A process for the synthesis of upadacitinib or a hydrate thereof

Abstract

A synthetic process for utpatinib or its hydrate is provided, belonging to the field of pharmaceutical synthesis. Specifically, it involves reacting compounds of formula (2) and formula (3) in an organic solvent and water. After the reaction is complete, the reaction system is mixed with inorganic base A and reacted to obtain compound (1) or its hydrate. This method is simple to operate, the product is readily available, the product purity is high, and it can stably achieve scale-up and large-scale production.

Description

A synthesis process of upadacitinib or its hydrate

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefits of Chinese Patent Application No. 202410041809.2 filed with the China Intellectual Property Office, and the entire contents of the above Chinese patent application are incorporated herein by reference. Technical Field

[0003] The present invention belongs to the field of drug synthesis, and particularly relates to a synthesis process of upadacitinib or a hydrate thereof. Background Art

[0004] Upadacitinib is a novel oral selective Janus kinase (JAK) inhibitor developed by AbbVie, a US company. It was approved for marketing by the US Food and Drug Administration (FDA) in August 2019. The marketed product is a hemihydrate crystal with the trade name Rinvoq. It is used to treat rheumatoid arthritis, psoriatic arthritis, atopic arthritis, ulcerative colitis, Crohn's disease, ankylosing spondylitis and radiographically negative axial spondyloarthritis.

[0005] The chemical name of upadacitinib is (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, and its structure is shown in Formula 1:

[0006] Although many documents have disclosed methods for preparing upadacitinib or its hydrates, such as CN108368121, CN102711476, CN115151529A, CN111217819, WO2023131978, etc., there is still an urgent need in the art for a method for preparing upadacitinib or its hydrates that is simple to operate and capable of large-scale production.

[0007] SUMMARY OF THE INVENTION

[0008] In a first aspect, the present invention provides a method for preparing upadacitinib or a hydrate thereof, characterized by comprising the following steps:

[0009] (1) reacting the compound of formula 2 and the compound of formula 3 in an organic solvent and water;

[0010] (2) mixing the reaction system obtained in step (1) with an inorganic base A and reacting them to obtain a compound of formula 1 or a hydrate thereof,

[0011] In a second aspect, the present invention further provides a method for preparing upadacitinib or a hydrate thereof, comprising the following steps:

[0012] (1a) reacting an acid addition salt of the compound of formula 2 with an inorganic base B in an organic solvent and water to obtain a compound of formula 2;

[0013] (1) reacting the compound of formula 2 and the compound of formula 3 in an organic solvent and water;

[0014] (2) mixing the reaction system obtained in step (1) with an inorganic base A and reacting them to obtain a compound of formula 1 or a hydrate thereof,

[0015] In a third aspect, the present invention further provides a method for preparing a compound of formula 3, characterized in that: N,N'-carbonyldiimidazole and trifluoroethylamine or a salt thereof are reacted in a solvent to obtain a compound of formula 3,

[0016] In a fourth aspect, the present invention provides a method for preparing upadacitinib or a hydrate thereof, characterized by comprising the following steps:

[0017] (1b) reacting N,N'-carbonyldiimidazole with trifluoroethylamine or a salt thereof in a solvent to obtain a compound of formula 3;

[0018] (1a) reacting an acid addition salt of the compound of formula 2 with an inorganic base B in a solvent to obtain a compound of formula 2;

[0019] (1) reacting a compound of formula 2 and a compound of formula 3 in a solvent;

[0020] (2) mixing the reaction system obtained in step (1) with an inorganic base A and reacting them to obtain a compound of formula 1-A,

[0021] Here, x is 0 to 0.65.

[0022] In a fifth aspect, the present invention also provides a method for preparing upadacitinib hemihydrate, characterized in that: an ethyl acetate solution of crude upadacitinib is added to a mixed solvent of ethyl acetate and water at 0°C to 80°C, after the addition, the mixture is kept warm for 1 to 12 hours, cooled to -10°C to 10°C, and crystallized for 0 to 4 hours.

[0023] In a sixth aspect, the present invention further provides a high-purity upadacitinib hemihydrate, characterized in that the content of the compound of formula 4 is less than 0.1%, and the purity of upadacitinib hemihydrate is higher than 98.0%.

[0024] Detailed Description of the Invention

[0025] In a first aspect, the present invention provides a method for preparing upadacitinib or a hydrate thereof, characterized by comprising the following steps:

[0026] (1) reacting the compound of formula 2 and the compound of formula 3 in an organic solvent and water;

[0027] (2) mixing the reaction system obtained in step (1) with an inorganic base A and reacting them to obtain a compound of formula 1 or a hydrate thereof,

[0028] In some embodiments of the present invention, the compound of formula 1 or its hydrate exists in the form of formula 1-A,

[0029] Here, x is 0 to 0.65.

[0030] In some typical embodiments of the present invention, x is 0 to 0.5; in some more typical embodiments of the present invention, x is 0 or 0.5; in some more typical embodiments of the present invention, x is 0; in some most typical embodiments of the present invention, x is 0.5.

[0031] In some embodiments of the present invention, the molar ratio of the compound of formula 2 to the compound of formula 3 in step (1) is 1:1, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:2, 1:2.1, 1:2.2, 1:2.5, 1:3, 1:4 or a range between any two of the above ratios; in some typical embodiments of the present invention, the molar ratio of the compound of formula 2 to the compound of formula 3 in step (1) is 1:1-4; in some more typical embodiments of the present invention, the molar ratio of the compound of formula 2 to the compound of formula 3 in step (1) is 1:1-3; In some more typical embodiments of the present invention, the molar ratio of the compound of formula 2 to the compound of formula 3 in step (1) is 1:1 to 2.5; in some most typical embodiments of the present invention, the molar ratio of the compound of formula 2 to the compound of formula 3 in step (1) is 1:1.4 to 2.2; in some most typical embodiments of the present invention, the molar ratio of the compound of formula 2 to the compound of formula 3 in step (1) is 1:1.4 to 1.5; in some most typical embodiments of the present invention, the molar ratio of the compound of formula 2 to the compound of formula 3 in step (1) is 1:2 to 2.2.

[0032] In some embodiments of the present invention, the compound of formula 3 in step (1) is added dropwise, and the addition time is 0 hours to 10 hours; in some typical embodiments of the present invention, the compound of formula 3 in step (1) is added dropwise, and the addition time is 1 hour to 5 hours; in some more typical embodiments of the present invention, the compound of formula 3 in step (1) is added dropwise, and the addition time is 2 hours to 4 hours; in some more typical embodiments of the present invention, the compound of formula 3 in step (1) is added dropwise, and the addition time is 2 hours to 3 hours.

[0033] In some embodiments of the present invention, the reaction temperature in step (1) is 0°C to 50°C; in some typical embodiments of the present invention, the reaction temperature in step (1) is 10°C to 40°C; in some more typical embodiments of the present invention, the reaction temperature in step (1) is 25°C to 35°C; in some more typical embodiments of the present invention, the reaction temperature in step (1) is 20°C to 30°C.

[0034] In some embodiments of the present invention, the reaction time after the addition of the compound of formula 3 in step (1) is 0 hours to 10 hours; in some typical embodiments of the present invention, the reaction time after the addition of the compound of formula 3 in step (1) is 0 hours to 5 hours; in some more typical embodiments of the present invention, the reaction time after the addition of the compound of formula 3 in step (1) is 1 hour to 3 hours; in some more typical embodiments of the present invention, the reaction time after the addition of the compound of formula 3 in step (1) is 1 hour to 2 hours.

[0035] In some embodiments of the present invention, the organic solvent in step (1) is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dichloromethane, and acetonitrile; in some typical embodiments of the present invention, the organic solvent in step (1) is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile; in some more typical embodiments of the present invention, the organic solvent in step (1) is selected from one of tetrahydrofuran and 2-methyltetrahydrofuran; in some more typical embodiments of the present invention, the organic solvent in step (1) is selected from tetrahydrofuran.

