Process for the preparation of deucravacitinib and intermediates thereof and method for purifying deucravacitinib

Abstract

The present application discloses a process to prepare an compound of formula (I), which is an intermediate to produce Deucravacitinib. The application also relates to a crystallization method to purify Deucravacitinib.

Description

[0001] PROCESS FOR THE PREPARATION OF DEUCRAVACITINIB AND INTERMEDIATES THEREOF AND METHOD FOR PURIFYING DEUCRAVACITINIB

[0002] Field of the Invention

[0003] The invention relates to a process for the preparation of compound of formula (I), which is a key intermediate in the synthesis of Deucravacitinib, and to a process for the preparation of Deucravacitinib. The invention also relates to a method for purifying Deucravacitinib.

[0004] Background of the Invention

[0005] Deucravacitinib, (6-(cyclopropanecarboxamido)-4-[2-methoxy-3-(1-methyl-1 H- 1 ,2,4- triazol-3-yl)anilino]-N-(2H3)methylpyridazine-3-carboxamide), is a tyrosine kinase 2 (TYK2) inhibitor used for the treatment of plaque psoriasis.

[0006] Several synthetic methods for preparing Deucravacitinib and intermediates thereof have been disclosed.

[0007] In the prior art, Deucravacitinib is generally obtained from the dichloro intermediate (A) by nucleophilic aromatic substitution with compound (V), followed by palladium catalyzed amidation with compound (VII) (e.g. WO2014074661 , W02020086616, WO2022193499, Wrobleski et al. , Journal of Medicinal Chemistry 2019, 62, 8973-8995).

[0008] However, the methods disclosed in the prior art for the preparation of the key dichloro intermediate (A) are not efficient. WO2014074661 and Moslin et al., Journal of Medicinal Chemistry 2019, 62, 8953- 8972, disclose the preparation of this key compound from 4,6-dihydroxy-pyridazine-3- carboxylic acid, by chlorination with POCh to provide a di-chloro acid chloride intermediate, followed by reaction with methyl-d3-amine hydrochloride. This process yields the desired product in only 33% yield.

[0009] A similar strategy is disclosed in W02020086616 (37% yield).

[0010] WO2022193499 describes the synthesis of the dichloro intermediate (A) from dichloro ester B1. This synthesis requires hydrolysis of the ester group to provide carboxylic acid B2 and reaction with oxalyl chloride to provide the activated acid chloride B3, which is then reacted with methyl-d3-amine hydrochloride. Therefore, this method requires an step of preparing the acid chloride before reaction with the amine. Further, the overall yield from the dichloro ester B1 is only 46%.

[0011] Liu et al., ACS Medicinal Chemistry Letters 2022, 13, 1730-1738 also discloses the preparation of the dichloro key intermediate (compound 35 in Liu et al.) starting from the dichloro ester (33). In this process, the ester is converted into the carboxylic acid lithium salt (34) followed by amidation with methyl-d3-amine hydrochloride in the presence of T3P and N,N-diisopropylethylamine. Though Liu et al. mention a 94% yield for the amidation of the lithium salt with methyl-d3-amine hydrochloride, the Supporting Information (available at https: / / pubs.acs.org / doi / 10.1021 / acsmedchemlett.2c00334) describes that 2.5 g of compound 35 were obtained starting from 5 g of compound 34, which corresponds to a 48% yield. Therefore, it is clear that there is an error either in the yield or on the grams of compound 35 obtained in the process according to this document. For this reason, the inventors of the present invention carried out the amidation reaction of compound 34 with methyl-d3-amine hydrochloride under the exact same conditions as disclosed by Liu et al. and found that said reaction proceeds with only 48% yield, thus confirming the error in the yield disclosed in this document (Comparative Example 10 in the present document). Consequently, the approach in Liu et al. also results in low yield of the desired product.

[0012] Though several processes for the preparation of Deucravacitinib and its key dichloro intermediate have been disclosed, they give rise to the desired product in low yield. It is therefore necessary to develop a new process for the preparation of this compound that overcomes all or part of the problems associated with the known processes belonging to the state of the art.

[0013] The methods disclosed in the prior art for the purification of crude Deucravacitinib include:

[0014] (a) recrystallization from NMP and iPrOH (as disclosed in WO2018 / 183649 or WO20 18 / 183656), or

[0015] (b) purification by column chromatography (as disclosed in WO2014 / 074661 or WO2022 / 193499).

[0016] Purification method (a), i.e. using NMP and iPrOH as disclosed in WO2018 / 183649, yields a very stable crystalline form of Deucravacitinib. However, this method gives rise to Deucravacitinib with a high content of residual solvents. As shown in Comparative Example 17 in the present document, the amount of residual iPrOH in Deucravacitinib purified according to this method is 7407 ppm, which is above the maximum acceptable amount of residual iPrOH for pharmaceutical products (5000 ppm). Accordingly, the product obtained by purification method (a) would be unsuitable for pharmaceutical applications without further purification.

[0017] The drawbacks of using purification method (b), i.e. column chromatography, are that this method is only suitable when the sample quantity is small and, further, it is a costly method and requires high solvent volumes. Thus, this method is not suitable for industrialization. WO2023 / 181075 discloses in Example 3 the preparation of crystalline deucravacitinib (Figure 3) by crystallization from methanol-water. When this example was carried out by the inventors of the present invention (Comparative Example 20 in the present document) it was not possible to obtain a solid even after letting the mixture to cool to room temperature or even after concentrating and cooling the mixture (Comparative Example 21 in the present document).

[0018] Accordingly, there is still a need for a new method for purifying Deucravacitinib that is applicable on industrial scale and that results in Deucravacitinib suitable for pharmaceutical applications without further purification (with amounts of residual solvents acceptable for pharmaceutical products).

[0019] Summary of the Invention

[0020] The invention faces the problem of providing a new process for the preparation of Deucravacitinib and intermediates thereof. In particular, the inventors have found that a compound of formula (I), or a salt or solvate thereof, which is a key intermediate in the manufacture of Deucravacitinib, can be very efficiently prepared by hydrolysis of an ester of formula (II), or a salt therefore, to provide the carboxylic acid of formula (III), followed by reaction of the free acid with an amine of formula (IV) or a salt or solvate thereof.

[0021] Accordingly, in a first aspect the invention is directed to a process for preparing a compound of formula (I) or a salt or solvate thereof, wherein each X is independently selected from halogen, the process comprising:

[0022] (a) hydrolysis of a compound of formula (II) or a salt or solvate thereof, wherein R1is C1-6 alkyl; to provide a compound of formula (III) and

[0023] (b) reaction of the compound of formula (III) with a compound of formula (IV) D3C-NH2

[0024] (IV) or a salt or solvate thereof, in the presence of T3P and a tertiary amine.

[0025] Methods for the subsequent conversion of the compound of formula (I) into Deucravacitinib are known in the art (e.g. WO2014074661 , W02020086616, WO2022193499, Wrobleski et al. , Journal of Medicinal Chemistry 2019, 62, 8973-8995).

[0026] Therefore, in a second aspect, the invention is directed to a process for preparing Deucravacitinib, or a salt or solvate thereof, comprising: preparing a compound of formula (I), or a salt or solvate thereof, by the method of the first aspect, and then converting the compound of formula (I), or a salt or solvate thereof, into Deucravacitinib.

[0027] The invention also faces the problem of providing a purification method that allows obtaining Deucravacitinib with levels of residual solvents that are acceptable according to the requirements of the US Pharmacopoeia or the ICH guideline of the European Medicines Agency.

[0028] Accordingly, in a third aspect, the invention is directed to a method for purifying Deucravacitinib, comprising:

[0029] (i) preparing a solution of crude Deucravacitinib in a mixture of dichloromethane and methanol,

[0030] (ii) removing the dichloromethane and optionally part of the methanol from the solution obtained in step (i) by distillation at atmospheric pressure,

[0031] (iii) cooling down the solution obtained in step (ii), and

[0032] (iv) separating the crystallized Deucravacitinib obtained in step (iii).

[0033] In a further aspect, the invention is directed to Deucravacitinib obtained or obtainable by the method of the third aspect.

[0034] Brief description of the drawings

[0035] FIG. 1 shows the x-ray powder diffraction pattern of crystalline Deucravacitinib obtained by the purification method of the invention.

[0036] FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of crystalline Deucravacitinib obtained by the purification method of the invention.

[0037] Detailed Description of the Invention

[0038] It should be understood that the scope of the present disclosure includes all the possible combinations of embodiments disclosed herein, either belonging to the same aspect or to different aspects of the disclosure.

[0039] As used herein, the singular forms “a” “an” and “the” include plural reference unless the context clearly dictates otherwise.

[0040] The term “comprises” encompasses the terms “consisting essentially of” and “consisting of’. Thus, at each occurrence in the present document, the term “comprising” may be replaced with the term “consisting essentially of” or “consisting of”. The term “consisting essentially of” means that the specified components represent at least 98wt%, or even at least 99wt%, of the total weight of the corresponding composition, solution or mixture.

[0041] In the present disclosure, the term “about” is meant to encompass variations of ±10%, or ±5%, or even ±1 %, of the specified amount.

[0042] When a range is indicated in the present document, both lower and upper limits are included in said range.

[0043] The term “Ci-Ce alkyl” refers to a linear or branched alkane derivative containing from 1 to 6, preferably from 1 to 3 (“C1-C3 alkyl”), carbon atoms and which is bound to the rest of the molecule through a single bond. Illustrative examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl. Preferably, it is methyl or ethyl.

[0044] The term “halogen” refers to bromine, chlorine, iodine or fluorine.

[0045] The invention also provides “salts” of some of the compounds described herein. By way of illustration, said salts can be acid addition salts, base addition salts or metal salts, and can be synthesized from the parent compounds containing a basic or acid moiety by means of conventional chemical processes known by the person skilled in the art. Such salts are generally prepared, for example, by reacting the free acid or base forms of said compounds with a stoichiometric amount of the suitable base or acid in water or in an organic solvent or in a mixture of the two. Non-aqueous media such as ether, ethyl acetate, ethanol, acetone, isopropanol or acetonitrile are generally preferred. Illustrative examples of acid addition salts include inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc., organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, camphorsulfonate, etc. Illustrative examples of base addition salts include inorganic base salts such as, for example, ammonium salts and organic base salts such as, for example, ethylenediamine, ethanolamine, / V, / V-dialkylenethanolamine, triethanolamine, glutamine, amino acid basic salts, etc. Illustrative examples of metal salts include, for example, sodium, potassium, calcium, magnesium, aluminium and lithium salts.

[0046] Likewise, the compounds described in the present description can be obtained or used both as free compounds or as solvates (e.g., hydrates, alcoholates, etc.), both forms being included within the scope of the present invention. The solvation methods are generally known in the state of the art. Preferably, the solvate is a hydrate.

[0047] The term “organic solvent” includes for example cyclic and acyclic ethers (e.g. Et20, iPr2O, tBu2O, MeOtBu, 1,4-dioxane, 1,3-dioxolane, 1,2-dimethoxyethane (DME), tetra hydrofuran (THF), methyltetrahydrofuran), hydrocarbon solvents (e.g. pentane, hexane, heptane), halogenated solvents (e.g. dichloromethane, chloroform), aromatic solvents (e.g. toluene, xylene), ketones (e.g. acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), esters (e.g. EtOAc, iPrOAc, nBuOAc), nitriles (e.g. acetonitrile, benzonitrile), amides (e.g. DMF, DMA, HMPA, NMP), alcohols (e.g. methanol, ethanol, propanol, i-propanol, s-butanol, t-butanol), sulfoxides (DMSO) and mixtures thereof.

