Solid form of methyl 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-YL)phenyl)amino)pyridazine-3-carboxylate or a salt thereof, method for the preparation thereof, and use thereof in the synthesis of deucravacitinib

Abstract

The present invention relates to a solid form of methyl 6-(cyclopropanecarboxamido)-4-((2- methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate, to a method for the preparation of said solid form, and to a method for the preparation of deucravacitinib.

Description

[0001] SOLID FORM OF METHYL 6-(CYCLOPROPANECARBOXAMIDO)-4-((2-METHOXY-3-(1- METHYL-1H-1,2,4-TRIAZOL-3-YL)PHENYL)AMINO)PYRIDAZINE-3-CARBOXYLATE OR A SALT THEREOF, METHOD FOR THE PREPARATION THEREOF, AND USE THEREOF IN THE SYNTHESIS OF DEUCRAVACITINIB

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a solid form of methyl 6-(cyclopropanecarboxamido)-4-((2- methoxy-3-(1-methyl-1 H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate, to a method for the preparation of said solid form, and to a method for the preparation of deucravacitinib.

[0004] BACKGROUND OF THE INVENTION

[0005] Deucravacitinib, the chemical name of which is 6-(cyclopropanecarboxamido)-4-((2-methoxy- 3-(1-methyl-1 H-1 ,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, is a Janus TYK2 kinase inhibitor pharmaceutical active ingredient which inhibits the release of proinflammatory cytokines and chemokines and is indicated for the treatment of moderate to severe plaque psoriasis in adult candidates for systemic treatment. Deucravacitinib is a compound of formula (VI)

[0006] Deucravacitinib was approved for medical use in the United States in September 2022 and in Europe in March 2023.

[0007] Several synthesis routes have been described for the preparation of deucravacitinib, see WO 2023 / 102085 A1 , for example.

[0008] WO 2023 / 102085 A1 describes several methods for the preparation of deucravacitinib describing, among others, the reaction of the compound of formula (VIII) with trideuteromethylamine hydrochloride salt in the presence of a strong nucleophilic base such as lithium bis(trimethylsilyl)amide:

[0009] This reaction provides deucravacitinib with a 79% yield. The authors do not mention the purity of the synthetic intermediates and products thus obtained. Moreover, the authors do not specify other bases which can be used for converting the compound of formula (VIII) to deucravacitinib. The authors do not suggest substituting ethyl ester in the compound of formula

[0010] (VIII) with another ester either.

[0011] On the other hand, WO 2024 / 088282 A1 describes a series of Janus TYK2 kinase inhibitor compounds structurally similar to deucravacitinib in which the trideuteromethyl group- substituted amide group is replaced by a hydrazide type group. Therefore, this application discloses compounds of formula (IX): wherein Ri is a C1-C3 alkylamino group. However, this document does not describe a method for the preparation of deucravacitinib. The synthesis described for the compounds of formula (IX) takes place by means of the preparation of the compound of formula (I), which can be obtained according to the following method for preparation:

[0012] The product of formula (I) is described as a brown oil. This application does not mention any possible solid forms of the compound of formula (I).

[0013] There is a need in the state of the art for improved methods for obtaining deucravacitinib, particularly methods with a higher overall synthesis yield.

[0014] SUMMARY OF THE INVENTION

[0015] The inventors have discovered that when 1,8-diazabicyclo(5.4.0)undec-7-ene is used as a base in the reaction of a compound formula (I’) with a compound of formula (VII) or a salt thereof in the preparation of deucravacitinib, a greater reaction yield is obtained in the preparation of deucravacitmib compared to methods described in the state of the art that are based on the use of lithium bis(trimethylsilyl)amide as a base. As described in greater detail in the section of examples of the present application, this improved yield is unexpected since none of the tested alternative bases allows achieving an improved yield of this reaction.

[0016] In particular, the inventors have found that this improved yield is particularly high when the compound of formula (I’) is a compound of formula (I)

[0017] Moreover, the inventors have isolated the compound of formula (I) in solid form for the first time. Therefore, a first aspect of the invention relates to a compound of formula (I) or a salt thereof characterized in that it is in solid form.

[0018] The second aspect of the invention relates to a method for the preparation of a compound of formula (I) according to the first aspect of the invention, comprising step (a) of causing a compound of formula (II) or a salt thereof to react with a compound of formula (III) or a salt thereof,

[0019] (H) (HI) to form the compound of formula (I) and characterized in that the compound of formula (I) is isolated in solid form by precipitation.

[0020] The third aspect relates to a method for the preparation of deucravacitinib of formula (VI) which comprises reacting a compound of formula (I’) with a compound of formula (VII) or a salt thereof in the presence of an efficient amount of 1 ,8-diazabicyclo[5.4.0]undec-7-ene wherein Ri is a (Ci-Ce) alkyl group in the compound of formula (I’). The invention also relates to a compound that is useful in the preparation of a compound of formula (I’) as defined above.

[0021] Thus, in a fourth aspect, the invention relates to a compound of formula (X) or a salt thereof

[0022] The invention also relates in a fifth aspect to the use of a compound of formula (X) or a salt thereof in the preparation of a compound of formula (I’) and / or in the preparation of deucravacitinib.

[0023] In a sixth aspect, the invention relates to a process for the preparation of a compound of formula (X) comprising the step of causing 3-bromo-2-methoxybenzonitrile to react with diphenylmethanimine to form a compound of formula (X).

[0024] In a seventh aspect, the invention relates to a process comprising the step of reacting a compound of formula (X) with an acid to form 3-amino-2-methoxybenzonitrile (XI).

[0025] In said aspect, 3-amino-2-methoxybenzonitrile (XI) may further be reacted to produce a compound of formula (V) according to procedures disclosed in the art.

[0026] In said aspect, the process may further comprise converting the compound of formula (V) to a compound of formula (I’) or deucravacitinib, preferably according to procedures as described herein for the second and third aspects of the invention.

[0027] DESCRIPTION OF THE FIGURES

[0028] Figure 1 shows the X-ray powder diffractogram (XRPD) obtained for the product of formula (I) which is methyl 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1 H-1 ,2,4-triazol-3- yl)phenyl)amino)-pyridazine-3-carboxylate and shows the peak intensity measured (in number of counts) based on the 20 angle. Figure 2 shows the differential scanning calorimetry (DSC) diagram obtained for the product of formula (I) which is methyl 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1 H- 1 ,2,4-triazol-3-yl)phenyl)amino)-pyridazine-3-carboxylate.

[0029] Figure 3 shows the shows the X-ray powder diffractogram (XRPD) obtained for the product of formula (X) and shows the peak intensity measured (in number of counts) based on the 20 angle.

[0030] DETAILED DESCRIPTION OF THE INVENTION

[0031] In the context of the invention, the term “salt” should be understood to mean an ionic compound formed by a cation of the amino group of the compound of formula (I) or (II) and a counterion (an anion) such as, for example, the anion of an inorganic acid (such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate, among others) or the anion of an organic acid (such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p- toluenesulfonate, among others).

[0032] In the context of the present invention, the terms “about” and “around” in reference to a value refer to any value that is comprised in the interval defined by the value ±5% of said value.

[0033] In the context of the present invention, the term “base” refers to a substance capable of accepting a proton (from an acid). Said substance can be inorganic, such as in the case of hydroxide salts of alkaline metals and carbonate salts of alkaline and alkaline earth metals, or organic, such as in the case of pyridine, imidazole, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, lithium bis(trimethylsilyl)amide, 2,2,6,6-tetramethylpiperidine, and tertiary amines of formula NRaRbRc, wherein each of Ra, Rb, or Rcis a (Ci-Ce) alkyl group.

[0034] In the context of the present invention, the term “catalytically effective amount” refers to an amount of a given catalytic substance at least equal to or greater than the amount of said substance for which the conversion of the reaction is greater than the conversion of the reaction carried out in the absence of said substance.

