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WO2025152147A1 - Procédé de préparation d'un intermédiaire clé d'ubiquitine ligase e3 - Google Patents

Procédé de préparation d'un intermédiaire clé d'ubiquitine ligase e3

Info

Publication number
WO2025152147A1
WO2025152147A1 PCT/CN2024/073249 CN2024073249W WO2025152147A1 WO 2025152147 A1 WO2025152147 A1 WO 2025152147A1 CN 2024073249 W CN2024073249 W CN 2024073249W WO 2025152147 A1 WO2025152147 A1 WO 2025152147A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
reaction
base
organic solvent
carried out
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/073249
Other languages
English (en)
Chinese (zh)
Other versions
WO2025152147A9 (fr
Inventor
郑锐
李峰
李斌
陈军莆
吴省付
陈翔宇
庄进
金瑶枫
陈方磊
付凌燕
舒磊
蔡磊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Apeloa Shanghai Pharma Solutions Co Ltd
Zhejiang Apeloa Jiayuan Pharmaceutical Co Ltd
Apeloa Pharmaceutical Co Ltd
Original Assignee
Apeloa Shanghai Pharma Solutions Co Ltd
Zhejiang Apeloa Jiayuan Pharmaceutical Co Ltd
Apeloa Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Apeloa Shanghai Pharma Solutions Co Ltd, Zhejiang Apeloa Jiayuan Pharmaceutical Co Ltd, Apeloa Pharmaceutical Co Ltd filed Critical Apeloa Shanghai Pharma Solutions Co Ltd
Priority to PCT/CN2024/073249 priority Critical patent/WO2025152147A1/fr
Publication of WO2025152147A1 publication Critical patent/WO2025152147A1/fr
Publication of WO2025152147A9 publication Critical patent/WO2025152147A9/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the invention belongs to the technical field of drug synthesis methods and relates to a method for preparing a key intermediate of an E3 ubiquitin ligase ligand.
  • KT-474 is an interleukin-1 receptor-associated kinase 4 (IRAK4) degrader developed by Kymera. It is a protein degradation targeting chimera (PROTAC). It mainly targets IRAK4 by acting as a heterobifunctional molecule, binds to IRAK4, recruits E3 ubiquitin ligase to "tag" IRAK4, and then uses the proteasome degradation system to degrade IRAK4.
  • KT-474 has the characteristics of high selectivity and high oral bioavailability.
  • KT-474 also contains the E3 ubiquitin ligase ligand part
  • the compounds used to synthesize the above-mentioned ligand part are likely to serve as key intermediates for the synthesis of KT-474.
  • This route uses nine steps to produce compound VI, which has many reaction steps, high cost, and a yield of only 4.2%.
  • thionyl chloride is used in the second step, which produces harmful sulfur dioxide
  • potassium tert-butoxide is used in the third and eighth steps, which is dangerous and explosive
  • Bechamp reduction is used in the sixth step, and a large amount of iron is used in the reaction process.
  • the ninth step uses highly corrosive methanesulfonic acid to Therefore, it is necessary to develop a new method for preparing the key intermediate of IRAK degradation agent KT-474.
  • the present invention aims to develop a method for preparing a key intermediate of an E3 ubiquitin ligase ligand, which has fewer synthesis steps, lower cost and higher yield.
  • the method not only avoids the use of dangerous, explosive or toxic reagents, but also solves the problem of three wastes discharge, and is suitable for commercial production.
  • the reaction in step 1) is carried out in an organic solvent
  • the organic solvent is at least one of tetrahydrofuran, methanol, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, preferably at least one of tetrahydrofuran and methanol, more preferably at least one of ultra-dry tetrahydrofuran and methanol.
  • step 1) when the base is sodium hydride, the molar ratio of the compound I to the base is 0.9:1 to 1:1.5, preferably 1:1.1.
  • the molar ratio of the compound II to the acylating agent is 1:0.4 to 1:0.6, preferably 1:0.5.
  • the molar ratio of the compound II to the base is 1:1 to 1:15, preferably 1:2 to 1:6.
  • the molar ratio of the compound III to the base is 1:1 to 1:5, preferably 1:2 to 1:2.5.
  • the usage ratio of the compound IV to the organic solvent is 1 g: 3 to 50 mL, preferably 1 g: 8 to 10 mL.
  • the molar ratio of the compound V to the acid is 1:1 to 1:5, preferably 1:2 to 1:3.
  • the reaction temperature in step 5 is from room temperature to 130°C, preferably 80°C.
  • the key intermediate preparation method of the present invention has few synthetic steps, low cost, is suitable for commercial production, and has a high yield.
  • R in the compound of the preparation method, R may be halogen.
  • the compound I in the preparation method may be compound IA or compound IB.
  • the methylating agent in step 1) may be at least one of iodomethane, paraformaldehyde and sodium borohydride.
  • step 1) when the methylating agent is methyl iodide, the molar ratio of compound I to the methylating agent may be 0.9:1 to 1:1.5.
  • step 1) when the methylating agent is methyl iodide, the molar ratio of compound I to the methylating agent may be 1:1.1.
