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WO2025186427A1 - Procédé de préparation de deucravacitinib et d'intermédiaires de celui-ci et procédé de purification de deucravacitinib - Google Patents

Procédé de préparation de deucravacitinib et d'intermédiaires de celui-ci et procédé de purification de deucravacitinib

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Publication number
WO2025186427A1
WO2025186427A1 PCT/EP2025/056245 EP2025056245W WO2025186427A1 WO 2025186427 A1 WO2025186427 A1 WO 2025186427A1 EP 2025056245 W EP2025056245 W EP 2025056245W WO 2025186427 A1 WO2025186427 A1 WO 2025186427A1
Authority
WO
WIPO (PCT)
Prior art keywords
deucravacitinib
methanol
compound
formula
dichloromethane
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/056245
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English (en)
Other versions
WO2025186427A8 (fr
Inventor
Jesús Miguel IGLESIAS RETUERTO
Juan José FERREIRO GIL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Curia Spain SA
Original Assignee
Curia Spain SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Curia Spain SA filed Critical Curia Spain SA
Publication of WO2025186427A1 publication Critical patent/WO2025186427A1/fr
Publication of WO2025186427A8 publication Critical patent/WO2025186427A8/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • 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.
  • Deucravacitinib (6-(cyclopropanecarboxamido)-4-[2-methoxy-3-(1-methyl-1 H- 1 ,2,4- triazol-3-yl)anilino]-N-( 2 H3)methylpyridazine-3-carboxamide), is a tyrosine kinase 2 (TYK2) inhibitor used for the treatment of plaque psoriasis.
  • TYK2 tyrosine kinase 2
  • 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).
  • 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%.
  • Purification method (a) i.e. using NMP and iPrOH as disclosed in WO2018/183649, yields a very stable crystalline form of Deucravacitinib.
  • this method gives rise to Deucravacitinib with a high content of residual solvents.
  • 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.
  • the invention faces the problem of providing a new process for the preparation of Deucravacitinib and intermediates thereof.
  • 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.
  • 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:
  • 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.
  • 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.
  • the invention is directed to a method for purifying Deucravacitinib, comprising:
  • step (ii) removing the dichloromethane and optionally part of the methanol from the solution obtained in step (i) by distillation at atmospheric pressure,
  • step (iv) separating the crystallized Deucravacitinib obtained in step (iii).
  • the invention is directed to Deucravacitinib obtained or obtainable by the method of the third aspect.
  • FIG. 1 shows the x-ray powder diffraction pattern of crystalline Deucravacitinib obtained by the purification method of the invention.
  • FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of crystalline Deucravacitinib obtained by the purification method of the invention.
  • compositions encompasses the terms “consisting essentially of” and “consisting of’.
  • the term “comprising” may be replaced with the term “consisting essentially of” or “consisting of”.
  • 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.
  • the term “about” is meant to encompass variations of ⁇ 10%, or ⁇ 5%, or even ⁇ 1 %, of the specified amount.
  • 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.
  • alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl. Preferably, it is methyl or ethyl.
  • halogen refers to bromine, chlorine, iodine or fluorine.
  • the invention also provides “salts” of some of the compounds described herein.
  • 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.
  • 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.
  • 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,
  • 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.
  • organic base salts such as, for example, ethylenediamine, ethanolamine, /V,/V-dialkylenethanolamine, triethanolamine, glutamine, amino acid basic salts, etc.
  • metal salts include, for example, sodium, potassium, calcium, magnesium, aluminium and lithium salts.
  • 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.
  • solvates e.g., hydrates, alcoholates, etc.
  • the solvation methods are generally known in the state of the art.
  • the solvate is a hydrate.
  • 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.
  • cyclic and acyclic ethers e.g. Et20, iPr2O, tBu2O, MeOtBu, 1,4-dioxane, 1,3-dioxolane, 1,2-dimethoxyethane (DME), tetra hydrofuran (THF), methyl
  • esters e.g. EtOAc, iPrOAc, nBuOAc
  • nitriles e.g. acetonitrile, benzonitrile
  • amides e.g. DMF, DMA, HMPA, NMP
  • alcohols e.g. methanol, ethanol, propanol,
  • 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)).
