WO2022111448A1 - Procédé de préparation d'un agent de dégradation de btk - Google Patents

Procédé de préparation d'un agent de dégradation de btk Download PDF

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WO2022111448A1
WO2022111448A1 PCT/CN2021/132332 CN2021132332W WO2022111448A1 WO 2022111448 A1 WO2022111448 A1 WO 2022111448A1 CN 2021132332 W CN2021132332 W CN 2021132332W WO 2022111448 A1 WO2022111448 A1 WO 2022111448A1
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acid
compound
solvents
reaction
preparation
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PCT/CN2021/132332
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Chinese (zh)
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易仕旭
陈曾飞
郭军辉
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四川海思科制药有限公司
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Priority to CN202180053137.1A priority Critical patent/CN116323594A/zh
Publication of WO2022111448A1 publication Critical patent/WO2022111448A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound represented by formula (I) and a method for preparing an intermediate thereof.
  • BTK Bruton's tyrosine kinase
  • BCR B cell antigen receptor
  • BTK mutations cause downstream tumor cell proliferation, differentiation, and activation of signaling pathways such as angiogenesis, leading to X-linked agammaglobulinemia, non-Hodgkin lymphoma (NHL), and many B-cell malignancies, including chronic lymphoid malignancies.
  • CLL Cellular leukemia
  • mantle cell lymphoma mantle cell lymphoma
  • diffuse large B-cell lymphoma Since it is mainly expressed in B cells and myeloid cells, BTK is a target with better targeting and safety.
  • PROTAC proteolysis targeting chimera
  • PROTAC proteolysis targeting chimera
  • PCT/CN2020/093455 describes a BTK-Protac small-molecule anti-tumor drug (shown in the structure of compound 1 below), which is composed of a small-molecule inhibitor targeting BTK protein, an E3 ubiquitin ligase recruiting ligand and connecting two molecules. A triplet consisting of a linker of each ligand. On the one hand, it can directly inhibit BTK activity by specifically binding to BTK; on the other hand, it can induce BTK ubiquitination and degrade it through the proteasome pathway, thereby blocking the transmission of the BCR signaling pathway and inhibiting the growth and development of B-cell lymphoma cells. Proliferation, play a dual anti-tumor effect.
  • the object of the present invention is to provide a preparation method of a compound represented by formula (I) and an intermediate thereof, the second step of the present invention reacts with oxidation reaction, and the third step reaction adopts reductive amination reaction; It is easy to handle and suitable for industrial production.
  • the present invention relates to a preparation method of compound (II), which is prepared by the following reaction formula,
  • X 1 is selected from electron withdrawing groups or leaving groups
  • compound (II-4) reacts with compound (II-6) in the presence of an acidic reagent and a reducing agent to obtain compound (II);
  • the acidic reagent is selected from one of hydrochloric acid, acetic acid, formic acid, propionic acid, butyric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and trifluoroacetic acid or variety.
  • X 1 is selected from halogen, sulfonate, sulfinate, silyl, silyloxy, alkylacyl, and boronate.
  • R 1 are each independently selected from H, C 1-4 alkyl, C 3-10 carbocyclyl or 4-10 membered heterocyclyl, and said alkyl, carbocyclyl or heterocyclyl is optionally further substituted by O , 1, 2, 3 or 4 are selected from F, Cl, Br, I, OH, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic or 4-10 membered heterocyclic substituent;
  • the two R 1 are directly connected to form a 3-7 membered ring optionally further surrounded by 0, 1, 2, 3 or 4 selected from F, Cl, Br, I, OH, cyano, Nitro , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclyl or Substituents of 4-10-membered heterocyclic groups are substituted.
  • each R 1 is independently selected from H, methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, phenyl, pyridine, Cyclohexyl, the methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, phenyl, pyridine, cyclohexyl are optionally further selected from F by 0, 1, 2, 3 or 4 , Cl, Br, I, OH, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 Substituents of alkoxy, C 3-6 carbocyclyl or 4-10 membered heterocyclyl.
  • X 1 is selected from F, Cl, Br, I,
  • the reducing agent is selected from boron reducing agents, preferably sodium borohydride, sodium triacetoxyborohydride, sodium triethylborohydride, sodium cyanoborohydride, One or more of potassium borohydride or lithium borohydride.
  • a desiccant is optionally added.
  • a desiccant is optionally added, and the desiccant is preferably anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate or molecular sieves. one or more.
  • a solvent is included in the reaction, and the solvent is selected from one or more of polar aprotic solvents, polar protic solvents or non-polar solvents species, preferably 1,2-dichloroethane, chloroform, dichloromethane, tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, N,N-diethylformamide , one or more of N,N-dimethylacetamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone.
