METHOD OF PRODUCING ABROCITINIB

Abstract

The invention relates to a method for producing abrocitinib of formula (I) using intermediates (V) and (VI). The invention also relates to intermediates (V) and (VI) and a method for producing them.

Description

[0001] PROCESS FOR THE PREPARATION OF ABROCITINIB

[0002] The invention relates to the preparation of abrocitinib of formula (I) and to novel pharmaceutical intermediates used in the process and their method of preparation.

[0003] Abrocitinib is a JAK1 selective inhibitor used to treat atopic dermatitis (eczema). In the abrocitinib molecule, the substituents linked to the cyclobutane ring are cis positioned.

[0004] Background of the invention

[0005] International patent application WO 2014128591A1 describes the first synthesis of abrocitinib, which was subsequently published in a scientific journal (J. Med. Chem. 2018, 61, 1130-1152) (Figure 1). The synthesis starts with the reductive amination of benzyl (3 -oxocyclobutyl) carbamate with methylamine (MeNFh) and lithium borohydride (LiBFU) reagents. The crystallization of the hydrochloric acid salt from the crude product leads to the cis isomer. In the next step, the secondary amine was arylated with 2,4-dichloro-7 / / -pyrrolo[2,3- <7]pyrimidine, and catalytic hydrogenation was used to dehalogenate the resulting intermediate one-pot and remove the benzyloxycarbonyl (Cbz) protecting group. Finally, after sulfonylation of the amino group, abrocitinib (I) was prepared by chromatographic purification.

[0006] Figure 1. International patent applications WO 2020088659A1 and WO 2020261041A1 described another process for the preparation of abrocitinib (I) (Figure 2). This synthesis was also published in scientific journal (J. Med. Chem. 2018, 61, 1130-1152). In this case, 4-chloro-7- tosylpyrrolo[2,3-<7]pyrimidine was used to arylate the c / .v-aminc. The arylated intermediate was reacted with a solution of hydrogen bromide in acetic acid at room temperature and the primary amino group was next acylated with 1 -propanesulfonyl chloride. Finally, the tosyl protecting group was removed in a hot alkaline medium and after neutralization of the aqueous solution, the crude abrocitinib was obtained.

[0007] Figure 2.

[0008] For the preparation of abrocitinib (I) in Org. Process Res. Dev. 2021, 25, 608-615, isopropyl 3 -oxocyclobutane- 1 -carboxylate was used as starting material (Figure 3). The reductive amination of the ketone was carried out in the presence of an enzyme catalyst to ensure the formation of the cis isomer. After arylation of the amino group, the ester was converted to hydroxamic acid, from which the phosphoric acid salt of the desired intermediate was obtained by Lessen rearrangement. The latter compound was sulfonylated to give abrocitinib.

[0009] Figure 3.

[0010] In the same article, the preparation of abrocitinib from cA-3-(methylamino)cyclobutane-l- carboxamide was also described (Figure 4). In this procedure, 4-chloro-7-tosyl-7 / / -pyrrolo[2,3- <7] pyrimidine was used for the acylation reaction. The resulting acid amide was converted to amine by Hofmann degradation and the amine was converted to hydrogen bromide salt. Abrocitinib (I) was synthesized from the dihydrogen bromide salt as described previously (Figure 4).

[0011] Figure 4.

[0012] The disadvantages of the above procedures are summarised below.

[0013] A mixture of intermediate cis / trans isomers obtained by reductive amination in the synthesis shown in Figure 1. This mixture of isomers in the form of base is a liquid, so the pure cis isomer was prepared by first forming a hydrochloric acid salt from the mixture and then recrystallizing it. In the same synthesis, 2,4-dichloro-7 / Z-pyrrolo[2,3-z / ]pyrimidine was used for the arylation. This arylating agent has several disadvantages, firstly, the chlorine atom at position 2 has to be subsequently removed and, secondly, the arylated intermediate is highly insoluble and thus difficult to use in chemical reactions. A chromatographic method was used to purify the product.