[0048] The term “vol.” or “V” refers to volume equivalents, that is, the milliliters of solvent per gram of reference starting material (in this case, the starting crude Deucravacitinib used to prepare the solution in step (i)). For instance, 1 vol. means 1 mL of solvent per 1 g of crude Deucravacitinib.

[0049] Methods disclosed in the prior art for the preparation of compounds of formula (I) comprise amidation of the corresponding acid chloride, rather than direct amidation of the free carboxylic acid of formula (III). Therefore, these methods require a first step of preparing the acid chloride by reaction of the carboxylic acid with oxalyl chloride or phosphoryl chloride (e.g. Moslin et al., Journal of Medicinal Chemistry 2019, 62, 8953- 8972; WO2014074661, W02020086616, WO2023284869, WO2022193499). Additionally, these methods provide low yields of the compound of formula (I). In contrast, the inventors have found that the amidation reaction can be directly performed with the carboxylic acid (III) leading to the compound of formula (I) with very high yield when the amidation reaction is performed in the presence of T3P (1-propylphosphonic acid cyclic anhydride) and a tertiary amine. Liu et al., ACS Medicinal Chemistry Letters 2022, 13, 1730-1738 discloses a process for preparing amide (35) by formation of the carboxylic acid lithium salt (34) followed by amidation in the presence of T3P and N,N-diisopropylethylamine.

[0050] Though this document mentions a 94% yield for the amidation of the lithium salt with methyl-d3-amine hydrochloride, the Supporting Information (available at https: / / pubs.acs.org / doi / 10.1021 / acsmedchemlett.2c00334) describes that 2.5 g of compound 35 were obtained starting from 5 g of compound 34, which corresponds to a 48% yield. Therefore, it is clear that there is an error either in the yield or on the grams of compound 35 obtained in the process according to this document. For this reason, the inventors of the present invention carried out the preparation of compound 35 from compound 34 under the exact same conditions as disclosed in Liu et al. and found that said reaction proceeds with only 48% yield, thus confirming the error in the yield disclosed by Liu et al. (Comparative Example 10 in the present document). Consequently, the approach in Liu et al. also results in low yield of the desired product.

[0051] In contrast, the process of the present invention where the amidation reaction is carried out with the free carboxylic acid, instead of the lithium salt, results in high yield of the amide of formula (I).

[0052] This improved result for the use of the free carboxylic acid of formula (III) in the amidation reaction was totally unexpected. Additionally, Treitler et al., Organic Process Research & Development 2022, 26, 1202-1222, considered the free carboxylic acid to be unstable and disclosed the use of a salt thereof instead (page 1210, 3rdparagraph in Treitler et al.). The inventors of the present invention have found that the free carboxylic acid (III) can be used very efficiently in the preparation of a compound of formula (I) and even in higher yield than the lithium salt disclosed in Liu et al.

[0053] Further, the use of HATU, a typical condensation agent, provided very poor results in the amidation reaction of the free carboxylic acid of formula (III) (see Comparative Examples 8 and 9 in the present document), in contrast to the use of T3P.

[0054] Accordingly, in an aspect the invention is directed to a process for preparing a compound of formula (I) or a salt or solvate thereof, wherein each X is independently selected from halogen, the process comprising:

[0055] (a) hydrolysis of a compound of formula (II) or a salt or solvate thereof, wherein R1is C1-6 alkyl; to provide a compound of formula (III) and

[0056] (b) reaction of the compound of formula (III), with a compound of formula (IV) D3C-NH2

[0057] (IV) or a salt or solvate thereof, in the presence of T3P and a tertiary amine.

[0058] The process of the invention for preparing a compound of formula (I), or a salt or solvate thereof, from a compound of formula (II), or a salt or solvate thereof, requires directly treating the free carboxylic acid (III) with a compound of formula (IV), or a salt or solvate thereof, in the presence of T3P and a tertiary amine, rather than a carboxylic acid salt (e.g. the lithium salt) as disclosed in Liu et al. Therefore, the process of the invention does not comprise treating a salt of the compound of formula (III) (such as the Li salt) with the compound of formula (IV), or a salt or solvate thereof, in the presence of T3P and a tertiary amine.

[0059] In an embodiment, R1is ethyl or methyl. In a particular embodiment, R1is methyl.

[0060] In an embodiment, each X is independently Cl or Br. In a particular embodiment, X is Cl.

[0061] In a further embodiment, R1is methyl and X is Cl. Hydrolysis of a compound of formula (II), ora salt or solvate thereof

[0062] The compound of formula (III), can be obtained by hydrolysis of a compound of formula (II), or a salt or solvate thereof.

[0063] Reaction conditions for the hydrolysis of an ester into the carboxylic acid are well known in the art. Hydrolysis of the compound of formula (II), or a salt or solvate thereof, may be performed under acidic or basic conditions.

[0064] In an embodiment, the hydrolysis of the compound of formula (II), or a salt or solvate thereof, is performed under basic conditions, i.e. in the presence of a base and water. Suitable bases include alkali metal hydroxides (e.g. NaOH, KOH, LiOH, CsOH), alkali metal alkoxides (e.g. NaOMe, KOMe, NaOEt, KOEt, NaOtBu, KOtBu), alkali metal carbonates or bicarbonates (e.g. Na2COs, K2CO3, CS2CO3, U2CO3, NaHCOs, KHCO3, CsHCOs, UHCO3), and alkali metal phosphates (e.g. NasPO4, K3PO4, Na2HPO4, K2HPO4, NaH2PO4, KH2PO4). In a particular embodiment, the hydrolysis reaction is performed in the presence of a base selected from an alkali metal hydroxide, such as NaOH, KOH, LiOH or CsOH. In a further embodiment, the hydrolysis reaction is performed in the presence of NaOH. An acid may be added after completion of the reaction to obtain the neutral carboxylic acid. Such an acid may be selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, HCI, HBr, HF, HCIO4, H2SO4, HNO3, H3PO4, formic acid, propionic acid, butyric acid, malic acid, citric acid, benzoic acid, p-toluenesulfonic acid, oxalic acid and succinic acid.

[0065] In another embodiment, the hydrolysis of the compound of formula (II), or a salt or solvate thereof, is performed under acidic conditions, i.e. in the presence of an acid and water. Suitable acids include acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, HCI, HBr, HF, HCIO4, H2SO4, HNO3, H3PO4, formic acid, propionic acid, butyric acid, malic acid, citric acid, benzoic acid, p-toluenesulfonic acid, oxalic acid and succinic acid. In a particular embodiment, the hydrolysis reaction is performed in the presence of an acid selected from HCI, HBr, H3PO4 and H2SO4.

[0066] In a particular embodiment, the base or the acid used for the hydrolysis reaction in an amount of from 0.05 to 1.5 molar equivalents, such as from 0.05 to 1.0 molar equivalents, with respect to the compound of formula (II), or a salt or solvate thereof.

[0067] In an embodiment, the reaction is carried out in the presence of water and an organic solvent. In a particular embodiment, the organic solvent is selected from an ether (e.g. Et20, iPr2O, tBu2O, MeOtBu, 1 ,4-dioxane, 1 ,3-dioxolane, 1 ,2-dimethoxyethane (DME), tetra hydrofuran (THF), methyltetrahydrofuran), a halogenated solvent (e.g. dichloromethane, chloroform), a ketone (e.g. acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), an ester (e.g. EtOAc, iPrOAc, nBuOAc), a nitrile (e.g. acetonitrile, benzonitrile), an amide (e.g. DMF, DMA, HMPA, NMP), an alcohol (e.g. methanol, ethanol, propanol, i-propanol, s-butanol, t-butanol), sulfoxides (DMSO) and mixtures thereof. In a particular embodiment, the organic solvent is selected from acetonitrile, THF, DMF and EtOAc; or even it is acetonitrile.

[0068] Preferably, upon completion of the reaction, at least the water is removed from the reaction mixture before compound (III) is subjected to the next reaction step. In a particular embodiment, said water can be removed by distillation. According to an embodiment, the reaction product is distilled to remove the reaction solvent (water + organic solvent). In order to ensure removal of water, additional organic solvent can be added to the distilled reaction product, and the resulting mixture distilled again. This step of adding organic solvent and distilling can be repeated until all the water is removed, for example from 2 to 20 times. Preferably, water is considered to be removed when the water content is equal to or lower than 0.14 wt%, i.e. from 0 to 0.14 wt%, determined by Karl Fischer method. According to an embodiment, the reaction product is distilled until the water content is equal to or lower than 0.14 wt% (determined by Karl Fischer method). This distillation can be performed in a single step or can comprise several repetitions (e.g. 2-20 times) of adding organic solvent and distilling.

[0069] In an embodiment, the reaction is carried out in the presence of a base, water and an organic solvent. In a further embodiment, the reaction is carried out in the presence of an alkali metal hydroxide, such as NaOH, KOH o LiOH; water and an organic solvent, such as acetonitrile.

[0070] According to a particular embodiment, the reaction is carried out in the presence of an alkali metal hydroxide, such as NaOH, KOH o LiOH; water and an organic solvent, such as acetonitrile and after completion of the reaction an acid is added until a pH of 6 or lower.

[0071] In a further embodiment, the reaction is carried out in the presence of an alkali metal hydroxide, such as NaOH, KOH o LiOH; water and an organic solvent, such as acetonitrile, after completion of the reaction an acid is added until a pH of 6 or lower, and the resulting product is subjected to distillation until water is removed, for example, until the water content is equal to or lower than 0.14 wt% (determined by Karl Fischer method). Optionally, said distillation may include the repeated addition of organic solvent (such as acetonitrile) followed by distillation; for example, said step of adding organic solvent + distilling can be repeated from 2 to 20 times.

[0072] In an embodiment, the reaction is performed at a temperature between 0°C and 60°C, such as 0-30°C, or even 0-10°C.

[0073] Reaction of a compound of formula (III) with a compound of formula (IV) or a salt or solvate thereof

[0074] The compound of formula (I), or a salt or solvate thereof, can be obtained by reaction of the compound of formula (III) with a compound of formula (IV), or a salt or solvate thereof.

[0075] In a particular embodiment, the compound of formula (IV) is in the form of its hydrochloride salt; that is, the compound of formula (IV) is D3C-NH2 HCI.

[0076] Reaction of the compound of formula (III) with the compound of formula (IV), or a salt or solvate thereof, is performed in the presence of T3P and a tertiary amine.

[0077] Tertiary amines include, among others, pyridine, triethylamine, trimethylamine, tri- n-propylamine, triisopropylamine, diisopropylethylamine, diethylmethylamine, N- methylmorpholine and dimethylaminopyridine. In a particular embodiment, the tertiary amine is selected from pyridine, triethylamine and diisopropylethylamine. In another embodiment, the tertiary amine is selected from pyridine and triethylamine. In a further embodiment, the tertiary amine is pyridine.

[0078] In an embodiment, the compound of formula (IV), or a salt or solvate thereof, is used in an amount of 1-6 equivalents for each equivalent of the compound of formula (III). In a further embodiment, it is used in an amount of 1-4 equivalents for each equivalent of the compound of formula (III).