  • polar aprotic solvents preferably 1,2-dichloroethane, chloroform, dichloromethane, tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, N,N-diethylformamide , one or more of N,N-dimethylacetamide, dimethyl sulfoxide or N-methyl-2-
  • an alkaline reagent is added, and the alkaline reagent is selected from alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal hydroxide
  • the alkaline reagent is selected from alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal hydroxide
  • reaction temperature of reaction formula (1) is 0°C to solvent reflux temperature, 0°C to 60°C, 0°C to 40°C or 20°C to 40°C;
  • the reaction temperature of the reaction formula (2) is 0°C to the solvent reflux temperature, 20°C to the solvent reflux temperature, and 40°C to the solvent reflux temperature.
  • the molar ratio of compound ((II-4) to compound (II-6) is ⁇ 10:1, preferably 1:1 to 3:1; compound (II) -5) The molar ratio to compound (II-6) ⁇ 10:1, preferably 1:1 to 3:1.
  • the basic reagent is selected from organic amine reagents, preferably triethylamine, diethylamine, propylamine, tert-butylamine, N,N-diisopropylethylamine, 4 -Dimethylaminopyridine, 2,6-lutidine, pyridine, 1,8-diazabicycloundec-7-ene, 1,8-bisdimethylaminonaphthalene, N-methylmorpholine or one or more of pyridine.
  • organic amine reagents preferably triethylamine, diethylamine, propylamine, tert-butylamine, N,N-diisopropylethylamine, 4 -Dimethylaminopyridine, 2,6-lutidine, pyridine, 1,8-diazabicycloundec-7-ene, 1,8-bisdimethylaminonaphthalene, N-methylmorpholine or one or more of pyridine
  • the solvent is selected from polar aprotic solvents, preferably acetonitrile, N,N-dimethylformamide, N,N-ethylformamide, N,N- One or more of N-dimethylacetamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone.
  • the solvent is selected from dimethyl sulfoxide.
  • X 1 is selected from Br
  • the solvent is selected from polar aprotic solvents, preferably 1,2-dichloroethane, chloroform , dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, dimethylformamide Sulfoxide or N-methyl-2-pyrrolidone
  • the reaction temperature is optionally 30°C to 120°C, 60°C to 110°C, or 60°C to 90°C.
  • X1 is selected from The solvent is selected from polar aprotic solvents, preferably 1,2-dichloroethane, chloroform, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N , N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone, the reaction temperature is optional 30 °C ⁇ solvent reflux temperature, 40 °C ⁇ 110 °C Or 40°C ⁇ 50°C.
  • polar aprotic solvents preferably 1,2-dichloroethane, chloroform, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N , N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or N
  • reaction temperature is optionally 30°C to solvent reflux temperature, 30°C to 120°C, 60°C to 110°C or 60°C to 100°C.
  • compound (II) after the reaction, compound (II) is obtained by post-treatment, and the post-treatment includes crystallization, filtration, and filtration of the filtrate after beating.
  • compound (II) is reacted with HY to prepare compound (I),
  • HY is selected from pharmaceutically acceptable salts, preferably fumaric acid, formic acid, acetic acid, succinic acid, hydrochloric acid, sulfuric acid, tartaric acid, p-toluic acid, methanesulfonic acid, malic acid, maleic acid, succinic acid;
  • m is selected from 0.5, 1, 1.5, 2 or 3.
  • the solvent used for the reaction of compound (II) with HY is selected from the group consisting of alkane solvents, halogenated alkane solvents, alcohol solvents, ketone solvents, esters One or more mixed solvents of solvent-like solvents, ether-based solvents, nitrile-based solvents and water.
  • the solvent for the reaction of compound (II) with HY is selected from the group consisting of dichloromethane, 1,2-dichloroethane, ethyl acetate, acetone , one or more of methanol, ethanol, ethylene glycol, polyethylene glycol, isopropanol, diethyl ether, tetrahydrofuran, 1,4-dioxane and water, preferably one or more of dichloromethane, methanol and water or more.
  • the present invention also relates to a preparation method of compound (II-4), which is prepared by the following reaction formula,
  • the oxidizing agent is selected from the group consisting of chromium-containing metal oxidant, manganese-containing metal oxidant, silver-containing metal oxidant, dimethyl sulfoxide-containing electrophile oxidizing agent, peroxide oxidizing agent, periodic acid or its salt, hypochlorous acid or its salt or hypervalent iodine reagent.
  • the oxidizing agent is selected from hypochlorous acid, sodium hypochlorite, periodic acid, sodium periodate, hydrogen peroxide, m-chloroperoxybenzoic acid, 2-iodoylbenzoic acid, Dess-Martin reagent, dimethyl sulfoxide-oxalyl chloride, dimethyl sulfoxide-acetic anhydride, dimethyl sulfoxide-methanesulfonic anhydride, dimethyl sulfoxide-carbodiimide, Jones reagent Or one or more of chromium trioxide pyridine reagents.