[0035] In the context of the present invention, the term “aromatic solvent” refers to a chemical compound which is liquid under standard conditions and contains at least one aromatic ring in its molecular structure. Common examples include benzene, toluene, xylene, and ethylbenzene. In the context of the present invention, the term “aprotic solvent” refers to a chemical compound which is liquid under standard conditions and does not contain hydrogen atoms attached to nitrogen, oxygen, sulfur, or fluorine atoms, which means that it is not capable of donating protons in a chemical reaction.

[0036] In the context of the present invention, the term “alkaline salt” refers to a salt comprising a cation derived from a metal selected from the group consisting of lithium, sodium, potassium, rubidium, cesium, and francium. Preferably, the alkaline metal is selected from the group consisting of lithium, sodium, and potassium; more preferably, sodium or potassium, and even more preferably, potassium.

[0037] In the context of the present invention, the term “(Ci-Ce) alkyl” refers to a group derived from a linear or branched saturated hydrocarbon comprising 1 to 6 carbon atoms. Examples of (Ci- Ce) alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, and n-hexane.

[0038] In the context of the present invention, the term “ligand” refers to an organic compound comprising in its molecular formula at least one phosphorus atom suitable for forming a coordination bond with palladium.

[0039] As indicated above, the first aspect of the invention relates to a compound of formula (I) or a salt thereof characterized in that it is in solid form.

[0040] In a particular embodiment of the first aspect of the invention, the compound of formula (I) of the first aspect of the invention is characterized by having an X-ray powder diffractogram measured with CuKa radiation comprising peaks at 4.2°, 4.9°, 8.0°, 8.8°, 10.2°, and 13.4° 20, all with a margin of error of ± 0.2° 20.

[0041] In a particular embodiment of the first aspect of the invention, the compound of formula (I) of the first aspect of the invention is characterized by having an X-ray powder diffractogram measured with CuKa radiation essentially as shown in Figure 1.

[0042] In a particular embodiment of the first aspect of the invention, the compound of formula (I) of the first aspect of the invention is characterized by having a differential scanning calorimetry (DSC) diagram comprising an endothermic peak with a threshold temperature of about 247.4°C and an exothermic peak with a threshold temperature of about 254.1 °C.

[0043] In a particular embodiment of the first aspect of the invention, the compound of formula (I) of the first aspect of the invention is characterized by having a differential scanning calorimetry (DSC) diagram essentially as shown in of Figure 2.

[0044] The invention also relates to a method for the preparation of a compound of formula (I) in solid form in a second aspect of the invention, comprising step (a) of causing a compound of formula (II) or a salt thereof to react with a compound of formula (III) or a salt thereof, as defined above, to form the compound of formula (I) and characterized in that the compound of formula (I) is isolated in solid form by precipitation.

[0045] In a particular embodiment of the second aspect of the invention, the method for the preparation of a compound of formula (I) is a method in which said precipitation is carried out by using an aqueous phase and an aromatic solvent.

[0046] In a particular embodiment of the second aspect of the invention, the method for the preparation of a compound of formula (I) is a method in which said aqueous phase comprises ammonium chloride. Preferably, the ammonium chloride is in a concentration of between 10% and 30% by weight; more preferably about 20% by weight.

[0047] In a particular embodiment of the second aspect of the invention, the method for the preparation of a compound of formula (I) is a method in which said aromatic solvent is toluene.

[0048] In a particular embodiment of the second aspect of the invention, the method for the preparation of a compound of formula (I) is a method in which the volume ratio of the aqueous phase with respect to the aromatic solvent is comprised between 2:1 and 1 :1 ; preferably about 100:73. Said amount of aromatic solvent is the total amount of aromatic solvent, i.e. , including the possible amount of aromatic solvent used to carry out the reaction for the preparation of the compound of formula (I).

[0049] In a particular embodiment of the second aspect of the invention, the method for the preparation of a compound of formula (I) is a method in which the reaction of the compound of formula (I I) or a salt thereof with the compound of formula (111) or a salt thereof is carried out in the presence of an effective amount of a base and of a catalytically effective amount of each of a palladium (II) salt and a ligand. In this embodiment, step (a) is a step of aminating aryl chlorides by palladium-ligand complex-mediated cross coupling.

[0050] In a preferred embodiment, step (a) of the method of the second aspect of the invention follows the following synthesis scheme:

[0051] The reaction conditions for carrying out this transformation are known in the art and will become apparent for one skilled in the art when reducing the invention to practice based on common general knowledge available. These conditions typically require the use of a palladium (II) source, a base, and a ligand. In these reactions, palladium (II) is reduced to the catalytically active species of palladium(O).

[0052] In a particular embodiment, the molar ratio of the compound of formula (II) with respect to the compound of formula (III) is comprised between 1 :1 and 1 :3; preferably 1 :2.

[0053] The palladium (II) source used to carry out step (a) of the method of the second aspect of the invention is preferably selected from the group consisting of palladium (II) chloride, palladium (II) bromide, palladium (II) nitrate, palladium (II) acetate, palladium trifluoroacetate, and the solvates thereof. Alternatively, palladium(O) sources, such as tris(dibenzylideneacetone)dipalladium(0), can be used. In a particular embodiment, the palladium (II) source of step (a) is preferably palladium (II) acetate or one of the solvates thereof.

[0054] In a particular embodiment, the molar ratio of the palladium (II) salt with respect to the compound of formula (II) is comprised between 1 :100 and 1 :20; preferably about 3:100.

[0055] The base used to carry out step (a) of the method of the second aspect of the invention is preferably selected from the group consisting of alkaline (C1-C3) alkyloxy salts, alkaline phosphate salts, alkaline hydroxyl salts, and the alkaline carbonate salts.

[0056] In a particular embodiment, the base used to carry out step (a) is an alkaline carbonate salt; preferably potassium carbonate.

[0057] In a particular embodiment of step (a), the molar ratio of the base with respect to the compound of formula (II) is comprised between 1 :1 and 2:1 ; preferably about 7:5.

[0058] The ligands suitable for carrying out step (a) of the method of the second aspect of the invention will become apparent for one skilled in the art when reducing the invention to practice based on common general knowledge available. Preferably, the ligand is a bidentate ligand comprising in its molecular formula two phosphorus atoms suitable to form a complex with a metal. Preferably, the ligand is selected from the group consisting of di(phenylphosphine)methane, di(phenylphosphine)ethane, di(phenylphosphine)propane, di(phenylphosphine)ferrocene, 1 ,2-bis(dicyclohexylphosphino)ethane, 1 ,2- bis(diisopropylphosphino)ethane, 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene

[0059] (Xantphos), and (R)-(-)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine (Josiphos). More preferably, the ligand is 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.

[0060] In a particular embodiment of step (a), the molar ratio of the ligand with respect to the palladium (II) salt is comprised between 1 :1 and 2:1 ; preferably 3:2.

[0061] In a particular embodiment, step (a) of the method of the second aspect of the invention is carried out in an aprotic solvent. Aprotic solvents suitable for carrying out said step by cross coupling will be apparent to one skilled in the art when reducing the invention to practice based on common general knowledge available. Preferably, step (a) of the method of the second aspect of the invention is carried out in a mixture of acetonitrile with an aromatic solvent, said aromatic solvent preferably being toluene, more preferably with a volumetric ratio of acetonitrile with respect to said aromatic solvent of about 3 to 5.

[0062] In a particular embodiment of step (a), the concentration of the compound of formula (II) in the solvent is comprised between 0.1 and 0.3 M; preferably about 0.21 M.