[0036] In some embodiments of the present invention, the mass volume ratio (g:mL) of the compound of formula 2 in step (1) to the organic solvent is 1:1, 1:8, 1:10, 1:11, 1:12, 1:16, 1:17, 1:18, 1:20, 1:22, 1:25 or a range between any two of the above ratios; in some typical embodiments, the mass volume ratio (g:mL) of the compound of formula 2 in step (1) to the organic solvent is 1:1 to 25; in some more typical embodiments, the mass volume ratio (g:mL) of the compound of formula 2 in step (1) to the organic solvent is 1:8 to 22; in some more typical embodiments, the mass volume ratio (g:mL) of the compound of formula 2 in step (1) to the organic solvent is 1:8 to 22. The mass volume ratio (g:mL) of the compound of formula 2 in step (1) to the organic solvent is 1:10 to 20; in some very typical embodiments, the mass volume ratio (g:mL) of the compound of formula 2 in step (1) to the organic solvent is 1:10 to 18; in some most typical embodiments, the mass volume ratio (g:mL) of the compound of formula 2 in step (1) to the organic solvent is 1:10 to 12; in some most typical embodiments, the mass volume ratio (g:mL) of the compound of formula 2 in step (1) to the organic solvent is 1:11 to 18; in some most typical embodiments, the mass volume ratio (g:mL) of the compound of formula 2 in step (1) to the organic solvent is 1:16 to 18.

[0037] In some embodiments of the present invention, the mass volume ratio (g:mL) of the compound of formula 2 in step (1) to water is 1:1 to 16; in some typical embodiments of the present invention, the mass volume ratio (g:mL) of the compound of formula 2 in step (1) to water is 1:1 to 10; in some more typical embodiments of the present invention, the mass volume ratio (g:mL) of the compound of formula 2 in step (1) to water is 1:2 to 8.

[0038] In some embodiments of the present invention, the inorganic base A in step (2) is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or lithium carbonate; in some typical embodiments of the present invention, the inorganic base A in step (2) is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide; in some more typical embodiments of the present invention, the inorganic base A in step (2) is selected from sodium hydroxide or potassium hydroxide; in some more typical embodiments of the present invention, the inorganic base A in step (2) is selected from potassium hydroxide.

[0039] In some embodiments of the present invention, the inorganic base A in step (2) is added in the form of its solid or its aqueous solution; in some typical embodiments of the present invention, the inorganic base A in step (2) is added in the form of its aqueous solution; in some more typical embodiments of the present invention, the inorganic base A in step (2) is added in the form of an aqueous solution with a mass fraction of 5% to 50%; in some more typical embodiments of the present invention, the inorganic base A in step (2) is added in the form of an aqueous solution with a mass fraction of 15% to 40%; in some extremely typical embodiments of the present invention, the inorganic base A in step (2) is added in the form of an aqueous solution with a mass fraction of 15% to 25%; in some most typical embodiments of the present invention, the inorganic base A in step (2) is added in the form of an aqueous solution with a mass fraction of 20%.

[0040] In some embodiments of the present invention, in step (2), the inorganic base A is calculated as a monovalent base ion, and the molar ratio of the compound of formula 2 to the inorganic base A is 1:1 to 5; in some typical embodiments of the present invention, in step (2), the inorganic base A is calculated as a monovalent base ion, and the molar ratio of the compound of formula 2 to the inorganic base A is 1:1 to 4; in some more typical embodiments of the present invention, in step (2), the inorganic base A is calculated as a monovalent base ion, and the molar ratio of the compound of formula 2 to the inorganic base A is 1:1.5 to 2.5; in the present invention In some more typical embodiments, in the step (2), the inorganic base A is calculated as a monovalent base ion, and the molar ratio of the compound of formula 2 to the inorganic base A is 1:2 to 2.5; in some extremely typical embodiments of the present invention, in the step (2), the inorganic base A is calculated as a monovalent base ion, and the molar ratio of the compound of formula 2 to the inorganic base A is 1:2 to 2.4; in some most typical embodiments of the present invention, in the step (2), the inorganic base A is calculated as a monovalent base ion, and the molar ratio of the compound of formula 2 to the inorganic base A is 1:2.1 to 2.4.

[0041] In some embodiments of the present invention, the mixing temperature in step (2) is 0°C to 50°C; in some typical embodiments of the present invention, the mixing temperature in step (2) is 10°C to 50°C; in some more typical embodiments of the present invention, the mixing temperature in step (2) is 15°C to 35°C; in some more typical embodiments of the present invention, the mixing temperature in step (2) is 20°C to 30°C.

[0042] In some embodiments of the present invention, the reaction time in step (2) is 0 hours to 10 hours; in some typical embodiments of the present invention, the reaction time in step (2) is 1 hour to 6 hours; in some more typical embodiments of the present invention, the reaction time in step (2) is 2 hours to 5 hours; in some more typical embodiments of the present invention, the reaction time in step (2) is 4 hours to 6 hours; in some more typical embodiments of the present invention, the reaction time in step (2) is 3 hours to 4 hours.

[0043] In some embodiments of the present invention, after mixing and reacting, step (2) optionally further comprises adjusting the pH value to 3-6; in some typical embodiments of the present invention, after mixing and reacting, step (2) further comprises, in sequence, adjusting the pH value to 4-6, extraction and liquid separation; in some more typical embodiments of the present invention, preferably, after mixing and reacting, step (2) further comprises, in sequence, adjusting the pH value to 4.8-6, extraction and liquid separation; in some more typical embodiments of the present invention, after mixing and reacting, step (2) further comprises, in sequence, adjusting the pH value to 4.8-5.5, extraction with ethyl acetate and liquid separation; in some more typical embodiments of the present invention, after mixing and reacting, step (2) further comprises, in sequence, adjusting the pH value to 5-6, extraction with ethyl acetate and liquid separation.

[0044] In a second aspect, the present invention provides a method for preparing upadacitinib or a hydrate thereof, comprising the following steps:

[0045] (1a) reacting an acid addition salt of the compound of formula 2 with an inorganic base B in an organic solvent and water to obtain a compound of formula 2;

[0046] (1) reacting the compound of formula 2 and the compound of formula 3 in an organic solvent and water;

[0047] (2) mixing the reaction system obtained in step (1) with an inorganic base A and reacting them to obtain a compound of formula 1 or a hydrate thereof,

[0048] In some embodiments of the present invention, step (1) and / or step (2) are as described above.

[0049] In some embodiments of the present invention, the compound of formula 1 or its hydrate exists in the form of formula 1-A,

[0050] Here, x is 0 to 0.65.

[0051] In some typical embodiments of the present invention, x is 0 to 0.5; in some more typical embodiments of the present invention, x is 0 or 0.5; in some more typical embodiments of the present invention, x is 0; in some most typical embodiments of the present invention, x is 0.5.

[0052] In some embodiments of the present invention, the acid addition salt of the compound of Formula 2 in step (1a) is selected from the hydrobromide, hydrochloride, sulfate or phosphate of the compound of Formula 2; in some typical embodiments of the present invention, the acid addition salt of the compound of Formula 2 in step (1a) is selected from the hydrobromide, hydrochloride or sulfate of the compound of Formula 2; in some more typical embodiments of the present invention, the acid addition salt of the compound of Formula 2 in step (1a) is selected from the hydrobromide or hydrochloride of the compound of Formula 2; in some more typical embodiments of the present invention, the acid addition salt of the compound of Formula 2 in step (1a) is selected from the hydrobromide of the compound of Formula 2.

[0053] In some embodiments of the present invention, the inorganic base B in step (1a) is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or lithium carbonate; in some typical embodiments of the present invention, the inorganic base B in step (1a) is selected from sodium hydroxide, potassium hydroxide or lithium hydroxide; in some more typical embodiments of the present invention, the inorganic base B in step (1a) is selected from sodium hydroxide or potassium hydroxide; in some more typical embodiments of the present invention, the inorganic base B in step (1a) is selected from potassium hydroxide.

[0054] In some embodiments of the present invention, in the step (1a), the inorganic base B is calculated as a monovalent base ion, and the molar ratio of the acid addition salt of the compound of formula 2 to the inorganic base B is 1:1 to 5; in some typical embodiments of the present invention, in the step (1a), the inorganic base B is calculated as a monovalent base ion, and the molar ratio of the acid addition salt of the compound of formula 2 to the inorganic base B is 1:1 to 4; in some more typical embodiments of the present invention, in the step (1a), the inorganic base B is calculated as a monovalent base ion, and the molar ratio of the acid addition salt of the compound of formula 2 to the inorganic base B is 1:1.5 to 2.5; In some more typical embodiments of the present invention, in the step (1a), the inorganic base B is calculated as a monovalent base ion, and the molar ratio of the acid addition salt of the compound of formula 2 to the inorganic base B is 1:1.8 to 2.2; in some most typical embodiments of the present invention, in the step (1a), the inorganic base B is calculated as a monovalent base ion, and the molar ratio of the acid addition salt of the compound of formula 2 to the inorganic base B is 1:2; in some most typical embodiments of the present invention, in the step (1a), the inorganic base B is potassium hydroxide, and the molar ratio of the acid addition salt of the compound of formula 2 to the inorganic base B is 1:2.