  • dimethyl sulfoxide-carbodiimide includes, but is not limited to, dimethyl sulfoxide-dicyclohexylcarbodiimide (ie, DMSO-DCC).
  • the electrophile described in "oxidizing agent containing dimethyl sulfoxide-electrophile” includes but is not limited to DCC (dicyclohexylcarbodiimide) amine), acetic anhydride, trifluoroacetic anhydride, methanesulfonic anhydride, SOCl2 , (COCl) 2 .
  • a solvent is included in the reaction.
  • the solvent for the reaction is selected from hydrocarbon solvents, halogenated alkane solvents, ketone solvents, ester solvents, ether solvents, nitrile solvents and water solvents
  • hydrocarbon solvents halogenated alkane solvents
  • ketone solvents ketone solvents
  • ester solvents ether solvents
  • nitrile solvents water solvents
  • water solvents One or more, preferably one or more of 1,2-dichloroethane, chloroform, dichloromethane, tetrahydrofuran, acetonitrile or 1,4-dioxane.
  • the temperature of the reaction is optionally 0°C to 60°C, 0°C to 40°C or 0°C to 10°C.
  • the molar ratio of the oxidizing agent to compound (II-3) is ⁇ 0.5:1, preferably 1:1 to 5:1.
  • compound (II-4) is obtained by post-treatment, and the post-treatment includes beating and filtering the crude product containing compound (II-4) to obtain compound (II-4) (II-4).
  • the present invention relates to a preparation method of compound (II-5), which is prepared by the following reaction formula,
  • X 1 is selected from electron withdrawing groups or leaving groups
  • X 1 is selected from halogen, sulfonate, sulfinate, silyl, silyloxy, alkylacyl, boronate base.
  • R 1 are each independently selected from H, C 1-4 alkyl, C 3-10 carbocyclyl or 4-10 membered heterocyclyl, and said alkyl, carbocyclyl or heterocyclyl is optionally further substituted by O , 1, 2, 3 or 4 are selected from F, Cl, Br, I, OH, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic or 4-10 membered heterocyclic substituent;
  • the two R 1 are directly connected to form a 3-7 membered ring optionally further surrounded by 0, 1, 2, 3 or 4 selected from F, Cl, Br, I, OH, cyano, Nitro , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclyl or Substituents of 4-10-membered heterocyclic groups are substituted.
  • R 1 is each independently selected from H, methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, phenyl, Pyridine, cyclohexyl, the methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, phenyl, pyridine, cyclohexyl are optionally further selected from 0, 1, 2, 3 or 4 From F, Cl, Br, I, OH, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1 -4 alkoxy, C 3-6 carbocyclic or 4-10 membered heterocyclic substituent.
  • X 1 is selected from F, Cl, Br, I,
  • the reagent containing X 1 group contains the reagent of X 1 group as a leaving group or electron withdrawing group.
  • R 1 are each independently selected from H, C 1-4 alkyl, C 3-10 carbocyclyl or 4-10 membered heterocyclyl, and said alkyl, carbocyclyl or heterocyclyl is optionally further substituted by O , 1, 2, 3 or 4 are selected from F, Cl, Br, I, OH, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic or 4-10-membered heterocyclic substituent, X is selected from F, Cl, Br or I, R 2 selected from Li, Na or K;
  • the two R 1 are directly connected to form a 3-7 membered ring optionally further surrounded by 0, 1, 2, 3 or 4 selected from F, Cl, Br, I, OH, cyano, Nitro , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclyl or Substituents of 4-10-membered heterocyclic groups are substituted.
  • R 1 in the reagent containing X 1 group is independently selected from H, methyl, ethyl, propyl, isopropyl base, tert-butyl, butyl, phenyl, pyridine, cyclohexyl, the methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, phenyl, pyridine, cyclohexyl are optionally further by 0, 1, 2, 3 or 4 selected from F, Cl, Br, I, OH, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl ) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclyl or 4-10 membered heterocyclyl substituent.
  • the reagent containing X 1 group is selected from sulfonyl halides (such as p-toluenesulfonyl halide, tosyl halide, benzenesulfonyl halide) , p-nitrobenzenesulfonyl halide, methanesulfonyl halide, oxalyl halide), sulfinyl halide (such as toluene sulfinyl halide, toluene sulfinyl halide, phenylsulfinyl halide, p-nitrophenyl sulfinyl halide) sulfonyl halide, methylsulfinyl halide), phosphorus trihalide, phosphorus pentahalide, phosphorus oxytrihalide,
  • the phosphine halide (R 1 ) 3 PX 2 is optionally prepared by directly adding (R 1 ) 3 P to the reaction system and reacting with the halide (R 1 ) 3 P and the halide ( R 1 ) 3 PX 2 , which is directly used as a halogenating agent;
  • the phosphine halide (R 1 ) 3 PX 2 can be obtained by direct use, purchased or prepared in advance.
