Benzyl (3-(methyl(7h-pyrrolo[2,3-d]pyrimidin-4yl)amino)cyclobutyl) carbamate or a salt thereof, method for the preparation thereof, and use thereof in the synthesis of abrocitinib

Abstract

Benzyl (3-(methyl(7h-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)carbamate or a salt thereof, method for the preparation thereof, and use thereof in the synthesis of abrocitinib The present invention relates to a new intermediate useful in the synthesis of abrocitinib, to a method for obtaining same, to the use of said intermediate for preparing abrocitinib, and to a method for preparing abrocitinib using said intermediate.

Description

[0001] DESCRIPTION

[0002] BENZYL (3-(METHYL(7 / 7-PYRROLO[2,3-D]PYRIMIDIN-4YL)AMINO)CYCLOBUTYL)

[0003] CARBAMATE OR A SALT THEREOF, METHOD FOR THE PREPARATION THEREOF, AND USE THEREOF IN THE SYNTHESIS OF ABROCITINIB

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to a new intermediate useful in the synthesis of abrocitinib, to a method for obtaining same, to the use of said intermediate for preparing abrocitinib, and to a method for preparing abrocitinib using said intermediate.

[0006] BACKGROUND OF THE INVENTION

[0007] Abrocitinib, the chemical name of which is / V-[c / s-3-(methyl-7 / 7-pyrrolo[2,3-d]pyrimidin-4- ylamino)cyclobutyl]-1 -propanesulfonamide, is a Janus kinase JAK1 -inhibiting pharmaceutical active ingredient indicated for the treatment of moderate to severe atopic dermatitis in adult candidates for systemic therapy. Abrocitinib is a compound of formula (VIII)

[0008] Abrocitinib was approved for medical use in the United States in January 2022 and in Europe in December 2021.

[0009] Several synthetic routes have been described for the preparation of abrocitinib (VIII), see for example, documents EP 2 958 921 B1 and WO 2020 / 008391A.

[0010] Document EP 2958921 B1 describes five alternative methods for the preparation of abrocitinib analogs. In particular, scheme 2 describes the following method:

[0011] In said method, benzyl cis-[3-(methylamino)cyclobutyl]carbamate is designated as the synthetic intermediate which reacts with 2,4-dichloro-7-H-pyrrolo-(2,3-d)pyrimidine through an aromatic nucleophilic substitution reaction. After the deprotection of the benzyl carbamate, which proceeds together with the dechlorination of the pyrimidine ring, formation of the desired sulfonamide takes place in the presence of trimethylsilane derivatives, which are used in superstoichiometric amounts.

[0012] Document WO 2020 / 008391A describes an alternative synthetic route for abrocitinib which proceeds according to the following synthetic scheme: A key step of this synthetic route is the Lossen rearrangement that allows preparing amine E from hydroxylamide D, the preparation of which is described with an overall yield of 38% for conversion steps A to D. The preparation of abrocitinib from compound D has an overall yield of 59.87%.

[0013] Vazquez et al., Journal of Medicinal Chemistry 2018, 61 , 1130-1152, describe a method of preparing abrocitinib through aromatic nucleophilic substitution following a route similar to the one described in document EP2 958 921 B1 , but using a derivative in which nitrogen of the pyrrole ring is protected by a tosyl group (compound 25 is prepared from compound 48a). A synthetic route is described for abrocitinib analogs using an unprotected heterocyclic system and following a route similar to the one described in document EP2 958 921 B1 :

[0014] According to this document, the 98% yield of the aromatic nucleophilic substitution step is due to the presence of the chlorine atom in position 2 of the pyrimidine ring which activates the chlorine atom in position 4 of said ring as a leaving group. Following this method, the sulfonamide formation step takes place with yields of between 21 and 65% according to the sulfonyl chloride compound used in said step.

[0015] Connor et al., Organic Process Research and Development 2021 , 25, 608-615, describe the development of a commercial method for the synthesis of abrocitinib based on a nitrene group rearrangement reaction, describing the Curtius, Hoffmann, and Lossen rearrangement reactions for introducing amino group in cyclobutyl moiety. In particular, the synthetic route described is the same as the one described in document WO 2020 / 008391 A and is described with the following yields:

[0016]

[0017] There is a need in the state of the art for methods for obtaining abrocitinib with a reduced number of synthetic steps and / or a higher overall synthetic yield.

[0018] SUMMARY OF THE INVENTION The inventors have discovered a new abrocitinib synthetic intermediate which allows preparing abrocitinib with a higher yield and savings in atoms.

[0019] In particular, the abrocitinib synthetic intermediate of the invention, which is a compound of formula (I), allows abrocitinib to be prepared with a high yield in two steps and with an overall yield of 78.6%, according to the following scheme

[0020] Abrocitinib yield 78.6%

[0021] The overall yield of said synthesis is surprisingly higher compared to that described in the state of the art using benzyl (cis-3-((2-chloro-7 / 7-pyrrolo[2,3-d]pyrimidin-4- yl)(methyl)amino)cyclobutyl)carbamate as the starting product, for which a yield of 76% is described for the step of benzyl carbamate group deprotection, which is lower than the overall yield observed using the synthetic intermediate of the invention. Furthermore, as shown in the examples, the compound of formula (I) can be prepared through aromatic nucleophilic substitution by means of the following reaction with a yield of 98.3%:

[0022] It is surprising because the presence of a Cl atom in position 2 of the pyrimidine ring system is known to activate the Cl atom in position 4 as a leaving group and it is necessary in order to ensure an efficient reaction and a high yield. Surprisingly, said reaction takes place at lower temperatures than the methods described in the state of the art using dichlorinated precursor without observing any significant loss in yield. Furthermore, by dispensing with this Cl group in position 2, the atom savings in the synthesis of abrocitinib are substantial, which allows synthetic residues to be generated with lower amounts of chlorinated species, giving rise to a more sustainable method.

[0023] Likewise, a first aspect of the invention relates to a compound of formula (I) or a salt thereof wherein the bonds represented by a wavy line are in the c / s configuration.