[0055] In some embodiments of the present invention, in step (1a), the pH of the reaction system is adjusted to 8-9 by adding an inorganic base B.

[0056] In some embodiments of the present invention, in step (1a), the inorganic base B is added in the form of its aqueous solution; in some typical embodiments, the inorganic base B is added in the form of its aqueous solution, and the mass of the inorganic base B accounts for 20% of the mass of its aqueous solution; in some more typical embodiments, the inorganic base B is added in the form of its potassium hydroxide aqueous solution, and the mass of the potassium hydroxide accounts for 20% of the mass of its aqueous solution.

[0057] In some embodiments of the present invention, the organic solvent in step (1a) is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dichloromethane, and acetonitrile; in some typical embodiments of the present invention, the organic solvent in step (1a) is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile; in some more typical embodiments of the present invention, the organic solvent in step (1a) is selected from tetrahydrofuran or 2-methyltetrahydrofuran; in some more typical embodiments of the present invention, the organic solvent in step (1a) is selected from tetrahydrofuran.

[0058] In some embodiments of the present invention, the mass volume ratio (g:mL) of the acid addition salt of the compound of Formula 2 in step (1a) calculated as its free base to the organic solvent is 1:1 to 16; in some typical embodiments, the mass volume ratio (g:mL) of the acid addition salt of the compound of Formula 2 in step (1a) calculated as its free base to the organic solvent is 1:1.5 to 5; in some more typical embodiments, the mass volume ratio (g:mL) of the acid addition salt of the compound of Formula 2 in step (1a) calculated as its free base to the organic solvent is 1:2.3 to 5; in some more typical embodiments, the mass volume ratio (g:mL) of the acid addition salt of the compound of Formula 2 in step (1a) calculated as its free base to the organic solvent is 1:2.3 to 4; in some most typical embodiments, the mass volume ratio (g:mL) of the acid addition salt of the compound of Formula 2 in step (1a) calculated as its free base to the organic solvent is 1:2.3 to 2.6.

[0059] In some embodiments of the present invention, the reaction temperature of step (1a) is 0°C to 50°C; in some typical embodiments of the present invention, the reaction temperature of step (1a) is 10°C to 50°C; in some more typical embodiments of the present invention, the reaction temperature of step (1a) is 15°C to 35°C; in some more typical embodiments of the present invention, the reaction temperature of step (1a) is 20°C to 30°C.

[0060] In a third aspect, the present invention further provides a method for preparing a compound of formula 3, characterized in that: N,N'-carbonyldiimidazole and trifluoroethylamine or a salt thereof are reacted in a solvent to obtain a compound of formula 3,

[0061] In some embodiments of the present invention, the reaction temperature of the reaction is -10°C to 30°C; in some typical embodiments of the present invention, the reaction temperature of the reaction is -10°C to 10°C; in some more typical embodiments of the present invention, the reaction temperature of the reaction is -5°C to 5°C.

[0062] In some embodiments of the present invention, the trifluoroethylamine or its salt is trifluoroethylamine or its hydrochloride; in some typical embodiments of the present invention, the trifluoroethylamine or its salt is trifluoroethylamine or its monohydrochloride; in some more typical embodiments of the present invention, the trifluoroethylamine or its salt is trifluoroethylamine free base; in some more typical embodiments of the present invention, the trifluoroethylamine or its salt is trifluoroethylamine monohydrochloride.

[0063] In some embodiments of the present invention, the trifluoroethylamine or its salt is a trifluoroethylamine acid addition salt, and the above preparation method further comprises adding a base to the reaction solution after the reaction; in some typical embodiments of the present invention, the trifluoroethylamine or its salt is a trifluoroethylamine acid addition salt, and the above preparation method further comprises adding an aqueous base solution to the reaction solution after the reaction; in some more typical embodiments of the present invention, the trifluoroethylamine or its salt is a trifluoroethylamine acid addition salt, and the above preparation method further comprises adding an aqueous potassium hydroxide solution to the reaction solution after the reaction; in some more typical embodiments of the present invention, the trifluoroethylamine or its salt is a trifluoroethylamine addition salt, and the above preparation method further comprises adding a 20% potassium hydroxide solution to the reaction solution after the reaction; in some most typical embodiments of the present invention, the trifluoroethylamine or its salt is trifluoroethylamine monohydrochloride, and further comprises adding a 20% potassium hydroxide solution to the reaction solution after the reaction, and the molar ratio of trifluoroethylamine monohydrochloride to potassium hydroxide is 1:1.

[0064] In some embodiments of the present invention, the molar ratio of trifluoroethylamine or its salt to N,N'-carbonyldiimidazole is 1:0.5, 1:0.8, 1:0.84, 1:0.9, 1:0.94, 1:0.95, 1:1, 1:1.5, 1:2 or a range between any two of the above ratios; in some typical embodiments of the present invention, the molar ratio of trifluoroethylamine or its salt to N,N'-carbonyldiimidazole is 1:0.5-2; in some more typical embodiments of the present invention, the molar ratio of trifluoroethylamine or its salt to N,N'-carbonyldiimidazole is 1:0.5-1.5; in this In some more classic embodiments of the invention, the molar ratio of trifluoroethylamine or its salt to N,N'-carbonyldiimidazole is 1:0.5-1; in some extremely typical embodiments of the invention, the molar ratio of trifluoroethylamine or its salt to N,N'-carbonyldiimidazole is 1:0.8-1; in some most typical embodiments of the invention, the molar ratio of trifluoroethylamine or its salt to N,N'-carbonyldiimidazole is 1:0.85-0.95; in some most typical embodiments of the invention, the molar ratio of trifluoroethylamine or its salt to N,N'-carbonyldiimidazole is 1:0.9-0.95.

[0065] In some embodiments of the present invention, the reaction solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dichloromethane, and acetonitrile; in some typical embodiments of the present invention, the reaction solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile; in some more typical embodiments of the present invention, the reaction solvent is tetrahydrofuran or 2-methyltetrahydrofuran; in some more typical embodiments of the present invention, the reaction solvent is tetrahydrofuran.

[0066] In some embodiments of the present invention, the mass volume ratio (g:mL) of the N,N'-carbonyldiimidazole to the solvent is 1:1, 1:5, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:14, 1:20, 1:25 or a range between any two of the above ratios; in some typical embodiments of the present invention, the mass volume ratio (g:mL) of the N,N'-carbonyldiimidazole to the solvent is 1:1 to 25; in some more typical embodiments of the present invention, the mass volume ratio (g:mL) of the N,N'-carbonyldiimidazole to the solvent is 1:5 to 20; in some more typical embodiments of the present invention, the N,N'-carbonyldiimidazole The mass volume ratio of imidazole to solvent (g:mL) is 1:7 to 14; in some extremely typical embodiments of the present invention, the mass volume ratio of N,N'-carbonyldiimidazole to solvent (g:mL) is 1:8 to 12; in some most typical embodiments of the present invention, the mass volume ratio of N,N'-carbonyldiimidazole to solvent (g:mL) is 1:7 to 10; in some most typical embodiments of the present invention, the mass volume ratio of N,N'-carbonyldiimidazole to solvent (g:mL) is 1:8 to 10; in some most typical embodiments of the present invention, the mass volume ratio of N,N'-carbonyldiimidazole to solvent (g:mL) is 1:9 to 10.

[0067] In some embodiments of the present invention, the reaction time is 0.5 hours to 3 hours; in some typical embodiments of the present invention, the reaction time is 1 hour to 2 hours.

[0068] In some embodiments of the present invention, the reaction is carried out under a nitrogen atmosphere.

[0069] In a fourth aspect, the present invention further provides a method for preparing upadacitinib or a hydrate thereof, characterized by comprising the following steps:

[0070] (1b) reacting N,N'-carbonyldiimidazole with trifluoroethylamine or a salt thereof in a solvent to obtain a compound of formula 3;

[0071] (1a) reacting an acid addition salt of the compound of formula 2 with an inorganic base B in a solvent to obtain a compound of formula 2;

[0072] (1) reacting the compound of formula 2 and the compound of formula 3 in an organic solvent and water;

[0073] (2) mixing the reaction system obtained in step (1) with an inorganic base A and reacting them to obtain a compound of formula 1-A,

[0074] Here, x is 0 to 0.65.

