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JP-7855657-B2 - Methods for the synthesis of froimidazopyridine compounds, polymorphs, and polymorphs of salts

JP7855657B2JP 7855657 B2JP7855657 B2JP 7855657B2JP-7855657-B2

Inventors

  • リァン コンシン
  • 王来宝
  • 劉海輝

Assignees

  • ハンチョウ ハイライトゥル ファーマシューティカル カンパニー リミテッド

Dates

Publication Date
20260508
Application Date
20241001
Priority Date
20190606

Claims (20)

  1. A crystal O of the compound tartrate of formula I, The X-ray powder diffraction pattern of the crystal O shows characteristic peaks at 2 theta angles of 6.3°±0.2°, 26.1°±0.2°, and 26.9°±0.2°.
  2. The crystalline tartrate of the compound of formula I according to claim 1, wherein the X-ray powder diffraction pattern of the crystal shows characteristic peaks at 2 theta angles of 6.3°±0.2°, 12.5°±0.2°, 15.1°±0.2°, 26.1°±0.2°, 26.9°±0.2°, and 27.5°±0.2°.
  3. Crystals of the tartrate salt of the compound of formula I according to claim 1 or 2, wherein the X-ray powder diffraction pattern of the crystals shows characteristic peaks at 2 theta angles of 6.3°±0.2°, 11.4°±0.2°, 12.5°±0.2°, 14.1°±0.2°, 14.4°±0.2°, 15.1°±0.2°, 26.1°±0.2 ° , 26.9°±0.2°, and 27.5°±0.2°.
  4. A method for preparing crystal O of a tartrate salt of a compound of formula I according to any one of claims 1 to 3, comprising : The compound of formula I is mixed with a first solvent, and the compound is dissolved until the solution becomes clear to obtain a first solvent solution of the compound of formula I; tartaric acid is mixed with a second solvent, and the compound is dissolved until the solution becomes clear to obtain a second solvent solution of tartaric acid; the second solvent solution of tartaric acid is added to the first solvent solution of the compound of formula I while stirring, and controlled cooling is performed while stirring, the solid is recovered and dried to obtain crystals O of the tartrate salt of the compound of formula I ; A preparation method in which the first solvent and the second solvent are selected from the group consisting of acetone, ethyl acetate, and any combination thereof .
  5. The preparation method according to claim 4 , wherein the molar ratio of the compound of formula I to tartaric acid is 1:(0.5 to 1.5 ) .
  6. The preparation method according to claim 4, wherein in the tartrate crystal O of the compound of formula I, the molar ratio of the compound of formula I to tartaric acid is 2:1.
  7. The preparation method according to claim 4, wherein the concentration of the acetone solution of the compound of formula I is 15 to 70 mg/mL.
  8. The preparation method according to claim 4, wherein the concentration of the acetone solution of tartaric acid is 5 to 35 mg/m.
  9. The preparation method according to claim 4, comprising mixing the compound of formula I with acetone, and then raising the temperature to 40-60°C to dissolve the compound of formula I until the solution becomes clear.
  10. The preparation method according to claim 4, comprising mixing tartaric acid with acetone and raising the temperature to 40-60°C to dissolve the tartaric acid until the solution becomes clear.
  11. The preparation method according to claim 4, comprising adding an acetone solution of tartaric acid to an acetone solution of the compound of formula I at 40 to 60°C.
  12. The preparation method according to claim 4, comprising drying the recovered solid at 40 to 60°C under reduced pressure or using a blower for 5 to 48 hours.
  13. The preparation method according to any one of claims 4 to 12 is achieved by the following steps: 1) Stir the system for 0.5 to 3 hours at room temperature of 35 to 60 °C; 2) Continue cooling the system to 15-35°C, maintain the temperature, and stir for 0.5-3 hours ; 3) Continue cooling the system to 5-15°C, maintain the temperature, and stir for 0.5-3 hours .
  14. The preparation method according to claim 13, wherein in step 1), the system is stirred at room temperature of 35 to 60 °C for 0.5 to 3 hours , and then the system is concentrated to one-third to two-thirds of its original volume.
  15. The preparation method according to claim 13, wherein in step 2), the system is continuously cooled to 15 to 35°C, the temperature is maintained, and after stirring for 0.5 to 3 hours, the system is concentrated to one-third to two-thirds of its original volume.
  16. The preparation method according to any one of claims 4 to 15 , wherein the purity of the compound of formula I is greater than 90%.
  17. A pharmaceutical composition comprising crystals O of a compound tartrate of formula I as described in any one of claims 1 to 3.
  18. A pharmaceutical preparation comprising crystals O of a compound tartrate of formula I as described in any one of claims 1 to 3.
  19. A pharmaceutical composition for treating a JAK1/TYK2-related disease or condition, comprising crystal O of a tartrate salt of a compound of formula I according to any one of claims 1 to 3.
  20. The pharmaceutical composition according to claim 19, wherein the disease or condition is an autoimmune disease or disorder.