[0024] As indicated above, this compound is useful in the preparation of abrocitinib. The second aspect of the invention relates to the use of the compound of formula (I) or a salt thereof according to the first aspect of the invention in the preparation of abrocitinib. A third aspect of the invention relates to a method of preparing a compound of formula (I) according to the first aspect of the invention which comprises step (a) of reacting a compound of formula (II), wherein the bonds represented by a wavy line are in the c / s configuration, or a salt thereof, with a compound of formula (III) or a salt thereof,

[0025] (H) (HI)

[0026] The fourth aspect of the invention relates to a method for preparing / V-[c / s-3-(methyl-7 / 7- pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclobutyl]-1 -propanesulfonamide (abrocitinib), or a salt thereof, characterized in that it comprises:

[0027] (f) reacting a compound of formula (I) or a salt thereof according to the first aspect of the invention to remove the benzyloxycarbonyl -CChC^Ph group, obtaining an amino -NH2 group; and

[0028] (g) reacting the compound resulting from step (f) to convert the amino group formed from the benzyl carbamate group of the compound of formula (I) or the salt thereof into a group of formula -NHSO2CH2CH2CH3.

[0029] DESCRIPTION OF THE FIGURES

[0030] Figure 1 shows the X-ray powder diffractogram (XRPD) obtained for the product of formula (I), i.e. , benzyl (3-(methyl(7 / 7-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)carbamate.

[0031] DETAILED DESCRIPTION OF THE INVENTION

[0032] In the context of the invention, the term “salt” must be understood as an ionic compound formed by a cation of the amino group of the compound of formula (I) or (II), and a counterion (an anion) such as, for example, an anion of an inorganic acid (such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate, among others) or an organic acid (such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate, among others). In the context of the present invention, the terms “approximate” and “about”, in reference to a value, refer to any value which is comprised in the interval defined by the value ± 5% of said value.

[0033] In the context of the present invention, the term “acid” refers to a substance capable of donating a proton (to a base). Said substance can be inorganic, as in the case of hydrochloric, nitric, sulfuric, phosphoric, hydrobromic, and boric acids, or organic as in the case of formic, acetic, trifluoroacetic, propionic, oxalic, malic, maleic, fumaric, succinic, citric, tartaric, mandelic, methanesulfonic, p-toluenesulfonic, and benzoic acids.

[0034] In the context of the present invention, the term “base” refers to a substance capable of accepting a proton (from an acid). Said substance can be inorganic, as in the case of hydroxide salts of alkaline metals and carbonate salts of alkaline metals and alkaline earth metals, or organic as in the case of pyridine, imidazole, and tertiary amines of formula NR1R2R3, wherein each R1 , R2, or R3 is an alkyl(Ci-Ce) group.

[0035] In the context of the present invention, the term “alkaline metal” refers to a metal selected from the group consisting of lithium, sodium, potassium, rubidium, cesium, and francium. Preferably, the alkaline metal is selected from the group consisting of lithium, sodium, and potassium; more preferably, it is sodium or potassium, and even more preferably potassium.

[0036] Compound of formula (I) or a salt thereof

[0037] In a particular embodiment of the first aspect of the invention, the compound of formula (I) or the salt thereof is in a solid form.

[0038] In a particular embodiment of the first aspect of the invention, the compound of formula (I) has an X-ray powder diffractogram measured with CuKa radiation comprising peaks at one or more of 12.0, 13.3, 14.4, 17.8, 19.8, and 23.9 20, all of them with a margin of error of ± 0.2° 20.

[0039] In a particular embodiment of the first aspect of the invention, the compound of formula (I) has an X-ray powder diffractogram measured with CuKa radiation comprising peaks at 12.0, 13.3, 14.4, 17.8, 19.8, and 23.9 20, all of them with a margin of error of ± 0.2° 20.

[0040] In a particular embodiment of the first aspect of the invention, the compound of formula (I) has an X-ray powder diffractogram measured with CuKa radiation essentially like the one of Figure 1. X-ray diffractograms can be recorded using a powder diffraction system with a copper anode which emits CuKa radiation with a wavelength of 1.54 A, particularly following the method described in the examples.

[0041] In a particular embodiment of the first aspect of the invention, the compound of formula (I) has a differential scanning calorimetry (DSC) diagram comprising an endothermic peak having a threshold temperature of about 180.5°C ± 2°C.

[0042] The differential scanning calorimetry diagram can be obtained as described in the examples.

[0043] The threshold temperature or “T onset” refers to the temperature resulting from extrapolating the baseline before the start of transition and the baseline during the absorption of energy (tangent of the curve). It can be calculated as defined in the DIN ISO 11357-1 :2016(E) standard.

[0044] Use of the compound of formula (I) or a salt thereof in the preparation of abrocitinib

[0045] As defined above, a second aspect of the invention relates to the use of the compound of formula (I) or a salt thereof in the preparation of abrocitinib.

[0046] Method of preparing the compound of formula (I) or a salt thereof

[0047] As defined above, the third aspect of the invention relates to a method of preparing a compound of formula (I) or a salt thereof which comprises step (a) of reacting a compound of formula (II), wherein the bonds represented by a wavy line are in the c / s configuration, or a salt thereof, with a compound of formula (III) or a salt thereof,

[0048] In a preferred embodiment of the third aspect of the invention, step (a) is carried out in the presence of a base. Said base is preferably an alkaline salt of carbonate such as, for example, sodium carbonate or potassium carbonate. More preferably, the base is potassium carbonate. The base is preferably present in an amount such that the molar ratio of the base with respect to the compound of formula (I) is between 2:1 and 3:1 , more preferably about 2.4:1.

[0049] In a preferred embodiment of the third aspect of the invention, step (a) is carried out in the presence of molar excess of the compound of formula (III) with respect to the compound of formula (II), said molar excess preferably being between 0.1% and 5% with respect to the amount of the compound of formula (II).

[0050] In a preferred embodiment of the third aspect of the invention, step (a) is carried out in the presence of water as a solvent.