  • phosphite halide (R 1 O) 3 PX 2 is optionally directly added to (R 1 O) 3 P and halide directly from the reaction system
  • the reaction produces (R 1 O) 3 PX 2 , which is directly used as a halogenating agent;
  • the triphenylphosphine halide is optionally directly added to the reaction system and reacted with the halide to prepare the triphenylphosphine halide, It is directly used as a halogenating agent;
  • triphenylphosphine halide that is purchased or prepared in advance.
  • the triphenyl phosphite halide is optionally directly added to the reaction system by directly adding tris(phenyloxy)phosphine and reacting with the halide to obtain phosphorous acid Triphenyl ester halides, which are used directly as halogenating agents;
  • triphenyl phosphite halide or by direct use of purchased or prepared triphenyl phosphite halide.
  • Halo means F, Cl, Br or I.
  • Halogenated means F generation, Cl generation, Br generation or I generation.
  • Halogenation refers to Fylation, Clylation, Brylation or Iylation.
  • the reagent containing X 1 group is selected from p-toluenesulfonyl chloride, toluenesulfonyl chloride, benzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, Methanesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, trimethylchlorosilane, tert-butyldimethylchlorosilane, triisopropylchlorosilane, tert-butyldiphenylchlorosilane, oxalyl chloride, Phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, triphenylphosphine/carbon tetrachloride,
  • a solvent is included in the reaction, and the solvent is selected from hydrocarbon solvents, halogenated alkane solvents, alcohol solvents, ketone solvents, ester solvents, One or more of ether solvent, nitrile solvent and water, preferably one or more of 1,2-dichloroethane, chloroform, dichloromethane, 1,4-dioxane, tetrahydrofuran or acetonitrile kind.
  • the temperature of the reaction is selected from -20°C to 60°C, -10°C to 50°C or 0°C to 40°C.
  • the present invention also relates to a preparation method of compound (II-3), which is prepared by the following reaction formula,
  • X 2 is selected from electron withdrawing group or leaving group
  • HY is selected from fumaric acid, formic acid, acetic acid, succinic acid, hydrochloric acid, sulfuric acid, tartaric acid, p-toluic acid, methanesulfonic acid, malic acid, maleic acid, succinic acid, etc.;
  • n is selected from 0 or 0.5, 1, 1.5, 2 or 3.
  • X 2 is selected from halogen, sulfonate, sulfinate, silyl, silyloxy, alkylacyl, boronate base.
  • R 1 are each independently selected from H, C 1-4 alkyl, C 3-10 carbocyclyl or 4-10 membered heterocyclyl, and said alkyl, carbocyclyl or heterocyclyl is optionally further substituted by O , 1, 2, 3 or 4 are selected from F, Cl, Br, I, OH, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic or 4-10 membered heterocyclic substituent;
  • the two R 1 are directly connected to form a 3-7 membered ring optionally further surrounded by 0, 1, 2, 3 or 4 selected from F, Cl, Br, I, OH, cyano, Nitro , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclyl or Substituents of 4-10-membered heterocyclic groups are substituted.
  • R 1 is each independently selected from H, methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, phenyl, Pyridine, cyclohexyl, the methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, phenyl, pyridine, cyclohexyl are optionally further selected from 0, 1, 2, 3 or 4 From F, Cl, Br, I, OH, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1 -4 alkoxy, C 3-6 carbocyclic or 4-10 membered heterocyclic substituent.
  • X 2 is selected from F, Cl, Br, I,
  • an alkaline reagent is added in the reaction, and the alkaline reagent is selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal phosphates, alkalis One or more of metal carbonates, alkaline earth metal carbonates and organic amines, preferably sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, cesium carbonate, potassium phosphate, Potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium phosphate, lithium hydroxide, triethylamine, diethylamine, propylamine, tert-butylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, 2,6- One or more of lutidine, pyridine, 1,8-diazabicycloundec-7-ene, 1,8-
  • the reaction includes a solvent, and the solvent is selected from one of polar protic solvents, polar aprotic solvents, and non-polar solvents, or Various, preferably acetonitrile, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, One or more of methanol, ethanol, water, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran or 1,4-dioxane.
  • solvent is selected from one of polar protic solvents, polar aprotic solvents, and non-polar solvents, or Various, preferably acetonitrile, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrol
  • the reaction temperature is optionally 0°C to solvent reflux temperature, preferably 0°C to 60°C, preferably 10°C to 40°C.