[0014] In the syntheses described in Figures 2 and 4, a highly corrosive hydrogen bromide in acetic acid (HBr / HOAc) reagent is used, which should be avoided on an industrial scale.

[0015] The aim of our invention is to develop a simple and economical process for the preparation of abrocitinib (I) on an industrial scale, by eliminating the disadvantages of the described processes.

[0016] Summary of the invention

[0017] The present invention is a new process for the preparation of abrocitinib (l) by reacting the commercially available 3-(tert-butyloxycarbonylamino)-cyclobutan- 1-one to formula (II), which can be easily prepared as described in patent application WO 2023091438A1, with compounds of formula (III) or (IV) and the intermediates (V) and (VI) are isolated.

[0018]

[0019] Compounds (V) and (VI) are then converted into hydrochloride salts (VII) and (VIII) in hydrochloric acid medium.

[0020] The salts of formulae (VII) and (VIII) are reacted with the sulfonic acid derivative of formula (IX) (X = F, Cl, imidazole) in the presence of a base to afford abrocitinib (I). In the latter case, the synthesis is carried out via the isolable intermediate of formula (X).

[0021] Our procedure is summarised in Figure 5.

[0022]

[0023] Figure 5.

[0024] Detailed description of the invention

[0025] In international patent applications WO 2014128591A1, WO 2020088659A1 and WO 2020261041A1, an analogue of the compound of formula (II) is disclosed as an intermediate of abrocitinib, wherein benzyloxycarbonyl (Cbz) is used instead of the protecting group tertbutyloxycarbonyl (Boc). The Cbz protecting group containing compound is a mixture of cis / trans isomers and it is a liquid. Therefore, it is first converted into a hydrochloride salt, which is recrystallized to give the pure cis isomer. In the course of our work, it was recognized that the compound of formula (II) described in patent application EP3939979A1 can be prepared from a cis / trans mixture by simple recrystallization without the use of chromatography.

[0026] According to the process of the invention, the compound of formula (II) is converted into the intermediate of formula (V) or (VI) by arylation with 4-chloro-l / Z-pyrrolo[2,3-<7]pyrimidine of formula (HI) or 4-chloro-7-tosyl-7 / Z-pyrrolo[2,3-<7]pyrimidine of formula (IV) in the presence of a base. Removal of the Boc protecting group of compounds of formulae (V) and (VI) under acidic conditions leads to salts of amines of formulae (VII) and (VIII). The compounds of formulae (VII) and (VIII) are converted to abrocitinib of formula (I) in the presence of a base by reacting with a sulfonylating agents of formula (IX).

[0027] The preparation of a cis / trans mixture of the compound of formula (II) is described in WO 2023091438A1 and EP 3939979A. An organic solvent is used to recrystallize the cis / trans mixture of formula (II) at a ratio of about 3: 1. Preferably a solvent containing 1 to 4 carbon atoms of alcohol or 2 to 4 carbon atoms of nitrile groups, preferably ethanol (96 % or absolute), or acetonitrile, particularly preferably acetonitrile. For recrystallization, acetonitrile is used in a volume of 3 to 8 times, preferably 5 times.

[0028] The compound of formula (II) is arylated with 4-chloro-l / Z-pyrrolo[2,3-<7]pyrimidine of formula (HI) or 4-chloro-7-tosyl-7 / Z-pyrrolo[2,3-<7]pyrimidine of formula (IV) in organic solvent in the presence of an acid scavenger. The solvent used is an alcohol of 1 to 4 carbon atoms, preferably ethanol, or propane-2-ol, particularly preferably propane-2-ol. The arylation reagent is used in 0.8 to 1.2 equiv., preferably equimolar. Inorganic and organic bases are used as acid scavengers. Preferably A,A-diisopropylethylamine or triethylamine, particularly preferably A,A-diisopropylethylamine is used. The reaction is carried out at the boiling temperature of the solvent.