[0063] Likewise, in a particularly preferred embodiment, step (a) of the method of the second aspect of the invention is carried out in the presence of an effective amount of a base and a catalytically effective amount of each of a palladium (II) salt and a ligand, wherein:

[0064] (i) the molar ratio of the compound of formula (II) with respect to the compound of formula (III) is 1 :2;

[0065] (ii) the palladium (II) salt is palladium (II) acetate and the molar ratio of the palladium (II) salt with respect to the compound of formula (II) is about 3:100;

[0066] (iii) the base is potassium carbonate and the molar ratio of the base with respect to the compound of formula (II) is about 7:5;

[0067] (iv) the ligand is 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and the molar ratio of the ligand with respect to the palladium (II) salt is 3:2;

[0068] (v) the solvent is a mixture of acetonitrile with toluene with a volumetric ratio of acetonitrile with respect to toluene of about 3 to 5;

[0069] (vi) the concentration of the compound of formula (II) in the solvent is about 0.21 M; and

[0070] (vii) it is isolated in solid form by precipitation using an aqueous phase comprising about 20% by weight of ammonium chloride and toluene, such that the volume ratio of the aqueous phase with respect to toluene is about 100:73.

[0071] In another preferred embodiment of the second aspect of the invention, the method further comprises the step (b), preceding step (a), of causing a compound of formula (IV) to react with a compound of formula (V)

[0072] (IV) (V) to form a compound of formula (II). Step (b) of the method of the second aspect of the invention is an aromatic nucleophilic substitution step.

[0073] In a preferred embodiment, in step (b) of the method of the second aspect of the invention, the molar ratio of the compound of formula (IV) with respect to the compound of formula (V) is comprised between 1 :1 and 1.5:1 ; preferably about 1.2.

[0074] In a preferred embodiment, step (b) of the method of the second aspect of the invention is carried out in the presence of a base.

[0075] Said base is preferably a non-nucleophilic base which can be, for example, any of lithium bis(trimethylsilyl)amide, 2,2,6,6-tetramethylpiperidine, and tertiary amines of formula NRaRbRc, wherein each of Ra, Rb, or Rcis a (Ci-Ce) alkyl group.

[0076] Preferably, said base is 2,2,6,6-tetramethylpiperidine.

[0077] In a preferred embodiment, in step (b) of the method of the second aspect of the invention, the molar ratio of the base with respect to the compound of formula (V) is comprised between 1 :1 and 1.5:1 ; preferably about 1.2:1.

[0078] In a preferred embodiment, step (b) of the method of the second aspect of the invention is carried out in an aprotic solvent; preferably in an aromatic solvent such as toluene.

[0079] In a preferred embodiment, the concentration of the compound of formula (V) in step (b) is comprised between 1 and 2 M; preferably about 1.63 M.

[0080] In a preferred embodiment, step (b) of the method of the second aspect of the invention is carried out at a temperature of between 80°C and 130°C; preferably about 110°C.

[0081] Likewise, in a particularly preferred embodiment, step (b) of the method of the second aspect of the invention is a method in which:

[0082] (i) the molar ratio of the compound of formula (I ) with respect to the compound of formula (V) is about 1.2;

[0083] (ii) the concentration of the compound of formula (V) in step (b) is comprised between 1 and 2 M; preferably about 1.63 M; (iii) the solvent is toluene;

[0084] (iv) the reaction is carried out in the presence of 2,2,6,6-tetramethylpiperidine in an amount such that the molar ratio of the base with respect to the compound of formula (V) is about 1.2:1 ; and

[0085] (v) the reaction is carried out at a temperature of about 110°C.

[0086] Likewise, a preferred embodiment of the method of the second aspect of the invention corresponds to the following synthesis scheme:

[0087] In another preferred embodiment of the second aspect of the invention, the method further comprises the step (c), preceding step (b), of providing the compound of formula (V).

[0088] Methods for providing the compound of formula (V) are known in the art and have been disclosed for instance in WO 2014 / 074661 A1 or WO 2018 / 183649 A1 , the content of which is incorporated herein by reference.

[0089] In a further preferred embodiment of the second aspect of the invention, step (c) comprises converting a compound of formula (X) as defined in the fourth aspect of the invention to a compound of formula (V). Preferably, said conversion of the compound of formula (X) to the compound of formula (V) is as defined in the embodiments of the seventh aspect of the invention describing said transformation and disclosed herein. As defined above, the third aspect of the invention relates to a method for the preparation of deucravacitinib of formula (VI) which comprises reacting a compound of formula (I’) with a compound of formula (VII) or a salt thereof in the presence of an efficient amount of 1 ,8-diazabicyclo[5.4.0]undec-7-ene

[0090] (I’) (VII) wherein Ri is a (Ci-Ce) alkyl group in the compound of formula (I’).

[0091] As mentioned above, the inventors have found that using 1 ,8-diazabicyclo[5.4.0]undec-7-ene as a base provided an improved reaction yield compared to using lithium bis(trimethylsilyl)amide described in the state of the art.

[0092] As will be obvious for one skilled in the art, the base is used to abstract a proton from the ammonium group comprised in the condensation product of the compound of formula (VII) with the compound of formula (I’). Therefore, an efficient amount of 1 ,8-diazabicyclo[5.4.0]undec- 7-ene is at least one mole of 1 ,8-diazabicyclo[5.4.0]undec-7-ene for every mole of the compound of formula (I’) or (VII), said compound of formula (I’) or (VII) being in limiting amounts. Moreover, when the compound of formula (VII) is in the form of a salt, an efficient amount of 1 ,8-diazabicyclo[5.4.0]undec-7-ene is at least two moles of 1 ,8- diazabicyclo[5.4.0]undec-7-ene for every mole of the compound of formula (I’) or the salt of the compound of formula (VII), said compound of formula (I’) or the salt of the compound of formula (VII) being in limiting amounts.

[0093] In a preferred embodiment of the method of the third aspect of the invention, the compound of formula (I’) is a compound wherein Ri is ethyl or methyl.

[0094] In a preferred embodiment of the method of the third aspect of the invention, the compound of formula (I’) is a compound of formula (I), i.e., a compound of formula (I’) wherein Ri is methyl. The method of the third aspect of the invention carried out using the compound of formula (I) in combination with 1 ,8-diazabicyclo[5.4.0]undec-7-ene unexpectedly provides particularly high reaction yields. Likewise, the third aspect of the invention relates particularly to a method for the preparation of deucravacitinib of formula (VI) which comprises reacting a compound of formula (I) with a compound of formula (VII) or a salt thereof in the presence of an efficient amount of 1 ,8-diazabicyclo[5.4.0]undec-7-ene. In a preferred embodiment of the method of the third aspect of the invention, the compound of formula (I’) is a compound of formula (I) as defined in the first aspect of the invention or in any of the particular and preferred embodiments of the first aspect of the invention defined above.

[0095] In a preferred embodiment of the method of the third aspect of the invention, the compound of formula (VII) or a salt thereof is the hydrochloride salt of the compound of formula (VII). In said embodiment, and as mentioned above, an efficient amount of 1 ,8-diazabicyclo[5.4.0]undec-7- ene is at least two moles of 1 ,8-diazabicyclo[5.4.0]undec-7-ene for every mole of the compound of formula (I’) or the salt of the compound of formula (VII), said compound of formula (I’) or the salt of the compound of formula (VII) being in limiting amounts.

[0096] In another preferred embodiment of the method of the third aspect of the invention, the molar ratio of the compound of formula (VII) or the salt thereof with respect to the compound of formula (I’) is comprised between 1 :1 and 1.4:1 ; preferably about 1.2:1.

[0097] In another preferred embodiment of the method of the third aspect of the invention, the molar ratio of 1 ,8-diazabicyclo[5.4.0]undec-7-ene with respect to the compound of formula (I’) is comprised between 2:1 and 3:1 ; preferably about 2.25:1.

[0098] In another preferred embodiment of the method of the third aspect of the invention, the reaction of the compound of formula (I’) with the compound of formula (VII) is carried out in the presence of an aprotic polar solvent. Aprotic polar solvents suitable for carrying out the reaction of the method of the third aspect include, among others, acetonitrile, dimethylsulfoxide, N,N- dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1 ,4-dioxane, and N- methylpyrrolidone. Preferably, the solvent is N,N-dimethylformamide.

[0099] In another preferred embodiment of the method of the third aspect of the invention, the concentration of the compound of formula (I’) is comprised between 0.3 and 0.6 M; preferably about 0.47 M.