[0075] In some embodiments of the present invention, step (1b), step (1a), step (1) and / or step (2) are as described above.

[0076] In some typical embodiments of the present invention, x is 0 to 0.5; in some more typical embodiments of the present invention, x is 0 or 0.5; in some more typical embodiments of the present invention, x is 0; in some most typical embodiments of the present invention, x is 0.5.

[0077] In some embodiments of the present invention, the molar ratio of the acid addition salt of the compound of formula 2 in step (1a) to the trifluoroethylamine or its salt in step (1b) is 1:1, 1:1.5, 1:1.6, 1:1.8, 1:2, 1:2.3, 1:2.4, 1:2.5, 1:3 or a range between any two of the above ratios; in some typical embodiments of the present invention, the molar ratio of the acid addition salt of the compound of formula 2 in step (1a) to the trifluoroethylamine or its salt in step (1b) is 1:1 to 3; in some more typical embodiments of the present invention, the molar ratio of the acid addition salt of the compound of formula 2 in step (1a) to the trifluoroethylamine or its salt in step (1b) is 1:1 to 2.5; in some more typical embodiments of the present invention, In the embodiment, the molar ratio of the acid addition salt of the compound of formula 2 in step (1a) to the trifluoroethylamine or its salt in step (1b) is 1:1-2; in some extremely typical embodiments of the present invention, the molar ratio of the acid addition salt of the compound of formula 2 in step (1a) to the trifluoroethylamine or its salt in step (1b) is 1:1.5-2.5; in some most typical embodiments of the present invention, the molar ratio of the acid addition salt of the compound of formula 2 in step (1a) to the trifluoroethylamine or its salt in step (1b) is 1:1.5-1.8; in some most typical embodiments of the present invention, the molar ratio of the acid addition salt of the compound of formula 2 in step (1a) to the trifluoroethylamine or its salt in step (1b) is 1:2.3-2.5.

[0078] In some embodiments of the present invention, the step (1b) is directly used in the next reaction without purification.

[0079] In a fifth aspect, the present invention also provides a method for preparing upadacitinib hemihydrate, characterized in that: an ethyl acetate solution of crude upadacitinib is added to a mixed solvent of ethyl acetate and water at 0°C to 80°C, after the addition, the mixture is kept warm for 1 to 12 hours, cooled to -10°C to 10°C, and crystallized for 0 to 4 hours.

[0080] In some embodiments of the present invention, the crude upadacitinib is upadacitinib free base or hydrate; in some typical embodiments of the present invention, the crude upadacitinib is upadacitinib free base; in some typical embodiments of the present invention, the crude upadacitinib is upadacitinib hydrate; in some more typical embodiments of the present invention, the crude upadacitinib is upadacitinib hemihydrate.

[0081] In some embodiments of the present invention, the mass ratio (kg:kg) of the crude upadacitinib to ethyl acetate in the ethyl acetate solution of the crude upadacitinib is 1:1, 1:2, 1:2.2, 1:2.5, 1:3, 1:3.2, 1:6, 1:9, 1:10, or a range between any two of the above ratios; in some typical embodiments of the present invention, the mass ratio (kg:kg) of the crude upadacitinib to ethyl acetate in the ethyl acetate solution of the crude upadacitinib is 1:1 to 10; in some more typical embodiments of the present invention, the mass ratio (kg:kg) of the crude upadacitinib to ethyl acetate in the ethyl acetate solution of the crude upadacitinib is 1:1 to 10. The mass ratio (kg:kg) of ethyl ester is 1:2-9; in some more typical embodiments of the present invention, the mass ratio (kg:kg) of the crude upadacitinib to ethyl acetate in the ethyl acetate solution of the crude upadacitinib is 1:2-6; in some extremely typical embodiments of the present invention, the mass ratio (kg:kg) of the crude upadacitinib to ethyl acetate in the ethyl acetate solution of the crude upadacitinib is 1:2.2-3.2; in some most typical embodiments of the present invention, the mass ratio (kg:kg) of the crude upadacitinib to ethyl acetate in the ethyl acetate solution of the crude upadacitinib is 1:2.5-3.

[0082] In some embodiments of the present invention, the molar ratio of the crude upadacitinib to water is 1:0.5-4; in some typical embodiments of the present invention, the molar ratio of the crude upadacitinib to water is 1:0.5-2; in some more typical embodiments of the present invention, the molar ratio of the crude upadacitinib to water is 1:0.8-2; in some more typical embodiments of the present invention, the molar ratio of the crude upadacitinib to water is 1:0.8-1.2.

[0083] In some embodiments of the present invention, the total mass of ethyl acetate refers to the total amount of ethyl acetate in the ethyl acetate solution of the crude upadacitinib product and the mixed solvent of ethyl acetate and water in the above-mentioned preparation method, and the ratio of the mass of water to the total mass of ethyl acetate is 1:200 to 1:32; in some more typical embodiments of the present invention, the total mass of ethyl acetate refers to the total amount of ethyl acetate in the ethyl acetate solution of the crude upadacitinib product and the mixed solvent of ethyl acetate and water in the above-mentioned preparation method, and the ratio of the mass of water to the total mass of ethyl acetate is 1:200 to 1:50; in some more typical embodiments of the present invention, the total mass of ethyl acetate refers to the total amount of ethyl acetate in the ethyl acetate solution of the crude upadacitinib product and the mixed solvent of ethyl acetate and water in the above-mentioned preparation method, and the ratio of the mass of water to the total mass of ethyl acetate is 1:100 to 1:50; in some most typical embodiments of the present invention, the total mass of ethyl acetate refers to the total amount of ethyl acetate in the ethyl acetate solution of the crude upadacitinib product and the mixed solvent of ethyl acetate and water in the above-mentioned preparation method, and the ratio of the mass of water to the total mass of ethyl acetate is 1:100 to 1:78.

[0084] In some embodiments of the present invention, the ethyl ester solution of crude upadacitinib is added dropwise.

[0085] In some embodiments of the present invention, the time for dropping the ethyl acetate solution of the crude upadacitinib product is 1 to 6 hours; in some typical embodiments of the present invention, the time for dropping the ethyl acetate solution of the crude upadacitinib product is 1 to 5 hours; in some more typical embodiments of the present invention, the time for dropping the ethyl acetate solution of the crude upadacitinib product is 2 to 5 hours; in some more typical embodiments of the present invention, the time for dropping the ethyl acetate solution of the crude upadacitinib product is 3 to 4 hours.

[0086] In some embodiments of the present invention, the insulation temperature is 0℃~50℃; in some typical embodiments of the present invention, the insulation temperature is 20℃~50℃; in some more typical embodiments of the present invention, the insulation temperature is 30℃~45℃; in some more typical embodiments of the present invention, the insulation temperature is 40℃~45℃.

[0087] In some embodiments of the present invention, the insulation time is 1 hour to 10 hours; in some typical embodiments of the present invention, the insulation time is 2 hours to 8 hours; in some more typical embodiments of the present invention, the insulation time is 3 hours to 6 hours; in some more typical embodiments of the present invention, the insulation time is 4 hours to 5 hours.

[0088] In some embodiments of the present invention, the cooling temperature is -5°C to 10°C; in some typical embodiments of the present invention, the cooling temperature is -5°C to 5°C; in some more typical embodiments of the present invention, the cooling temperature is 0°C to 5°C.

[0089] In some embodiments of the present invention, the cooling rate is 0.15℃ / min to 1.0℃ / min; in some typical embodiments of the present invention, the cooling rate is 0.15℃ / min to 0.75℃ / min; in some more typical embodiments of the present invention, the cooling temperature is 0.15℃ / min to 0.5℃ / min; in some more typical embodiments of the present invention, the cooling temperature is 0.15℃ / min to 0.3℃ / min.

[0090] In some embodiments of the present invention, the crystallization time is 0 hours to 3 hours; in some typical embodiments of the present invention, the crystallization time is 0.5 hours to 3 hours; in some more typical embodiments of the present invention, the crystallization time is 0.5 hours to 2 hours.

