate of Formula Ila in Crystalline Form B were suspended in 5 mL of ethanol . The temperature was increased to 50-60°C and stirring was maintained for 30 minutes . 0.5 mL of water were added and stirring was maintained until complete dissolution. The temperature was lowered to 30°C and stirring was maintained for 1-2 hours . The solid was then filtered, and the panel washed with 2 mL of ethanol . The wet product was dried at 45°C under vacuum for 16 hours, obtaining Adagrasib Oxalate of Formula Ila in Crystalline Form A, with a yield of 90% .

[0130] Example 6. Possible Purification of Adagrasib Oxalate of Formula Ila in Crystalline Form A.

[0131] 500 mg of the compound of Formula Ila in Crystalline Form A were suspended in 4 mL of methanol, the temperature was increased to 50-60°C until complete dissolution, and stirring was maintained for 30 minutes . The temperature was lowered to 2 °-8 °C and stirring was maintained for 1-2 hours . The solid was then filtered and the panel washed with 2 mL of methanol . The wet product was dried at 45°C under vacuum for 16 hours, obtaining Adagrasib Oxalate of Formula Ila in Crystalline Form A, with a yield of 90% .

[0132] Example 7. Possible Purification of Adagrasib Oxalate of Formula Ila in Crystalline Form A.

[0133] 500 mg of Adagrasib Oxalate of Formula Ila in Crystalline Form A were suspended in 5 mL of ethanol . The temperature was increased to 50°-60°C and stirring was maintained for 30 minutes . 0.5 mL of water were added and stirring was maintained until complete dissolution. The temperature was lowered to 30°C and stirring was maintained for 1-2 hours . The solid was then filtered, and the panel washed with 2 mL of ethanol . The wet product was dried at 45°C under vacuum for 16 hours, obtaining Adagrasib Oxalate of Formula Ila in Crystalline Form A, with a yield of 90% .

[0134] Example 8. Analysis of the purity of Adagrasib Oxalate of Formula Ila in Crystalline Form A by HPLC .

[0135] 8.0 g of the compound of Formula I with a purity of 88.92% was dissolved in 40 ml of ethanol and stirring was maintained at 25°C until dissolution. A solution of 1.44 g ( 0.016 mol) of oxalic acid dissolved in 40 ml of ethanol was then added. The temperature was increased to 50°C and stirred for another 2 hours . During this time, precipitation of the product was observed. The temperature was then lowered to 25°C and stirring was maintained for 1 hour . The solid was then filtered and the cake washed with 40 ml of ethanol . The wet product was dried at 45°C under vacuum for 16 hours, obtaining Adagrasib oxalate of Formula Ila in crystalline Form A with a purity of 99.80% . The results of the HPLC analyses are summarized in Table 2.

[0136] Table 2. HPLC Purity; "Imp" columns refer to impurities, identified by their relative retention times (RRT) .

[0137] Imp Imp Imp Imp Adagrasib

[0138] RRT=0 . 48 RRT=0 . 66 RRT=0 .70 RRT=1 .04 Adagrasib

[0139] 0. 45% 1.38% 4 .35% 88 . 92% 0.37% Base

[0140] Adagrasib

[0141] oxalate 0. 01% 0. 04% 0 .01% 99.80% 0 .06% Form A

[0142]

[0143] Example 9. Stability data of Adagrasib Oxalate of Formula Ila in crystalline Form A.

[0144] Adagrasib Oxalate (Formula Ila) in Crystalline Form A was put into accelerated stability at a temperature of 40 ± 2 °C and relative humidity of 75 ± 5% RH and the purity was re-evaluated after 1 month, 3 months and 10 months . The results are summarized in Table 3, from which it can be verified that the product is stable over time .

[0145] Table 3. HPLC stability data at 40°C, "Imp" columns refer to impurities, identified by their relative retention times (RRT) .

[0146] Imp Imp Imp Imp Imp Imp time

[0147] RRT=0 . 60 RRT=0 . 61 RRT=0 . 72 RRT=0 .75 RRT=1 . 03 RRT=1 .04 0 0 . 03% 0. 01% 0. 01% 0 . 02% 0 .04% 0 . 07% 1

[0148] 0 . 03% 0. 01% 0. 01% 0 . 03% 0 .06% 0 . 07% month

[0149] 3

[0150] 0 .04% 0. 01% 0. 03% 0 . 03% 0 . 05% 0 .01% months

[0151] 10

[0152] 0 .06% 0. 01% 0. 03% 0 .04% 0 . 07% 0 .01% months

[0153]