[0100] In another preferred embodiment of the method of the third aspect of the invention, the product of formula (VI) is isolated from the reaction medium by means of precipitation induced by the addition of water to the reaction medium.

[0101] In another preferred embodiment of the method of the third aspect of the invention, the product of formula (VI) is isolated with a yield above 80%; preferably, above 90%; more preferably, above 94%; even more preferably, above 99%. In another preferred embodiment of the method of the third aspect of the invention, the reaction of the compound of formula (I’) with the compound of formula (VII) is a reaction in which:

[0102] (i) the compound of formula (I’) is a compound of formula (I);

[0103] (ii) the compound of formula (VII) or a salt thereof is the hydrochloride salt of the compound of formula (VII);

[0104] (iii) the molar ratio of the compound of formula (VII) or the salt thereof with respect to the compound of formula (I’) is about 1.2:1 ;

[0105] (iv) the molar ratio of 1 ,8-diazabicyclo[5.4.0]undec-7-ene with respect to the compound of formula (I’) is about 2.25:1 ; and

[0106] (v) the solvent is N,N-dimethylformamide.

[0107] In another preferred embodiment of the method of the third aspect of the invention, the reaction of the compound of formula (I’) with the compound of formula (VII) is a reaction in which:

[0108] (i) the compound of formula (I’) is a compound of formula (I);

[0109] (ii) the compound of formula (VII) or a salt thereof is the hydrochloride salt of the compound of formula (VII);

[0110] (iii) the molar ratio of the compound of formula (VII) or the salt thereof with respect to the compound of formula (I’) is about 1.2:1 ;

[0111] (iv) the molar ratio of 1 ,8-diazabicyclo[5.4.0]undec-7-ene with respect to the compound of formula (I’) is about 2.25:1 ;

[0112] (v) the solvent is N,N-dimethylformamide; and

[0113] (vi) the compound of formula (VI) is isolated with a yield above 94%.

[0114] The method of the third aspect of the invention may comprise the additional step of converting the product of formula (VI) into a pharmaceutically acceptable salt or into one of the solid forms of the compound of formula (VI) known in the art and described, for example, in WO 2023 / 102085 A1 , the content of which is incorporated herein by reference.

[0115] As mentioned above, in a fourth aspect, the invention relates to a compound of formula (X) or a salt thereof

[0116] Said salt of a compound of formula (X) may be a salt formed by a cation of the imine group of the compound of formula (X) and a counterion (an anion) such as, for example, the anion of an inorganic acid (such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate, among others) or the anion of an organic acid (such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate, among others).

[0117] In a preferred embodiment of the fourth aspect of the invention, the compound of formula (X) is characterized by having an X-ray powder diffractogram measured with CuKa radiation comprising peaks at 9.7°, 10.3°, 19.6°, 20.1°, and 21.3° 20, all with a margin of error of ± 0.2° 20.

[0118] In a more preferred embodiment of the fourth aspect of the invention, the compound of formula (X) is characterized by having an X-ray powder diffractogram measured with CuKa radiation comprising peaks at 9.7°, 10.3°, 19.6°, 20.1°, and 21.3° 20, and having from one to five of the peaks selected from 8.9°, 11.4°, 17.5°, 18.1°, and 19.2° 20, all with a margin of error of ± 0.2° 20.

[0119] In a more preferred embodiment of the fourth aspect of the invention, the compound of formula (X) is characterized by having an X-ray powder diffractogram measured with CuKa radiation essentially as shown in Figure 3.

[0120] In a more preferred embodiment of the fourth aspect of the invention, the compound of formula (X) is characterized by having a differential scanning calorimetry (DSC) diagram comprising an endothermic peak with a threshold temperature of 93.2 °C ± 2 °C. As mentioned above, the fifth aspect of the invention relates to the use of a compound of formula (X) or a salt thereof in the preparation of a compound of formula (I’) and / or in the preparation of deucravacitinib.

[0121] The sixth aspect, the invention relates to a process for the preparation of a compound of formula (X) comprising the step of causing 3-bromo-2-methoxybenzonitrile to react with diphenylmethanimine to form a compound of formula (X).

[0122] The process of the sixth aspect of the invention is preferably carried out in the presence of an effective amount of a base and of a catalytically effective amount of each of a palladium (II) salt and a ligand.

[0123] The reaction conditions for carrying out this transformation are known in the art and will become apparent for one skilled in the art when reducing the invention to practice based on common general knowledge available. These conditions typically require the use of a palladium (II) source, a base, and a ligand. In these reactions, palladium (II) is reduced to the catalytically active species of palladium(O).

[0124] In a particular embodiment, the molar ratio of 3-bromo-2-methoxybenzonitrile with respect to diphenylmethanimine is comprised between 1 :1 and 1.5:1 ; such as about 1.2:1.

[0125] The palladium (II) source used to carry out the method of the sixth aspect of the invention is preferably selected from the group consisting of palladium (II) chloride, palladium (II) bromide, palladium (II) nitrate, palladium (II) acetate, palladium trifluoroacetate, and the solvates thereof. Alternatively, palladium(O) sources, such as tris(dibenzylideneacetone)dipalladium(0), can be used.

[0126] In a particular embodiment, the palladium (II) source of the process of the sixth aspect is selected from the group consisting of palladium (II) acetate tris(dibenzylideneacetone)dipalladium(0) and a solvate thereof.

[0127] In a particular embodiment, the molar ratio of palladium in the palladium (II) salt or palladium(O) source with respect to 3-bromo-2-methoxybenzonitrile is comprised between 1 :100 and 1 :20; preferably between 2:100 and 4:100. The base used to carry out the method of the sixth aspect of the invention is preferably selected from the group consisting of alkaline (C1-C4) alkyloxy salts, alkaline phosphate salts, alkaline hydroxyl salts, and the alkaline carbonate salts.

[0128] In a particular embodiment, the base used to carry out the method of the sixth aspect of the invention is an alkaline carbonate salt; preferably cesium carbonate.

[0129] In another particular embodiment, the base used to carry out the method of the sixth aspect of the invention is an alkaline (C1-C4) alkyloxy salts, such as sodium tert-butoxide.

[0130] In a particular embodiment of the sixth aspect of the invention, the molar ratio of the base with respect to 3-bromo-2-methoxybenzonitrile is comprised between 1 :1 and 2:1 ; preferably about 1.4:1.

[0131] The ligands suitable for carrying out the method of the sixth aspect of the invention will become apparent for one skilled in the art when reducing the invention to practice based on common general knowledge available. Preferably, the ligand is a bidentate ligand comprising in its molecular formula two phosphorus atoms suitable to form a complex with a metal. Preferably, the ligand is selected from the group consisting of di(phenylphosphine)methane, di(phenylphosphine)ethane, di(phenylphosphine)propane, di(phenylphosphine)ferrocene, 1 ,2- bis(dicyclohexylphosphino)ethane, 1 ,2-bis(diisopropylphosphino)ethane, 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (Xantphos), 2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthyl (Bl NAP) and (R)-(-)-1-[(S)-2-Diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine (Josiphos). More preferably, the ligand is 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene or 2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthyl.

[0132] In a particular embodiment of step (a), the molar ratio of the ligand with respect to palladium in the palladium source is comprised between 1 :1 and 2:1 ; preferably 2:1 or 3:2.

[0133] In a particular embodiment, the method of the sixth aspect of the invention is carried out in an aprotic solvent. Aprotic solvents suitable for carrying out said step by cross coupling will be apparent to one skilled in the art when reducing the invention to practice based on common general knowledge available. Preferably, the method of the sixth aspect of the invention is carried out in an aprotic solvent selected from the group consisting of toluene, 1 ,4-dioxane, tetra hydrofuran and acetonitrile. More preferably, the solvent is toluene or 1 ,4-dioxane.

[0134] In a particular embodiment of the sixth aspect of the invention, the concentration of 3-bromo- 2-methoxybenzonitrile in the solvent is comprised between 0.4 and 0.7 M; preferably about 0.59 M or about 0.47 M.