[0091] In some embodiments of the present invention, the preparation method optionally further comprises decolorizing the crude upadacitinib product with activated carbon before dissolving it in ethyl acetate. In some typical embodiments of the present invention, the preparation method optionally further comprises decolorizing the crude upadacitinib product with activated carbon in a mixed solvent of ethyl acetate and ethanol or in a single solvent of ethyl acetate before dissolving it in ethyl acetate. In some more typical embodiments of the present invention, the preparation method optionally further comprises decolorizing the crude upadacitinib product with activated carbon in a mixed solvent of ethyl acetate and ethanol or in a single solvent of ethanol before dissolving it in ethyl acetate, filtering, and distilling the filtrate to dryness.

[0092] In the present invention, the sources of the crude upadacitinib include but are not limited to those prepared according to existing technologies such as CN108368121, CN102711476, CN115151529A, CN111217819 or WO2023131978, or prepared by the upadacitinib preparation method of the present invention.

[0093] In a sixth aspect, the present invention further provides a high-purity upadacitinib hemihydrate, characterized in that the content of the compound of formula 4 is less than 0.1%, and the purity of upadacitinib hemihydrate is higher than 98.0%.

[0094] In some embodiments of the present invention, the content of the compound of formula 4 is less than 0.05%; in some typical embodiments of the present invention, the content of the compound of formula 4 is less than 0.03%; in some more typical embodiments of the present invention, the content of the compound of formula 4 is less than 0.015%.

[0095] In some embodiments of the present invention, the purity of upadacitinib hemihydrate is higher than 98.5%; in some typical embodiments of the present invention, the purity of upadacitinib hemihydrate is higher than 99.0%; in some more typical embodiments of the present invention, the purity of upadacitinib hemihydrate is higher than 99.5%; in some more typical embodiments of the present invention, the purity of upadacitinib hemihydrate is higher than 99.8%.

[0096] In the present invention, the purity of upadacitinib and its hydrate and the content of the compound of formula 4 can be measured by the following method:

[0097] 1. Chromatographic conditions

[0098] Table 1 Chromatographic conditions

[0099] 2. Reagents

[0100] Ammonium acetate: chromatographic grade or analytical grade Acetonitrile: chromatographic grade

[0101] Isopropyl alcohol: chromatographic pure water: purified water

[0102] 3. Solution Preparation

[0103] Diluent: Acetonitrile: Water = 50:50 (% V / V)

[0104] Blank solution: diluent

[0105] Test solution: Weigh 25 mg of the test sample into a 50 mL volumetric flask, dissolve it in the diluent and dilute to the mark, then mix well.

[0106] 4. Steps

[0107] Inject 1 injection of blank solution and 1 injection of test solution respectively, and record the chromatographic process.

[0108] 5. Calculation

[0109] According to the area normalization method, the detection limit of the above HPLC method was 0.015%.

[0110] The preparation method provided by the present invention can obtain high-purity upadacitinib hemihydrate with a high yield, without requiring strict control of changes in the pH value of the reaction system during the reaction. The method is simple to operate and the product is readily available. More importantly, the method is not only suitable for small-scale preparation of upadacitinib hemihydrate but also can stably achieve scale-up and large-scale production. The upadacitinib hemihydrate prepared by the present invention has good purity.

[0111] Unless otherwise specified, the terms in this invention have the following meanings:

[0112] The percentages of solution contents are all mass fractions. For example, “20% KOH aqueous solution (11.14 g)” means that the mass of solute KOH accounts for 20% of the total mass of solute KOH and solvent water, that is, the mass of solute KOH is 2.228 g.

[0113] "CDI" is N,N'-carbonyldiimidazole.

[0114] "EA" is ethyl acetate.

[0115] "KOH" is potassium hydroxide.

[0116] "THF" is tetrahydrofuran.

[0117] "Crude product" refers to a substance that may contain impurities and needs to be further purified. In the present invention, "crude upadacitinib" refers to the substance obtained after preliminary purification during the synthesis of upadacitinib hemihydrate.

[0118] “Higher than” means “≥”.

[0119] “Below” means “≤”.

[0120] In the present invention, the reaction endpoint can be confirmed by silica gel thin layer chromatography.

[0121] In the present invention, the amount of a mixture added represents the total mass or total volume of all substances constituting the mixture. For example, "20% KOH aqueous solution (11.14 g)" means that the total mass of the solute KOH and the solvent water is 11.14 g, i.e., the total mass of the KOH aqueous solution is 11.14 g.

[0122] In the present invention, “the preparation method is the same as that of Example n” or “prepared with reference to Example n” means that only the reactants, catalyst and / or solvent required for the reaction are enlarged or reduced in the same molar ratio as in Example n, and the other conditions remain basically unchanged to obtain the desired amount of compound or mixture; “other conditions” include but are not limited to reaction environment, reaction temperature, reaction time, feeding method or post-treatment operation, etc.; “Example n” means that the example numbered as the reference basis is n.

[0123] In the present invention, when the preparation method includes other previous steps before step (1), the amount of water in step (1) includes the amount of water in the aqueous solution of alkali added in step (1a) and / or step (1b) of the preparation method; the amount of organic solvent in step (1) includes the amount of organic solvent added in step (1a) and / or step (1b) of the preparation method.

[0124] In the present invention, those skilled in the art will readily appreciate that materials can be added in a variety of ways without affecting the essence of the invention. For example, the methods for adding N,N'-carbonyldiimidazole include, but are not limited to, direct addition or addition in the form of a solution thereof; and the methods for adding trifluoroethylamine or its salt include, but are not limited to, direct addition or addition in the form of a solution thereof.

[0125] It is easy for those skilled in the art to understand that experimental errors, technical errors and instrument errors may cause numerical fluctuations in the technical solution, but in essence they still belong to the inventive content of the present invention.

[0126] It is easy for those skilled in the art to understand that the operation time sequence of steps (1b) and (1a) in the present invention can be adjusted according to actual needs, for example, they can be performed simultaneously or in any order. DETAILED DESCRIPTION

[0127] The present invention will be further described below by way of specific examples, but they are not intended to limit the scope of protection of the present invention. Without departing from the concept of the present invention, any modifications or variations that are easily realized by those skilled in the art will fall within the scope of the present invention.

[0128] Example 1-1. Synthesis of N-(2,2,2,2-trifluoroethyl)-1H-imidazole-1-carboxamide (Formula 3)

[0129] Add CDI (4.84 g) and THF (20 mL) to a reaction flask under nitrogen, cool to -5°C to 5°C, then add trifluoroethylamine free base (3.17 g) and THF (26 mL). During the addition, control the system temperature to ≤ 5°C. Incubate at -5°C to 5°C for 1 to 2 hours to obtain a solution of the compound of Formula 3. Use the solution directly in the next reaction without purification.

[0130] Example 1-2. Synthesis of Upadacitinib Hemihydrate

[0131] To a reaction flask, add the compound of formula 2-1 (8.31 g), THF (13 mL), water (13 mL), and 20% KOH aqueous solution (11.14 g), stir to dissolve, control the reaction temperature at 20°C to 30°C, and add the solution of the compound of formula 3 obtained in Example 1-1 dropwise for 2 to 3 hours. After the addition is complete, react at 20°C to 30°C for 1 to 2 hours. After the reaction is complete, add 20% KOH aqueous solution (13.0 g) and react at 20°C to 30°C for 3 to 4 hours. After the reaction, 36% aqueous hydrochloric acid was added to adjust the pH to 4.8-5.5, and then EA (26 mL) was added for extraction. The aqueous layer was separated and removed. The organic layer was washed sequentially with saturated aqueous NaHCO3 solution (26 mL) and 20% aqueous NaCl solution (13 mL) and concentrated. No compound of formula 4 was detected. EA (37.4 g) and water (0.74 g) were added for crystallization to obtain 6.68 g of upadacitinib hemihydrate with a purity of 99.74%. ESI-MS m / z: 390 [M+H] + , the compound of formula 4 was not detected.

[0132] Example 2-1. Scaled-up synthesis of N-(2,2,2,2-trifluoroethyl)-1H-imidazole-1-carboxamide (Formula 3)

[0133] Add CDI (13.5 kg) and THF (92.8 kg) to a reaction flask under nitrogen atmosphere. Cool to -5°C to 5°C. Add trifluoroethylamine hydrochloride (12.1 kg) in 10 batches, maintaining the system temperature at -5°C to 5°C during addition. Incubate the reaction for 1 to 2 hours. After incubation, add 20% aqueous KOH (25 kg), maintaining the system temperature at -5°C to 5°C during addition. Incubate for 0.5 to 1 hour after addition is complete. Filter, rinse the filter cake with THF (20.2 kg), and combine the filtrates to obtain a solution of the compound of Formula 3.