[0079] In an embodiment, the compound of formula (IV), or a salt or solvate thereof, is used in an amount of 1-6 equivalents for each equivalent of the compound of formula (II), or a salt or solvate thereof. In a further embodiment, it is used in an amount of 1-4 equivalents for each equivalent of the compound of formula (II), or a salt or solvate thereof.

[0080] In an embodiment, T3P is used in an amount of 1-15 equivalents for each equivalent of the compound of formula (III). In a further embodiment, it is used in an amount of 1-10 equivalents for each equivalent of the compound of formula (III). In a particular embodiment, it is used in an amount of 2-10 equivalents for each equivalent of the compound of formula (III). In a particular embodiment, T3P is used in an amount of 4-15 equivalents, or even 4-10 equivalents, for each equivalent of the compound of formula (III).

[0081] In an embodiment, T3P is used in an amount of 1-15 equivalents for each equivalent of the compound of formula (II), or a salt or solvate thereof. In a further embodiment, it is used in an amount of 1-10 equivalents for each equivalent of the compound of formula (II), or a salt or solvate thereof. In a particular embodiment, it is used in an amount of 2-10 equivalents for each equivalent of the compound of formula (II), or a salt or solvate thereof. In a particular embodiment, T3P is used in an amount of 4-15 equivalents, or even 4-10 equivalents, for each equivalent of the compound of formula (II), or a salt or solvate thereof.

[0082] The T3P can be used as a solution in an organic solvent, such as a solution in acetonitrile, EtOAc, dichloromethane, DMF, or 2-methyltetrahydrofuran.

[0083] In an embodiment, the tertiary amine is used in an amount of 2-15 equivalents for each equivalent of the compound of formula (III). In a further embodiment, it is used in an amount of 2-10 equivalents for each equivalent of the compound of formula (III). In a particular embodiment, it is used in an amount of 3-10 equivalents for each equivalent of the compound of formula (III). In a particular embodiment, the tertiary amine is used in an amount of 4-15 equivalents, or even 4-10 equivalents, for each equivalent of the compound of formula (III).

[0084] In an embodiment, the tertiary amine is used in an amount of 2-15 equivalents for each equivalent of the compound of formula (II), or a salt or solvate thereof. In a further embodiment, it is used in an amount of 3-10 equivalents for each equivalent of the compound of formula (II), or a salt or solvate thereof. In a particular embodiment, it is used in an amount of 4-10 equivalents for each equivalent of the compound of formula (II), or a salt or solvate thereof. In a particular embodiment, the tertiary amine is used in an amount of 4-15 equivalents, or even 4-10 equivalents, for each equivalent of the compound of formula (II), or a salt or solvate thereof.

[0085] In an embodiment, the reaction is carried out in the presence of an organic solvent. In a particular embodiment, the organic solvent is selected from an ether (e.g. Et20, iPr2O, tBu2O, MeOtBu, 1 ,4-dioxane, 1 ,3-dioxolane, 1 ,2-dimethoxyethane (DME), tetra hydrofuran (THF), methyltetrahydrofuran), a halogenated solvent (e.g. dichloromethane, chloroform), a ketone (e.g. acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), an ester (e.g. EtOAc, iPrOAc, nBuOAc), a nitrile (e.g. acetonitrile, benzonitrile), an amide (e.g. DMF, DMA, HMPA, NMP), sulfoxides (DMSO) and mixtures thereof. In a particular embodiment, the organic solvent is selected from acetonitrile, THF, DMF, EtOAc and CH2CI2. In a particular embodiment, the organic solvent is selected from acetonitrile, THF and CH2CI2. In a further embodiment, the organic solvent is acetonitrile.

[0086] In an embodiment, the reaction is carried out in the presence of T3P, a tertiary amine and an organic solvent. In another embodiment, the reaction is carried out in the presence of T3P, a tertiary amine selected from pyridine, triethylamine and diisopropylethylamine, and an organic solvent, such as acetonitrile, THF, DMF, EtOAc or CH2CI2. In a further embodiment, the reaction is carried out in the presence of T3P, pyridine, and an organic solvent, such as acetonitrile, THF, DMF, EtOAc or CH2CI2.

[0087] According to an embodiment of the invention, the reaction is carried out in the presence of T3P, pyridine, and acetonitrile.

[0088] In an embodiment, the reaction is performed at a temperature between 0°C and 60°C, such as 10-40°C. In a particular embodiment, the reaction is carried out at a temperature of 15-30°C.

[0089] In a particular embodiment, steps (a) and (b) are performed in a one-pot process; that is, step (b) is performed without previous isolation and / or purification of the compound of formula (III). The one-pot process may require changing a solvent to a different solvent, for example by evaporation under reduced pressure. In an embodiment, after step (a), the reaction mixture is distilled or evaporated to ensure removal of water and the resulting crude product is subjected to step (b). In a particular embodiment, the one-pot process is performed in a single reaction vessel, but also steps (a) and (b) can be carried out in two different reaction vessels, without isolation and / or purification of the compound of formula (III).

[0090] Conversion of a compound of formula (I), ora salt or solvate thereof into Deucravacitinib, or a salt or solvate thereof

[0091] Methods for the conversion of the compound of formula (I), or a salt or solvate thereof, into Deucravacitinib, or a salt or solvate thereof, are known in the art (e.g. WO2014074661 , W02020086616, WO2022193499, Wrobleski et al., Journal of Medicinal Chemistry 2019, 62, 8973-8995).

[0092] In an embodiment, the compound of formula (I), o a salt or solvate thereof, is converted into Deucravacitinib, or a salt or solvate thereof, by a process comprising:

[0093] (c) reaction of the compound of formula (I), or a salt or solvate thereof, with a compound of formula (V) or a salt or solvate thereof, to provide a compound of formula (VI) or a salt or solvate thereof; and

[0094] (d) reaction of the compound of formula (VI), or a salt or solvate thereof, with a compound of formula (VII) or a salt or solvate thereof.

[0095] Therefore, in another aspect, the invention is directed to a process for preparing Deucravacitinib, or a salt or solvate thereof, which comprises steps (a) and (b) as defined herein. In a further aspect, the invention is directed to a process for preparing Deucravacitinib, or a salt or solvate thereof, which comprises steps (a), (b), (c) and (d) as defined herein.

[0096] Step (c)

[0097] Reaction of the compound of formula (I), or a salt or solvate thereof, with a compound of formula (V), or a salt or solvate thereof (step (c)), can be performed in the presence of a base and an organic solvent.

[0098] Suitable bases for step (c) include alkali metal bases, such as organic and inorganic alkali metal bases; for example, alkali metal hydroxides (e.g. NaOH, KOH, LiOH), alkali metal amides (e.g. LiHMDS, NaHMDS, KHMDS, LDA), and C1-6 alkyllithium compounds (n-BuLi, n-HexLi, s-BuLi). In a particular embodiment, reaction of the compound of formula (I), or a salt or solvate thereof, with a compound of formula (V), or a salt or solvate thereof, is performed in the presence of an alkali metal amide, such as LiHMDS, NaHMDS, KHMDS or LDA. In a further embodiment, the reaction is performed in the presence of LiHMDS.

[0099] In an embodiment, the compound of formula (V), or a salt or solvate thereof, is used in an amount of 0.7-1 .5 equivalents for each equivalent of the compound of formula

[0100] (I), or a salt or solvate thereof. In a further embodiment, it is used in an amount of 0.8- 1.2 equivalents for each equivalent of the compound of formula (I), or a salt or solvate thereof. In a particular embodiment, it is used in an amount of 0.8-1.0 equivalents for each equivalent of the compound of formula (I), or a salt or solvate thereof.

[0101] In an embodiment, the base is used in an amount of 1-6 equivalents for each equivalent of the compound of formula (I), or a salt or solvate thereof. In a further embodiment, it is used in an amount of 2-5 equivalents for each equivalent of the compound of formula (I), or a salt or solvate thereof.

[0102] Suitable organic solvents for step (c) include cyclic and acyclic ethers (e.g. Et20, iPr2O, tBu2O, MeOtBu, 1 ,4-dioxane, 1 ,3-dioxolane, 1 ,2-dimethoxyethane (DME), tetra hydrofuran (THF), methyltetrahydrofuran), halogenated solvents (e.g. dichloromethane, chloroform), ketones (e.g. acetone, butanone, pentanone, methyl ethyl ketone, ethyl isopropyl ketone), esters (e.g. EtOAc, iPrOAc, nBuOAc), nitriles (e.g. acetonitrile, benzonitrile), amides (e.g. DMF, DMA, HMPA, NMP), sulfoxides (DMSO) and mixtures thereof. In a particular embodiment, the organic solvent is selected from acetonitrile, THF, DMF, EtOAc and CH2CI2. In a particular embodiment, the organic solvent is THF.

[0103] In a particular embodiment, the reaction of the compound of formula (I), or a salt or solvate thereof, with a compound of formula (V), or a salt or solvate thereof, is performed in the presence of an alkali metal base and an organic solvent. In a further embodiment, the reaction of the compound of formula (I), or a salt or solvate thereof, with a compound of formula (V), or a salt or solvate thereof, is performed in the presence of an alkali metal amide, such as LiHMDS, and an organic solvent, such as THF.

[0104] In an embodiment, the reaction is performed at a temperature between 0°C and 60°C, such as 10-40°C, or even 15-30°C.

[0105] Step (d)

[0106] Reaction of the compound of formula (VI), or a salt or solvate thereof, with a compound of formula (VII), or a salt or solvate thereof (step (d)), can be performed in the presence of a palladium catalyst, a ligand, a base and an organic solvent.

[0107] In an embodiment, the compound of formula (VII), or a salt or solvate thereof, is used in an amount of 1-5 equivalents for each equivalent of the compound of formula (VI), or a salt or solvate thereof. In a further embodiment, it is used in an amount of 1.2- 3 equivalents for each equivalent of the compound of formula (VI), or a salt or solvate thereof.

[0108] The Pd catalyst can be selected from Pd3(dba)3, Pd(dba)2, Pd(OAc)2, PdCI2(MeCN)2, [(allyl)PdCI]2, Pd(PPh3)4, Pd(P‘Bu3)2, Pd(PCy3)2, Pd(PPh3)2CI2, Pd(P(o- tol)3)2CI2, Pd(PCy3)2CI2, Pd(PtBu2Ph)2CI2, Pd(PtBuCy2)2CI2, Pd(PtBu2nBu)2CI2, Pd(amphos)CI2, Pd(dppe)2CI2, Pd(dppp)2CI2, Pd(dppb)2CI2, Pd(dppf)CI2, Pd(dtbpf)CI2, and Pd(dcypp)CI2. In a particular embodiment, the Pd catalyst is selected from Pd2(dba)3, Pd(dba)2, Pd(OAc)2, PdCI2(MeCN)2, [(allyl)PdCI]2. In an embodiment, the Pd catalyst is Pd2(dba)3or Pd(OAc)2. In a further embodiment, the Pd catalyst is Pd2(dba)3.

[0109] Typically, the amount of the Pd catalyst may be 0.05-20 mol%, such as 0.05-10 mol%, with respect to the compound of formula (VI), or a salt or solvate thereof. In a particular embodiment, the amount of the Pd catalyst may be 0.06-5 mol% with respect to the compound of formula (VI), or a salt or solvate thereof.