  • 1 vol. means 1 mL of solvent per 1 g of crude Deucravacitinib.
  • 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.
  • T3P 1-propylphosphonic acid cyclic anhydride
  • 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.
  • HATU a typical condensation agent
  • 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:
  • 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.
  • R 1 is ethyl or methyl. In a particular embodiment, R 1 is methyl.
  • each X is independently Cl or Br. In a particular embodiment, X is Cl.
  • R 1 is methyl and X is Cl.
  • the compound of formula (III) can be obtained by hydrolysis of a compound of formula (II), or a salt or solvate thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • the hydrolysis reaction is performed in the presence of an acid selected from HCI, HBr, H3PO4 and H2SO4.
  • 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.
  • the reaction is carried out in the presence of water and an organic solvent.
  • 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.
  • the organic solvent is selected from acetonitrile, THF, DMF and EtOAc; or even it is acetonitrile.
  • the water is removed from the reaction mixture before compound (III) is subjected to the next reaction step.
  • said water can be removed by distillation.
  • the reaction product is distilled to remove the reaction solvent (water + organic solvent).
  • 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.
  • 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.
  • 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.
  • the reaction is carried out in the presence of a base, water and an organic solvent.
  • 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.
  • 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.
  • an alkali metal hydroxide such as NaOH, KOH o LiOH
  • water and an organic solvent such as acetonitrile
  • 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).
  • 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.
  • the reaction is performed at a temperature between 0°C and 60°C, such as 0-30°C, or even 0-10°C.
  • 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.
  • the compound of formula (IV) is in the form of its hydrochloride salt; that is, the compound of formula (IV) is D3C-NH2 HCI.
  • 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.
  • Tertiary amines include, among others, pyridine, triethylamine, trimethylamine, tri- n-propylamine, triisopropylamine, diisopropylethylamine, diethylmethylamine, N- methylmorpholine and dimethylaminopyridine.
  • the tertiary amine is selected from pyridine, triethylamine and diisopropylethylamine.
  • the tertiary amine is selected from pyridine and triethylamine.
  • the tertiary amine is pyridine.
  • 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).
  • 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.
  • 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).
  • 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.
  • the T3P can be used as a solution in an organic solvent, such as a solution in acetonitrile, EtOAc, dichloromethane, DMF, or 2-methyltetrahydrofuran.
  • organic solvent such as a solution in acetonitrile, EtOAc, dichloromethane, DMF, or 2-methyltetrahydrofuran.
  • 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).
  • 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.
  • the reaction is carried out in the presence of an organic solvent.
  • 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.
  • 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.
  • the reaction is carried out in the presence of T3P, a tertiary amine and an organic solvent.
  • 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.
  • the reaction is carried out in the presence of T3P, pyridine, and an organic solvent, such as acetonitrile, THF, DMF, EtOAc or CH2CI2.
  • the reaction is carried out in the presence of T3P, pyridine, and acetonitrile.
  • 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.
  • 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.
  • the reaction mixture is distilled or evaporated to ensure removal of water and the resulting crude product is subjected to step (b).
  • 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).
  • 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:
  • 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.
  • 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.
  • 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.
  • 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).
  • alkali metal bases such as organic and inorganic alkali metal bases
  • alkali metal hydroxides e.g. NaOH, KOH, LiOH
  • alkali metal amides e.g. LiHMDS, NaHMDS, KHMDS, LDA
  • C1-6 alkyllithium compounds n-BuLi, n-HexLi, s-BuLi
  • 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
  • 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
  • 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.
  • 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.
  • cyclic and acyclic ethers e.g. Et20, iPr2O, tBu2O, MeOtBu, 1 ,4-dioxane, 1 ,3-dioxolane, 1 ,2-dimethoxyethan
  • the organic solvent is selected from acetonitrile, THF, DMF, EtOAc and CH2CI2. In a particular embodiment, the organic solvent is THF.
  • 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.
  • 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.
  • the reaction is performed at a temperature between 0°C and 60°C, such as 10-40°C, or even 15-30°C.
  • 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.
  • 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.