[0134] Example 2-2. Scale-up synthesis of upadacitinib hemihydrate

[0135] Add the compound of formula 2-1 (23.2 kg), THF (32.3 kg), water (36.3 kg), and 20% KOH aqueous solution (31.1 kg) to the reaction flask, stir to dissolve, control the reaction temperature at 20°C to 30°C, and add the solution of the compound of formula 3 obtained in Example 2-1 dropwise for 2 to 3 hours. After the addition is complete, react at 20°C to 30°C for 1 to 2 hours. After the reaction is complete, add 20% KOH aqueous solution (36.18 kg) and react at 20°C to 30°C for 3 to 4 hours. After the reaction, 36% aqueous hydrochloric acid was added to adjust the pH to 4.8-5.5, and then EA (66.8 kg) was added for extraction. The aqueous layer was separated and removed, and the organic layer was washed sequentially with saturated aqueous NaHCO (73 kg) and 20% aqueous NaCl (42.2 kg) and concentrated. No compound of formula 4 was detected. EA (104.4 kg) and water (2.06 kg) were added, and the mixture was kept at 40° C. to 45° C., then cooled to 0° C. to 5° C. and crystallized for 0.5 h to 1 h. Solid-liquid separation was performed, and the filter cake was dried to obtain 19.1 kg of upadacitinib hemihydrate with a purity of 99.90%. ESI-MS m / z: 390 [M+H] + , the compound of formula 4 was not detected.

[0136] Example 3-1. Synthesis of N-(2,2,2,2-trifluoroethyl)-1H-imidazole-1-carboxamide (Formula 3)

[0137] Add CDI (18.19 kg) and THF (136.44 kg) to the reaction flask and stir. Control the temperature at 0-5°C and add trifluoroethylamine hydrochloride (17.74 kg) in portions. Incubate for 1-2 hours. After the reaction is complete, slowly add 20% KOH aqueous solution (36.61 kg) dropwise. Filter and rinse with THF (29.79 kg). Combine the filtrates to obtain a solution of the compound of Formula 3.

[0138] Example 3-2. Synthesis of Upadacitinib Hemihydrate

[0139] Add the compound of Formula 2-1 (22.74 kg), THF (47.75 kg), and water (36.61 kg) to the reaction flask. Control the temperature in the kettle at 15-25°C. Adjust the pH to 8-9 with a 20% aqueous KOH solution. Control the temperature at 20-25°C and slowly add the solution of the compound of Formula 3 obtained in Example 3-1 dropwise. After the addition is complete, adjust the pH to 8-9 with a 20% aqueous KOH solution. Incubate at 20-25°C for 1-3 hours. After the reaction is complete, control the temperature at 20-30°C, add a 20% aqueous KOH solution (32.06 kg), and incubate for 4-6 hours. After the reaction is complete, cool to 5-15°C, adjust the pH to 5-6 with hydrochloric acid, add ethyl acetate (65.49 kg), and stir at this temperature for 20-30 minutes. Allow to stand and separate the layers. Extract the aqueous phase with ethyl acetate (65.49 kg), and combine the organic phases. The organic phase was washed with an aqueous potassium dihydrogen phosphate solution (prepared from potassium dihydrogen phosphate (2.96 kg) and water (16.37 kg)), then with an aqueous sodium bicarbonate solution (prepared from sodium bicarbonate (5.91 kg) and water (73.45 kg)), and finally with an aqueous sodium chloride solution (prepared from sodium chloride (8.41 kg) and water (33.43 kg)). Activated carbon (4.55 kg) was added, and the mixture was stirred at 20-30°C for 1 hour ± 10 minutes. The mixture was filtered, rinsed with THF (22.74 kg) and ethyl acetate (11.37 kg), and the filtrates were combined and distilled under reduced pressure until no significant fraction remained. Ethyl acetate (11.37 kg) was added, and distillation was continued under reduced pressure until no significant fraction remained. Distillation was continued for 1-2 hours. Water (2.05 kg) and ethyl acetate (102.33 kg) were added, and the temperature was raised to 40-45°C. Stirring was continued until solid precipitated, and stirring was continued for 1 hour ± 10 minutes while maintaining the temperature. The mixture was slowly cooled to 0-5°C, stirred at this temperature for 1-2 hours, filtered, and the filter cake was rinsed with pre-cooled ethyl acetate. Water (43.43 kg) was added, stirred at 5-15°C for 1-2 hours, filtered, and the filter cake was rinsed with pre-cooled water. The mixture was dried to obtain 16.62 kg of upadacitinib hemihydrate with a purity of 99.89%. ESI-MS m / z: 390 [M+H] + , the compound of formula 4 was not detected.

[0140] Example 4. Preparation of Upadacitinib Hemihydrate

[0141] To Reactor 1, add ethanol (95 kg) and upadacitinib (19.0 kg, prepared according to the method of Example 2-2). Stir to dissolve the reaction system. Add activated carbon (0.95 kg) and stir at 25°C-30°C for 2 h. Filter, rinse the filter residue with ethanol (19 kg), and combine the filtrates in Reactor 2. Concentrate the filtrate to constant weight at 45°C. During the concentration process, add EA (34.2 kg x 2) in two portions. After distillation, add EA (38 kg) and stir to dissolve the solids. Transfer the mixture to Reactor 3. Wash Reactor 2 with EA (19 kg), and transfer the solution to Reactor 3. Add EA (28.5 kg) and water (0.87 kg) to Reactor 1, filter, and transfer to Reactor 2. Add the solution in Reactor 3 dropwise to Reactor 2 at 40°C-45°C for 3-4 h. Stir at 40°C-45°C for 1 h. After stirring, cool to 0-5°C at a rate of 0.16-0.25°C / min and maintain stirring for 1-2 hours. Filter, rinse the filter cake with EA (9.5 kg), and filter until no significant liquid flows out of the mother liquor outlet of the centrifuge. Dry the wet product in an oven at a water temperature of 45-55°C and a vacuum gauge pressure of ≤-0.08 MPa for 8-12 hours to obtain 17.88 kg of upadacitinib hemihydrate with a purity of 99.93%. ESI-MS m / z: 390 [M+H] + , the compound of formula 4 was not detected.

[0142] Example 5. Preparation of Upadacitinib Hemihydrate

[0143] Add ethanol (86.32 kg) and upadacitinib (16.6 kg, prepared according to the method of Example 3-2) to Reactor 1, stir until the reaction system is clear, add activated carbon (0.83 kg) at 20-30°C, and stir for 1 hour ± 10 minutes. Filter, rinse with ethanol (33.2 kg), combine the filtrates in Reactor 2, and distill under reduced pressure until no significant fraction is present. Add ethyl acetate (29.88 kg), distill under reduced pressure until no significant fraction is present, then add more ethyl acetate (29.88 kg), distill under reduced pressure until no significant fraction is present, and continue distillation for 1 hour to 2 hours. Add ethyl acetate (33.2 kg), heat to 40-45°C, stir until the reaction system is clear, and transfer to Reactor 3. Rinse Reactor 2 with EA (8.3 kg), transfer to Reactor 3, and maintain at 40-45°C. A mixed solution of ethyl acetate (24.9 kg) and water (0.83 kg) was added to reactor 2. The solution in reactor 3 was slowly added dropwise at 40-45°C. After the addition was complete, reactor 3 was rinsed with EA and transferred to reactor 2. The mixture was stirred at this temperature for 1 hour ± 10 minutes. The temperature was lowered to 0-5°C, stirred for 1-2 hours, filtered, and the filter cake was rinsed with pre-cooled EA. Drying afforded 15.14 kg of upadacitinib hemihydrate with a purity of 99.9%. ESI-MS m / z: 390 [M+H]+ , the compound of formula 4 was not detected.