[0051] In a preferred embodiment of the third aspect of the invention, step (a) is carried out in the presence of a salt of the compound of formula (II). Said salt is formed from the amino groups of the compound of formula (II) and an acid. The acid used to form the salt of the compound of formula (II) can be organic or inorganic, as described above. Preferably, the salt of the compound of formula (II) is a hydrochloride salt.

[0052] In a preferred embodiment of the third aspect of the invention, step (a) is carried out at a temperature of at least 50°C, preferably between 50°C and 95°C, more preferably between 50°C and 70°C, and even more preferably about 60°C.

[0053] In a preferred embodiment of the third aspect of the invention, step (a) is carried out in the presence of an aqueous base solution, preferably an alkaline salt of carbonate, and / or at a temperature of between 50°C and 70°C, preferably about 60°C.

[0054] The aqueous solution of the alkaline salt of carbonate of the particular embodiments of step (a) of the third aspect of the invention preferably has a concentration of between 1 M and 2 M, preferably 1.45 M.

[0055] In other preferred embodiments of the third aspect, the method of preparing the compound of formula (I) or a salt thereof comprises the previous step (b) of preparing the compound of formula (II), wherein said step (b) comprises:

[0056] (b-1) reacting a compound of formula (IV) with methylamine to convert the carbonyl group of the compound of formula (IV) into a methylimine group or a salt thereof, and

[0057] (b-2) reacting the product of step (b-1) to convert the methylimine group or a salt thereof into a methylamine group.

[0058] In a preferred embodiment of the third aspect of the invention, steps (b-1) and (b-2) are carried out in the presence of a polar protic solvent, such as methanol, ethanol, or isopropanol. Preferably, the solvent is methanol. In a preferred embodiment of the third aspect of the invention, steps (b-1) and (b-2) are carried out without isolating the product of step (b-1).

[0059] In a preferred embodiment of the third aspect of the invention, step (b-1) is carried out in the presence of an acid. Said acid is preferably an organic acid and more preferably acetic acid. The function of the acid is to catalyze the formation of the methylimine group and facilitate the reduction of said group into a methylamine group in step (b-2), when it is carried out by means of catalytic hydrogenation.

[0060] Likewise, in other preferred embodiments of the third aspect, step (b-2) is carried out by means of catalytic hydrogenation. In said embodiment, it is preferred that the catalyst is platinum, preferably Pt / C.

[0061] In other preferred embodiments of the third aspect of the invention, step (b-2) further comprises converting the product of step (b-2), i.e. , the compound of formula (II), into a hydrochloride salt. When step (b-2) is carried out in the presence of an acid, for example in the presence of acetic acid, the hydrochloride salt can be prepared by means of treatment using a base, for example using an aqueous solution of an alkaline carbonate such as potassium carbonate, followed by treatment with an aqueous hydrochloric acid solution. Such deprotonation / protonation exchanges are known in the art and one skilled in the art will have no difficulty in reducing same to practice.

[0062] In other preferred embodiments of the third aspect, the method of preparing the compound of formula (I) or a salt thereof comprises the previous step (c) of preparing the compound of formula (IV), wherein said step (c) comprises reacting a compound of formula (V) to form a compound of formula (IV)

[0063] Methods of deprotecting an acetal group to form the corresponding carbonyl compound are known in the art and can be used for step (c). However, it is preferred that step (c) is carried out by means of the acid hydrolysis of the compound of formula (V). Preferably, the compound of formula (V) is treated with hydrochloric acid in a 1 :1 v / v mixture of tetrahydrofuran with water.

[0064] In other preferred embodiments of the third aspect, the method of preparing the compound of formula (I) or a salt thereof comprises the previous step (d) of preparing the compound of formula (V), wherein said step (d) comprises reacting a compound of formula (VI) to form a compound of formula (V)

[0065] In other preferred embodiments, step (d) comprises:

[0066] (d-1) reacting a compound of formula (VI) to convert the -CONHOH group into an isocyanate group, and

[0067] (d-2) reacting the product of step (d-1) with benzyl alcohol.

[0068] Likewise, said transformation preferably comprises step (d-1) of converting the compound of formula (VI) into a compound of formula (VI’) by means of reacting the compound of formula (VI) with phosgene or carbonyldiimidazole; preferably with carbonyldiimidazole.

[0069] It is preferred that the compound of formula (VI’) is not isolated from the reaction medium before carrying out step (d-2) and is brought to step (d-2) without isolation or purification. Step (d) is preferably carried out in an apolar aprotic solvent such as, for example, hexane, cyclohexane, heptane, and toluene, preferably toluene.

[0070] Step (d) is preferably carried out at a temperature of between 60°C and 110°C, preferably at a temperature of about 90°C.

[0071] The amount of benzyl alcohol in step (d-2) is preferably between 1 and 3 equivalents with respect to the compound of formula (VI), preferably between 2 and 2.5 equivalents.

[0072] In other preferred embodiments of the third aspect, the method of preparing the compound of formula (I) or a salt thereof comprises the previous step (e) of preparing the compound of formula (VI), wherein said step (e) comprises:

[0073] (e-1) reacting 3-oxocyclobutane-1 -carboxylic acid with trimethyl orthoformate to provide a compound of formula (VII)

[0074] (e-2) reacting the compound of formula (VII) resulting from step (e-1) with hydroxylamine or a salt thereof to produce a compound of formula (VI).

[0075] Step (e-1) is preferably carried out in the presence of an acid catalyst, preferably a heterogenous acid catalyst, such as an ion exchange resin, for example Amberlyst 15®.

[0076] Methanol is preferably used as a solvent in step (e-1).

[0077] In preferred embodiments, the product of step (e-1) is isolated before use thereof in step (e- 2). It is particularly preferred that the acid catalyst and / or trimethyl orthoformate are removed from the reaction medium during this isolation step.

[0078] In other preferred embodiments, step (e-2) comprises using a hydroxylamine salt, for example a hydrochloride salt. When a hydroxylamine salt is used in step (e-2), the reaction medium must comprise enough media, for example a base, to provide the free form of hydroxylamine. Said base can be an alkaline alkoxide (Ci-Ce) such as, for example, sodium methoxide. In other preferred embodiments, step (e-2) is carried out in an alcohol-type solvent, preferably methanol.