[0029] The removal of the Boc protecting group in compounds of formulae (V) and (VI) is carried out in an organic solvent with the addition of acid. The solvent used is an alcohol with 1 to 4 carbon atoms, preferably ethanol, or propane-2-ol, particularly preferably propane-2-ol. Inorganic and organic acids are used to remove the protecting group. Preferably trifluoroacetic acid or hydrogen chloride, more preferably hydrogen chloride is used. The temperature of the reaction mixture is maintained between 0 and 50 °C, preferably at room temperature between 22 and 27 °C.

[0030] The process for the preparation of abrocitinib (I) from HC1 salts of formulae (VII) and (VIII) using the acyl donor (IX) in organic solvent in the presence of a base is also the subject of our invention. The compound of formula (VII) is acylated with the propane sulfonic acid derivative of formula (IX), preferably propane sulfonic acid chloride. The reaction is carried out in the heterogeneous phase under Schotten-Baumann conditions, preferably in the presence of an aqueous sodium hydroxide base and in an organic solvent 2-methyltetrahydrofuran. The reaction temperature is maintained between 0 and 50 °C, preferably between 5 and 15 °C.

[0031] The compound of formula (VIII) is acylated with a propane sulfonic acid derivative of formula (IX), preferably propane sulfonic acid chloride. The reaction is carried out in an organic solvent, preferably ether, more preferably 2-methyltetrahydrofuran. Inorganic and organic bases are used as acid scavengers, preferably A-diisopropylcthylaminc or triethylamine, more preferably triethylamine. The isolation of the intermediate (X) is preferably carried out under heterogeneous conditions, preferably in a mixture of aqueous base and a water-immiscible organic solvent, in particular preferably aqueous sodium hydroxide and 2- methyltetrahydrofuran, at the boiling temperature of the solvent, in order to obtain a higher yield.

[0032] Examples

[0033] The invention is illustrated by the following examples, without limiting the scope of protection to these.

[0034] Preparation of compound (II) compound

[0035] 10.00 g (54.0 mmol) of tert-butyl (3 -oxocyclobutyl) carbamate was dissolved in a mixture of 50 mL ethanol and 5.2 mL acetic acid. The solution was cooled in an ice-water bath and 59.0 mL of a 33% ethanol solution of methylamine was added. After immersion, the reaction mixture was stirred for 1.5 h at 0 °C and then for 2 h at room temperature. It was then cooled again to 0 °C and 4.20 g (111.0 mmol) NaBPU was added portionwise over about 1.5 h. After the addition of the reducing agent, the reaction mixture was stirred at room temperature for a further 15-20 hours, stirred at room temperature for a further 15 minutes after the addition of 24 mL water and the ethanol was distilled off. To the residue 100 mL of water and 100 mL of dichloromethane were added, vigorously mixed in a separatory funnel and the phases separated. The aqueous phase was extracted with 2 * 60 mL dichloromethane, the combined organic phase was washed with 100 mL water and 60 mL saturated NaCl solution, dried over NaiSCL, filtered and evaporated.

[0036] A white crystalline crude product of 10.78 g was obtained with a cis / trans isomer ratio of 3: 1. The isomer mixture was recrystallized from 50 mL acetonitrile. 6.03 g (56% yield) of white crystalline solid with a cis / trans isomer ratio of ~ 98:2 was obtained.

[0037] Mp.: 112-113 °C.

[0038] IR (KBr): 3282, 3198, 2978, 1693, 1563, 1364, 1287, 1176 cm1.XH-NMR (CDCI3, 600 MHz): 4.65 (bs, 1H), 3.85-3.78 (m, 1H), 2.92-2.85 (m, 1H), 2.70-2.62 (m, 2H), 2.33 (s, 3H), 1.54-1.47 (m, 2H), 1.43 (s, 9H) ppm.

[0039] 13C NMR (CDCI3, 150 MHz): 154.9, 79.3, 48.5, 39.4, 39.2, 33.4, 28.4 ppm.