  • the Pd catalyst can be selected from Pd 3 (dba) 3 , Pd(dba)2, Pd(OAc)2, PdCI 2 (MeCN) 2 , [(allyl)PdCI] 2 , Pd(PPh 3 ) 4 , Pd(P‘Bu 3 ) 2 , Pd(PCy 3 ) 2 , Pd(PPh 3 ) 2 CI 2 , Pd(P(o- tol) 3 ) 2 CI 2 , Pd(PCy 3 ) 2 CI 2 , Pd(P t Bu 2 Ph) 2 CI 2 , Pd(P t BuCy 2 ) 2 CI 2 , Pd(P t Bu 2 n Bu) 2 CI 2 , Pd(amphos)CI 2 , Pd(dppe) 2 CI 2 , Pd(dppp) 2 CI 2 , Pd(dppb) 2 CI 2 , Pd(dppf)CI 2 , Pd(d
  • the Pd catalyst is selected from Pd 2 (dba) 3 , Pd(dba) 2 , Pd(OAc) 2 , PdCI 2 (MeCN) 2 , [(allyl)PdCI] 2 .
  • the Pd catalyst is Pd 2 (dba) 3 or Pd(OAc) 2 .
  • the Pd catalyst is Pd 2 (dba) 3 .
  • 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.
  • the amount of the Pd catalyst such as Pd 2 (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.
  • 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
  • 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.
  • 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.
  • 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.
  • the base is selected from alkaline carbonates, bicarbonates and phosphates, such as Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaHCO 3 , Na 3 PC>4 or K 3 PC>4.
  • the base is selected from K 2 CO 3 , Cs 2 CO 3 , and K 3 PC>4.
  • the base is K 2 CO 3 .
  • 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.
  • 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.
  • ethers e.g. Et20, iP ⁇ O, tBu2O, MeOtBu, 1 ,4-dioxane, 1 ,3-dioxolane, 1 ,2- dimethoxyethane (DME),
  • the organic solvent is an ether, such as 1 ,4-dioxane,
  • the organic solvent is 1 ,4-dioxane.
  • the organic solvent is acetonitrile, toluene or a mixture thereof.
  • 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.
  • the organic solvent is selected from an ether, an aromatic solvent, acetonitrile or a mixture thereof.
  • 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.
  • said solvent is
  • 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.
  • the reaction is performed also in the presence of water.
  • the volume ratio of organic solventwater may be in the range 10:1 to 250:1 v/v.
  • 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.
  • 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.
  • WO2023/181075 discloses in Example 3 the preparation of crystalline deucravacitinib (Figure 3) from methanol-water.
  • 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).
  • 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.
  • the invention is directed to a method for purifying crude Deucravacitinib, comprising:
  • step (ii) removing the dichloromethane and optionally part of the methanol from the solution obtained in step (i) by distillation at atmospheric pressure,
  • step (iv) separating the crystallized Deucravacitinib obtained in step (iii).
  • This method does not include the addition of other solvents different from dichloromethane and methanol.
  • 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.
  • crude Deucravacitinib is obtained by a process as described herein.
  • 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.
  • 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.
  • 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).
  • the v/v ratio CFLCF ⁇ MeOH is 1 :10 to 10:1.
  • the v/v ratio CFLCF ⁇ MeOH is 1 :5 to 5:1.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a step of removing the decolorization agent from the solution of Deucravacitinib in dichloromethane and methanol is not required.
  • 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.
  • 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).
  • step (i) in the method for purifying Deucravacitinib comprises:
  • step (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;
  • a decolorization agent for example with activated carbon, either as such or in the form of a filter or cartridge;
  • step (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
  • step (i””) if step (i”) is present, optionally washing the decolorization agent with methanol.
  • step (i) a solution of crude Deucravacitinib in dichloromethane and methanol is obtained.
  • the solution of crude Deucravacitinib in a mixture of dichloromethane and methanol 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.
  • the solution of crude Deucravacitinib in a mixture of dichloromethane and methanol 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.
  • 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.
  • 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.
  • step (i) 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.
  • Part of the methanol can be also removed in step (ii).