[0144] Comparative Example 1-1. Synthesis of Upadacitinib Hemihydrate

[0145] Add the compound of formula 2-1 (8.31 g), THF (13 mL), water (13 mL), and 20% KOH solution (11.14 g) to the reaction flask, stir to dissolve, and add K2HPO4 (6.9 g) to adjust the pH to 7.5-8.5. At 20°C-30°C, add the solution of the compound of formula 3 (49.0 g) in Example 1-1 dropwise for 2-3 hours. During the addition, adjust the pH of the aqueous phase with 20% KOH solution to maintain the pH at 7.5-8.5. After the addition is complete, react at 20°C-30°C to complete the reaction of the compound of formula 2-1. During the reaction, adjust the pH of the aqueous phase with 20% KOH solution to maintain it at 7.5-8.5. After the reaction is complete, add EA (26 mL) and 20% citric acid aqueous solution (26 mL) to quench the reaction, and separate the aqueous layer. The organic layer was washed sequentially with 15% KH2PO4 solution (26 mL), saturated NaHCO3 solution (26 mL), and 20% NaCl solution (13 mL), concentrated, and crystallized by adding EA (37.4 g) and water (0.74 g) to obtain 6.43 g of upadacitinib hemihydrate with a purity of 99.74%. ESI-MS m / z: 390 [M+H] + , the content of the compound of formula 4 is 0.12%.

[0146] Comparative Example 1-2. Scale-up Synthesis of Upadacitinib Hemihydrate

[0147] To a reaction flask, add the compound of Formula 2-1 (0.83 kg), THF (1.3 L), water (1.3 L), and 20% KOH solution (1.11 kg), stir to dissolve, and add K2HPO4 (0.7 kg) to adjust the pH to 7.5-8.5. Add a solution of the compound of Formula 3 (4.9 kg, prepared as in Example 1-1, i.e., 484 g CDI, 317 g trifluoroethylamine free base, and 2 L and 2.6 L THF, respectively) dropwise at 20-30°C for 2-3 hours. During the addition, adjust the pH of the aqueous phase with 20% KOH solution to maintain it between 7.5 and 8.5. After the addition is complete, allow the reaction to proceed at 20-30°C to complete the reaction of the compound of Formula 2-1. During the reaction, adjust the pH of the aqueous phase with 20% KOH solution to maintain it between 7.5 and 8.5. After the reaction was completed, EA (2.6 L) and 20% aqueous citric acid (2.6 L) were added to quench the reaction. The layers were separated, and the aqueous layer was extracted with EA (2.6 L). The organic layers were combined. The organic layer was washed sequentially with 15% KH2PO4 solution (26 L), saturated NaHCO3 solution (26 L), and 20% NaCl solution (13 L). The product was concentrated, and EA (3.74 kg) and water (74 g) were added for crystallization to obtain 0.57 kg of upadacitinib hemihydrate with a purity of 99.52%. ESI-MS m / z: 390 [M+H] + , the content of the compound of formula 4 is 0.12%;

[0148] Among them, the monitoring data of the purity of upadacitinib or its hydrate and the content of the compound of formula 4 during the post-treatment process of Comparative Examples 1-2 are shown in Table 2:

[0149] Table 2 Purity of upadacitinib or its hydrate and content of compound of formula 4

Claims

1. A method for preparing upadacitinib or its hydrate, characterized in that It includes the following steps: (1) The compound of formula 2 and the compound of formula 3 react in an organic solvent and water; (2) Mix the reaction system obtained in step (1) with inorganic base A and react to obtain the compound of formula 1 or its hydrate, 2. According to the preparation method described in claim 1, the compound of formula 1 or its hydrate exists in the form of formula 1-A, Among them, x is from 0 to 0.65, preferably x is from 0 to 0.5, more preferably x is 0 or 0.5, still more preferably x is 0, and most preferably x is 0.

5.

3. The preparation method according to claim 1 or 2, wherein the molar ratio of the compound of formula 2 to the compound of formula 3 in step (1) is 1:1, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:2, 1:2.1, 1:2.2, 1:2.5, 1:3, 1:4 or the range between any two of the above ratios, preferably 1:1 to 4, more preferably 1:1 to 3, still more preferably 1:1 to 2.5, further preferably 1:1.4 to 2.2, most preferably 1:1.4 to 1.5, and most preferably 1:2 to 2.2; the feeding mode of the compound of formula 3 in step (1) is dropwise addition, and the dropwise addition time is 0 hour to 10 hours, preferably 1 hour to 5 hours, more preferably 2 hours to 4 hours, still more preferably 2 hours to 3 hours; the reaction temperature in step (1) is 0°C to 50°C, preferably 10°C to 40°C, more preferably 25°C to 35°C, still more preferably 20°C to 30°C; the reaction time after the addition of the compound of formula 3 in step (1) is completed is 0 hour to 10 hours, preferably 0 hour to 5 hours, more preferably 1 hour to 3 hours, still more preferably 1 hour to 2 hours; the organic solvent in step (1) is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dichloromethane, and acetonitrile, preferably selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile, more preferably selected from one of tetrahydrofuran and 2-methyltetrahydrofuran, and still more preferably tetrahydrofuran; the mass-volume ratio (g:mL) of the compound of formula 2 to the organic solvent in step (1) is 1:1, 1:8, 1:10, 1:11, 1:12, 1:16, 1:17, 1:18, 1:20, 1:22, 1:25 or the range between any two of the above ratios, preferably 1:1 to 25, more preferably 1:8 to 22, still more preferably 1:10 to 20, further preferably 1:10 to 18, most preferably 1:10 to 12, most preferably 1:11 to 18, and most preferably 1:16 to 18; the mass-volume ratio (g:mL) of the compound of formula 2 to water in step (1) is 1:1 to 16, preferably 1:1 to 10, more preferably 1:2 to 8.

4. The preparation method according to any one of claims 1 - 3, wherein the inorganic base A in step (2) is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, or lithium carbonate, preferably selected from sodium hydroxide, potassium hydroxide, or lithium hydroxide, more preferably selected from sodium hydroxide or potassium hydroxide, and still more preferably potassium hydroxide; The inorganic base A in step (2) is added in its solid form or its aqueous solution form, preferably in its aqueous solution form, more preferably in its aqueous solution form with a mass fraction of 5% to 50%, still more preferably in its aqueous solution form with a mass fraction of 15% to 40%, further more preferably in its aqueous solution form with a mass fraction of 15% to 25%, and most preferably in its aqueous solution form with a mass fraction of 20%; In step (2), based on the monovalent basic radical ion, the molar ratio of the compound of formula 2 to the inorganic base A is 1:1 to 5, preferably 1:1 to 4, more preferably 1:1.5 to 2.5, still more preferably 1:2 to 2.5, further more preferably 1:2 to 2.4, and most preferably 1:2.1 to 2.4; The mixing temperature in step (2) is 0°C to 50°C, preferably 10°C to 50°C, more preferably 15°C to 35°C, still more preferably 20°C to 30°C; The reaction time in step (2) is 0 hour to 10 hours, preferably 1 hour to 6 hours, more preferably 2 hours to 5 hours, still more preferably 4 hours to 6 hours, still more preferably 3 hours to 4 hours; After mixing and reacting in step (2), optionally further includes adjusting the pH value to 3 to 6, preferably further sequentially includes adjusting the pH value to 4 to 6, extraction and liquid separation, more preferably further sequentially includes adjusting the pH value to 4.8 to 6, extraction and liquid separation, still more preferably further sequentially includes adjusting the pH value to 4.8 to 5.5, extraction with ethyl acetate and liquid separation, still more preferably further sequentially includes adjusting the pH value to 5 to 6, extraction with ethyl acetate and liquid separation.

5. The preparation method according to any one of claims 1-4, characterized in that Before step (1), the following step is further included: (1a) reacting the acid addition salt of the compound of formula 2 with an inorganic base B in an organic solvent and water to obtain the compound of formula 2.