[0040] Preparation of compound (V)

[0041] To 5 mL of propan-2-ol was added 1.00 g (5.0 mmol) of compound formula (II), 0.77 g (5.0 mmol) of 4-chloro-l / Z-pyrrolo[2,3-<7]pyrimidine (III) and 1.13 mL (0.84 g, 6.5 mmol) of diisopropylethylamine. The reaction mixture was boiled for 24 hours, cooled in an ice-water bath, the precipitated crystalline material was filtered off and washed with 0.5 mL of cold propane-2-ol, dried in vacuo at 50 °C. 1.25 g of white crystalline compound was obtained. An additional 0.15 g of product was recovered from the mother liquor by column chromatography (silica gel, CH2CI2 / MeOH = 19 / 1). Yield 1.40 g (88%).

[0042] Mp.: 143-144 °C.

[0043] IR (KBr): 3300, 3110, 1699, 1673, 1565, 1533, 1176, 712 cm1.

[0044] ’ H-NMR (DMSO , 600 MHz): 11.63 (br s, 1H), 8.10 (s, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.16-7.12 (m, 1H), 6.65-6.60 (m, 1H), 4.98-4.87 (m, 1H), 3.81-3.73 (m, 1H), 3.25 (s, 3H), 2.49-2.43 (m, 2H), 2.24-2.16 (m, 2H), 1.39 (s, 9H) ppm.

[0045] 13C NMR (DMSO , 150 MHz): 157.0, 154.8, 151.9, 150.8, 121.0, 102.6, 101.7, 77.8, 44.3, 38.9, 35.7, 31.5, 28.5 ppm.

[0046] Elemental analysis C16H23N5O2 (317.39): calculated % C 60.55, H 7.30, N 22.07, measured % C 60.49, H 7.17, N 22.01.

[0047] Preparation of compound (VI)

[0048] To 10 mL of propan-2-ol was added 2.00 g (10.0 mmol) of compound formula (II), 3.08 g (10.0 mmol) of 4-chloro-7-tosyl-7 / Z-pyrrolo[2,3-r / ]pyrimidine (IV) and 2.26 mL (1.68 g, 13.0 mmol) of diisopropylethylamine. The reaction mixture was boiled for 24 h, cooled in an ice-water bath and stirred for 1 h. The solid was filtered off, the flask was rinsed with about 20 mL of cold propane-2-ol and the suspension was filtered off. 3.47 g of solid was obtained. A further 1.22 g of product was recovered from the mother liquor by column chromatography (silica gel, CH2 Cl2 / MeOH = 50 / 1). Yield 4.69 g (99%).

[0049] Mp.: 160-161 °C.

[0050] IR (KBr): 3444, 1672, 1575, 1369, 1175, 707, 604 cm’1.

[0051] ’ H-NMR (DMSO , 600 MHz): 8.24 (s, 1H), 7.98-7.95 (m, 2H), 7.62 (d, J = 4.1 Hz, 1H), 7.45-7.41 (m, 2H), 7.22 (br d, J = 8.6 Hz, 1H), 6.98 (d, J = 4.1 Hz, 1H), 4.88-4.80 (m, 1H), 3.80-3.72 (m, 1H), 3.21 (s, 3H), 2.48-2.42 (m, 2H), 2.35 (s, 3H), 2.21-2.13 (m, 2H), 1.38 (s, 9H) ppm.

[0052] 13C-NMR (DMSO , 150 MHz): 156.9, 154.7, 152.5, 151.4, 145.2, 134.6, 130.2, 127.9, 121.6, 106.7, 104.6, 77.9, 44.6, 38.7, 35.6, 31.8, 28.4, 21.3 ppm.

[0053] Preparation of compound (VII)

[0054] To 6.9 mL of hydrochloric acid in propane-2-ol (5.9 M) was added 1.00 g (3.15 mmol) of compound formula (V). After almost complete dissolution of the starting material, a white precipitate was formed. The reaction mixture was stirred at room temperature for 24 hours, the solid product obtained was filtered off, washed with propane-2-ol (2 x 1.5 mL) and finally dried in vacuo at 40 °C. Yield 0.90 g (98%).