  • the molar ratio of compound (II-1) and compound (II-2) is ⁇ 10:1, preferably 1:1 ⁇ 3:1.
  • compound (II-3) is obtained by post-treatment, and the post-treatment includes crystallization, filtration, and filtrate is filtered after beating.
  • the present invention relates to a preparation method of compound (II), comprising the following reaction,
  • X 1 is selected from electron withdrawing groups or leaving groups
  • X 2 is selected from electron withdrawing groups or leaving groups
  • HY is selected from fumaric acid, formic acid, acetic acid, succinic acid, hydrochloric acid, sulfuric acid, tartaric acid, p-toluic acid, methanesulfonic acid, malic acid, maleic acid, succinic acid, etc.;
  • n is selected from 0 or 0.5, 1, 1.5, 2 or 3;
  • compound (II-3) obtains compound (II) by reacting d) and e);
  • X 2 is selected from halogen, sulfonate, sulfinate, silyl, silyloxy, alkylacyl, and boronate.
  • R 1 are each independently selected from H, C 1-4 alkyl, C 3-10 carbocyclyl or 4-10 membered heterocyclyl, and said alkyl, carbocyclyl or heterocyclyl is optionally further substituted by O , 1, 2, 3 or 4 are selected from F, Cl, Br, I, OH, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic or 4-10 membered heterocyclic substituent;
  • the two R 1 are directly connected to form a 3-7 membered ring optionally further surrounded by 0, 1, 2, 3 or 4 selected from F, Cl, Br, I, OH, cyano, Nitro , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclyl or Substituents of 4-10-membered heterocyclic groups are substituted.
  • each R 1 is independently selected from H, methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, phenyl, pyridine, Cyclohexyl, the methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, phenyl, pyridine, cyclohexyl are optionally further selected from F by 0, 1, 2, 3 or 4 , Cl, Br, I, OH, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 Substituents of alkoxy, C 3-6 carbocyclyl or 4-10 membered heterocyclyl.
  • X 2 is selected from F, Cl, Br, I,
  • X 1 is selected from halogen, sulfonate, sulfinate, silyl, silyloxy, alkylacyl, and boronate.
  • R 1 are each independently selected from H, C 1-4 alkyl, C 3-10 carbocyclyl or 4-10 membered heterocyclyl, and said alkyl, carbocyclyl or heterocyclyl is optionally further substituted by O , 1, 2, 3 or 4 are selected from F, Cl, Br, I, OH, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic or 4-10 membered heterocyclic substituent;
  • the two R 1 are directly connected to form a 3-7 membered ring optionally further surrounded by 0, 1, 2, 3 or 4 selected from F, Cl, Br, I, OH, cyano, Nitro , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclyl or Substituents of 4-10-membered heterocyclic groups are substituted.
  • X 1 is selected from F, Cl, Br, I,
  • an alkaline reagent is added in reaction a) or e), and the alkaline reagent is selected from alkali metal hydroxides, alkaline earth metal hydroxides, One or more of alkali metal phosphates, alkali metal carbonates, alkaline earth metal carbonates and organic amines, preferably sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, Cesium carbonate, potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium phosphate, lithium hydroxide, triethylamine, diethylamine, propylamine, tert-butylamine, N,N-diisopropylethylamine, 4-dimethylamino of pyridine, 2,6-lutidine, pyridine, 1,8-diazabicycloundec-7-ene, 1,8-bisdimethyla
  • the oxidizing agent in reaction b) is selected from the group consisting of chromium-containing metal oxidant, manganese-containing metal oxidant, silver-containing metal oxidant, dimethyl sulfoxide-electrophile-containing oxidant, peroxide oxidant, periodic acid or its salt, Hypochlorous acid or its salts or hypervalent iodine reagents;
  • Reaction c) optionally add desiccant is selected from one or more in anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate or molecular sieve, and described acid reagent is selected from hydrochloric acid, acetic acid , one or more of formic acid, propionic acid, butyric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, trifluoroacetic acid, the reducing agent is selected from boron reducing agents, preferably sodium borohydride, triacetoxy One or more of sodium borohydride, sodium triethylborohydride, sodium cyanoborohydride, potassium borohydride or lithium borohydride;
  • the reagent containing X 1 group described in reaction d) is selected from p-toluenesulfonyl chloride, toluenesulfonyl chloride, benzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride , methylsulfinyl chloride, trimethylchlorosilane, tert-butyldimethylsilyl chloride, triisopropylchlorosilane, tert-butyldiphenylchlorosilane, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride , phosphorus oxychloride, thionyl chloride, triphenylphosphine/carbon tetrachloride, tripheny