[0110] In a particular embodiment, the amount of the Pd catalyst, such as Pd2(dba)3, may be 0.06-0.3 mol%, or even 0.07-0.2 mol%, with respect to the compound of formula (VI), or a salt or solvate thereof.

[0111] The ligand may be a phosphine ligand, such as SL-J009-1 ((R)-1-[(S)-2- (dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine), SL-J009-2 ((S)-1-[(R)-2- (dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine), SL-J002-1 ((R)-1-[(S)-2- (diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine), SL-J002-2 ((S)-1-[(R)-2- (diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine), DPEphos (bis(2- diphenylphosphinophenyl)ether), Xantphos ((9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane)), DPPF (1 ,1’-bis(diphenylphosphino)ferrocene), DCyPF (1 ,1’-bis(dicyclohexylphosphino)ferrocene), or Bl NAP (2,2'-bis(diphenylphosphino)-1 ,T- binaphthyl). In an embodiment, the ligand is selected from SL-J009-1 , SL-J009-2, Xantphos and DPPF. In a particular embodiment, the ligand is selected from SL-J009-1 and SL-J009-2. In a further embodiment, the ligand is SL-J009-2.

[0112] Typically, the amount of the ligand may be 1-50 mol%, such as 5-40 mol%, with respect to the compound of formula (VI), or a salt or solvate thereof.

[0113] Suitable bases for the reaction of the compound of formula (VI), or a salt or solvate thereof, with a compound of formula (VII), or a salt or solvate thereof, include alkaline and alkaline earth metal carbonates, bicarbonates, phosphates, acetates, alkoxides, hydroxides and halides. In an embodiment, the base is selected from alkaline carbonates, bicarbonates and phosphates, such as Na2CO3, K2CO3, Cs2CO3, NaHCO3, Na3PC>4 or K3PC>4. In a particular embodiment, the base is selected from K2CO3, Cs2CO3, and K3PC>4. In a further embodiment, the base is K2CO3.

[0114] The base is typically used in an amount of 1-10 equivalents, such as 2-6 equivalents, for each equivalent of compound of formula (VI), or a salt or solvate thereof.

[0115] Suitable organic solvents for the reaction of the compound of formula (VI), or a salt or solvate thereof, with a compound of formula (VII), or a salt or solvate thereof, include ethers (e.g. Et20, iP^O, tBu2O, MeOtBu, 1 ,4-dioxane, 1 ,3-dioxolane, 1 ,2- dimethoxyethane (DME), tetrahydrofuran (THF), methyltetrahydrofuran), aromatic solvents (e.g. toluene, xylene), nitriles (e.g. acetonitrile, benzonitrile), and alcohols (e.g. methanol, ethanol, propanol, i-propanol, s-butanol, t-butanol), sulfoxides (DMSO) and mixtures thereof. In an embodiment, the organic solvent is an ether, such as 1 ,4-dioxane,

[0116] 1.3-dioxolane, DME, THF, methyltetrahydrofuran or a mixture thereof. In a particular embodiment, the organic solvent is 1 ,4-dioxane. In another embodiment, the organic solvent is acetonitrile, toluene or a mixture thereof.

[0117] In a particular embodiment, reaction of the compound of formula (VI), or a salt or solvate thereof, with a compound of formula (VII), or a salt or solvate thereof, is performed in the presence of a palladium catalyst selected from Pd2(dba)s or Pd(OAc)2, a ligand selected from SL-J009-1 , SL-J009-2, Xantphos or DPPF, a base selected from K2CO3, CS2CO3, or K3PO4, and an organic solvent. Preferably, the organic solvent is selected from an ether, an aromatic solvent, acetonitrile or a mixture thereof.

[0118] In a particular embodiment, reaction of the compound of formula (VI), or a salt or solvate thereof, with a compound of formula (VII), or a salt or solvate thereof, is performed in the presence of Pd2(dba)s, SL-J009-2, K2CO3, and an organic solvent selected from an ether, such as 1 ,4-dioxane, 1 ,3-dioxolane, DME, THF, methyltetrahydrofuran or a mixture thereof. In a particular embodiment, said solvent is

[0119] 1.4-dioxane. In an embodiment, said Pd2(dba)s is used in amount of 0.06-0.3 mol%, or even 0.07-0.2 mol%, with respect to the compound of formula (VI), or a salt or solvate thereof.

[0120] According to a particular embodiment, the reaction is performed also in the presence of water. For example, the volume ratio of organic solventwater may be in the range 10:1 to 250:1 v / v.

[0121] In an embodiment, the organic solvent is an ether, such as1 ,4-dioxane, and the reaction is performed in a volume ratio of etherwater of 10:1 to 250:1 v / v.

[0122] The reaction of the compound of formula (VI), or a salt or solvate thereof, with a compound of formula (VII), or a salt or solvate thereof, may be carried out under heating, for example at a temperature of 50-150°C, such as 70-140°C.

[0123] Method for purifying Deucravacitinib, ora salt or solvate thereof

[0124] As shown in Comparative Example 17 herein, purification of crude Deucravacitinib by crystallization from NMP and iPrOH results in Deucravacitinib with a high iPrOH content of 7407 ppm. According to the US Pharmacopoeia and the ICH guidelines (Q3C impurities, November 2022), pharmaceutical products should contain no more than 5000 ppm of iPrOH. Therefore, purification of Deucravacitinib using NMP and iPrOH as crystallization solvents (as disclosed in WO2018 / 183649 or WO2018 / 183656) results in Deucravacitinib with an amount of residual solvents higher than the maximum limits set forth by the US Pharmacopoeia or the ICH guidelines. Consequently, this product would be unsuitable for pharmaceutical applications without further purification.

[0125] WO2023 / 181075 discloses in Example 3 the preparation of crystalline deucravacitinib (Figure 3) from methanol-water. However, when this example was carried out by the inventors (Comparative Example 20 in the present document) it was not possible to obtain a solid even after letting the mixture to cool to room temperature or even after concentrating and cooling the mixture (Comparative Example 21 in the present document).

[0126] Purification of Deucravacitinib by column chromatography has also been disclosed in the prior art. However, column chromatography is not suitable for industrial application.

[0127] The inventors have surprisingly found that purification of crude Deucravacitinib using a mixture of dichloromethane and methanol as disclosed herein yields very stable crystalline Deucravacitinib, for example a crystalline form as described in WO2018 / 183656 that meets the Pharmacopoeia and the ICH guidelines purity standards (with residual solvents within the acceptable limits) without the need of additional purification steps. This method is easy to carry out, highly efficient and applicable to production of Deucravacitinib on an industrial scale.

[0128] The use of other solvents different from dichloromethane and methanol also resulted in Deucravacitinib with unacceptable limits of residual solvents. For example, when the process of the present invention was carried out using THF and methanol, instead of dichloromethane and methanol, in different amounts, Deucravacitinib with unacceptable limits of THF of or THF and methanol was obtained. Also, purification using THF and EtOAc (comparative example 18) or THF, water and EtOAc (comparative example 19) resulted in Deucravacitinib with amounts of residual THF and EtOAc above the limits established by the EP and US Pharmacopoeia.

[0129] Therefore in another aspect, the invention is directed to a method for purifying crude Deucravacitinib, comprising:

[0130] (i) preparing a solution of crude Deucravacitinib in a mixture of dichloromethane and methanol,

[0131] (ii) removing the dichloromethane and optionally part of the methanol from the solution obtained in step (i) by distillation at atmospheric pressure,

[0132] (iii) cooling down the solution obtained in step (ii),

[0133] (iv) separating the crystallized Deucravacitinib obtained in step (iii).

[0134] This method does not include the addition of other solvents different from dichloromethane and methanol.

[0135] Step (i)

[0136] Preparation of crude Deucravacitinib is not specifically limited in the present invention. Crude Deucravacitinib that can be purified according to the method of the present invention, can be any crude product as obtainable or obtained according to any method for its preparation, for example according to Moslin et al., Journal of Medicinal Chemistry 2019, 62, 8953-8972; Wrobleski et al., Journal of Medicinal Chemistry 2019, 62, 8973-8995; WO2014074661 , W02020086616, WO2023284869, WO2022193499, or Liu et al., ACS Medicinal Chemistry Letters 2022, 13, 1730-1738. In an embodiment, crude Deucravacitinib is obtained by a process as described herein.

[0137] Crude Deucravacitinib may also refer to Deucravacitinib previously purified by other means, to which the method of purification of the invention is applied in order to obtain crystalline Deucravacitinib with acceptable levels of residual solvents.

[0138] First, a solution of crude Deucravacitinib in a mixture of dichloromethane and methanol is prepared.

[0139] The solution of crude Deucravacitinib in the mixture of dichloromethane and methanol can be prepared by mixing crude Deucravacitinib, dichloromethane and methanol and heating the resulting mixture. In an embodiment, step (i) is performed by heating at a temperature of from 30°C to reflux temperature. In a particular embodiment, it is performed by heating at a temperature of 25-40°C. In an embodiment, it is performed by heating at a temperature of 30-40°C. In a further embodiment, it is performed by heating at reflux.

[0140] In an embodiment, the volume ratio (v / v) of dichloromethane and methanol in the mixture of dichloromethane and methanol in step (i) is from 1 :50 to 50:1 (CFLCF^MeOH). In a further embodiment, the v / v ratio CFLCF^MeOH is 1 :10 to 10:1. In another embodiment, the v / v ratio CFLCF^MeOH is 1 :5 to 5:1.

[0141] In a particular embodiment, the amount of mixture of dichloromethane + methanol in the solution of crude Deucravacitinib in a mixture of dichloromethane and methanol in step (i) is equal to or higher than 20 vol. (i.e. 20 mL of dichloromethane + methanol per each gram of crude Deucravacitinib). Since the dichloromethane and part of the methanol can be removed later on in the process, the higher limit of the amount of solvent (mixture of dichloromethane + methanol) in step (i) is not particularly limited. In an embodiment, the amount of dichloromethane + methanol in step (i) is equal to or higher than 40 vol. In a further embodiment, the amount of dichloromethane + methanol in step (i) is equal to or higher than 50 vol. In another embodiment, the amount of dichloromethane + methanol in step (i) is equal to or higher than 60 vol.

[0142] In a particular embodiment, the amount of mixture of dichloromethane + methanol in step (i) is from 20 to 250 vol. In a further embodiment, it is from 50 to 200 vol., or even from 50 to 150 vol.

[0143] According to an embodiment, the solution of crude Deucravacitinib in a mixture of dichloromethane and methanol is prepared by mixing crude Deucravacitinib with at least 10 vol. of dichloromethane and at least 10 vol. of methanol. In a particular embodiment, it is prepared by mixing crude Deucravacitinib with at least 15 vol. of dichloromethane and at least 15 vol. of methanol.

[0144] According to an embodiment, the solution of crude Deucravacitinib in a mixture of dichloromethane and methanol is prepared by mixing crude Deucravacitinib with 10-100 vol. of dichloromethane and 10-150 vol. of methanol. In a particular embodiment, it is prepared by mixing crude Deucravacitinib with 15-80 vol. of dichloromethane and 15- 100 vol. of methanol.

