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KR-20260063684-A - Manufacturing method of high purity amorphous Upadacitinib

KR20260063684AKR 20260063684 AKR20260063684 AKR 20260063684AKR-20260063684-A

Abstract

The present invention relates to high-purity upadacitinib compliant with drug approval standards and a method for manufacturing the same in an amorphous form. By overcoming the disadvantages of conventional manufacturing methods, the invention provides a method for manufacturing amorphous upadacitinib suitable for industrial-scale mass production without separate facility investment.

Inventors

  • 류형선
  • 노경탁
  • 안진우
  • 이주철

Assignees

  • 주식회사 다산제약

Dates

Publication Date
20260507
Application Date
20241031

Claims (9)

  1. 1) A step of forming anisoyl tartarate represented by the following chemical formula 4 by adding a compound represented by the following chemical formula 1 and di-para-anisoyl-L-tartaric acid represented by the following chemical formula 2 under 2,2,2-trifluoroethylamine; 2) A step of dissociating the salt formed above; 3) a step of generating amorphous upadacitinib after dissociating the above salt; a method for manufacturing amorphous upadacitinib comprising <Chemical Formula 1><Chemical Formula 2> <Chemical Formula 4>
  2. A method for manufacturing according to claim 1, wherein the solvent used for salt formation in step 1) is selected from the group consisting of methanol, ethanol, isopropanol, isopropyl acetate, ethyl acetate, acetone, acetonitrile, tetrahydrofuran, water, and mixtures of one or more of these.
  3. A manufacturing method according to claim 1, characterized in that the reaction temperature of step 1) is 40 to 80 ℃.
  4. A manufacturing method according to claim 1, characterized in that the desalination of the salt in step 2) is performed with sodium hydroxide or potassium hydroxide.
  5. A method for manufacturing according to claim 1, wherein in step 2), the solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, water, and mixtures of one or more of these.
  6. A manufacturing method according to claim 1, characterized in that the temperature of step 2) is 10 to 40 ℃.
  7. A manufacturing method according to claim 1, characterized in that the temperature of step 3) is -5 ℃ to 20 ℃.
  8. A method for manufacturing according to claim 1, wherein in step 3), the solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, water, and mixtures of one or more of these.
  9. Upadacitinib para-anisoyl-L-tartrate represented by the following chemical formula 4 <Chemical Formula 4>

Description

Manufacturing method of high purity amorphous Upadacitinib The present invention relates to a method for producing amorphous upadacitinib, and more specifically, to a method for producing high-purity upadacitinib anisoyl tartrate salt by purifying (3S, 4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidin-1-carboxamide) with di-p-anisoyl-L-tartaric acid salt, and then purifying and desalting the same to produce amorphous upadacitinib with high purity and high yield. (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Chemical Formula 1) was first disclosed in international application WO2011/068881A1, the entirety of which is incorporated herein by reference. This compound has activity as a Janus kinase (JAK) inhibitor, particularly as a JAK-1 inhibitor. Upadacitinib, marketed under the brand name Rinvoq, is a selective Janus kinase 1 (JAK-1) inhibitor approved by the FDA for the treatment of moderate to severe active rheumatoid arthritis in adults for whom methotrexate is ineffective or unacceptable. The chemical name of upadacitinib is (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, represented by the following chemical formula 1, and is first disclosed in International Application Publication WO 2011/068881 A1. <Chemical Formula 1> JAK inhibitors are one of the effective treatments for these immune system diseases. Among them, upadacitinib, an innovative new drug from AbbVie for the treatment of rheumatoid arthritis and psoriatic arthritis, is a novel targeted JAK1 inhibitor. JAK1 is a kinase that plays a crucial role in the pathophysiological processes of various inflammatory diseases, including rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), and psoriatic arthritis (PsA). Recently, AbbVie has also been evaluating the potential effects of upadacitinib on other immune diseases, including PsA, ankylosing spondylitis (AS), and atopic dermatitis. Although various methods for the synthesis of upadacitinib are described in the literature, they are all based primarily on the same approach. As shown in the general reaction scheme below, two substances, Fragment A (pyrrolopyrazine derivative) and Fragment B (pyrrolidine derivative), are combined through a coupling reaction. Then, ring annulation is performed to create an imidazopyrrolopyrazine structural framework, followed by the preparation of upadacitinib through derivative modification. General reaction equation Polymorphism refers to the existence of two or more different crystal forms of a compound. Polymorphism is widespread in organic compounds. There are significant differences in solubility, melting point, density, and stability among different crystal forms of the same compound, which affect the stability and uniformity of the compound to varying degrees. Different crystal forms result in distinct differences in the ability to purify compounds through crystallization during the purification process. Therefore, comprehensive and systematic polymorphic screening and the selection of the most suitable crystal form are critical and indispensable aspects of pharmaceutical process research and development. Effective control of impurities is vital in drug production and is essential for guaranteeing drug quality. To fulfill its responsibility to patients, pharmaceutical R&D must pay meticulous attention to impurity control. Research into the salt forms, crystal forms, and purification processes of pharmaceutical intermediate compounds helps control the quality of APIs, thereby guaranteeing the quality and stability of medicines. Methods such as solvent evaporation, spray drying, and freeze-drying have typically been used to synthesize amorphous solid active pharmaceutical ingredients (APIs). Solvent evaporation allows for the formation of a foam-like solid by removing the solvent through vacuum concentration on a laboratory scale and then grinding it; however, due to manufacturing characteristics, purification of impurities is impossible, and obtaining the material in powder form within the reactor is difficult, making it unsuitable for commercial production scales. Spray drying involves spraying a liquid sample into a high-temperature stream of hot air to instantaneously evaporate and dry it, thereby obtaining a powder-like solid; however, this method has the disadvantage of exposing the sample to high temperatures. Freeze-drying minimizes damage to heat-sensitive materials and allows for the stable production of amorphous forms; however, it requires specialized equipment and involves multiple steps—freezing, sublimation, and additional drying to remove residual moisture—resulting in high energy consumption and a very long process time. As such, although amorphous solids of active pharmaceutical ingredients can generally be pharmaceutically useful, they have be