Description

Detailed description of the invention [Technical Field] The present invention relates to the field of drug synthesis, and more particularly to a method for synthesizing compound 2-[(2R,5S)-5-[2-methylfluor[3,2-b]imidazo[4,5-d]pyridine-1-yl]tetrahydropyran-2-yl]acetonitrile (hereinafter referred to as compound I or compound I) as a selective JAK1/TYK2 kinase inhibitor. The present invention also relates to the crystalline forms of compound I and its salts, and methods for preparing them. Furthermore, the present invention relates to pharmaceutical compositions and pharmaceutical formulations comprising the crystalline form of compound I and/or its salts, and to the use of the crystalline forms of compound I and its salts in the treatment of JAK1/TYK2-related diseases and conditions. [Background technology] Protein kinases are a family of proteins that regulate multiple cellular processes and play a crucial role in maintaining cellular function. These kinases include at least: non-receptor tyrosine kinases such as the Janus kinase family (JAK1, JAK2, JAK3, and TYK2); receptor tyrosine kinases such as platelet-derived growth factor receptor (PDGFR); and serine/threonine kinases such as β-RAF. The Janus kinase family includes four known family members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). These cytoplasmic tyrosine kinases are associated with membrane cytokine receptors (such as common gamma chain receptors and glycoprotein 130 (gp130) transmembrane protein) (Murray, J. Immunol. 178 (5): 2623 - 2629, 2007). Approximately 40 cytokine receptors transmit signals through combinations of these four JAK family members and their seven downstream substrates: signaling and activator of transcription (STAT) family members (Ghoreschi et al., Immunol Rev. 228 (l): 273 - 287, 2009). Cytokines that bind to their receptors activate JAK through phosphate transfer and/or autophosphorylation. Next, activated JAK family kinases phosphorylate cytokine receptors, generating binding sites for Src homology 2 (SH2)-containing proteins (such as STAT factors and other regulatory factors), which are then activated by JAK phosphorylation. Activated STAT enters the cell nucleus and begins to promote the expression of leukocyte transport survival factors, cytokines, chemokines, and molecules (Schindler et al., J. Biol. Chem. 282(28):20059-20063, 2007). JAK activation also triggers cell proliferation via pathways mediated by phosphoinositide-3-kinase (PI3K) and protein kinase B. JAK3 and JAK1 are components of common gamma-chain cytokine receptor compounds, and blocking either one of them can inhibit the signaling of inflammatory cytokines (interleukin (IL)-2, 4, 7, 9, 15, and 21) (Ghoreschi et al., Immunol. Rev. 228 (l): 273 - 287, 2009). In contrast, other pathologically relevant cytokines (such as IL-6) are dependent only on JAK1. Therefore, JAK1 blocking inhibits the signaling of many pro-inflammatory cytokines (Guschin et al., EMBO J. 14 (7): 1421 - 1429, 1995). The clinical efficacy of the IL-6 receptor neutralizing antibody tocilizumab against rheumatoid arthritis (RA) has been recognized (Maini et al, Arthritis Rheum. 54(9):2817-2829, 2006). International patent application WO2018067422A1 discloses 1H-flou[3,2-b]imidazo[4,5-d]pyridine derivatives as selective JAK1 kinase inhibitors, including compound I and a method for preparing them, and methods for preparing them. The synthetic route is as follows: Biological studies demonstrate that compound I is a potent and selective JAK1 inhibitor, exhibiting selective inhibition of IL-6-induced STAT3 phosphorylation and not selective inhibition of thrombopoietin-induced STAT3 phosphorylation. However, international patent application WO2018067422A1 does not disclose the biological activity of TYK2. Furthermore, the disclosed method for preparing compound I involves high temperatures, generates too many impurities, and results in low yields, making it unsuitable for large-scale production. Therefore, it is necessary to develop a method for preparing compound I that has milder reaction conditions, higher product yields, higher purity, and is suitable for large-scale/industrial production. Currently, there are no reports on the crystalline forms of Compound I and its salts. Comprehensive and systematic polymorphic screening and selection of the optimal crystalline form for development are essential and important research topics. Therefore, further screening of the crystalline forms of Compound I and its salts is necessary to develop a crystalline form with good stability and low hygroscopicity, which would be suitable for large-scale production and provide more and better options for the subsequent development of the drug. [Summary of the Invention] The object of the present invention is to provide a method for producing a compound of formula I (i.e., compound I) suitable for industrial production under mild reaction conditions, with high product yield and high purity. The synthetic r