[0145] In embodiments of the invention, step (i) may further comprise decolorization of the solution of Deucravacitinib in the mixture of dichloromethane and methanol. Decolorization may be performed by any method known by the skilled person. For example, by treatment with a decolorization agent, such as activated carbon, silica gel, alumina or molecular sieves. In a particular embodiment, decolorization is carried out by treatment of the dissolution of Deucravacitinib in dichloromethane and methanol with activated carbon. The decolorization agent can be used as such (e.g. in the form of powder or granules) or in the form of a filter or cartridge comprising it.

[0146] If decolorization is performed, the method may further comprise a step of removing the decolorization agent from the solution of Deucravacitinib in dichloromethane and methanol. This step may be performed by decantation and / or filtration. Alternatively, treatment with a decolorization agent can be performed by passing the solution of Deucravacitinib in the mixture of dichloromethane and methanol through a filter or cartridge with decolorization agent. In this later case, a step of removing the decolorization agent from the solution of Deucravacitinib in dichloromethane and methanol is not required.

[0147] In an embodiment, when step (i) comprises decolorization of the dissolution of Deucravacitinib in dichloromethane and methanol, the method may optionally further comprise washing the decolorization agent (or the filter or cartridge comprising it) with methanol. Since the methanol can be removed later on in the process, the amount of methanol used in this washing step is not particularly limited. In a particular embodiment, the decolorization agent (or the filter or cartridge comprising it) may be washed with an amount of methanol of 1-50 vol., or even 2-25 vol. (i.e. 1-50 mL or 2-25 mL of methanol per each gram of crude Deucravacitinib used to prepare the solution of crude Deucravacitinib in a mixture of dichloromethane and methanol).

[0148] In a particular embodiment, step (i) in the method for purifying Deucravacitinib comprises:

[0149] (i’) preparing a solution of crude Deucravacitinib in a mixture of dichloromethane and methanol, for example by heating;

[0150] (i”) optionally, treating the solution of step (i’) with a decolorization agent, for example with activated carbon, either as such or in the form of a filter or cartridge;

[0151] (i’”) if step (i”) is present and a decolorization agent as such is used (not in the form of a filter or cartridge), removing the decolorization agent from the solution of Deucravacitinib in dichloromethane and methanol, for example by decantation and / or filtration; and

[0152] (i””) if step (i”) is present, optionally washing the decolorization agent with methanol.

[0153] After step (i), a solution of crude Deucravacitinib in dichloromethane and methanol is obtained.

[0154] According to an embodiment, the solution of crude Deucravacitinib in a mixture of dichloromethane and methanol, irrespective of whether it includes additional decolorization and / or washing steps, consists essentially of crude Deucravacitinib, dichloromethane and methanol, where the amount of dichloromethane is at least 10 vol. and the amount of methanol is at least 10 vol. In a particular embodiment, the amount of dichloromethane is at least 15 vol. and the amount of methanol is at least 15 vol. In a further embodiment, the amount of dichloromethane is 10-100 vol., or even 15-80 vol., and the amount of methanol is 10-250 vol., or even 15-200 vol.

[0155] In a particular embodiment, the solution of crude Deucravacitinib in a mixture of dichloromethane and methanol, irrespective of whether it includes additional decolorization and / or washing steps, consists essentially of crude Deucravacitinib and a mixture of dichloromethane and methanol, where the amount of mixture of dichloromethane + methanol is equal to or higher than 20 vol. In a further embodiment, the amount of mixture of dichloromethane + methanol in step (i) is equal to or higher than 40 vol. In a particular embodiment, the amount of mixture of dichloromethane and methanol is 20-250 vol., or even 40-250 vol.

[0156] Step (ii)

[0157] In step (ii), at least all the dichloromethane, and optionally part of the methanol, present in the solution of crude Deucravacitinib in a mixture of dichloromethane and methanol obtained in step (i) is removed. This removal is performed by distillation at atmospheric pressure.

[0158] The term “atmospheric pressure” means a pressure within the normal range of meteorological atmospheric pressure for a particular altitude; for example, a pressure between 70 and 101.3 KPa, or even between 80 and 101.3 KPa.

[0159] The skilled person can readily determine when the dichloromethane has been removed from the solution of crude Deucravacitinib in the mixture of dichloromethane and methanol obtained in step (i). For example, when the boiling temperature of the solution that is under distillation is higher than 40°C, this means that the dichloromethane present in the solution has been removed. Alternatively, when the volume of the solution reaches a value that is lower than the volume of the solution obtained in step (i) minus the volume of dichloromethane used to prepare said solution, this also means that the dichloromethane present in the solution has been removed.

[0160] Part of the methanol can be also removed in step (ii).

[0161] In a particular embodiment, step (ii) comprises removing the dichloromethane and also part of the methanol by distillation at atmospheric pressure.

[0162] According to an embodiment of the invention, step (ii) is performed by distilling at atmospheric pressure from the solution obtained in step (i) a volume corresponding to at least 101 %, or even 105%, the volume of dichloromethane added in step (i). That is, if the solution obtained in step (i) comprises 20 vol. of dichloromethane, step (ii) could be performed by distilling at least 20.2 vol., or even 21 vol., from said solution. In this way, it is ensured that all the dichloromethane and part of the methanol are removed. In an embodiment, step (ii) is performed by distilling at atmospheric pressure from the solution obtained in step (i) a volume corresponding to at least 110% the volume of dichloromethane added in step (i).

[0163] In a particular embodiment, step (ii) is performed by distillation at atmospheric pressure until removal of the dichloromethane and to a final volume of 2-50 vol (i.e. a volume of 2-50 mL per each gram of starting crude Deucravacitinib; that is, per each gram of crude Deucravacitinib used to prepare the solution of crude Deucravacitinib in the mixture of dichloromethane and methanol in step (i)). In a further embodiment, step (ii) is performed by distillation at atmospheric pressure until removal of the dichloromethane and to a final volume of 3-40 vol.

[0164] Step (ii) requires removal of the dichloromethane present in the solution obtained in step (i). Therefore, if needed, additional methanol can be added during step (i) and / or step (ii) to ensure that the desired final volume (e.g 2-50 vol., or even 3-40 vol.) corresponds to a volume that cannot include dichloromethane; that is, a volume that is lower than the volume of the solution before the distillation in step (ii) minus the volume of dichloromethane used to prepare said solution.

[0165] In an embodiment, step (ii) is performed by distillation of the solution obtained in step (i) at atmospheric pressure until the boiling temperature of the solution reaches the boiling point of methanol (which means that all the dichloromethane has been removed in the distillation and the methanol is starting to distil), and optionally continuing distillation to remove also part of the methanol. In an embodiment, step (ii) is performed by distillation of the solution obtained in step (i) at atmospheric pressure until the boiling temperature of the solution reaches the boiling point of methanol and optionally continuing distillation until a final volume of 2-50 vol., or even 3-40 vol.

[0166] In a particular embodiment, step (ii) is performed by distillation of the solution obtained in step (i) at atmospheric pressure at a boiling temperature of about 38-42°C and when the boiling temperature of the solution reaches a temperature of about 63- 68°C (which means that all the dichloromethane has been removed in the distillation and the methanol is starting to distil), optionally continuing distillation to remove also part of the methanol. In an embodiment, step (ii) is performed by distillation of the solution obtained in step (i) at atmospheric pressure at a boiling temperature of about 38-42°C and when the boiling temperature of the solution reaches a temperature of about 63- 68°C optionally continuing distillation until a final volume of 2-50 vol., or even 3-40 vol.

[0167] In a particular embodiment, removal of the dichloromethane, and optionally part of the methanol, to the desired final volume can be performed in a single distillation. Alternatively, step (ii) may comprise several distillations, such as two, three or four distillations. Therefore, in an embodiment step (ii) comprises:

[0168] (ii’) removing the dichloromethane and optionally part of the methanol from the solution obtained in step (i) by distillation at atmospheric pressure;

[0169] (ii”) optionally, adding methanol to the solution obtained in step (ii’); and

[0170] (ii’”) if step (ii”) is present, removing part of the methanol from the solution obtained in step (ii”) by distillation at atmospheric pressure.

[0171] Steps (ii”) and (ii’”) can be performed one or more times, for example one, two or three times.

[0172] In an embodiment, step (ii) comprises only step (ii’). In another embodiment, step

[0173] (ii) comprises steps (ii’)-(ii’”).

[0174] In step (ii’), all the dichloromethane and optionally part of the methanol present in the solution obtained in step (i) is removed by distillation at atmospheric pressure. Particular and preferred embodiments for said removal are as defined herein above.

[0175] The amount of methanol added in step (ii”), if present, is not particularly limited. In a particular embodiment, the amount of methanol added in step (ii”), if present, is from 5 to 150 vol. In an embodiment, it is from 10 to 100 vol., or even from 10 to 50 vol.

[0176] If step (ii”) is present, then the method includes a further step (ii’”) of removing part of the methanol from the solution obtained in step (ii”) by distillation at atmospheric pressure. Preferably, is present, step (ii’”) is performed until a final volume of 2-50 vol., or even 3-40 vol.

[0177] In an embodiment, the method for purifying crude Deucravacitinib, comprises:

[0178] (i) (i’) preparing a solution of crude Deucravacitinib in a mixture of dichloromethane and methanol, for example by heating;

[0179] (i”) optionally, treating the solution of step (i’) with a decolorization agent, for example with activated carbon;

[0180] (i’”) if step (i”) is present and a decolorization agent as such is used (not in the form of a filter or cartridge), removing the decolorization agent from the solution of Deucravacitinib in dichloromethane and methanol, for example by decantation and / or filtration; and

[0181] (i””) if step (i”) is present, optionally washing the decolorization agent with methanol;

[0182] (ii) (ii’) removing the dichloromethane and optionally part of the methanol from the solution obtained in step (i) by distillation at atmospheric pressure;

[0183] (ii”) optionally, adding methanol to the solution obtained in step (ii’); and

[0184] (ii’”) if step (ii”) is present, removing part of the methanol from the solution obtained in step (ii”) by distillation at atmospheric pressure;

[0185] (iii) cooling down the solution obtained in step (ii); and

[0186] (iv) separating the crystallized Deucravacitinib obtained in step (iii).

[0187] In a particular embodiment, the solution obtained in step (ii), irrespective of whether this step includes only step (ii’) or steps (ii’-ii’”), has a volume of 2-50 vol. In another embodiment, is has a volume of 3-40 vol.

[0188] In an embodiment, step (ii) is performed by distilling from the solution obtained in step (i) a volume corresponding to at least 101 % the volume of dichloromethane in said solution and to a final volume of 2-50 vol., or even 3-40 vol.

[0189] In an embodiment, step (ii) is performed by distilling from the solution obtained in step (i) a volume corresponding to at least 105% the volume of dichloromethane in said solution and to a final volume of 2-50 vol., or even 3-40 vol.

[0190] In an embodiment, step (ii) is performed by distilling from the solution obtained in step (i) a volume corresponding to at least 110% the volume of dichloromethane in said solution and to a final volume of 2-50 vol., or even 3-40 vol.

[0191] Step (Hi)

[0192] In some embodiments, Deucravacitinib may start to crystallize during step (ii), for example at the end of the distillation, without the need to cool down the solution. Nevertheless, in order to either crystalize or to complete crystallization of Deucravacitinib, in step (iii) the solution obtained in step (ii) is cooled down.