Claims

CLAIMS1 . Adagrasib oxalate of Formula I la in crystalline Form A:N O VCl NFormula I la having a characteristic X-ray powder di f f ractogram (XRPD) comprising at least two characteristic peaks expressed as 2-Theta ( 20 ) values selected from 10 . 67 ° ± 0 . 2 ° , 11 . 43 ° ± 0 . 2 ° , 13 . 67 ° ± 0 . 2 ° , 14 . 14 ° ± 0 . 2 ° , 15 . 58 ° ± 0 . 2 ° , 16 . 73 ° ± 0 . 2 ° , 16 . 99 ° ± 0 . 2 ° , 17 . 22 ° ± 0 . 2 ° , 17 . 97 ° ± 0 . 2 ° , 18 . 20 ° ± 0 . 2 ° , 20 . 28 ° ± 0 . 2 ° , 20 . 89 ° ± 0 . 2 ° , 21 . 08 ° ± 0 . 2 ° , 21 . 64 ° ± 0 . 2 ° , 22 . 01 ° ± 0 . 2 ° , 23 . 29 ° ± 0 . 2 ° , 23 . 94 ° ± 0 . 2 ° .2 . Adagrasib oxalate of Formula I la in crystalline Form A according to claim 1 , having a characteristic XRPD di f f ractogram comprising at least three characteristic peaks expressed as 2 -Theta ( 20 ) values selected from 10 . 67 ° ± 0 . 2 ° , 11 . 43 ° ± 0 . 2 ° , 13 . 67 ° ± 0 . 2 ° , 14 . 14 ° ± 0 . 2 ° , 15 . 58 ° ± 0 . 2 ° , 16 . 73 ° ± 0 . 2 ° , 16 . 99 ° ± 0 . 2 ° ,17 . 22 ° ± 0 . 2 ° , 17 . 97 ° ± 0 . 2 ° , 18 . 20 ° ± 0 . 2 ° , 20 . 28 ° ± 0 . 2 ° , 20 . 89 ° ± 0 . 2 ° , 21 . 08 ° ± 0 . 2 ° , 21 . 64 ° ± 0 . 2 ° , 22 . 01 ° ± 0 . 2 ° , 23 . 29 ° ± 0 . 2 ° , 23 . 94 ° ± 0 . 2 ° .3 . Adagrasib oxalate of Formula I la in crystalline Form A according to claim 1 , having a characteristic XRPD di f f ractogram comprising at least four characteristic peaks expressed as 2 -Theta ( 20 ) values selected from 10 . 67 ° ± 0 . 2 ° , 11 . 43 ° ± 0 . 2 ° , 13 . 67 ° ± 0 . 2 ° , 14 . 14 ° ± 0 . 2 ° , 15 . 58 ° ± 0 . 2 ° , 16 . 73 ° ± 0 . 2 ° , 16 . 99 ° ± 0 . 2 ° , 17 . 22 ° ± 0 . 2 ° , 17 . 97 ° ± 0 . 2 ° , 18 . 20 ° ± 0 . 2 ° , 20 . 28 ° ± 0 . 2 ° , 20 . 89 ° ± 0 . 2 ° , 21 . 08 ° ± 0 . 2 ° , 21 . 64 ° ± 0 . 2 ° , 22 . 01 ° ± 0 . 2 ° , 23 . 29 ° ± 0 . 2 ° , 23 . 94 ° ± 0 . 2 ° .4 . Adagrasib oxalate of Formula I la in crystalline Form A according to any one of claims 1 to 3 , wherein the molar ratio of the compound of Formula IFormula Iand oxalic acid is 1 : 1 .

5. Adagrasib oxalate of Formula Ila in crystalline Form A according to any one of claims 1 to 4, having characteristic endothermic peaks at 175. 9°C and 190.99°C in the differential scanning calorimetry (DSC) analysis .

6. Process for obtaining Adagrasib dicarboxylate salt of Formula II in crystalline form :OHFormula IIsaid process comprising the steps of :a) dissolving Adagrasib base of Formula IFormulain a solvent;adding a dicarboxylic acid of Formula H00C- (CH2)n-C00H, wherein n is comprised between 0 and 6, toobtain a solution of Adagrasib base of Formula I and dicarboxylic acid;c) heating the solution obtained in step b) to obtain a suspension of Adagrasib dicarboxylate salt of Formula II in crystalline form;d) cooling the suspension of Adagrasib dicarboxylate salt of Formula II in crystalline form obtained in step c) ;e) isolating Adagrasib dicarboxylate salt of Formula II in crystalline form.

7. Process according to claim 6, wherein in step a) Adagrasib base of Formula I is selected from any amorphous or crystalline form.

8. Process according to any one of claims 6-7, wherein in step a) the solvent is selected from alcohols, preferably methanol, ethanol, propanol, butanol, isopropanol; esters, preferably ethyl acetate; ethers, preferably methyl tert-butyl ether (MTBE) , 2-methyl tetrahydrofuran, tetrahydrofuran (THF) ; water, or mixtures thereof .

9. Process according to any one of claims 6-8, wherein in said dicarboxylic acid of Formula H00C- (CH2)n- COOH used in step b) n is comprised between 0 and 4,preferably n=0.

10. Process according to any one of claims 6-9, wherein said dicarboxylic acid in step b) is oxalic acid, with n=0.

11. Process according to any one of claims 6-10, wherein in step b) the molar ratio between the dicarboxylic acid and the compound of Formula I is comprised between 0.5 and 2.0, preferably between 0.8 and 1.5.

12. Process according to any one of claims 6-11, wherein step c) is carried out at a temperature comprised between 30°C and 80°C, preferably between 40°C and 70°C .

13. Process according to any one of claims 6-12, wherein step d) is carried out at a temperature comprised between 0°C and 30°C, preferably between 15°C and 28 °C .

14. Process according to any one of claims 6-13, wherein in step e) , the isolation of Adagrasib dicarboxylate salt of Formula II in crystalline form is obtained through a process comprising the following steps :e' ) filtering the suspended solid;e' ' ) drying Adagrasib dicarboxylate salt of Formula II in crystalline form obtained in step e' ) .

15. Process according to any one of claims 6-14, wherein said process is to obtain Adagrasib oxalate of Formula Ila in crystalline Form AFormula Ila,said process comprising the steps of :a) dissolving Adagrasib base of Formula I in a solvent ;b) adding oxalic acid to obtain a solution of Adagrasib base of Formula I and oxalic acid;c) heating the solution obtained in step b) to obtain a suspension of Adagrasib oxalate of Formula Ila in crystalline form A;d) cooling the suspension of Adagrasib oxalate of Formula Ila in crystalline Form A obtained in step c) ;e) isolating Adagrasib oxalate of Formula Ila in crystalline Form A.

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