[0055] Mp.: decomposes above 308 °C.

[0056] IR (KBr): 3355, 3032, 1631, 1408, 1345, 1231 cm’1.

[0057] XH-NMR (DMSO-6, 600 MHz): 12.86 (br s, 1H), 8.59 (br s, 3H), 8.36 (s, 1H), 7.49 (s, 1H), 7.02 (s, 1H), 5.09-4.90 (m, 1H), 3.60-3.50 (m, 1H), 3.50 (s, 3H), 2.70-2.60 (m, 4H) ppm.

[0058] 13C-NMR (DMSO , 150 MHz): 152.7, 143.5, 124.2, 104.5, 102.1, 47.2, 38.5, 33.6, 32.9 ppm.

[0059] Preparation of compound (VIII)

[0060] To 24.5 mL of hydrochloric acid in propane-2-ol (5.9 M) was added 2.50 g (5.30 mmol) of compound (VI). After dissolution of the starting material, a white precipitate was formed after about 5 min. The reaction mixture was stirred at room temperature for 24 hours, the solid product obtained was filtered off, washed with propane-2-ol (2 x 10 mL) and dried in vacuo at 40 °C. Yield 2.07 g (97%).

[0061] Mp.: 180-182 °C

[0062] IR (KBr): 3426, 1626, 1589, 1393, 1176, 676 cm1.

[0063] ’ H-NMR (DMSO-6, 600 MHz): 8.43 (br d, J = 4.2 Hz, 3H), 8.28 (s, 1H), 7.99-7.96 (m, 2H), 7.69 (d, J = 4.1 Hz, 1H), 7.46-7.42 (m, 2H), 7.04 (d, J = 4.2 Hz, 1H), 5.05-4.97 (m, 1H), 3.53-3.46 (m, 1H), 3.31 (s, 3H), 2.50-2.47 (m, 4H), 2.36 (s, 3H) ppm.

[0064] 13C-NMR (DMSO , 150 MHz): 156.4, 151.8, 151.1, 146.1, 134.5, 130.2, 128.0, 122.1, 106.7, 104.8, 45.4, 38.6, 32.9, 32.3, 21.3 ppm.

[0065] Preparation of abrocitinib (I) from intermediate (VII)

[0066] 1.00 g (3.45 mmol) of compound (VII) was dissolved in 6 mL deionized water at room temperature and diluted with 1.4 mL of 10 M NaOH solution. After stirring for 10 minutes, 4 mL of 2-methyltetrahydrofuran was added to the solution and cooled to between 0-10 °C using an ice-water bath. Then 0.53 mL of 1 -propanesulfonyl chloride was added by droppwise and stirred for 2 hours at room temperature. A white crystalline solid was formed. To the reaction mixture was added 6 mL of water and stirred at 0-10 °C for a further 30 minutes. The crystalline compound obtained was filtered off and dried in vacuo at 40 °C to give 0.76 g of product. The mother liquor was extracted with 2-methyltetrahydrofuran (2 x 10 mL), dried over NaiSCU, filtered and evaporated to give an additional 40 mg of product.

[0067] Yield 0.80 g (72%).

[0068] Mp.: 187.6-189.3 °C.

[0069] IR (KBr): 3272, 3098, 1565, 1312, 1148, 734, 595 cm’1.

[0070] ’ H-NMR (DMSO , 600 MHz): 11.64 (br s, 1H), 8.10 (s, 1H), 7.51 (d, J = 9.3 Hz, 1H), 7.15 (dd, Ji = 2.5 Hz, J2= 3.4 Hz, 1H), 6.64 (ddd, Ji = 1.2 Hz, J2= 1.8 Hz, h = 3.5 Hz, 1H), 4.95-4.87 (m, 1H), 3.60-3.53 (m 1H), 3.25 (s, 3H), 2.95-2.91 (m, 2H), 2.62-2.56 (m, 2H), 2.25-2.19 (m, 2H), 1.71-1.64 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H) ppm.