[0193] In an embodiment, in step (iii), the solution obtained in step (ii) is cooled to a temperature below 25°C, or even below 10°C. In an embodiment, it is cooled to a temperature from -20 to 25°C. In a particular embodiment, it is cooled to a temperature from -10 to 10°C. In a further embodiment, it is cooled to a temperature from 0 to 10°C.

[0194] The time range for cooling down the solution obtained in step (ii) is not particularly limited. In an embodiment, cooling of the solution can be performed in a time ranging from 0.5 to 4 h, for example from 0.5 to 3 h, to bring the temperature of the mixture preferably to a temperature below 25°C, or even below 10°C.

[0195] After step (iii), crystallized Deucravacitinib in methanol is obtained. Step (iii) can be performed for as long as needed. For example, until sufficient amount of Deucravacitinib has crystallized or until no more crystallization of Deucravacitinib is observed.

[0196] Step (iv)

[0197] In step (iv), crystallized Deucravacitinib obtained in step (iii) is separated from the mother liquor (methanol).

[0198] Separation or recovery of crystallized Deucravacitinib in step (iv) can be performed by any known technique, for example by decantation and / or filtration. In a particular embodiment, it is performed by filtration.

[0199] After separation of crystallized Deucravacitinib, step (iv) may optionally comprise washing the separated crystallized Deucravacitinib with methanol. For example, with an amount of methanol from 0.5 to 10 vol. (0.5-10 mL of methanol per each gram of starting crude Deucravacitinib; that is, per each gram of crude Deucravacitinib used to prepare the solution of crude Deucravacitinib in the mixture of dichloromethane and methanol in step (i)). In another embodiment, is may be washed with an amount of methanol from 0.5 to 5 vol.

[0200] A step of drying after separating the crystallized Deucravacitinib is not essential. For example, the inventors have observed that a dried product can be already obtained after filtration of the crystallized Deucravacitinib obtained in step (iii).

[0201] In a particular embodiment, after separation of crystallized Deucravacitinib, and optional washing of the crystallized Deucravacitinib, step (iv) may optionally comprise drying of the separated crystallized Deucravacitinib. Drying can be performed by any know technique; for example, under reduced pressure and / or under heat. In a particular embodiment, drying can be performed at a temperature of 20 to 70 °C, or even 20 to 60 °C, either at atmospheric pressure or at reduced pressure.

[0202] The Deucravacitinib obtained by the method of the invention may have a purity of at least 98%, or at least 99%. In a particular embodiment, the Deucravacitinib obtained by the method of the invention has a purity of at least 99.5%, or at least 99.6%, or even at least 99.8%. Purity can be determined by HPLC.

[0203] The Deucravacitinib obtained by the method of the invention complies with the requirements for residual solvents content set forth by the ICH guidelines (Q3C impurities, November 2022). Therefore, the Deucravacitinib obtained by the method of the invention has an amount of dichloromethane less than 600 ppm and an amount of methanol less than 3000 ppm, based on the total amount of the product.

[0204] In a particular embodiment, the Deucravacitinib obtained by the method of the invention has a total amount of residual solvents less than 3000 ppm, or even less than 2000 ppm, based on the total amount of the product. In an embodiment, the Deucravacitinib obtained by the method of the invention has a total amount of residual solvents less than 1500 ppm based on the total amount of the product. The content of residual solvents can be determined by gas chromatography.

[0205] Deucravacitinib obtained by the method of purification of the present invention is a crystalline form of Deucravacitinib preferably characterized by a X-ray powder diffraction pattern comprising peaks at 20 values (Cu-Ka radiation) of about 10.0, 12.3, 14.4, 18.9,

[0206] 19.3, 20.4, 23.6, 25.3 and 31.5 (± 0.2 degrees). In an embodiment, it comprises the following peaks at 20 values (Cu-Ka radiation): 10.0, 12.3, 14.4, 14.7, 15.8, 18.9, 19.3,

[0207] 20.4, 21.5, 23.6, 25.3, 25.4 and 31.5 (± 0.2 degrees).

[0208] According to a particular embodiment, deucravacitinib obtained by the method of purification of the present invention is a crystalline form of Deucravacitinib preferably characterized by a X-ray powder diffraction pattern comprising peaks at 20 values (Cu- Ka radiation) of about 10.0, 12.3, 12.6, 13.0, 14.4, 14.7, 15.8, 18.9, 19.3, 19.9, 20.4, 21.5, 23.6, 25.3, 25.4, 26.2, 27.2 and 31.5 (± 0.2 degrees). In an embodiment, the X-ray powder diffraction pattern further comprises one or more peaks at 20 values (Cu-Ka radiation) selected from about: 11.9, 14.0, 17.3, 18.3, 22.0, 28.2, 29.1 , 29.7, 30.3 and 30.8 (± 0.2 degrees).

[0209] In an embodiment, the X-ray powder diffraction pattern of crystalline Deucravacitinib obtained by the method of purification of the present invention is substantially as depicted in Figure 1.

[0210] Deucravacitinib obtained by the method of purification of the present invention is crystalline form of Deucravacitinib preferably characterized by:

[0211] - a Differential Scanning Calorimetry (DSC) curve showing an endothermic peak with a peak temperature of about 268.1 °C, such as from 266 to 269°C; and / or

[0212] - a Differential Scanning Calorimetry (DSC) curve showing an endothermic peak with an onset temperature of about 265.9°C, such as from 264 to 267°C; and / or

[0213] - a Differential Scanning Calorimetry (DSC) curve showing an endothermic peak with a melting enthalpy of about 95.4 J / g, such as from 95 to 96 J / g.

[0214] In an embodiment, the Differential Scanning Calorimetry (DSC) curve of crystalline Deucravacitinib obtained by the method of purification of the present invention is substantially as depicted in Figure 2.

[0215] The crystalline form obtained by the method of the invention can be stable for at least 6 months under accelerated conditions. Therefore, the claimed method allows to obtain a very stable crystalline form of deucravacitinib in high purity and with amounts of residual solvents acceptable for pharmaceutical products.

[0216] In an embodiment, the method for purifying Deucravacitinib according to the present invention is also a method for preparing said crystalline form of Deucravacitinib.

[0217] EXAMPLES

[0218] Example 1 : Synthesis of 4,6-dichloro-N-trideuteromethylpyridazine-3- carboxamide (3) from 4,6-dichloropyridazine-3-carboxylic acid methyl ester (1)

[0219] 4,6-Dichloropyridazine-3-carboxylic acid methyl ester (1) (20 g, 96.6 mmol) and acetonitrile (600 mL) were charged to a reactor at 0 / 5 °C. An aqueous solution of sodium hydroxide 10% (8 mL, 20 mmol) was added slowly to the reactor maintaining the internal temperature below 5°C. The resulting mixture was stirred at 5°C for 15 minutes. Phosphoric acid (3.2 mL, 52.2 mmol) was added. More acetonitrile was charged and concentrated under vacuum and this process was repeated more additional times to ensure removal of water. Then methyl-d3-amine hydrochloride (14 g, 198.6 mmol), T3P (50% EtOAc solution, 416 mL, 699 mmol) and pyridine (60 mL, 744.9 mmol) were added and the resulting mixture stirred at 20°C for 30 minutes. The reaction was quenched with a solution of HCI and extracted with ethyl acetate. The organic layers were washed with sodium bicarbonate and brine. The solvent was changed by distillations with heptane and the product isolated by filtration. 4,6-Dichloro-N-trideuteromethylpyridazine-3- carboxamide (3) was obtained (16 g, 79% yield).

[0220] The reaction was also carried out very efficiently using a solution of sodium hydroxide 5% (8 mL, 10 mmol), instead of the solution of sodium hydroxide 10%.

[0221] Example 2: Hydrolysis reaction

[0222] 4,6-Dichloropyridazine-3-carboxylic acid methyl ester (1) (2.0 g, 9.66 mmol) and acetonitrile (10 mL) were charged to a reactor at 0 / 5°C. An aqueous solution of sodium hydroxide 5% (8 mL, 1.0 mmol) was added slowly to the reactor maintaining the internal temperature below 5°C. The reaction was quenched with a solution of HCI. More acetonitrile was charged and concentrated under vacuum and this process was repeated more additional times to ensure removal of water. The product was isolated by filtration and washed with 4 mL of acetonitrile below 5°C to obtain 4,6-dichloropyridazine-3- carboxylic acid (2) (2.34 g, HPLC purity 98.73%).

[0223] This product can be used without further purification in the next synthetic step.

[0224] Example 3: Amidation reaction in the presence of T3P and pyridine (acetonitrile)

[0225] To a solution of 4,6-Dichloropyridazine-3-carboxylic acid (2) (15.0 g, 77.7 mmol) in acetonitrile (450 mL) were charged at 20 °C methyl-d3-amine hydrochloride (9.0 g, 127.4 mmol), T3P (50% EtOAc solution, 312 mL, 525 mmol) and pyridine (45 mL, 559 mmol) and the resulting mixture stirred at 20°C for 60 minutes. The reaction was quenched with an aqueous solution of HCI 10%. Water (300 mL) and EtOAc (450 mL) were added and the mixture was stirred for 1h. Then the aqueous phase was extracted with EtOAc 150 mL (5 times). The organic layers were washed with 300 mL of an aqueous solution of NaHCOs 7% and 300 mL of brine. The solvent of the organic phase was removed by distillation until 30V, heptane (225 mL) was added and solvents of the organic phase were removed by distillations until 30V (this step was repeated 6 times). The mixture was allowed to rise to 20°C, DCM (90 mL) was added and the mixture was heated to 40°C and was stirred for about 30 minutes. The mixture was cooled to 20 / 25°C, the solvent was removed by distillation until 30V. The mixture was stirred at 20°C for about 30 minutes and the solid was filtered off. 4,6-Dichloro-N-trideuteromethylpyridazine-3- carboxamide (3) was obtained (12.75 g)

[0226] Example 4: Amidation reaction in the presence of T3P and pyridine (dichloromethane)

[0227] 4,6-Dichloropyridazine-3-carboxylic acid (2) (1.0 g, 5.20 mmol) and DCM (30 mL) were charged to a reactor at 20 / 25 °C. Then methyl-d3-amine hydrochloride (0,7g, 9.92 mmol), T3P (50% EtOAc solution, 20.8 mL, 35 mmol) and pyridine (3,0 mL, 37.3 mmol) were added and the mixture stirred at 20 °C for 60 minutes. Analysis of the reaction by HPLC showed 82.89% conversion to compound (3).

[0228] Example 5: Amidation reaction in the presence of T3P and pyridine (tetrahydrofuran)

[0229] 4,6-Dichloropyridazine-3-carboxylic acid (2) (1.0 g, 5.20 mmol) and THF (30 mL) were charged to a reactor at 20 / 25 °C. Then methyl-d3-amine hydrochloride (0,7g, 9.92 mmol), T3P (50% EtOAc solution, 20.8 mL, 35 mmol) and pyridine (3.0 mL, 37.3 mmol) were added and the mixture stirred at 20 °C for 60 minutes. Analysis of the reaction by HPLC showed 68.37% conversion to compound (3).