  • a solvent is included, and the solvent is selected from one or more of polar protic solvents, polar aprotic solvents, and non-polar solvents, preferably acetonitrile, N,N-dimethylformamide , N,N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, methanol, ethanol, water, dichloromethane, 1,2-dichloromethane One or more of chloroethane, chloroform, carbon tetrachloride, tetrahydrofuran or 1,4-dioxane;
  • the reaction b) includes a solvent, and the solvent for the reaction is selected from one or more of hydrocarbon solvents, halogenated alkane solvents, ketone solvents, ester solvents, ether solvents, nitrile solvents and water, preferably 1,2- One or more of dichloroethane, chloroform, dichloromethane, tetrahydrofuran, 1,4-dioxane or acetonitrile;
  • the reaction c) or e) includes a solvent, and the solvent is selected from one or more of polar aprotic solvents, polar protic solvents or non-polar solvents, preferably 1,2-dichloroethane , chloroform, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, One or more of dimethyl sulfoxide or N-methyl-2-pyrrolidone;
  • polar aprotic solvents preferably 1,2-dichloroethane , chloroform, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, One or more of dimethyl sulfoxide or N
  • a solvent is included, and the solvent of the reaction is selected from one or more of hydrocarbon solvents, halogenated alkane solvents, alcohol solvents, ketone solvents, ester solvents, ether solvents, nitrile solvents and water, preferably One or more of 1,2-dichloroethane, chloroform, dichloromethane, tetrahydrofuran, 1,4-dioxane or acetonitrile.
  • the reaction a) includes a solvent, and the solvent includes 1,2-dichloroethane, chloroform or dichloromethane, or N,N-dimethylformamide, N,N-diethylformamide, N,N- One or more of N-dimethylacetamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone;
  • the reaction b) includes a solvent, and the solvent is selected from polar aprotic solvents or polar protic solvents, preferably dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1 , one or more of 4-dioxane, methanol, ethanol and water;
  • polar aprotic solvents or polar protic solvents preferably dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1 , one or more of 4-dioxane, methanol, ethanol and water;
  • the reaction c) includes a solvent, and the solvent includes a polar aprotic solvent, preferably 1,2-dichloroethane, chloroform, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N , one or more of N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone;
  • a polar aprotic solvent preferably 1,2-dichloroethane, chloroform, dichloromethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, N , one or more of N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone;
  • the solvent in the reaction d) includes one or more of methanol, ethanol and water, and a polar aprotic solvent is optionally added in the reaction, and the polar aprotic solvent includes dichloromethane, 1,2-dichloromethane, and 1,2-dichloromethane.
  • a polar aprotic solvent includes dichloromethane, 1,2-dichloromethane, and 1,2-dichloromethane.
  • the reaction e) includes a solvent, and the solvent includes a polar aprotic solvent, preferably including dichloromethane, 1,2-dichloroethane, chloroform, N,N-dimethylformamide, N,N- One or more of diethylformamide, N,N-dimethylacetamide, dimethylsulfoxide or N-methyl-2-pyrrolidone.
  • a polar aprotic solvent preferably including dichloromethane, 1,2-dichloroethane, chloroform, N,N-dimethylformamide, N,N- One or more of diethylformamide, N,N-dimethylacetamide, dimethylsulfoxide or N-methyl-2-pyrrolidone.
  • reaction temperature of reaction a) is 0°C to 40°C, preferably 20°C to 40°C;
  • reaction temperature of reaction b) is 0°C to 40°C, preferably 0°C to 10°C;
  • reaction temperature of reaction c) is 0°C to 40°C, preferably 20°C to 40°C;
  • reaction temperature of reaction d) is 0°C to 40°C, preferably 10°C to 40°C;
  • the reaction solvent of reaction e) is selected from N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide or N-methyl-2-
  • the reaction temperature is 30°C to 120°C, preferably 60°C to 110°C, more preferably 60°C to 70°C;
  • reaction temperature is 10°C to 60°C, preferably 20°C to 50°C, more preferably 30°C ⁇ 50°C.
  • the present invention relates to a compound shown below,
  • X 2 is selected from electron withdrawing groups or leaving groups.
  • X 2 is selected from halogen, sulfonate, sulfinate, silyl, silyloxy, alkylacyl, boronate.
  • R 1 are each independently selected from H, C 1-4 alkyl, C 3-10 carbocyclyl or 4-10 membered heterocyclyl, and said alkyl, carbocyclyl or heterocyclyl is optionally further substituted by O , 1, 2, 3 or 4 are selected from F, Cl, Br, I, OH, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic or 4-10 membered heterocyclic substituent;
  • the two R 1 are directly connected to form a 3-7 membered ring optionally further surrounded by 0, 1, 2, 3 or 4 selected from F, Cl, Br, I, OH, cyano, Nitro , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclyl or Substituents of 4-10-membered heterocyclic groups are substituted.