[0071] 13C NMR (DMSO , 150 MHz): 157.0, 151.9, 150.7, 121.1, 102.6, 101.6, 53.7, 44.4, 41.3, 36.5, 31.5, 17.1, 13.0 ppm.

[0072] Preparation of compound (X) 1.00 g (2.25 mmol) of the compound of formula (VIII) was added to a mixture of 12 mL of 2- methyltetrahydrofuran and 4.25 mL (3.08 g, 30.5 mmol) of triethylamine, in three parts. It was stirred for 1 hour at room temperature and 0.45 mL (0.57 g, 4.00 mmol) of 1 -propanesulfonyl chloride was added by dropwise. The reaction mixture was stirred at room temperature for 1 day to achieve a conversion of about 50%, which did not increase after the addition of additional sulfonating agent (1 -propanesulfonyl chloride) and triethylamine. The reaction mixture was extracted by the addition of 30 mL water and 30 mL 2-methyltetrahydrofuran and the phases were separated. The aqueous phase was extracted with 30 mL of 2-methyltetrahydrofuran, and finally the combined organic layers were washed with 30 mL of water, dried over NaiSCL, filtered and evaporated. The crude product was purified by column chromatography (silica gel, CfLCh / McOH gradient) to give a pale-yellow oil. Yield 0.46 g (43%).

[0073] IR (KBr): 3561, 3277, 1571, 1496, 1418, 1318, 1147, 1058, 676, 580 cm’1.

[0074] ’ H-NMR (CDC13, 600 MHz): 8.39 (s, 1H), 8.05-8.03 (m, 2H), 7.47 (d, J = 4.1 Hz, 1H), 7.29-7.27 (m, 2H), 6.63 (d, J = 4.1 Hz, 1H), 5.04 (d, J = 8.6 Hz, 1H), 4.76-4.73 (m, 1H), 3.70-3.66 (m, 1H), 3.25 (s, 3H), 2.99-2.96 (m, 2H), 2.80-2.77 (m, 2H), 2.38 (s, 3H), 2.22-2.17 (m, 2H), 1.87-1.80 (m, 2H), 1.05 (d, J = 7.4 Hz, 3H) ppm.

[0075] 13C-NMR (CDCI3, 150 MHz): 157.0, 152.3, 151.6, 145.5, 134.9, 129.7, 128.2, 121.6, 105.3, 55.1, 45.7, 42.0, 37.5, 32.9, 21.6, 17.3, 12.9 ppm.

[0076] Preparation of abrocitinib (I) from intermediate (X)

[0077] 0.45 g (0.94 mmol) of compound (X) was dissolved in 5 mL of 2-methyltetrahydrofuran, and 5 mL of 3 M NaOH solution was added. The reaction mixture was then boiled for 1 h, cooled to room temperature and the phases separated. The organic phase was extracted with 3 M NaOH solution (2 x 2 mL). The combined aqueous alkaline solution was acidified to pH ~ 6 with 6 M HC1 solution. The resulting suspension was stirred in an ice-water bath for 45 min and filtered. The crystalline abrocitinib was dried to constant weight in vacuo at 40 °C. Yield 0.22 g (73%).

Claims

Claims1. The compound of formula (V)and the compound of formula (VI).

2. A process for preparing a compound of formula (V) and (VI) characterized in that the compound of formula (II) a.) reacted with 4-chloro-lH-pyrrolo[2,3-d]pyrimidine to give compound (V), or b.) Reacted with 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine to give compound(VI).

3. The process according to claim 2, characterized in that the reactions are carried out in an organic solvent.

4. The process according to claim 3, characterized in that the reactions are carried out in a low carbon alcohol, preferably in propane-2-ol.

5. The process according to any one of claims 2-4, characterized in that the reactions are carried out in the presence of a base.