[0230] Example 6: Amidation reaction in the presence of T3P and triethylamine (acetonitrile)

[0231] 4,6-Dichloropyridazine-3-carboxylic acid (2) (200 mg) and acetonitrile (6 mL) were charged to a reactor at 0 / 5 °C. Then, methyl-d3-amine hydrochloride (140 mg, 1.98 mmol), T3P (50% EtOAc solution, 4.1 mL, 6.9 mmol) and TEA (1.0 mL, 7.4 mmol) were added and the resulting mixture was stirred at 20°C for 60 minutes. Reaction was completed after 1 h and a conversion of 90.45% was observed by HPLC. Example 7: Hydrolysis followed by amidation reaction in the presence of T3P and diisopropylethylamine (dichloromethane)

[0232] 4,6-Dichloropyridazine-3-carboxylic acid methyl ester (1) (3.0 g, 14.49 mmol) and acetonitrile (90 mL) were charged to a reactor at 5 / 10°C. A solution of sodium hydroxide 5% (12 mL, 15 mmol) was added slowly to the reactor maintaining the internal temperature below 5°C. The reaction was quenched with orthophosphoric acid (0.36 mL). ACN (90 mL) was added and solvent was removed by distillations until a final volume of 90 mL twice, DCM (60 mL) was added and solvent was removed by distillation to obtain 4,6-dichloropyridazine-3-carboxylic acid (2) (2.85 g, 14.49 mmol).

[0233] DCM was charged to the solid residue. Then methyl-d3-amine hydrochloride (1.22 g, 17.38 mmol), T3P (50% solution in AcOEt, 10.36 mL, 17.38 mmol) and DIPEA (12.6 mL, 74.42 mmol) were added and the mixture was stirred at 20°C for 30 minutes. The reaction mixture was concentrated and purified by column chromatography with AcOEt / Heptane 1 :1 , to provide compound (3) (1.8 g, 60% overall yield; purity by HPLC: 94.39%).

[0234] Comparative Example 8: Amidation reaction in the presence of HATU and pyridine

[0235] 4,6-Dichloropyridazine-3-carboxylic acid (2) (200 mg, 0.96 mmol) and acetonitrile (6 mL) were charged to a reactor at 0 / 5 °C. Then methyl-d3-amine hydrochloride (140 mg, 1 .98 mmol), HATU (2.65 g, 6.97 mmol) and pyridine (0.6 mL) were added and the resulting mixture was stirred at 20 / 25 °C for 60 minutes. The reaction mass was analyzed by HPLC, where the compound 3 was only 28% of the reaction mass.

[0236] Comparative Example 9: Amidation reaction in the presence of HATU and diisopropylethylamine

[0237] 4,6-Dichloropyridazine-3-carboxylic acid (2) (200 mg, 0.96 mmol) and acetonitrile (6 mL) were charged to a reactor at 0 / 5 °C. Then methyl-d3-amine hydrochloride (140 mg, 1 .98 mmol), HATLI (2.65 g, 6.97 mmol) and DI PEA (1.3 mL) were added and the resulting mixture was stirred at 20 / 25 °C for 60 minutes. The reaction mass was analyzed by HPLC, wherein the compound 3 was hardly 1 % of the reaction mass.

[0238] Thus, Comparative Examples 8 and 9 show that this reaction using a typical condensation agent, such as HATLI did not proceed efficiently. Formation of only 28% or hardly 1%, respectively, of compound 3 was observed by HPLC in the crude mixture.

[0239] Comparative Example 10: Amidation reaction of the lithium salt (process according to Liu et al., ACS Medicinal Chemistry Letters 2022, 13, 1730-1738)

[0240] The inventors carried out the preparation of compound 35 by amidation of the lithium salt 34 under the exact same conditions as disclosed in the Supporting Information of Liu et al. and found that said reaction proceeds with only 48% yield, thus confirming the error in the yield disclosed by Liu et al.

[0241] To a suspension of 4,6-dichloropyridazine-3-carboxylic acid methyl ester (33) (2.75 g, 13.28 mmol) in acetonitrile (25 mL) and water 3 mL, was added LiBr (3.11 g) and DIPEA (6.48 mL, 4.81 g). The mixture was stirred at 25°C for 10h. The reaction mixture was filtered off and washed with acetonitrile (1 .5 mL). The product was dried under vaccuum at 55°C to give 4,6-dichloropyridazine-3-carboxylic acid lithium salt (34) (2.45 g).

[0242] To a solution of 4,6-dichloropyridazine-3-carboxylic acid lithium salt (34) (2.00 g, 10.04 mmol) in T3P (50% solution in DMF, 9.6 g) was added methyl-d3-amine hydrochloride (0.8 g, 11.39 mmol), and DIPEA (3.5 mL, 2.6 g, 20.12 mmol). The mixture was stirred 25 °C for 10h. Then, water was added (40 mL) and the product extracted with AcOEt (2 x 40 mL). The organic layer was washed with saturated aqueous NaHCCh solution (20 mL) and NH4CI (20 mL). The product was concentrated under vacuum to provide 4,6- dichloro-N-trideuteromethylpyridazine-3-carboxamide (3) (1.0 g, 48% yield; Purity by HPLC: 88.29%).

[0243] Example 11 : Synthesis of 6-chloro-4-((2-methoxy-3-(1-methyl-1 H-1,2,4-triazol-3- yl)phenyl)amino)pyridazine-3-carboxamide (4)

[0244] To a solution of 4,6-dichloro-N-trideuteromethylpyridazine-3-carboxamide (3) (8.77 g, 42.1 mmol) and 2-methoxy-3-(1-methyl-1 H-1 ,2,4-triazol-3-yl)aniline (7.8 g, 38.4 mmol) in THF (262 mL) under nitrogen atmosphere was added lithium bis(trimethylsilyl)amide (24wt% in THF) (91.8 mL, 115.94 mmol) in a dropwise manner. Under nitrogen atmosphere, the reaction was stirred for 30 minutes and then quenched with a solution of aqueous HCI (96.4 mL). Water (132 mL) was added and the solvent removed under vacuum until a final volume of 396 mL. This process was repeated 3 times. The resulting slurry was stirred at 40°C for 30 minutes, stirred at 20°C for 30 minutes, filtered and washed with water (264 mL). Then, it was dried to provide compound 4 (12.23 g, 77.4%, HPLC purity: 98.50%).

[0245] Example 12: Synthesis of Deucravacitinib (5)

[0246] 6-Chloro-4-((2-methoxy-3-(1-methyl-1 H-1 ,2,4-triazol-3-yl)phenyl)amino)-N-(methyl- d3)piridazine-3-carboxamide (4) (6 g, 15.9 mmol), cyclopropanecarboxamide (2.9 g, 34.0 mmol), Pd2(dba)3(0.030 g, 0.032 mmol), Josiphos SL-J009-2 ((S)-1-[( ?P)-2- (dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine, 0.9 g, 1.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were added to a mixture of dioxane (180 mL) and water (1 .2 mL) at room temperature. Under nitrogen atmosphere, the reaction vessel was heated to 120°C for 2 hours. The slurry was filtered and washed with dioxane (180 mL). The dioxane was removed under vacuum until a final volume of 180 mL, water (90 mL) was added and solvents were removed under vacuum until a final volume of 180 mL (repeated 3 times). Dioxane (12 mL) was added. The slurry was stirred at 40°C for 30 minutes, at 20°C for 30 minutes, filtered and washed with water (180 mL). The wet cake was suspended in 2-propanol (180 mL) at 20 / 25°C, 2-propanol (180 mL) was added, solvents were removed under vacuum until a final volume of 180 mL (repeated 3 times). The resulting slurry was stirred at 40°C for 30 minutes, stirred at 5°C for 30 minutes, filtered and washed with 2-propanol (12 mL) at 5°C, to provide Deucravacitinib (5) (4.4 g, 73.3%, HPLC purity: 99.62%).

[0247] Example 13: Synthesis of Deucravacitinib (5)

[0248] This coupling reaction was also carried out very efficiently using a very low amount of the Pd catalyst (0.08 mol%).

[0249] 6-Chloro-4-((2-methoxy-3-(1-methyl-1 H-1 ,2,4-triazol-3-yl)phenyl)amino)-N-(methyl- d3)piridazine-3-carboxamide (4) (8 g, 21.2 mmol), cyclopropanecarboxamide (3.9 g, 45.7 mmol), Pd2(dba)3(0.016 g, 0.017 mmol), Josiphos SL-J009-2 ((S)-1-[(RP)-2- (dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine, 1.2 g, 2.1 mmol) and potassium carbonate (13.6 g, 98 mmol) were added, then a mixture of dioxane (240 mL) with water (1.2 mL) was added. Under nitrogen atmosphere, the reaction vessel was heated to 130 °C for 3 hours. The slurry was filtered and the dioxane was removed under vacuum and changed for water. Dioxane (12 mL) was added. The slurry was filtered and washed with water. The wet cake was first purified by changing the water for 2-propanol. The resulting slurry was filtered and washed with 2-propanol, to provide Deucravacitinib (5) (8.0 g, 88.6 %).

[0250] Deucravacitinib obtained according to Examples 12 and 13 was used as crude Deucravacitinib in the purification process disclosed in Examples 14-19 below.

[0251] Example 14: Purification of Deucravacitinib

[0252] Crude Deucravacitinib (5) (19.24 g, 226.07 mmol), methylene chloride (20V, 385 mL) and methanol (45V, 865 mL) were charged to a reactor. The mixture was heated to 30 / 35°C to form a solution. The solution was then filtered using a carbon cartridge and the filter was washed with methanol (480 mL). The methylene chloride was removed by distillation at atmospheric pressure until a final volume of 30V (576 mL). Methanol (576 mL) was added and removed by distillation at atmospheric pressure until a final volume of 30V (576 mL). The mixture was cooled down slowly to 0 / 5°C for 90 minutes, the slurry was stirred at 0 / 5°C for 30 minutes. Product was isolated by filtration and the wet cake was washed with methanol (38 mL) and dried using vacuum oven. Pure crystalline Deucravacitinib was obtained (17.63 g, 91.6 % yield, HPLC purity: 99.88%). The product was analyzed by gas chromatography and found to have 208 ppm of CH2CI2 and 168 ppm of MeOH as residual solvents. Other residual solvents were not detected.

[0253] Example 15: Purification of Deucravacitinib

[0254] Crude Deucravacitinib (5) (1.0 g, 2.35 mmol), methylene chloride (45 mL) and methanol (20 mL) were charged to a reactor. The mixture was heated to 30 / 35°C to form a solution. The methylene chloride was removed by distillation at atmospheric pressure until a final volume of 5 mL. Methanol (5 mL) was added and solvent was removed by distillation at atmospheric pressure until a final volume of 5 mL. Product was cooled down to 0 / 5°C, isolated by filtration and the wet cake was washed with methanol (2 mL) and dried in an oven at 60°C Pure crystalline Deucravacitinib was obtained (0.92 g, 92% yield, HPLC purity: 100%). The product was analyzed by gas chromatography and found to have 400 ppm of CH2CI2 and 150 ppm of MeOH as residual solvents. Other residual solvents were not detected.