[0079] Likewise, in preferred embodiments, the compound of formula (I) can be prepared according to the following synthetic scheme:

[0080] Compounds (V) and (VI) are not described in the state of the art. Likewise, another aspect of the invention relates to a compound of formula (V) As described herein, the compound of formula (V) is useful in the preparation of a compound of formula (I) and abrocitinib. Another aspect of the invention relates to the use of the compound of formula (V) in the preparation of a compound of formula (I) or in the preparation of abrocitinib.

[0081] Moreover, another aspect of the invention relates to a compound of formula (VI)

[0082] As described herein, the compound of formula (VI) is useful in the preparation of a compound of formula (I) and abrocitinib. Another aspect of the invention therefore relates to the use of the compound of formula (VI) in the preparation of a compound of formula (I) or in the preparation of abrocitinib.

[0083] The methods described herein are useful for reducing the uses mentioned above to practice.

[0084] Method of preparing abrocitinib from the compound of formula (I) or a salt thereof

[0085] A fourth aspect of the invention relates to a method of preparing abrocitinib from the compound of formula (I) or a salt thereof. Said method comprises:

[0086] (f) reacting a compound of formula (I) or a salt thereof as defined in the first aspect of the invention to remove the benzyloxycarbonyl -CChCF^Ph group, obtaining an amino -NH2 group; and

[0087] (g) reacting the compound resulting from step (f) to convert the amino group formed from the benzyl carbamate group of the compound of formula (I) or the salt thereof into a group of formula -NHSO2CH2CH2CH3.

[0088] In a particular embodiment of the method of the fourth aspect of the invention, step (f) is a catalytic hydrogenation step. Said step comprises reacting the compound of formula (I) with hydrogen or a hydrogen precursor such as, for example, cyclohexene, in the presence of a catalyst. Said catalyst is preferably Pd / C. In a particular embodiment of the method of the fourth aspect of the invention, step (f) is carried out in the presence of a polar protic organic solvent such as, for example, methanol, ethanol, or isopropanol. It is preferable that step (f) is carried out in the presence of methanol.

[0089] In a particular embodiment of the method of the fourth aspect of the invention, step (g) comprises reacting the product of step (f) with a compound of formula C3H7-SO2X, wherein X represents a leaving group, preferably selected from chloride and triazolyl. Preferably, step (g) comprises reacting the product of step (f) with 1 -propanesulfonyl chloride.

[0090] In another particular embodiment of the method of the fourth aspect of the invention, step (g) is carried out in the presence of a solvent, wherein the reaction product, i.e. , / V-[c / s-3-(methyl- 7 / 7-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclobutyl]-1-propanesulfonamide, precipitates substantially. The term “substantially” refers to the fact that at least 90% of the compound precipitates in said reaction medium.

[0091] In another particular embodiment of the method of the fourth aspect of the invention, step (g) is carried out in the presence of a solvent which is a mixture of acetonitrile with an aqueous solution of an alkaline salt of carbonate, preferably a mixture of acetonitrile with a 20% by weight aqueous solution of potassium carbonate, and the acetonitrile content of which is between 30% and 80% by volume.

[0092] The inventors have found that the N atom comprised in the pyrrole ring can react with the compound of formula C3H7-SO2X, giving rise to unwanted byproducts. The formation of this byproduct can be minimized by carrying out the first few hours of the reaction at a low temperature.

[0093] Likewise, in a particular embodiment of the method of the fourth aspect of the invention, step (g) comprises maintaining the reaction temperature between -5°C and 5°C for the first few hours of said step and for a time of between 2 and 4 hours. More particularly, step (g) comprises maintaining the reaction temperature at about 0°C for the first three hours of said step.

[0094] After this treatment, step (g) preferably further comprises maintaining the reaction temperature at a temperature of between 20°C and 25°C. Likewise, in preferred embodiments, abrocitinib can be prepared according to the following synthetic scheme:

[0095] Abrocitinib

[0096] 78.6% yield

[0097] Some examples of the experimental methods and embodiments of the present invention are described below in order to facilitate the understanding of the preceding ideas. Said examples are merely illustrative and non-limiting.

[0098] EXAMPLES

[0099] Ultra-high performance liquid chromatography

[0100] The purity of the products obtained in Examples 1 and 2 was analyzed by means of ultra-high performance liquid chromatography (UHPLC) using the Waters Acquity apparatus provided with a photodiode detector, a mass detector, and a thermostated oven for the column. An HSS T3 column (1.8 pm, 2.1x150 mm) and mobile phases A (monobasic potassium phosphate 5 mM, pH 3) and B (acetonitrile) were used with the following analysis conditions:

[0101] - Flow rate: (mL / min): 0.3

[0102] - Column temp. (°C): 40

[0103] - Wavelength (nm): 210

[0104] - Inj. vol. (pL): 1

[0105] - Diluent: methanol

[0106] - Gradient: t (min) %A %B

[0107] 0 95 5

[0108] 0.5 95 5

[0109] 5 20 80

[0110] 6 20 80

[0111] 6.5 95 5

[0112] 8 95 5 The purity of the products obtained in Examples 3 and 4 was analyzed by means of ultra-high performance liquid chromatography (LIHPLC) using the Waters Acquity apparatus provided with a photodiode detector, a mass detector, and a thermostated oven for the column. An HSS T3 column (1.8 pm, 2.1x150 mm) and mobile phases A (ammonium acetate 10 mM, pH 5), B (acetonitrile), and C (water) were used with the following analysis conditions:

[0113] - Flow rate: (mL / min): 0.3

[0114] - Column temp. (°C): 40

[0115] - Wavelength (nm): 210

[0116] - Inj. vol. (pL): 1

[0117] - Diluent: methanol

[0118] - Gradient: t (min) %A %B %C

[0119] 0 5 15 80

[0120] 0.3 5 15 80

[0121] 5 5 95 0

[0122] 7 5 95 0

[0123] 7.5 5 15 80

[0124] 10 5 15 80

[0125] The purity of the product obtained in Example 5 was analyzed by means of ultra-high performance liquid chromatography (LIHPLC) using the Waters Acquity apparatus provided with a photodiode detector, a mass detector, and a thermostated oven for the column. A Premier BEH C18 column (1.8 pm, 2.1x100 mm) and mobile phases A (ammonium bicarbonate 30 mM, pH 8.5) and B (acetonitrile) were used with the following analysis conditions:

[0126] - Flow rate: (mL / min): 0.3

[0127] - Column temp. (°C): 45

[0128] - Wavelength (nm): 210

[0129] - Inj. vol. (pL): 1

[0130] - Diluent: methanol

[0131] - Gradient: t (min) %A %B

[0132] 0 85 15

[0133] 1 85 15

[0134] 6 60 40 7 5 95

[0135] 8.5 5 95

[0136] 9 85 15

[0137] 12 85 15

[0138] The purity of the products obtained in Examples 6 and 8 was analyzed by means of ultra-high performance liquid chromatography (LIHPLC) using the Waters Acquity apparatus provided with a photodiode detector, a mass detector, and a thermostated oven for the column. A Premier BEH C18 column (1.8 pm, 2.1x100 mm) and mobile phases A (ammonium bicarbonate 10 mM, pH 8.5), B (acetonitrile), and C (methanol) were used with the following analysis conditions:

[0139] - Flow rate: (mL / min): 0.3

[0140] - Column temp. (°C): 45

[0141] - Wavelength (nm): 210 / 290

[0142] - Inj. vol. (pL): 1

[0143] - Diluent: methanol

[0144] - Gradient: t (min) %A %B %C

[0145] 0 85 5 10

[0146] 1 85 5 10

[0147] 6 60 30 10

[0148] 7 5 85 10

[0149] 8.5 5 85 10

[0150] 9 85 5 10

[0151] 12 85 5 10

[0152] Differential scanning calorimetry (DSC)

[0153] DSC analysis was performed in a Mettler Toledo 822e apparatus with STARe SW15 software using the following parameters: heating interval of 30 to 300°C with a 10°C / min ramp and a 50 ml / min N2 flow. Measurement was taken with a closed perforated capsule.

[0154] Nuclear magnetic resonance

[0155] Proton nuclear magnetic resonance (1H-NMR) and13C-NMR analyses were performed in a 400 MHz Brucker Avance III spectrometer. Chemical shifts referred to the DMSO-cfe signal (2.49 ppm for proton and 39.5 ppm for carbon) for the compound of formula (VI) and to the CDCh signal (7.26 ppm for proton and 77.0 ppm for carbon) for the compounds of formula (I) and (V).

[0156] X-ray crystallography (XRPD)

[0157] XRPD analysis was performed using a BRLIKER D2 PHASER X-ray powder diffractometer with a copper anode. The radiation used is CuKa with a wavelength of 1 .54060 A. The following scan parameters were used: 3-50° 20, continuous scan, ratio: 5.6 degrees / minute. In one embodiment, the present invention contemplates that the compound of the invention is prepared and used in the preparation of abrocitinib following the following synthetic scheme: Example 1. Synthesis of methyl 3,3-dimethoxy-cyclobutanecarboxylate (VII)

[0158] 200.85 g (1.76 mol, 1 eq) of cyclobutanone-3-carboxylic acid and 20.7 g (0.066 mol, 0.04 eq) of Amberlyst 15® resin were mixed under N2 atmosphere with 600 mL of MeOH at a temperature of about 20°C. 470 mL (4.38 mol, 2.5 eq) of 99% trimethyl orthoformate were then added. The resulting reaction mass was kept under stirring for 30 min and then heated to a temperature of about 50°C and kept under stirring for 16 hours at said temperature.

[0159] Thereafter, the resulting reaction mass was cooled to a temperature of about 20°C and filtered to remove the Amberlyst 15® resin. The filtrate was washed with two fractions of 100 mL each of methanol and the solvent was removed by means of vacuum distillation. 200 mL of methanol were added to the obtained residue and the solvent was again removed by means of vacuum distillation to obtain 305.5 g (99.2% purity by means of UHPLC) of a slightly yellowish oil corresponding to methyl 3,3-dimethoxy-cyclobutanecarboxylate which were dissolved in 760 mL of MeOH and used in the subsequent reaction step without further treatment.

[0160] Example 2. Synthesis of 3,3-dimethoxy-cyclobutanecarbohydroxamic acid (VI)

[0161] 180 g (7.75 mol, 4.5 eq) of the hydrochloric acid salt of ammonium hydroxide were dissolved in 600 mL of MeOH. 1772 mL (2.58 mol, 1.5 eq) of a sodium methoxide solution in 25% by weight MeOH were then slowly added, maintaining a temperature of about 25°C. The suspension obtained was filtered to remove the sodium chloride produced and the resulting solution was cooled to a temperature of about 0°C. The solution of 305.5 g of methyl 3,3- dimethoxy-cyclobutanecarboxylate (1.72 mol, 1 eq) and 760 mL of MeOH obtained by means of the reaction step described in Example 1 were then added slowly at said temperature. The thus resulting reaction mass was kept under stirring at the indicated temperature for 3 hours.

[0162] Thereafter, the solvent was removed by means of vacuum distillation. 900 mL of methanol were added to the obtained residue and the solvent was again removed by means of vacuum distillation. Next, 1050 mL of MeOH were added and 1200 mL of a previously prepared 22% by weight HOI solution in 2-propanol were slowly added, while maintaining the temperature in the interval of between 20 and 25°C. The resulting solid was filtered and the solvent of the solution thus obtained was removed by means of vacuum distillation to obtain 310 g (5.1% of ash, 97.26% purity by means of UHPLC) of a slightly orange solid corresponding to 3,3- dimethoxy-cyclobutanecarbohydroxamic acid, which was used in the subsequent reaction step without further treatment.1H-NMR (DMSO-cfe, 400 MHz) 5(ppm): 10.50 (1 H, s), 8.77 (1 H, s), 3.07 (3H, s), 3.02 (3H, s), 2.23-2.11 (5H, m).