6. According to the preparation method according to claim 5, wherein, The acid addition salt of the compound of formula 2 in step (1a) is selected from the hydrobromate, hydrochloride, sulfate or phosphate of the compound of formula 2, preferably from the hydrobromate, hydrochloride or sulfate of the compound of formula 2, more preferably from the hydrobromate or hydrochloride of the compound of formula 2, and still more preferably from the hydrobromate of the compound of formula 2; The inorganic base B in step (1a) is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or lithium carbonate, preferably from sodium hydroxide, potassium hydroxide or lithium hydroxide, more preferably from sodium hydroxide or potassium hydroxide, and still more preferably from potassium hydroxide; In step (1a), based on the monovalent basic radical ion, the molar ratio of the acid addition salt of the compound of formula 2 to the inorganic base B is 1:1 to 5, preferably 1:1 to 4, more preferably 1:1.5 to 2.5, still more preferably 1:1.8 to 2.2, and most preferably 1:

2. Most preferably, the inorganic base B is potassium hydroxide, and the molar ratio of the acid addition salt of the compound of formula 2 to the inorganic base B is 1:2; In step (1a), the pH of the reaction system is adjusted to 8 to 9 by adding the inorganic base B; In step (1a), the inorganic base B is added in the form of its aqueous solution. Preferably, the inorganic base B is added in the form of its aqueous solution, and the mass of the inorganic base B accounts for 20% of the mass of its aqueous solution. More preferably, the inorganic base B is added in the form of an aqueous solution of potassium hydroxide, and the mass of potassium hydroxide accounts for 20% of the mass of its aqueous solution; The organic solvent in step (1a) is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dichloromethane, and acetonitrile. Preferably, it is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile. More preferably, it is selected from tetrahydrofuran or 2-methyltetrahydrofuran. Even more preferably, it is tetrahydrofuran; The mass-volume ratio (g:mL) of the acid addition salt of the compound of formula 2 to the organic solvent in step (1a), calculated as its free base, is 1:1 to 16. Preferably, it is 1:1.5 to 5. More preferably, it is 1:2.3 to 5. Even more preferably, it is 1:2.3 to 4. Most preferably, it is 1:2.3 to 2.6; The reaction temperature of step (1a) is 0 °C to 50 °C. Preferably, it is 10 °C to 50 °C. More preferably, it is 15 °C to 35 °C. Even more preferably, it is 20 °C to 30 °C.

7. The preparation method according to any one of claims 1-6, characterized in that Before step (1), the following step is further included: (1b) N,N'-carbonyldiimidazole and trifluoroethylamine or its salt react in a solvent to obtain a compound of formula 3.

8. According to the preparation method of claim 7, wherein, The reaction temperature of the reaction in step (1b) is -10 °C to 30 °C. Preferably, it is -10 °C to 10 °C. More preferably, it is -5 °C to 5 °C; The trifluoroethylamine or its salt in step (1b) is trifluoroethylamine or its hydrochloride. Preferably, it is trifluoroethylamine or its monohydrochloride. More preferably, it is free trifluoroethylamine. Even more preferably, it is trifluoroethylamine monohydrochloride; The trifluoroethylamine or its salt in step (1b) is an acid addition salt of trifluoroethylamine. The above preparation method further includes adding a base to the reaction solution after the reaction. Preferably, the trifluoroethylamine or its salt in step (1b) is an acid addition salt of trifluoroethylamine. The above preparation method further includes adding an aqueous solution of a base to the reaction solution after the reaction. More preferably, the trifluoroethylamine or its salt in step (1b) is an acid addition salt of trifluoroethylamine. The above preparation method further includes adding an aqueous solution of potassium hydroxide to the reaction solution after the reaction. Even more preferably, the trifluoroethylamine or its salt in step (1b) is an addition salt of trifluoroethylamine. The above preparation method further includes adding a 20% aqueous solution of potassium hydroxide to the reaction solution after the reaction. Most preferably, the trifluoroethylamine or its salt in step (1b) is trifluoroethylamine monohydrochloride. It further includes adding a 20% aqueous solution of potassium hydroxide to the reaction solution after the reaction, and the molar ratio of trifluoroethylamine monohydrochloride to potassium hydroxide is 1:1; In the step (1b), the molar ratio of trifluoroethylamine or its salt to N,N'-carbonyldiimidazole is 1:0.5, 1:0.8, 1:0.84, 1:0.9, 1:0.94, 1:0.95, 1:1, 1:1.5, 1:2 or a range between any two of the above ratios, preferably 1:0.5 to 2, more preferably 1:0.5 to 1.5, still more preferably 1:0.5 to 1, further preferably 1:0.8 to 1, most preferably 1:0.85 to 0.95, and most preferably 1:0.9 to 0.95; In the step (1b), the reaction solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dichloromethane, and acetonitrile, preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile, more preferably tetrahydrofuran or 2-methyltetrahydrofuran, and still more preferably tetrahydrofuran; In the step (1b), the mass-volume ratio (g:mL) of N,N'-carbonyldiimidazole to the solvent is 1:1, 1:5, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:14, 1:20, 1:25 or a range between any two of the above ratios, preferably 1:1 to 25, more preferably 1:5 to 20, still more preferably 1:7 to 14, further preferably 1:8 to 12, most preferably 1:7 to 10, most preferably 1:8 to 10, and most preferably 1:9 to 10; In the step (1b), the reaction time of the reaction is 0.5 hour to 3 hours, preferably 1 hour to 2 hours; The reaction in the step (1b) is carried out under a nitrogen atmosphere.

9. According to the preparation method according to any one of claims 5-8, wherein, In the step (1a), the molar ratio of the acid addition salt of the compound of formula 2 to trifluoroethylamine or its salt in the step (1b) is 1:1, 1:1.5, 1:1.6, 1:1.8, 1:2, 1:2.3, 1:2.4, 1:2.5, 1:3 or a range between any two of the above ratios, preferably 1:1 to 3, more preferably 1:1 to 2.5, still more preferably 1:1 to 2, further preferably 1:1.5 to 2.5, most preferably 1:1.5 to 1.8, and most preferably 1:2.3 to 2.5; The step (1b) does not require purification and is directly used for the next reaction.

10. A method for preparing upadacitinib hemihydrate, characterized in that: At 0°C to 80°C, add the ethyl acetate solution of upadacitinib crude product to the mixed solvent of ethyl acetate and water. After adding, keep warm for 1 hour to 12 hours, cool down to -10°C to 10°C, and crystallize for 0 hour to 4 hours.

11. According to the preparation method according to claim 10, wherein, The upadacitinib crude product is upadacitinib free base or hydrate, preferably upadacitinib free base, preferably upadacitinib hydrate, and more preferably upadacitinib hemihydrate; The mass ratio (kg:kg) of the upadacitinib crude product to ethyl acetate in the ethyl acetate solution of the upadacitinib crude product is 1:1, 1:2, 1:2.2, 1:2.5, 1:3, 1:3.2, 1:6, 1:9, 1:10 or the range between any two of the above ratios, preferably 1:1 to 10, more preferably 1:2 to 9, still more preferably 1:2 to 6, further preferably 1:2.2 to 3.2, and most preferably 1:2.5 to 3; The molar ratio of the upadacitinib crude product to water is 1:0.5 to 4, preferably 1:0.5 to 2, more preferably 1:0.8 to 2, and still more preferably 1:0.8 to 1.2; The total mass of the ethyl acetate refers to the total amount of ethyl acetate used in the ethyl acetate solution of the upadacitinib crude product and the mixed solvent of ethyl acetate and water in the above preparation method, and the mass ratio of the water to the total mass of the ethyl acetate is 1:200 to 1:32, preferably 1:200 to 1:50, more preferably 1:100 to 1:50, and still more preferably 1:100 to 1:78; The preparation method further includes that the dropping time of the ethyl acetate solution of the upadacitinib crude product is 1 hour to 6 hours, preferably 1 hour to 5 hours, more preferably 2 hours to 5 hours, and still more preferably 3 hours to 4 hours; The heat preservation temperature is 0°C to 50°C, preferably 20°C to 50°C, more preferably 30°C to 45°C, and still more preferably 40°C to 45°C; The heat preservation time is 1 hour to 10 hours, preferably 2 hours to 8 hours, more preferably 3 hours to 6 hours, and still more preferably 4 hours to 5 hours; The temperature reduction temperature is -5°C to 10°C, preferably -5°C to 5°C, more preferably 0°C to 5°C; The temperature reduction rate is 0.15°C / min to 1.0°C / min, preferably 0.15°C / min to 0.75°C / min, more preferably 0.15°C / min to 0.5°C / min, and still more preferably 0.15°C / min to 0.3°C / min; The crystallization time is 0 hour to 3 hours, preferably 0.5 hour to 3 hours, and more preferably 0.5 hour to 2 hours.

12. A high-purity upadacitinib hemihydrate, characterized in that The content of the compound of formula 4 is less than 0.1%, and the purity of upadacitinib hemihydrate is higher than 98.0%.

13. The upadacitinib hemihydrate according to claim 12, wherein, The content of the compound of formula 4 is less than 0.05%, preferably less than 0.03%, and more preferably less than 0.015%; The purity of the upadacitinib hemihydrate is higher than 98.5%, preferably higher than 99.0%, more preferably higher than 99.5%, and still more preferably higher than 99.8%.

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