[0135] In a particular embodiment of the sixth aspect of the invention, the method is one wherein:

[0136] (i) the palladium source is palladium (II) acetate; preferably in an amount such that the molar ratio of palladium in the palladium (II) salt or palladium(O) source with respect to 3-bromo-2- methoxybenzonitrile is of about 2.5:100; and / or

[0137] (ii) the ligand is 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene; preferably in an amount such that the molar ratio of the ligand with respect to palladium in the palladium source is of about 2:1 ; and / or

[0138] (iii) the base is cesium carbonate, preferably in an amount such that the molar ratio of the base with respect to 3-bromo-2-methoxybenzonitrile is about 1.4:1 ; and / or

[0139] (iv) the solvent is 1 ,4-dioxane, preferably in an amount such that the concentration of 3-bromo- 2-methoxybenzonitrile in the solvent is about 0.59 M.

[0140] In another particular embodiment of the sixth aspect of the invention, the method is one wherein:

[0141] (i) the palladium source is tris(dibenzylideneacetone)dipalladium(0); preferably in an amount such that the molar ratio of palladium in the palladium(O) source with respect to 3-bromo-2- methoxybenzonitrile is of about 4:100; and / or

[0142] (ii) the ligand is 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl; preferably in an amount such that the molar ratio of the ligand with respect to palladium in the palladium source is of about 3:2; and / or

[0143] (iii) the base is sodium tert-butoxide, preferably in an amount such that the molar ratio of the base with respect to 3-bromo-2-methoxybenzonitrile is about 1.4:1 ; and / or

[0144] (iv) the solvent is toluene, preferably in an amount such that the concentration of 3-bromo-2- methoxybenzonitrile in the solvent is about 0.47 M.

[0145] The process of the sixth aspect of the invention is preferably carried out at a temperature of between 90 °C and 120 °C, such as about 100 °C. As mentioned above, in a seventh aspect, the invention relates to a process comprising the step of reacting a compound of formula (X) with an acid to form 3-amino-2-methoxybenzonitrile (XI).

[0146] The reaction of the compound of formula (X) with an acid is preferably one wherein the acid is hydrochloric acid. Other acids, such as hydrobromic acid or trifluoroacetic acid, may be used. An amount of acid of at least 30 moles of acidic proton per mole of compound of formula (X) is preferably used. Said amount may preferably not exceed 80 moles of acidic proton per mole of compound of formula (X).

[0147] The reaction of the compound of formula (X) with an acid is preferably carried out in an organic solvent. To this end, solutions of the acid in an organic solvent, such as isopropanol, 1 ,4- dioxane or tetra hydrofuran, may be used.

[0148] The reaction of the compound of formula (X) with an acid is preferably carried out in a solvent allowing for the precipitation of the salt of the compound of formula (XI) with the base associated to the acid. In the case of hydrochloric acid, said base is a chloride anion. In this particular case, mixtures of isopropanol and tetrahydrofuran may preferably be used, such as a combination of isopropoanol and tetrahydrofuran whereby the volume ratio of isopropanol to tetrahydrofuran is between 1 :1 and 3:1 , preferably of about 2:1.

[0149] As mentioned above, the process of formation of the compound (XI) is preferably carried out in conditions allowing for the precipitation of a salt of the compound (XI). The compound (XI) is thus preferably isolated from the reaction mixture following solid-liquid separation techniques, such as filtration.

[0150] In a further embodiment of the seventh aspect, 3-amino-2-methoxybenzonitrile (XI) may further be reacted to produce a compound of formula (V) according to adapted procedures disclosed in the art, such as in WO 2018 / 143649 A1 , Example 7, the content of which is incorporated herein by reference.

[0151] In a further embodiment of the seventh aspect, the process may further comprise converting the compound of formula (V) to a compound of formula (I’) or deucravacitinib, preferably according to procedures as described herein for the second and third aspects of the invention. To facilitate the understanding of the preceding ideas, some examples of the experimental methods and embodiments of the present invention are described below. Said examples are merely illustrative, non-limiting examples.

[0152] EXAMPLES

[0153] Differential Scanning Calorimetry (DSC)

[0154] DSC analysis was performed in a Mettler Toledo 822e apparatus with STARe SW15 software, using the following parameters: heating range of 30 to 300°C with a ramp of 10°C / min and an N2 flow of 50 mL / min. The measurement is taken with a closed perforated capsule.

[0155] X-ray Crystallography

[0156] XRPD analysis was performed using a Malvern PANalytical X’Pert PRO model X-ray powder diffractometer having a radius of 240 mm and equipped with a copper anode. The radiation used is CuKa with a wavelength of 1.54 A. The following scan parameters were used: 3-40 degrees 20, continuous scan, ratio: 0.328 degrees / minute.

[0157] UHPLC Chromatographic analysis

[0158] The purity of the obtained products was analyzed by means of the ultra-high resolution liquid chromatography technique in a Waters Acquity model apparatus provided with a photodiode detector, a mass detector, and a thermostatted oven for the column. A BEH C18 Acquity column (100 x 2.1 mm; 1.7 pm) and mobile phases A (200 mM of ammonium formate, pH 4.8), B (acetonitrile), and C (water) were used with the following analysis conditions:

[0159] Flow rate: 0.5 mL / min

[0160] Column temperature: 45°C

[0161] Wavelength: 225 nm

[0162] Injection volume: 1 pL

[0163] Diluent: Methanol, except for the case of methyl 6-chloro-4-((2-methoxy-3-(1-methyl- 1 H-1 ,2,4-triazol-3-yl))phenyl)amino)-pyridazine-3-carboxylate in which acetonitrile is used

[0164] Gradient:

[0165] Comparative example 1. Synthesis of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1- methyl-1 H-1,2,4-triazol-3-yl))phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (deucravacitinib)

[0166] Comparative example 1 represents a reproduction of Example 30 described in WO 2023 / 102085 A1 using a compound of formula (I) in substitution of the compound of formula XIV described therein. Said Example 30 describes a 79% yield in the preparation of deucravacitinib

[0167] 0.5 g (1.18 mmol) of methyl 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1 H- 1 ,2,4-triazol-3-yl))phenyl)amino)pyridazine-3-carboxylate and 0.1 g (1.42 mmol) of trideuteromethylamine hydrochloride salt were mixed in 2.5 ml of dimethylformamide to obtain a suspension to which 2.36 ml (2.36 mmol) of a solution of 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran were slowly added. The resulting solution was kept under stirring at the temperature of about 20°C until the conversion of the starting materials was completed.

[0168] Thereafter, 7.5 ml of water were slowly added to the reaction mixture and a 1 M aqueous HCI solution was then added to a pH of about 7.0. The resulting mixture was cooled at a temperature of about 0 °C and kept under stirring at said temperature for 1 hour. The resulting solid was filtered, washed successively with two fractions of 3 ml of water each, and dried with the help of vacuum at the temperature of about 80 °C to obtain 0.35 g (69.7% yield) of a white solid corresponding to 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1 H-1 ,2,4- triazol-3-yl))phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.

[0169] Comparative example 2: Synthesis of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3- (1 -methyl-1 H-1 ,2,4-triazol-3-yl))phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (deucravacitinib)

[0170] Comparative example 2 was carried out following the method of Comparative example 1 , substituting lithium bis(trimethylsilyl)amide with another base. In particular, the following bases were tested: diisopropylethylamine, triethylamine, 2, 2, 6, 6, -tetramethylpiperazine, sodium methoxide, potassium carbonate. In all these cases, the product was isolated from the reaction medium with a yield comprised between 40% and 60%, i.e., below the yield of Example 30 of WO 2023 / 102085 A1.

[0171] Example 1. Synthesis of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1 H- 1,2,4-triazol-3-yl))phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (deucravacitinib)

[0172] Example 1 represents a reproduction of Example 30 described in WO 2023 / 102085 A1 using 1 ,8-diazabicyclo[5.4.0]undec-7-ene as a base instead of lithium bis(trimethylsilyl)amide.