[0163] 13C-NMR (DMSO- d6, 400 MHz) 5(ppm): 170.66, 100.08, 48.55, 48.22, 35.01 , 26.83.

[0164] Example 3. Synthesis of benzyl N-(3,3-dimethoxycyclobutyl)carbamate (V)

[0165] 305 g of 3,3-dimethoxy-cyclobutanecarbohydroxamic acid (1.65 mol, 1 eq) obtained by means of the reaction step described in Example 2 were dissolved in 2790 mL of toluene at a temperature of about 20°C. 358.7 g (2.2 mol, 1.33 eq) of 1 ,1 -carbonyldiimidazole (GDI) were slowly added to said solution, maintaining the temperature between 20 and 25°C. The reaction mixture was heated to a temperature of about 90°C and kept under stirring at said temperature for 16 hours. The reaction mixture was then cooled to a temperature of between 25 and 30°C and 394 g (3.83 mol, 2.3 eq) of benzyl alcohol were added. The reaction mixture was heated to a temperature of about 80°C and kept under stirring at said temperature for 24 hours.

[0166] Thereafter, the reaction mass was washed with two 1500 mL fractions of a 20% by weight aqueous ammonium chloride solution each and with an additional 1500 mL fraction of water. The combined aqueous phases were washed with a 900 mL fraction of toluene. The solvent was removed from the resulting organic phase by means of vacuum distillation to obtain 689.6 g of an oily residue comprising 58.9% by weight (406.2 g), by means of UHPLC, of the compound benzyl N-(3,3-dimethoxycyclobutyl)carbamate, which was used in the subsequent reaction step without further treatment.

[0167] 1H-NMR (CDCI3, 400 MHz) 5(ppm): 11.52 (1 H, s), 7.37-7.31 (5H, m), 5,10 (2H, broad s), 4.10- 4.05 (1 H, m), 3.16 (3H, s), 3.15 (3H, s), 2.64 (2H, t), 1.98 (2H, dd).

[0168] 13C-NMR (CDCh, 400 MHz) 5(ppm): 155.67, 136.47, 128.53, 128.38, 128.15, 99.10, 66.68, 49.01 , 48.62, 40.23, 38.29.

[0169] Example 4. Synthesis of benzyl N-(3-oxocyclobutyl)carbamate (IV)

[0170] 689.6 g of the residue obtained in the previous step comprising about 406.2 g (1 .53 mol, 1 eq) of benzyl N-(3,3-dimethoxycyclobutyl)carbamate were dissolved in 800 mL of tetra hydrofuran and 800 mL of water at a temperature of about 20°C. 86 mL (1.04 mol, 0.7 eq) of a 37% by weight aqueous HCI solution were added to the reaction mixture (pH = 0.7-1) and the resulting reaction mixture was heated to a temperature of about 55°C and kept under stirring at said temperature for 3 hours. Thereafter, the reaction mixture was cooled to a temperature of about 20°C and a 20% by weight aqueous K2CO3 solution was added up to a pH value of between 8 and 9. 2435 mL of ethyl acetate were added and the phases were separated. The organic phase was washed with a 2000 mL fraction of a 20% by weight aqueous K2CO3 solution and with a 2030 mL fraction of a 10% by weight aqueous NaCI solution. The solvent was removed from the resulting organic phase by means of vacuum distillation to obtain 564 g of an oily residue comprising 52.0% by weight (293.3 g), by means of UHPLC, of the compound benzyl N-(3- oxocyclobutyl)carbamate.

[0171] 490 mL of toluene were slowly added to 470 g (comprising 244.4 g of benzyl N-(3- oxocyclobutyl)carbamate) of the previously obtained residue at a temperature of between 20 and 25°C, obtaining a solution once the addition ended. The resulting solution was kept under stirring at a temperature of about 20°C for 3 hours, with the appearance of a precipitated solid being observed. 365 mL of heptane were then added at a temperature of about 20°C and the resulting suspension was slowly cooled to a temperature of about -5°C and kept under stirring at said temperature for 4 hours. The resulting solid was filtered and washed with a 245 mL fraction of heptane previously cooled to a temperature of between 5 and 10°C. Finally, it was dried in an air oven at a temperature of 45°C to obtain 236.1 g (99.82% purity by means of UHPLC) of a practically white solid corresponding to benzyl N-(3-oxocyclobutyl)carbamate.

[0172] The overall yield of the four reaction steps described by means of Examples 1 to 4 is 71.8%.

[0173] Example 5. Synthesis of the hydrochloric acid salt of benzyl cis-[3- (methylamino)cyclobutyl]carbamate (ll)-HCI

[0174] 110.0 g (0.502 mol, 1 eq) of benzyl N-(3-oxocyclobutyl)carbamate obtained by means of the reaction step described according to Example 4 were dissolved in 770 mL of methanol and 410 mL of a 40% by weight methylamine solution in methanol were then added, maintaining a temperature of between 20 and 25°C. The reaction mixture was cooled to a temperature of about 0°C and 14.4 mL (0.250 mol, 0.5 eq) of glacial acetic acid were slowly added, maintaining said temperature. The reaction mixture was heated to a temperature of between 25 and 30°C and kept under stirring at said temperature for 4 hours. 11 g of platinum on carbon (Pt / C) were then added and the reaction mixture was kept under 2 bars of pressure at a temperature of about 30°C for 24 hours.

[0175] Thereafter, the reaction mixture was cooled to a temperature of about 20°C and filtered to separate the Pt / C. The solvent was removed from the reaction mixture by means of vacuum distillation and 110 mL of ethyl acetate were added. The solvent was again removed from the reaction mixture by means of vacuum distillation and 330 mL of water were added and the pH was adjusted to a value of between 9 and 10 by means of a 20% by weight aqueous K2CO3 solution. 330 mL of ethyl acetate were added and the phases were separated. The organic phase was washed with a 330 mL fraction of water and the combined aqueous phases were washed with a 330 mL fraction of ethyl acetate. The solvent was removed from the combined organic phases thus obtained to yield 103.5 g of an oily residue comprising 91.0%, by means of UHPLC, of the hydrochloric acid salt of benzyl cis-[3-(methylamino)cyclobutyl]carbamate.