  • each R 1 is independently selected from H, methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, phenyl, pyridine, cyclic Hexyl, the methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, phenyl, pyridine, cyclohexyl are optionally further selected from F, 1, 2, 3 or 4 Cl, Br, I, OH, cyano, nitro, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkane Substituents of oxy, C 3-6 carbocyclyl or 4-10 membered heterocyclyl.
  • X 2 is selected from F, Cl, Br, I,
  • the method of extraction used in the post-treatment of the reaction in the present invention is a conventional method in the field, and the solvent for extraction can be selected according to the solubility of the product and the solubility of the organic solvent in water.
  • Common extraction solvents include but are not limited to dichloromethane, chloroform, One or more mixed solvents of ethyl acetate, methyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether, methanol and ethanol.
  • the number of extractions can be appropriately increased or decreased according to the amount of product remaining in the aqueous phase.
  • the extracted organic phase is optionally further washed or/and dried as conventional in the art.
  • the elements carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention all include their isotopic conditions, and the elements carbon, hydrogen, oxygen involved in the groups and compounds of the present invention , sulfur or nitrogen is optionally further replaced by 1 to 5 of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, and hydrogen isotopes include protium (H), deuterium (D, also known as deuterium ), tritium (T, also known as super heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N , the isotope of fluorine is 19 F, the isotope of chlorine includes 35 Cl and 37 Cl, and the isotope of bromine includes 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • Chromium-containing metal oxidant refers to a metal compound containing chromium in its molecular structure, and the valence state of chromium includes hexavalent.
  • Manganese-containing metal oxidant refers to a metal compound containing manganese in the molecular structure, and the valence of manganese includes divalent, trivalent, tetravalent, hexavalent, and 7valent.
  • Silicon-containing metal oxidizing agent refers to a metal compound containing silver in the molecular structure, and the valence state of silver includes 1 valence.
  • a “leaving group” is an atom or functional group that is removed from a molecule in a chemical reaction, non-limiting examples include halogen, sulfonate, carbonate, phosphate, boronate, nitro, CN , alkoxy, amino, amine, silyl, siloxy, alkylthio or alkanoyl.
  • Alkyl refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms Alkyl of carbon atoms, alkyl of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched-chain isomers.
  • Halogen means F, Cl, Br or I.
  • Carbocyclyl or “carbocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which may be a 3- to 8-membered monocyclic, 4- to 12-membered A bicyclic or 10- to 15-membered tricyclic ring system, the carbocyclic group can be attached to an aromatic ring or a non-aromatic ring, and the aromatic or non-aromatic ring is optionally monocyclic, bridged or spirocyclic.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring,
  • a "carbocyclyl” or “carbocycle” can be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, the aromatic or non-aromatic ring may be a 3- to 8-membered monocyclic, 4- to 12-membered Bicyclic or 10- to 15-membered tricyclic ring system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, selected from the ring of heterocyclyl The substituted N and S can be oxidized to various oxidation states.
  • the heterocyclyl group can be attached to a heteroatom or a carbon atom, the heterocyclyl group can be attached to an aromatic ring or a non-aromatic ring, the heterocyclyl group can be attached to a bridged ring or a spiro ring, non-limiting examples include oxirane , azetidine, oxetanyl, azetidine, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpho Linyl, 1,3-Dithiyl, Dihydrofuranyl, Dihydropyranyl, Dithiopenyl
  • Alcohol-based solvent refers to a solvent containing a hydroxyl group in the molecular structure, non-limiting examples include ethylene glycol, methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol, sec-pentanol, 3 - Amyl alcohol, isoamyl alcohol, p-amyl alcohol, n-hexanol and cyclohexanol etc.
  • Ether solvent refers to the solvent of the ether bond in the molecular structure, non-limiting examples include tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol Dimethyl ether, diisopropyl ether, ethyl butyl ether, dibutyl ether, dipentyl ether, diethylene glycol dimethyl ether, triglyme and anisole, etc.
  • Aromatic solvent refers to a solvent containing 0-3 heteroatoms (heteroatoms are selected from O, S or N) aromatic rings in the molecular structure, non-limiting examples include benzene, pyridine, toluene, ethylbenzene, xylene , chlorobenzene and o-dichlorobenzene, etc.
  • Halogenated alkane solvents refer to alkane solvents containing halogens (fluorine, chlorine, bromine, iodine) in the molecular structure, non-limiting examples include dichloromethane, 1,2-dichloroethane, chloroform, trichloroethane alkane, carbon tetrachloride, pentachlorohexane, 1-chlorobutane and bromomethane, etc.