[0173] 0.5 g (1.14 mmol) of ethyl 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1 H-1 ,2,4- triazol-3-yl))phenyl)amino)pyridazine-3-carboxylate and 0.097 g (1.37 mmol) of trideuteromethylamine hydrochloride salt were mixed in 2.5 ml of dimethylformamide to obtain a suspension to which 0.40 ml (2.65 mmol mmol) of 2,3,4,6,7,8,9,10-octahydropyrimido[1 ,2- a]azepine were slowly added. The resulting solution was kept under stirring at the temperature of about 20 °C until the conversion of the starting materials was completed.

[0174] Thereafter, 7.5 ml of water were slowly added to the reaction mixture. The resulting mixture was cooled at a temperature of about 0 °C and kept under stirring at said temperature for 1 hour. The resulting solid was filtered, washed successively with two fractions of 3 ml of water each, and dried with the help of vacuum at the temperature of about 80 °C to obtain 0.42 g (85.7% yield; 98,05% purity by means of HPLC) of a white solid corresponding to 6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1 H-1 ,2,4-triazol-3-yl))phenyl)amino)- N-(methyl-d3)pyridazine-3-carboxamide.

[0175] Example 1 demonstrates that the use of 1 ,8-diazabicyclo[5.4.0]undec-7-ene allows increasing reaction yield. It is particularly surprising given that Comparative example 2 demonstrates that other bases do not allow increasing reaction yield.

[0176] Example 2. Synthesis of methyl 6-chloro-4-((2-methoxy-3-(1-methyl-1 H-1,2,4-triazol-3- yl))phenyl)amino)-pyridazine-3-carboxylate

[0177] 50.0 g (0.245 mol) of 2-methoxy-3-(1-methyl-1 H-1 ,2,4-triazol-3-yl)aniline and 60.8 g (0.294 mol) of methyl 4,6-dichloropyridazine-3-carboxylate were mixed in 150 ml of toluene to obtain a suspension to which 49.6 ml (0.294 mol) of 2,2,6, 6-tetramethylpiperidine were slowly added, 1 maintaining a temperature of about 20 °C. The resulting mixture was heated at the temperature of about 110 °C and kept under stirring at the indicated temperature for 20 hours.

[0178] Thereafter, 125 ml of toluene and then 225 ml of water were slowly added to the reaction mixture. The resulting mixture was cooled at a temperature of about 20 °C and kept under stirring at said temperature for 1 hour. The resulting solid was filtered, washed successively with two fractions of 50 ml of toluene each and with two fractions of 50 ml of water each, and dried with the help of vacuum at the temperature of about 50 °C to obtain 69.1 g (75.3% yield; 98.35% purity by means of HPLC) of a white solid corresponding to methyl 6-chloro-4-((2- methoxy-3-(1-methyl-1 H-1 ,2,4-triazol-3-yl))phenyl)amino)-pyridazine-3-carboxylate.

[0179] Example 3. Synthesis of methyl 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1- methyl-1 H-1,2,4-triazol-3-yl))phenyl)amino)-pyridazine-3-carboxylate

[0180] 50.0 g (0.133 mol) of methyl 6-chloro-4-((2-methoxy-3-(1-methyl-1 H-1 ,2,4-triazol-3- yl))phenyl)amino)pyridazine-3-carboxylate and 22.7 g (0.267 mol) of cyclopropanecarboxamide, 25.8 g (0.187 mol) of potassium carbonate, 0.90 g (4.0 mmol) of palladium (II) acetate, and 3.47 g (6 mmol) of 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthene (known commercially as Xantphos) were mixed in 230 ml of acetonitrile and 380 ml of toluene to obtain a suspension that was degassed by means of a nitrogen stream. The resulting mixture was heated at the temperature of about 80 °C and kept under stirring at the indicated temperature for 4 hours.

[0181] Thereafter, 1000 ml of a 20% aqueous NH4CI solution and then 350 ml of toluene were slowly added to the reaction mixture. The resulting mixture was cooled at a temperature of about 20 °C and kept under stirring at said temperature for 1 hour. The resulting solid was filtered, washed successively with two fractions of 50 ml of water each and with two fractions of 50 ml of toluene each, and dried with the help of vacuum at the temperature of about 50 °C to obtain 51.6 g (91.2% yield, 97.94% purity by means of HPLC) of a slightly brownish solid corresponding to methyl 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1 H-1 ,2,4- triazol-3-yl))phenyl)amino)-pyridazine-3-carboxylate.

[0182] XRPD: 4.2° 20, 4.9° 20, 8.0° 20, 8.8° 20, 10.2° 20, and 13.4° 20, all with a margin of error of ± 0.2° 20. The X-ray powder diffractogram of the compound is shown in Figure 1 . The differential scanning calorimetry (DSC) diagram of the compound obtained has an endothermic peak with a threshold temperature of about 247.4°C and an exothermic peak with a threshold temperature of about 254.1 °C. The differential scanning calorimetry (DSC) diagram of the compound obtained is shown in Figure 2.

[0183] Example 4. Synthesis of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1 H-

[0184] 1.2.4-triazol-3-yl))phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (deucravacitinib)

[0185] 0.5 g (1.18 mmol) of methyl 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1 H-

[0186] 1.2.4-triazol-3-yl))phenyl)amino)piridazin-3-carboxylate and 0.1 g (1. 42 mmol) of trideuteromethylamine hydrochloride salt were mixed in 2.5 ml of dimethylformamide to obtain a suspension to which 0.40 ml (2.65 mmol ) of 2,3,4,6,7,8,9,10-octahydropyrimido[1 ,2- a]azepine were slowly added. The resulting solution was kept under stirring at the temperature of about 25 °C for 3 hours.

[0187] Thereafter, 7.5 ml of water were slowly added to the reaction mixture. The resulting mixture was cooled at a temperature of about 0 °C and kept under stirring at said temperature for 1 hour. The resulting solid was filtered, washed successively with two fractions of 3 ml of water each, and dried with the help of vacuum at the temperature of about 80 °C to obtain 0.47 g (94.5% yield, 98.73% purity by means of HPLC) of a white solid corresponding to 6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1 H-1 ,2,4-triazol-3-yl))phenyl)amino)- N-(methyl-d3)pyridazine-3-carboxamide.

[0188] The X-ray powder diffraction (XRPD) pattern of the product obtained coincides with that disclosed for the so-called Form A in the patent application with publication number WO 2018 / 183656 A1 , incorporated herein by reference.

[0189] The results of Example 4 show that the use of a combination of the compound of formula (I) with the use of 1 ,8-diazabicyclo[5.4.0]undec-7-ene as a base in the reaction for the preparation of deucravacitinib allows obtaining particularly high reaction yields.

[0190] Example 5. Synthesis of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1 H-

[0191] 1,2,4-triazol-3-yl))phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (deucravacitinib) 68.0 g (0.161 mol) of methyl 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1 H- 1 ,2,4-triazol-3-yl))phenyl)amino)pyridazine-3-carboxylate and 13.6 g (0.193 mol) of trideuteromethylamine hydrochloride salt were mixed in 680 ml of dimethylformamide to obtain a suspension to which 53.0 ml (0.352 mol mmol) of 2,3,4,6,7,8,9,10-octahydropyrimido[1 ,2- a]azepine were slowly added. The resulting solution was kept under stirring at the temperature of about 25 °C for 3 hours.

[0192] Thereafter, 2040 ml of water were slowly added to the reaction mixture. The resulting mixture was cooled at a temperature of about 0 °C and kept under stirring at said temperature for 1 hour. The resulting solid was filtered, washed successively with two fractions of 34 ml of water each, and dried with the help of vacuum at the temperature of about 80 °C to obtain 68.0 g (99.5% yield, 99.29% purity by means of HPLC) of a white solid corresponding to 6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1 H-1 ,2,4-triazol-3-yl))phenyl)amino)- N-(methyl-d3)pyridazine-3-carboxamide.