  • step (ii) comprises removing the dichloromethane and also part of the methanol by distillation at atmospheric pressure.
  • 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.
  • 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).
  • 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)).
  • step (ii) is performed by distillation at atmospheric pressure until removal of the dichloromethane and to a final volume of 3-40 vol.
  • 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.
  • the desired final volume e.g 2-50 vol., or even 3-40 vol.
  • 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.
  • 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.
  • 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.
  • 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.
  • step (ii) comprises:
  • step (ii’) removing the dichloromethane and optionally part of the methanol from the solution obtained in step (i) by distillation at atmospheric pressure;
  • step (ii”) optionally, adding methanol to the solution obtained in step (ii’);
  • step (ii’”) if step (ii”) is present, removing part of the methanol from the solution obtained in step (ii”) by distillation at atmospheric pressure.
  • Steps (ii”) and (ii’”) can be performed one or more times, for example one, two or three times.
  • 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.
  • 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.
  • step (ii) 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.
  • step (ii’) is performed until a final volume of 2-50 vol., or even 3-40 vol.
  • the method for purifying crude Deucravacitinib comprises:
  • step (i”) optionally, treating the solution of step (i’) with a decolorization agent, for example with activated carbon;
  • step (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
  • step (ii) removing the dichloromethane and optionally part of the methanol from the solution obtained in step (i) by distillation at atmospheric pressure;
  • step (ii”) optionally, adding methanol to the solution obtained in step (ii’);
  • step (ii’”) if step (ii”) is present, removing part of the methanol from the solution obtained in step (ii”) by distillation at atmospheric pressure;
  • step (iv) separating the crystallized Deucravacitinib obtained in step (iii).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the time range for cooling down the solution obtained in step (ii) is not particularly limited.
  • 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.
  • 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.
  • step (iv) crystallized Deucravacitinib obtained in step (iii) is separated from the mother liquor (methanol).
  • 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.
  • step (iv) may optionally comprise washing the separated crystallized Deucravacitinib with methanol.
  • 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)).
  • is may be washed with an amount of methanol from 0.5 to 5 vol.
  • 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.
  • the Deucravacitinib obtained by the method of the invention may have a purity of at least 98%, or at least 99%.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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).
  • 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.
  • DSC Differential Scanning Calorimetry
  • DSC Differential Scanning Calorimetry
  • DSC Differential Scanning Calorimetry
  • 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.
  • 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.
  • the method for purifying Deucravacitinib according to the present invention is also a method for preparing said crystalline form of Deucravacitinib.
  • Example 1 Synthesis of 4,6-dichloro-N-trideuteromethylpyridazine-3- carboxamide (3) from 4,6-dichloropyridazine-3-carboxylic acid methyl ester (1)
  • 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.
  • 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%.
  • This product can be used without further purification in the next synthetic step.
  • 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.
  • 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).
  • 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), Pd 2 (dba) 3 (0.016 g, 0.017 mmol), Josiphos SL-J009-2 ((S)-1-[(R P )-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.
  • 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 %).
  • Deucravacitinib obtained according to Examples 12 and 13 was used as crude Deucravacitinib in the purification process disclosed in Examples 14-19 below.
  • 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.
  • This product was found to be stable for at least 6 months under accelerated conditions.
  • 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).
  • DSC Differential Scanning Calorimetry
  • Deucravacitinib was purified with NMP and IPA following the method disclosed in WO2018/183656 (page 16) and WO2018/183649 (page 21).
  • 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).
  • Comparative Example 20 Preparation of crystalline form of Deucravacitinib (process according to Example 3 in WO2023/181075)
  • the mixture was stirred at 20/25°C 24 hours. No solid was generated.
  • 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.
  • 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.

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Abstract

La présente invention concerne un procédé de préparation d'un composé de formule (I), qui est un intermédiaire pour produire du deucravacitinib. L'invention concerne également un procédé de cristallisation pour purifier le deucravacitinib.
PCT/EP2025/056245 2024-03-08 2025-03-07 Procédé de préparation de deucravacitinib et d'intermédiaires de celui-ci et procédé de purification de deucravacitinib Pending WO2025186427A1 (fr)

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