[0255] Example 16: Purification of Deucravacitinib

[0256] Crude Deucravacitinib (5) (19.0 g, 44.65 mmol), methylene chloride (855 mL) and methanol (380 mL) were charged to a reactor. The mixture was heated to form a solution. The solution was filtered through a Carbon active cartridge and the cartridge was washed with methanol (475 mL). The methylene chloride was removed by distillation at atmospheric pressure until a final volume of 570 mL. Methanol (570 mL) was added and solvent was removed by distillation at atmospheric pressure until a final volume of 570 mL. Product was cooled down to 0 / 5°C, isolated by filtration and the wet cake was washed with methanol (38 mL) and dried in an oven at 60°C. Pure crystalline Deucravacitinib was obtained (17.29 g, 91 % yield; Purity HPLC: 99.89%). The product was analyzed by gas chromatography and found to have 126 ppm of CH2CI2 and 92 ppm of MeOH as residual solvents. Other residual solvents were not detected.

[0257] Crystalline Deucravacitinib obtained according to Example 16 showed an X-ray powder diffraction pattern using Cu-Ka radiation as depicted in Figure 1 and a Differential Scanning Calorimetry (DSC) curve as depicted in Figure 2, with an endothermic peak at 268.1°C. The main XRPD date are listed in Table 1 below.

[0258] This product was found to be stable for at least 6 months under accelerated conditions.

[0259] This same crystalline form was obtained in the Examples 14, 15 and 17. Table 1

[0260] X-Ray Powder Difraction

[0261] X-Ray Powder Difraction (XRPD) patterns of the samples were obtained using a Bruker D8 Advance X-Ray diffractometer with DaVinci Geometry, with motor support between Gobel mirror for parallel-beam geometry and a motorized divergence slit for Bragg- Brentano geometry equipped with goniometer radius 420 mm and LynxEye XE detector under the following conditions: using Cu-Ka source with a wavelength of 1.5418 A without monochromator in 4-60° 2 Theta range (step size 0.0170°; time / step 1 s; Soller slit 2.5°, antiscatter slit 9 mm, divergence slit 6 mm; current 40 mA and voltage 40 KV).

[0262] DSC

[0263] Differential Scanning Calorimetry (DSC) experiments were performed using a Differential Scanning Calorimeter: Perkin-Elmer DSC7, connected to a computer with a Perkin- Elmer TAC 7 / DX interface. The sample (about 1-10 mg) was weighed in an aluminum pan. The instrument was purged with nitrogen gas at 50 mL / min. Data were collected between room temperature and 300 °C at a heating rate of 10 °C / min.

[0264] Comparative Example 17: Purification of Deucravacitinib with NMP / IPA

[0265] Deucravacitinib was purified with NMP and IPA following the method disclosed in WO2018 / 183656 (page 16) and WO2018 / 183649 (page 21).

[0266] Crude Deucravacitinib (5) (0.70 g) and NMP (4.2 mL) were heated to 70°C to form a solution. Isopropanol (2.1 mL) was added followed by compound (5) seeds (0.0030 g). After 1 h at 70°C, isopropanol (4.2 mL) was added over the course of 2 h and the mixture heated at 70°C for 1 h. The solution was cooled down and stirred overnight at 0°C. The product was isolated by filtration and the wet cake was washed with isopropanol (2 x 2.8 mL) and dried at 65°C under vacuum. Deucravacitinib (5) was obtained in 0.5235 g (74.5% yield). The product was analyzed by gas chromatography and found to have 7407 ppm of isopropanol (the limit of IPA for pharmaceutical products is 5000 ppm).

[0267] Comparative Example 18: Purification of Deucravacitinib with THF / EtOAc

[0268] Crude Deucravacitinib (5) (1.1 g, 2.58 mmol), THF (40 mL) and EtOAc (33 mL) were charged to a reactor. EtOAc (33 mL) was added and solvents were removed by distillation at atmospheric pressure until 33 mL of mixture (3 times addition EtOAc and distillation). The mixture was heated to reflux for about 90 minutes to form a solution. The mixture was cooled down to 20 / 25°C during 1 h, it was stirred at 20 / 25°C for 30 minutes and the solid was isolated by filtration and the wet cake was washed with EtOAc (3 mL) and dried in an oven at 70°C. Pure crystalline Deucravacitinib was obtained (0.845 g, 84% yield). The product was analyzed by gas chromatography and found to have 4578 ppm of THF and 8702 ppm of EtOAc as residual solvents (the limit of THF and EtOAc for pharmaceutical products is 720 ppm and 5000 ppm, respectively).

[0269] Comparative Example 19: Purification of Deucravacitinib with THF / tW / EtOAc

[0270] Crude Deucravacitinib (5) (0.5 g, 1.17 mmol), THF (15 mL) and H2O (2 mL) were charged to a reactor. THF (15 mL) was added and solvents were removed by distillation at atmospheric pressure until 15 mL of mixture, EtOAc (15 mL) was added and solvents were removed by distillation at atmospheric pressure until 15 mL of mixture (3 times addition EtOAc and distillation). The mixture was cooled down to 20 / 25°C during 1 h, it was stirred at 20 / 25°C for 30 minutes and the solid was isolated by filtration and the wet cake was washed with EtOAc (1 mL) and dried in an oven at 70°C. Pure crystalline Deucravacitinib was obtained (0.424 g, 84% yield). The product was analyzed by gas chromatography and found to have 2511 ppm of THF and 7809 ppm of EtOAc as residual solvents (the limit of THF and EtOAc for pharmaceutical products is 720 ppm and 5000 ppm, respectively).

[0271] Comparative Example 20: Preparation of crystalline form of Deucravacitinib (process according to Example 3 in WO2023 / 181075)

[0272] Deucravacitinib (200 mg) was dissolved in methanol (90 mL) at 65°C. Water (50 mL) was added to the solution at 31 °C and stirred the mixture at the same temperature for 6 hours. No solid was generated.

[0273] The mixture was stirred at 20 / 25°C 24 hours. No solid was generated.

[0274] Comparative Example 21 : Preparation of crystalline form of Deucravacitinib (process according to Example 3 in WO2023 / 181075)

[0275] Deucravacitinib (200 mg) was dissolved in methanol (90 mL) at 65°C. Water (50 mL) was added to the solution at 31 °C and stirred the mixture at the same temperature for 6 hours. No solid was generated.

[0276] The mixture was stirred at 20 / 25°C 24 hours. No solid was generated. The mixture was concentrated under vacuum and it was cooled down at 0 / 5°C. No solid was generated.

Claims

CLAIMS1 . A process for preparing a compound of formula (I) o xD3C'«VNix(I) or a salt or solvate thereof, wherein each X is independently selected from halogen, the process comprising:(a) hydrolysis of a compound of formula (II)or a salt or solvate thereof, wherein R1is C1-6 alkyl; to provide a compound of formula (III) o x■ N' x(III) and(b) reaction of the compound of formula (III), with a compound of formula (IV) D3C-NH2(IV) or a salt or solvate thereof, in the presence of T3P and a tertiary amine.

2. Process according to claim 1 , wherein the tertiary amine in step (b) is selected from the group consisting of pyridine, triethylamine, trimethylamine, tri-n-propylamine, triisopropylamine, diisopropylethylamine, diethylmethylamine, N-methylmorpholine and dimethylaminopyridine; preferably pyridine.

3. Process according to any one of claims 1 or 2, wherein step (b) is performed in the presence of an organic solvent.

4. Process according to any one of claims 1 to 3, wherein:R1is methyl, and / or X is Cl.

5. Process according to any one of claims 1 to 4, wherein step (b) is performed in the presence of T3P, pyridine and an organic solvent, such as acetonitrile.

6. Process according to any one of claims 1 to 5, wherein step (a) is performed under basic conditions, such as in the presence of an alkali metal hydroxide.

7. Process according to any one of claims 1 to 6, wherein the process further comprises converting the compound of formula (I), or a salt thereof, into Deucravacitinib or a salt or solvate thereof8. Process according to claim 7, wherein conversion of the compound of formula (I), or a salt thereof, into Deucravacitinib or a salt or solvate thereof comprises:(c) reaction of the compound of formula (I), or a salt or solvate thereof, with a compound of formula (V)or a salt or solvate thereof, to provide a compound of formula (VI)or a salt or solvate thereof; and(d) reaction of the compound of formula (VI), or a salt or solvate thereof, with a compound of formula (VII)or a salt or solvate thereof.

9. Process according to any one of claims 8 or 9, wherein step (d) is performed in the presence of Pd2(dba)3 and (2R)-1-[(1 R)-1-[Bis(1 ,1-dimethylethyl)phosphino]ethyl]- 2-(dicyclohexylphosphino)ferrocene.

10. Method for purifying Deucravacitinib, comprising:(i) preparing a solution of crude Deucravacitinib in a mixture of dichloromethane and methanol,(ii) removing the dichloromethane and optionally part of the methanol from the solution obtained in step (i) by distillation at atmospheric pressure,(iii) cooling down the solution obtained in step (ii), and(iv) separating the crystallized Deucravacitinib obtained in step (iii).

11. Method according to claim 10, wherein:- the v / v ratio of dichloromethane and methanol in the mixture of dichloromethane and methanol in step (i) is from 50:1 to 1 :50 (CH2CH2:MeOH), such as from 10:1 to 1 :10; and / or- the amount of mixture of dichloromethane and methanol in the solution of crude Deucravacitinib in a mixture of dichloromethane and methanol in step (i) is equal to or higher than 20 vol., such as equal to or higher than 40 vol.; and / or- the solution of crude Deucravacitinib in a mixture of dichloromethane and methanol in step (i) comprises 10-100 vol. of dichloromethane and 10-150 vol. of methanol, such as 15-80 vol. of dichloromethane and 15-100 vol. of methanol; and / or- step (i) is performed by heating crude Deucravacitinib, dichloromethane and methanol at a temperature from 30°C to reflux temperature.

12. Method according to any one of claims 10 or 11 , wherein step (ii) is performed by distillation at atmospheric pressure until removal of the dichloromethane and to a final volume of 2-50 vol., such as 3-40 vol.

13. Method according to any one of claims 10 to 12, wherein step (iii) comprises cooling down the solution obtained in step (ii) to a temperature between -20°C and 20°C, such as between -10°C and 10°C.

14. Method according to any one of claims 10 to 13, wherein step (iii) comprises:(i) (i’) preparing a solution of crude Deucravacitinib in a mixture of dichloromethane and methanol, for example by heating;(i”) optionally, treating the solution of step (i’) with a decolorization agent, for example with activated carbon;(i’”) if step (i”) is present and a decolorization agent as such is used (not in the form of a filter or cartridge), removing the decolorization agent from the solution of Deucravacitinib in dichloromethane and methanol, for example by decantation and / or filtration; and(i””) if step (i”) is present, optionally washing the decolorization agent with methanol;(ii) (ii’) removing the dichloromethane and optionally part of the methanol from the solution obtained in step (i) by distillation at atmospheric pressure;(ii”) optionally, adding methanol to the solution obtained in step (ii’); and(ii’”) if step (ii”) is present, removing part of the methanol from the solution obtained in step (ii”) by distillation at atmospheric pressure;(iii) cooling down the solution obtained in step (ii); and(iv) separating the crystallized Deucravacitinib obtained in step (iii), and optionally washing and / or drying.

15. Method according to any one of claims 10 to 14, wherein crystalline Deucravacitinib with a X-ray powder diffraction pattern comprising peaks at 20 values (Cu-Ka radiation) of about 10.0, 12.3, 12.6, 13.0, 14.4, 14.7, 15.8, 18.9, 19.3, 19.9, 20.4, 21.5, 23.6, 25.3, 25.4, 26.2, 27.2 and 31.5 (± 0.2 degrees) is obtained.

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