[0176] 75.93 g (294.9 mmol, 1 eq) of the previously obtained residue were dissolved in 76 mL of methanol and the resulting solution was cooled to a temperature of about 0°C. 89.1 mL (356.4 mmol, 1.2 eq) of a 4 M hydrochloric acid solution in 1 ,4-dioxane were added at said temperature. The suspension obtained was heated to a temperature between about 70 and 75°C, obtaining total dissolution; it was slowly cooled to a temperature of about 20°C and kept under stirring at said temperature for 3 hours. The resulting solid was filtered and washed with a 150 mL fraction of 1 ,4-dioxane. Finally, it was dried in an air oven at a temperature of 45°C to obtain 59.4 g (98.71% purity by means of UHPLC) of a white solid corresponding to the hydrochloric acid salt of benzyl cis-[3-(methylamino)cyclobutyl]carbamate.

[0177] The overall yield of the hydrochloric acid salt of benzyl cis-[3- (methylamino)cyclobutyl]carbamate obtained from benzyl N-(3-oxocyclobutyl)carbamate is 59.6%.

[0178] The purity of the obtained solid can be increased by means of recrystallization in a suitable solvent. For example, recrystallization using 5 volumes (in mL) of isopropanol per gram of initial product allows obtaining the hydrochloric acid salt of benzyl cis-[3- (methylamino)cyclobutyl]carbamate with a yield of 90.0% and a purity by means of UHPLC of 99.96%.

[0179] Example 6. Synthesis of benzyl cis-N-[3-(methyl(7H-pyrrol[2,3-d]pyrimidin-4- yl)amino)cyclobutyl]carbamate (I)

[0180] 26.5 g (98.1 mmol, 0.98 eq) of the hydrochloric acid salt of benzyl cis-[3- (methylamino)cyclobutyl]carbamate were dissolved in 160.0 mL (231.5 mmol, 2.36 eq) of a 20% by weight aqueous K2CO3 solution at a temperature of about 20°C. 15.3 g (100.1 mmol, 1 eq) of 4-chloropyrrolopyrimidine were then added at said temperature and the reaction mixture was heated to a temperature of about 60°C and kept under stirring at said temperature for 20 hours.

[0181] Thereafter, the reaction mixture was cooled to a temperature of about 20°C, kept under stirring at said temperature for 2 hours, the resulting solid was filtered and washed with two fractions of 50 mL each of water. Finally, the solid was dried in an air oven at a temperature of 50°C to obtain 33.85 g (98.3% yield, 99.58% purity by means of LIHPLC) of a practically white solid corresponding to benzyl cis-N-[3-(methyl(7 / 7-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclobutyl]carbamate.

[0182] 1H-NMR (CDCI3, 400 MHz) b(ppm): 11.57 (1 H, s), 8.35 (1 H, s), 7.40-7.33 (4H, m) 7.07 (1 H, d), 6.58 (1 H, d), 5.20 (2H, m), 5.15 (1 H, s), 4.97 (1 H, m), 3.97 (1 H, m), 3.36 (3H, s), 2.80 (2H, d), 2.25 (2H, s).

[0183] 13C-NMR (CDCh, 400 MHz) b(ppm): 157.62, 155.49, 151.93, 150.67, 136.39, 128.60, 128.23, 120.41 , 103.37, 101.77, 66.75, 45.57, 40.28, 36.57, 32.21 ; XRPD: 12.0° 20, 13.3° 20, 14.4° 20, 17.8° 20, 19.8° 20, 21 .6° 20, 23.9° 20, and 26.5° 20, all of them with a margin of error of ± 0.2° 20. The X-ray powder diffractogram of the compound of formula (I) is shown in Figure 1 .

[0184] The differential scanning calorimetry (DSC) diagram has an endothermic peak having a threshold temperature of about 180.5°C.

[0185] Example 7. Synthesis of cis-N1-methyl-N1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclobutan- 1,3-diamine

[0186] 15.0 g (42.7 mmol) of benzyl cis-N-[3-(methyl(7 / 7-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclobutyl]carbamate were dissolved in 300 mL of methanol. 1.5 g of 5% by weight Pd / C were then added and two successive inerting sequences with N2 and vacuum were performed, and lastly the interior pressure of the flask was adjusted to 4 bars by means of H2 atmosphere. The reaction mixture was heated to about 40°C and kept under stirring at said temperature for 18 hours.

[0187] Thereafter, the reaction mixture was cooled to a temperature of about 20°C, the catalyst was filtered and washed with a 30 mL fraction of methanol. The solvent was removed from the obtained solution by means of vacuum distillation to obtain 9.42 g of a solid comprising cis-N1- methyl-N1-(7 / 7-pyrrolo[2,3-d]pyrimidin-4-yl)cyclobutan-1 ,3-diamine, which was used in the subsequent reaction step without further treatment. Example 8. Synthesis of N-[cis-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino]cyclobutyl]-propane-1 -sulfonamide) (abrocitinib)

[0188] The solid obtained by means of the reaction step described in Example 7 was mixed at a temperature of about 20°C with 95 mL of acetonitrile and 60 mL of a 20% by weight K2CO3 solution. The reaction mixture was cooled to a temperature of about 0°C, 6.7 g (47.0 mmol, 1.1 eq) of propanesulfony chloride were slowly added at said temperature, and the resulting reaction mixture was kept under stirring at said temperature for 3 hours and then at a temperature of between 20 and 25°C for 16 hours.

[0189] Thereafter, the resulting solid was filtered and washed with two fractions of 30 mL each of water. The solid thus isolated was dried in an air oven at a temperature of 50°C to obtain 10.84 g (99.17% purity by means of LIHPLC) of a practically white solid corresponding to N-[cis-3- [methyl-(7 / 7-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1 -sulfonamide) (abrocitinib). The overall yield of the two reaction steps described in the examples 7 and 8 is 78.6%.