[0193] The X-ray powder diffraction (XRPD) pattern of the product obtained coincides with that disclosed for the so-called Form A in the patent application with publication number WO 2018 / 183656 A1 , incorporated herein by reference.

[0194] The results of Example 5 show that the use of a combination of the compound of formula (I) with the use of 1 ,8-diazabicyclo[5.4.0]undec-7-ene as a base in the reaction for the preparation of deucravacitinib allows obtaining particularly high reaction yields.

[0195] Example 6. Synthesis of 3-(benzhydrylideneamino)-2-methoxy-benzonitrile (X)

[0196] 10.0 g (0.0472 mol) of 3-bromo-2-methoxy-benzonitrile, 265 mg (1.18 mmol) of palladium (II) acetate, 1.36 g (2.35 mmol) of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and 21.5 g (0.066 mol) of cesium carbonate were mixed with 80 ml of dioxane under N2 atmosphere. 9.50 ml (10.3 g, 0.0566 mol) of benzophenone imine were slowly added. The reaction mixture was heated at the temperature of about 95°C and kept under stirring at said temperature for 18 hours.

[0197] Thereafter, the reaction mixture was cooled at the temperature of about 20°C and 40 ml of ethyl acetate, 40 ml of water and 20 ml of an aqueous solution of NaCI 20% (w / w) were added and the mixture was kept under stirring at said temperature for 10 minutes. The phases were separated and 20 ml of water and 10 ml of an aqueous solution of NaCI 20% (w / w) were added to the resulting organic phase. The resulting mixture was kept under stirring for 10 minutes at the temperature of about 20°C. The phases were separated and the solvent of the organic phase was removed by means of vacuum distillation to obtain a residue comprising 3- (benzhydrylideneamino)-2-methoxy-benzonitrile.

[0198] Example 7. Synthesis of 3-(benzhydrylideneamino)-2-methoxy-benzonitrile (X)

[0199] 10.0 g (0.0472 mol) of 3-bromo-2-methoxy-benzonitrile, 864 mg (0.943 mmol) of tris(dibenzylideneacetone)dipalladium (0), 1.76 g (2.83 mmol) of (±)-2,2'- bis(diphenylphosphino)-1 ,1'-binaphthalene and 6.34 g (0.066 mol) of sodium tert-butoxide were mixed with 100 ml of toluene under N2 atmosphere. 9.50 ml (10.3 g, 0.0566 mol) of benzophenone imine were slowly added. The reaction mixture was heated at the temperature of about 100°C and kept under stirring at said temperature for 3 hours.

[0200] Thereafter, the reaction mixture was cooled at the temperature of about 20°C, 100 ml of water were added and the mixture was kept under stirring at said temperature for 10 minutes. The phases were separated and 100 ml of an aqueous solution of NaCI 20% (w / w) were added to the resulting organic phase. The resulting mixture was kept under stirring for 10 minutes at the temperature of about 20°C. The phases were separated and the solvent of the organic phase was removed by means of vacuum distillation to obtain a residue. 10 ml of diethyl ether were added to the residue and the obtained suspension was kept under stirring at the temperature of about 35°C for 10 minutes. The mixture obtained was slowly cooled at the temperature of about 0°C and kept under stirring at said temperature for 2 hours. The resulting solid was filtered and washed successively with 3 fractions of 10 ml of cold diethyl ether each. Finally, it was dried in a vacuum oven at the temperature of 40°C to obtain 11.6 g of a yellowish solid corresponding to 3- (benzhydrylideneamino)-2-methoxy-benzonitrile (78.9% yield, 99.92% purity by means of UHPLC).

[0201] XRPD: 8.9° 20, 9.7° 2 0, 10.3° 2 0, 11.4° 2 0, 17.5° 2 0, 18.1° 2 0, 19.2° 2 0, 19.6° 2 0, 20.1° 2 0 and 21.3° 2 0, all of them with a margin of error of ± 0.2° 2 0. The X-ray powder diffractogram of the compound is shown in Figure 3.

[0202] The differential scanning calorimetry (DSC) spectrum of the compound of formula (X) comprises an endothermic peak having a threshold temperature of about 99.3°C.1H-NMR (DMSO-d6, 400 MHz) 6 (ppm): 7.76 - 7.68 (m, 2H), 7.63 - 7.54 (m, 1 H), 7.55 - 7.46 (m, 2H), 7.37 - 7.31 (m, 3H), 7.29 (dd, J = 7.5, 1.9 Hz, 2H), 7.20 - 7.12 (m, 1 H), 7.06 - 6.97 (m, 1 H), 6.97 (dd, J = 8.0, 1.9 Hz, 1 H), 3.88 (s, 3H)

[0203] 13C-NMR (DMSO-d6, 400 MHz) 6 (ppm): 169.9, 151.2, 144.8, 138.0, 135.3, 131.6, 129.0, 128.6, 128.1 , 128.0, 126.7, 124.3, 116.3, 105.4, 60.1 , 40.1 , 39.9, 39.7, 39.5, 39.3, 39.1 , 38.9.

[0204] Example 8. Synthesis of the hydrochloride salt of 3-amino-2-methoxy-benzonitrile (XI)

[0205] The residue obtained by means of the methodology disclosed in example 6 comprising 83.4% of 3-(benzhydrylideneamino)-2-methoxy-benzonitrile (X) (as obtained by LIHPLC analysis) was dissolved in a mixture consisting of 44 ml of 2-propanol and 22 ml of THF. A 3.2 M solution previously prepared of hydrochloric acid in isopropanol (73.5 ml, 0.235 mol) was slowly added at a temperature between 20 and 25°C. The suspension obtained was kept under stirring at said temperature for 1 hour. The resulting solid was filtered and washed successively with 2 fractions of 15 ml of isopropanol each. Finally, it was dried in a vacuum oven at the temperature of 40°C to obtain 8.0 g of a white solid corresponding to the hydrochloride salt of 3-amino-2- methoxy-benzonitrile (88.9% yield of two steps, 96.57% purity by means of LIHPLC).

[0206] Example 9. Synthesis of hydrochloride salt of 3-amino-2-methoxy-benzonitrile (XI)

[0207] 7.35 g (0.023 mol) of 3-(benzhydrylideneamino)-2-methoxy-benzonitrile (X) obtained following the methodology disclosed in example 7 were dissolved in a mixture consisting of 22 ml of 2- propanol and 11 ml of THF. A 3.2 M solution previously prepared of hydrochloric acid in isopropanol (36.7 ml, 0.117 mol) was slowly added at a temperature between 20 and 25 °C. The suspension obtained was kept under stirring at said temperature for 1 hour. The resulting solid was filtered and washed successively with 2 fractions of 8 ml of isopropanol each. Finally, it was dried in a vacuum oven at the temperature of 40 °C to obtain 3.18 g of a white solid corresponding to the hydrochloride salt of the hydrochloride salt of 3-amino-2-methoxy- benzonitrile (91.1% yield of two steps, 99.17% purity by means of LIHPLC).

[0208] Example 10. Synthesis of hydrochloride salt of 3-methoxy-3-(1-methyl-1,2,4-triazole-3- yl)aniline (V) 2.5 g (0.013 mol) of the hydrochloride salt of 3-amino-2-methoxy-benzonitrile (XI) obtained following the methodology of example 9 were suspended in 12.5 ml of THF and 13.5 ml of a 1 M solution of potassium tert-butoxide in THF were added at a temperature of about 20 °C. 4.01 g (0.054 mol) of N-methylformohydrazide were added at a temperature of about 20 °C to obtain a suspension. This suspension was slowly added to 54 ml of a 1 M solution of potassium tert-butoxide in THF previously heated at a temperature of about 65 °C. The obtained mixture was kept under stirring at said temperature for 6 hours.