  • the reaction in step 1) is carried out in an organic solvent, which may be at least one of tetrahydrofuran, methanol, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.
  • organic solvent which may be at least one of tetrahydrofuran, methanol, ethylene glycol dimethyl ether, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.
  • the usage ratio of compound I and organic solvent in step 1) can be 1 g: 10-1000 mL.
  • the usage ratio of compound I to the organic solvent in step 1) can be 1 g:14-620 mL.
  • step 1) when the methylating agent is methyl iodide, the reaction temperature can be -40°C to 50°C.
  • reaction time in step 1) can be 7 h to 19 h.
  • the acylating agent in step 2) may be at least one of triphosgene, phosgene and N,N'-carbonyldiimidazole.
  • the acylating agent in step 2) may be triphosgene.
  • the molar ratio of compound II to the acylating agent in step 2) can be 1:0.5.
  • the reaction in step 2) is carried out in an organic solvent, which can be at least one of dichloromethane, dichloroethane, tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, ethyl acetate and toluene.
  • organic solvent can be at least one of dichloromethane, dichloroethane, tetrahydrofuran, ethylene glycol dimethyl ether, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, ethyl acetate and toluene.
  • the usage ratio of compound III to the organic solvent in step 3) can be 1 g:4-100 mL.
  • the usage ratio of compound III to the organic solvent in step 3) can be 1 g:11-19 mL.
  • the molar ratio of compound III to the base in step 3) can be 1:2 to 1:2.5.
  • the reaction in step 3) is carried out in the presence of a catalyst, which may be at least one of 4-dimethylaminopyridine and 1,4-diazabicyclo[2.2.2]octane.
  • a catalyst which may be at least one of 4-dimethylaminopyridine and 1,4-diazabicyclo[2.2.2]octane.
  • reaction in step 3 can be carried out in the presence of 4-dimethylaminopyridine.
  • the molar ratio of compound III to the catalyst in step 3) can be 1:0.01 to 1:0.2.
  • the molar ratio of compound III to the catalyst in step 3) may be 1:0.03.
  • the reaction temperature in step 3) can be from room temperature to 110°C.
  • the reaction time in step 3) can be 1 h to 24 h.
  • reaction time in step 3 can be 15.5 h to 16 h.
  • the reaction in step 4) is carried out in an organic solvent.
  • the organic solvent is at least one of dimethyl sulfoxide, acetonitrile, 1,4-dioxane, N-methylpyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide.
  • reaction in step 4) can be carried out in dimethyl sulfoxide.
  • the usage ratio of compound IV and organic solvent in step 4) can be 1 g: 3-50 mL.
  • reaction in step 4) may be carried out in the presence of 1,8-diazabicycloundec-7-ene.
  • the reaction in step 4) is carried out in the presence of a catalyst, which may be at least one of cuprous oxide, cuprous iodide, cuprous bromide, cuprous chloride, copper-cuprous oxide and copper-cuprous iodide.
  • a catalyst which may be at least one of cuprous oxide, cuprous iodide, cuprous bromide, cuprous chloride, copper-cuprous oxide and copper-cuprous iodide.
  • the reaction in step 4) is carried out in the presence of a catalyst, which may be at least one of cuprous oxide and cuprous iodide.
  • the reaction in step 4) is carried out under nitrogen protection.
  • the reaction time in step 4) can be 0.2 h to 24 h.
  • the molar ratio of compound V to the acid in step 5) may be 1:1 to 1:5.
  • the reaction temperature in step 5) can be from room temperature to 130°C.
  • pyridine 100 mL was added to a solution of triphosgene (58.7 g, 0.198 mol) in DCM (1.0 L), and the reaction mixture was stirred at -30 ° C for 30 minutes. Then 2,6-dibromo-N-methylaniline (104.9 g, 0.396 mol) was slowly added to the reaction mixture at -30 ° C. After the addition, the mixture was warmed to room temperature and stirred at room temperature for 6 hours. LCMS showed that the reaction was completely completed. The reaction mixture was carefully quenched with 0.5N HCl (600 mL) and extracted with DCM (800 mL*3).
  • Step 3 Synthesis of tert-butyl 5-amino-4-(3-(2,6-dibromophenyl)-3-methylureido)-5-oxopentanoate
  • Step 4 Synthesis of tert-butyl 5-amino-4-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxopentanoate
  • 1,4-Dibromo-2-nitrotoluene (100 g, 0.356 mol) was dissolved in ethyl acetate (1500 mL), acetic acid (500 mL) and water (50 mL), and then the solution was heated to 50 ° C, and iron powder (79.52 g, 1.424 mol) was added in batches.
  • the reaction mixture was stirred at 80 ° C for 3 h. After the reaction was completed, the reaction was quenched with saturated Na 2 CO 3 aqueous solution (1000 mL), and extracted with ethyl acetate (500 mL) three times. The combined organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a white solid (85 g, yield: 95%), i.e. 2,5-dibromoaniline.
  • Step 3 Synthesis of tert-butyl 5-amino-4-(3-(2,5-dibromophenyl)-3-methylureido)-5-oxopentanoate
  • Step 4 Synthesis of tert-butyl 5-amino-4-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxopentanoate

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Saccharide Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention se rapporte au domaine technique des procédés de synthèse de médicament, et concerne un procédé de préparation d'un intermédiaire clé d'un ligand d'ubiquitine ligase E3. Plus particulièrement, le procédé de préparation selon la présente invention comprend des étapes telles que la N-méthylation, l'acylation, le couplage et la substitution. Par comparaison avec des procédés de préparation de l'état de la technique, la présente invention a une voie de synthèse simple, utilise des matières premières bon marché et à un rendement élevé, évite l'utilisation de réactifs dangereux, réduit l'évacuation d'eaux usées, de gaz résiduaire et de déchets solides, et est appropriée pour une production industrielle.
PCT/CN2024/073249 2024-01-19 2024-01-19 Procédé de préparation d'un intermédiaire clé d'ubiquitine ligase e3 Pending WO2025152147A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2024/073249 WO2025152147A1 (fr) 2024-01-19 2024-01-19 Procédé de préparation d'un intermédiaire clé d'ubiquitine ligase e3

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2024/073249 WO2025152147A1 (fr) 2024-01-19 2024-01-19 Procédé de préparation d'un intermédiaire clé d'ubiquitine ligase e3

Publications (2)

Publication Number Publication Date
WO2025152147A1 true WO2025152147A1 (fr) 2025-07-24
WO2025152147A9 WO2025152147A9 (fr) 2025-08-28

Family

ID=96470649

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/073249 Pending WO2025152147A1 (fr) 2024-01-19 2024-01-19 Procédé de préparation d'un intermédiaire clé d'ubiquitine ligase e3

Country Status (1)

Country Link
WO (1) WO2025152147A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020205361A1 (fr) * 2019-03-29 2020-10-08 Exxonmobil Chemical Patents Inc. Complexes de métaux de transition benzazole et pseudoindole diamido et leur utilisation dans la polymérisation d'oléfines
CN113423427A (zh) * 2018-11-30 2021-09-21 凯麦拉医疗公司 Irak降解剂和其用途
CN116761633A (zh) * 2020-06-03 2023-09-15 凯麦拉医疗公司 Irak降解剂的结晶型
CN117157286A (zh) * 2021-04-06 2023-12-01 百时美施贵宝公司 经吡啶基取代的氧代异吲哚啉化合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113423427A (zh) * 2018-11-30 2021-09-21 凯麦拉医疗公司 Irak降解剂和其用途
WO2020205361A1 (fr) * 2019-03-29 2020-10-08 Exxonmobil Chemical Patents Inc. Complexes de métaux de transition benzazole et pseudoindole diamido et leur utilisation dans la polymérisation d'oléfines
CN116761633A (zh) * 2020-06-03 2023-09-15 凯麦拉医疗公司 Irak降解剂的结晶型
CN117157286A (zh) * 2021-04-06 2023-12-01 百时美施贵宝公司 经吡啶基取代的氧代异吲哚啉化合物

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Publication number Publication date
WO2025152147A9 (fr) 2025-08-28

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