[0190] 9 g of N-[cis-3-[methyl-(7 / 7-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1- sulfonamide) (abrocitinib) thus obtained were dissolved in a mixture of 63 mL of isopropanol and 27 mL of water at the reflux temperature. The solution was kept under stirring for

[0191] 10 minutes and then slowly cooled to a temperature of about 20°C, and the reaction mixture was kept under stirring at said temperature for 2 hours. Thereafter, the resulting solid was filtered and washed with two fractions of 20 mL each of a 70:30 isopropanol / water mixture. The solid thus isolated was dried in an air oven at a temperature of 50°C to obtain 8.19 g (91.0% yield, 99.74% purity by means of UHPLC) of a white solid corresponding to N-[cis-3- [methyl-(7 / 7-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl]-propane-1 -sulfonamide) (abrocitinib).

Claims

CLAIMS1. A compound of formula (I) or a salt thereofwherein the bonds represented by a wavy line are in the c / s configuration.

2. The compound according to claim 1 , characterized in that it has an X-ray powder diffractogram measured with CuKa radiation comprising peaks at 12.0, 13.3, 14.4, 17.8, 19.8, and 23.9 20, all of them with a margin of error of ± 0.2° 20.

3. The compound according to any of claims 1 and 2, characterized in that it has an X-ray powder diffractogram measured with CuKa radiation essentially like the one of Figure 1.

4. The compound according to any of claims 1 to 3, characterized in that it has a differential scanning calorimetry (DSC) diagram comprising an endothermic peak having a threshold temperature of about 180.5°C ± 2°C.

5. Use of a compound of formula (I) or a salt thereof according to any of claims 1 to 4 in the preparation of abrocitinib.

6. A method of preparing a compound of formula (I) according to any of claims 1 to 4 which comprises step (a) of reacting a compound of formula (II), wherein the bonds represented by a wavy line are in the c / s configuration, or a salt thereof, with a compound of formula (III) or a salt thereof,7. The method according to claim 8, characterized in that step (a) is carried out in the presence of an aqueous base solution, preferably an alkaline salt of carbonate, and / or at a temperature of between 50°C and 70°C, preferably about 60°C.

8. The method according to any of claims 6 to 7, characterized in that it comprises the previous step (b) of preparing the compound of formula (II), wherein said step (b) comprises:(b-1) reacting a compound of formula (IV) with methylamine to convert the carbonyl group of the compound of formula (IV) into a methylimine group or a salt thereof, and(b-2) reacting the product of step (b-1) to convert the methylimine group or a salt thereof into a methylamine group.

9. The method according to claim 8, characterized in that step (b-2) is carried out by means of catalytic hydrogenation.

10. The method according to claim 9, characterized in that the catalyst of step (b-2) is platinum.

11. The method according to any of claims 8 to 10, characterized in that it comprises the previous step (c) of preparing the compound of formula (IV), wherein said step (c) comprises reacting a compound of formula (V) to form a compound of formula (IV)12. The method according to claim 11 , characterized in that step (c) is carried out by means of the acid hydrolysis of the compound of formula (V).

13. The method according to any of claims 11 to 12, characterized in that it comprises the previous step (d) of preparing the compound of formula (V), wherein said step (d) comprises reacting a compound of formula (VI) to form a compound of formula (V)14. The method according to claim 13, characterized in that step (d) comprises:(d-1) reacting a compound of formula (VI) to convert the -CONHOH group into an isocyanate group, and(d-2) reacting the product of step (d-1) with benzyl alcohol.

15. The method according to claim 14, characterized in that step (d-1) comprises reacting a compound of formula (VI) with carbonyldiimidazole.

16. The method according to any of claims 13 to 15, characterized in that it comprises the previous step (e) of preparing the compound of formula (VI), wherein said step (e) comprises: (e-1) reacting 3-oxocyclobutane-1 -carboxylic acid with trimethyl orthoformate to provide a compound of formula (VII)(e-2) reacting the compound of formula (VII) resulting from step (e-1) with hydroxylamine or a salt thereof to produce a compound of formula (VI).

17. A method for preparing / V-[c / s-3-(methyl-7 / 7-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclobutyl]- 1 -propanesulfonamide (abrocitinib), or a salt thereof, characterized in that it comprises:(f) reacting a compound of formula (I) or a salt thereof according to any of claims 1 to 4 to remove the benzyloxycarbonyl -CChCF^Ph group, obtaining an amino -NH2 group; and(g) reacting the compound resulting from step (f) to convert the amino group formed from the benzyl carbamate group of the compound of formula (I) or the salt thereof into a group of formula -NHSO2CH2CH2CH3.

18. The method according to claim 17, characterized in that step (f) is a catalytic hydrogenation step.

19. The method according to claim 18, characterized in that the catalyst of step (f) is palladium on carbon.

20. The method according to any of claims 18 to 19, characterized in that step (f) is carried out in the presence of methanol.

21. The method according to any of claims 17 to 20, characterized in that step (g) comprises reacting the product of step (f) with 1 -propanesulfonyl chloride.

22. The method according to claim 21 , characterized in that step (g) is carried out in the presence of a solvent, wherein the reaction product, i.e., / V-[c / s-3-(methyl-7 / 7-pyrrolo[2,3- d]pyrimidin-4-ylamino)cyclobutyl]-1 -propanesulfonamide, precipitates substantially.

23. The method according to claim 22, characterized in that step (g) is carried out in the presence of a solvent which is a mixture of acetonitrile with an aqueous solution of an alkaline salt of carbonate, preferably a mixture of acetonitrile with a 20% by weight aqueous solution of potassium carbonate, and the content in acetonitrile of which is between 30% and 80% by volume.

24. The method according to any of claims 21 to 23, characterized in that step (g) comprises maintaining the reaction temperature between - 5°C and 5°C for the first few hours of said step and for a time between 2 and 4 hours.

25. The method according to claim 24, characterized in that step (g) comprises maintaining the reaction temperature at about 0°C for the first three hours of said step.

26. The method according to any of claims 24 to 25, characterized in that step (g) further comprises maintaining the reaction temperature at a temperature between 20°C and 25°C after the heat treatment described in any of claims 24 to 25.

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