[0209] Thereafter, the reaction mixture was cooled at the temperature of about 20 °C, 50 ml of water were added and the mixture was kept under stirring at a temperature of about 40 °C for 10 minutes. The phases were separated and 50 ml of an aqueous solution of NaCI 20% (w / w) were added to the resulting organic phase. The phases were separated and the solvent of the organic phase was removed by means of vacuum distillation to obtain a residue. 25 ml of ethyl acetate and 5 ml of methanol were added to the residue and the obtained suspension was cooled at the temperature of about 0 °C. 4.5 ml of hydrochloride acid 37% were slowly added and 25 ml of isopropanol were added at the temperature of about 0 °C and the suspension was kept under stirring for 10 minutes at the cited temperature for 2 hours. The resulting solid was filtered and washed successively with 3 fractions of 5 ml of isopropanol each. Finally, it was dried in a vacuum oven at the temperature of 40 °C to obtain 2.59 g of a white solid corresponding to the hydrochloride salt of 3-methoxy-3-(1-methyl-1 ,2,4-triazole-3-yl)aniline (V) (75.0% yield, 99.91% purity by means of LIHPLC).

Claims

1. CLAIMS1. Compound of formula (I) or a salt thereofcharacterized in that it is in solid form.

2. Compound according to claim 1 , characterized in that it has an X-ray powder diffractogram measured with CuKa radiation comprising peaks at 4.2°, 4.9°, 8.0°, 8.8°, 10.2°, and 13.4° 20, all with a margin of error of ± 0.2° 20.

3. Compound according to any of claims 1 and 2, characterized in that it has an X-ray powder diffractogram measured with CuKa radiation essentially as shown in Figure 1.

4. Compound according to any of claims 1 to 3, characterized in that it has a differential scanning calorimetry (DSC) diagram comprising an endothermic peak with a threshold temperature of about 247.4°C and an exothermic peak with a threshold temperature of about 254.1°C.

5. Compound according to any of claims 1 to 4, characterized in that it has a differential scanning calorimetry (DSC) diagram essentially as shown in Figure 2.

6. Method for the preparation of a compound of formula (I) according to any of claims 1 to 5, comprising step (a) of causing a compound of formula (II), or a salt thereof, to react with a compound of formula (III) or a salt thereof,(H) (HI) to form the compound of formula (I) and characterized in that the compound of formula (I) is isolated in solid form by precipitation.

7. Method for the preparation of a compound of formula (I) according to claim 6, wherein said precipitation is carried out by using an aqueous phase and an aromatic solvent.

8. Method for the preparation of a compound of formula (I) according to claim 7, wherein said aqueous phase comprises ammonium chloride.

9. Method for the preparation of a compound of formula (I) according to any of claims 7 and 8, wherein said aromatic solvent is toluene.

10. Method for the preparation of a compound of formula (I) according to any of claims 7 to 9, wherein the volume ratio of the aqueous phase with respect to the aromatic solvent is comprised between 2:1 and 1 :1 ; preferably about 100:73.11 . Method for the preparation of a compound of formula (I) according to any of claims 6 to 10, wherein the reaction of the compound of formula (II) or a salt thereof with the compound of formula (III) or a salt thereof is carried out in the presence of an effective amount of a base and a catalytically effective amount of each of a palladium (II) salt and a ligand.

12. Method for the preparation of a compound of formula (I) according to claim 11 , wherein the palladium (II) salt is palladium (II) acetate or one of the solvates thereof.

13. Method for the preparation of a compound of formula (I) according to any of claims 11 to12, wherein the base is an alkaline carbonate salt; preferably potassium carbonate.

14. Method for the preparation of a compound of formula (I) according to any of claims 11 to13, wherein the ligand is 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.

15. Method for the preparation of a compound of formula (I) according to any of claims 11 to14, wherein:(i) the molar ratio of the compound of formula (II) with respect to the compound of formula (III) is comprised between 1 :1 and 1 :3; preferably 1 :2;(ii) the molar ratio of the palladium (II) salt with respect to the compound of formula (II) is comprised between 1 :100 and 1 :20; preferably about 3:100;(iii) the molar ratio of the base with respect to the compound of formula (II) is comprised between 1 :1 and 2:1 ; preferably about 7:5; and / or(iv) the molar ratio of the ligand with respect to the palladium (II) salt is comprised between 1 :1 and 2:1 ; preferably 3:2.

16. Method for the preparation of a compound of formula (I) according to any of claims 6 to 15, wherein the reaction of the compound of formula (II) with the compound of formula (III) is carried out in an aprotic solvent.

17. Method for the preparation of a compound of formula (I) according to claim 16, wherein said aprotic solvent is a mixture of acetonitrile with an aromatic solvent, preferably toluene, more preferably with a volumetric ratio of acetonitrile with respect to said aromatic solvent of about 3 to 5.

18. Method for the preparation of a compound of formula (I) according to any of claims 6 to 17, comprising the step (b), preceding step (a), of preparing the compound of formula (II) which comprises causing a compound of formula (IV) to react with a compound of formula (V)in conditions sufficient to form a compound of formula (II).

19. Method for the preparation of a compound of formula (I) according to claim 18, wherein step (b) is carried out in the presence of a base.

20. Method for the preparation of a compound of formula (I) according to claim 19, wherein said base is 2,2,6,6-tetramethylpiperidine.21 . Method for the preparation of a compound of formula (I) according to any of claims 18 to20, wherein step (b) is carried out at a temperature of between 80 °C and 130 °C.

22. Method for the preparation of a compound of formula (I) according to any of claims 18 to21 , wherein the molar ratio of the compound of formula (IV) with respect to the compound of formula (V) is comprised between 1 :1 and 1.5:1 ; preferably about 1.2.

23. Method for the preparation of a compound of formula (I) according to any of claims 18 to22, wherein the molar ratio of the base with respect to the compound of formula (V) is comprised between 1 :1 and 1.5:1 ; preferably about 1.2:1.

24. Method for the preparation of deucravacitinib of formula (VI)which comprises reacting a compound of formula (I’) with a compound of formula (VII) or a salt thereof in the presence of an efficient amount of 1 ,8-diazabicyclo[5.4.0]undec-7-ene(I’) (VII) wherein Ri is a (Ci-Ce) alkyl group in the compound of formula (I’).

25. Method for the preparation of deucravacitinib of formula (VI) according to claim 24, wherein, in the compound of formula (I’), Ri is ethyl or methyl.

26. Method for the preparation of deucravacitinib of formula (VI) according to any of claims 24 to 25, wherein, in the compound of formula (I’), Ri is methyl.

27. Method for the preparation of deucravacitinib of formula (VI) according to claim 26, wherein the compound of formula (I’) is a compound of formula (I) as defined in any of claims 1 to 5.

28. Method for the preparation of deucravacitinib of formula (VI) according to any of claims 24 to 27, wherein the compound of formula (VII) or a salt thereof is the hydrochloride salt of the compound of formula (VII).

29. Method for the preparation of deucravacitinib of formula (VI) according to any of claims 24 to 28, wherein the molar ratio of the compound of formula (VII) or the salt thereof with respect to the compound of formula (I’) is comprised between 1 :1 and 1.4:1 ; preferably about 1.2:1.

30. Method for the preparation of deucravacitinib of formula (VI) according to any of claims 24 to 29, wherein the molar ratio of 1 ,8-diazabicyclo[5.4.0]undec-7-ene with respect to the compound of formula (I’) is comprised between 2:1 and 3:1 ; preferably about 2.25:1.31 . Method for the preparation of deucravacitinib of formula (VI) according to any of claims 24 to 30, wherein the reaction of the compound of formula (I’) with the compound of formula (VII) is carried out in the presence of an aprotic polar solvent.

32. Method for the preparation of deucravacitinib of formula (VI) according to claim 31 , wherein the solvent is N,N-dimethylformamide.

33. Method for the preparation of deucravacitinib of formula (VI) according to any of claims 31 to 32, wherein the product of formula (VI) is isolated from the reaction medium by means of precipitation induced by the addition of water to the reaction medium.

34. Method for the preparation of deucravacitinib of formula (VI) according to any of claims 24 to 33, wherein the product of formula (VI) is isolated with a yield above 80%; preferably, above 90%; more preferably, above 94%; even more preferably, above 99%.

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