6. The process according to claim 5, characterized in that the reactions are carried out in the presence of an organic base, preferably diisopropylethylamine.

7. The process according to any one of claims 3 to 6, characterized in that the reactions are carried out at the boiling point of the solvent.

8. A process for the preparation of a compound of formula (VII) and (VIII) characterized bya.) compound (V) is reacted with acid to give compound (VII), or b.) a compound of formula (VI) is reacted with acid to give a compound of formula(VIII).

9. The process according to claim 8, characterized in that the reactions are carried out with hydrogen chloride.

10. The process according to any one of claims 8, 9, characterized in that the reactions are carried out in organic or inorganic solvents.

11. The process according to claim 10, characterized in that the reactions are carried out in a low carbon alcohol, preferably in propane-2-ol.

12. The process according to any one of claims 8 to 11, characterized in that the reactions are carried out between 0 and 50 °C, preferably at room temperature.

13. Preparation of the compound of formula (I) characterized by reacting the compound of formula (II) with 4-c / z / oro-7 / Z-pyrro / o[2,3-<7]pyrimidine and the resulting compound (V) is reacted with acid the resulting compound of formula (VII) is acylated with a sulfonic acid derivative of formula (IX) in the presence of a base to give the abrocitinib molecule of formula (I).

14. The process according to claim 13, characterised in that the compound of formula (II) is obtained by recrystallization of cis / trans terc-butyl (3-methylamino-cyclobutyl) carbamate from acetonitrile.

15. The process according to any one of claims 13, 14, characterized in that the acylation step is carried out in a heterogeneous aqueous, alkalinic and water-immiscible organic solvent medium.

16. The process according to claim 15, characterized in that the acylation is carried out in an ether type solvent, preferably 2-methyltetrahydrofuran.

17. The process according to claim 16, characterized in that the acylation is carried out in the presence of a base, preferably sodium hydroxide.

18. The process according to any one of claims 13 to 17 characterized in that the acylation is carried out with 1- propane sulfonic acid chloride.

19. The process according to any one of claims 13 to 18, characterized in that the acylation is carried out between 0 and 50 °C, preferably between 10 and 20 °C.

20. Preparation of the compound of formula (I) characterized by reacting the compound of formula (II) with 4-chloro-7- to5y / -7 / Z-pyrro / o[2,3-<7]pyrimidine and the resulting compound (VI) is reacted with acid and the resulting compound (VIII) is acylated with the sulfonic acid derivative (IX) in the presence of a basefinally, the resulting compound of formula (X) is hydrolysed to the abrocitinib molecule of formula (I).

21. The process according to claim 20, characterized in that the compound of formula (II) is obtained by recrystallization of cis / trans terc-butyl (3 -methylaminocyclobutyl) carbamate from acetonitrile.

22. The process according to claims 20-21, characterized in that the acylation step is carried out in an organic solvent medium.

23. The process according to claim 22, characterized in that the acylation is carried out in an ether type solvent, preferably 2-methyltetrahydrofuran.

24. The process according to claim 23, characterized in that the acylation is carried out in the presence of a base, preferably triethylamine.

25. The process according to any one of claims 20 to 24, characterized in that the acylation is carried out with 1- propane sulfonic acid chloride.

26. The process according to any one of claims 20 to 25, characterized in that the acylation is carried out between 0 and 50 °C, preferably between 20 and 25 °C.

27. The process according to any one of claims 20 to 26, characterized in that the compound of formula (X) is isolated from the reaction mixture.

28. A process according to claim 27, characterized in that the hydrolysis of the compound of formula (X) is carried out in a heterogeneous phase, preferably in an alkaline aqueous solution and in an organic solvent which is not miscible with water.

29. The process according to claim 28, characterized in that the hydrolysis is carried out in a mixture of aqueous sodium hydroxide and 2-methyltetrahydrofuran.

30. The process according to claim 29, characterized in that the hydrolysis is carried out at the boiling point of the solvent mixture.

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