  • alkane-based solvent refers to a solvent containing only alkanes in its molecular structure, and non-limiting examples include n-hexane, n-heptane, n-octane, n-pentane, cyclohexane, and cycloheptane.
  • Ester solvent refers to a solvent containing a carboxylic acid ester in its molecular structure, non-limiting examples include ethyl acetate, isopropyl acetate, triacetin, ethyl acetoacetate, isoamyl acetate, isopropyl acetate ester, n-butyl acetate, n-propyl acetate, n-pentyl acetate, methyl acetate, sec-butyl acetate, butyl formate, propyl formate, n-pentyl formate and diethyl carbonate, etc.
  • Ketone solvent refers to a solvent containing a ketone carbonyl group in its molecular structure, non-limiting examples include acetone, butanone, acetophenone, methyl isobutyl ketone, 2,6-dimethyl-2,5- Heptadien-4-one, 3,5,5-trimethyl-2-cyclohexenone and mesityl oxide, etc.
  • Nirile-based solvent refers to a solvent containing a cyano group in the molecular structure, and non-limiting examples include acetonitrile, propionitrile, butyronitrile, phenylacetonitrile, and the like.
  • Amide solvent refers to a solvent containing an amide in the molecular structure, non-limiting examples include N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide , hexamethylphosphoramide and N-methylpyrrolidone, etc.
  • Poly aprotic solvent refers to a solvent that does not contain hydrogen atoms directly bonded to electronegative atoms, and has no hydrogen bonding ability.
  • Non-limiting examples include acetone, dimethyl sulfoxide, HMF (Hydroxymethylfurfural), crown ethers, acetonitrile, N,N-dimethylformamide, N,N-ethylformamide, N,N-bismuth Methylacetamide, dimethyl sulfoxide or N-methyl-2-pyrrolidone, etc.
  • Polar protic solvents refers to solvents that are capable of hydrogen bonding (since they contain at least one hydrogen atom directly attached to an electronegative atom (eg, an O-H or N-H bond), non-limiting examples include methanol, water, ethanol) , ammonia, acetic acid, etc.
  • the reaction process is tracked by HPLC, HNMR or thin-layer chromatography to determine whether the reaction is over.
  • the internal temperature refers to the temperature of the reaction system.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the reaction After the reaction is completed, it is cooled to 15 to 25 ° C, filtered, and the filter cake is rinsed with dichloromethane. After the filtrate is combined, the pH of the aqueous phase is adjusted to 9 to 10 with a 15% mass concentration of sodium hydroxide aqueous solution.
  • the temperature is lowered to 15 to 25 ° C, the upper layer containing most of the triethylamine is removed by liquid separation, the lower layer reaction solution is poured into 3 L of water for crystallization, filtered and then slurried with 1.0 L of absolute ethanol for 1 hour, and filtered.
  • Mino human mantle cell lymphoma cell line purchased from ATCC, culture conditions: RPMI-1640+15% FBS+1% double antibody, cultured at 37°C, 5% CO 2 incubator. Cells were plated in 6-well plates, 5 ⁇ 10 5 cells/well. After plating, different concentrations of compounds were added and incubated for 48 hours in a 37°C, 5% CO 2 incubator. After the incubation, cells were collected, lysed on ice for 15 minutes by adding RIPA lysis buffer (beyotime, Cat.P0013B), centrifuged at 12,000 rpm and 4°C for 10 minutes, and the supernatant protein samples were collected, using BCA kit (Beyotime, Cat.P0009).
  • RIPA lysis buffer beyotime, Cat.P0013B
  • BTK CST, Cat. 8547S
  • internal reference BTK and internal reference were detected using an automatic western blot quantitative analyzer (Proteinsimple) using a kit (Protein simple, Cat. SM-W004).
  • Expression of ⁇ -actin CST, Cat. 3700S
  • the expression level of BTK relative to the internal reference was calculated using compass software and the DC 50 value was calculated according to formula (1) using Origen9.2 software.
  • BTK administration is the expression of BTK in different dosage groups
  • BTK vehicle is the expression of BTK in the vehicle control group.
  • BTK% BTK administration/BTK vehicle ⁇ 100 Formula (1)
  • mice Female ICR mice, 6-8 weeks old, were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., and the experiment was started after 3 days of adaptation. After 3 consecutive days of intragastric administration of different doses of compounds, the mouse spleen was taken, spleen cells were collected, added RIPA lysis buffer (beyotime, Cat. The supernatant protein sample was quantified with BCA kit (Beyotime, Cat. P0009), the protein was diluted to 0.25 mg/mL, and BTK (CST, Cat. 8547S) was detected using an automatic western blot quantitative analyzer (Proteinsimple). And the expression of internal reference ⁇ -actin (CST, Cat.3700S).
  • BTK administration is the expression of BTK in different dose administration groups
  • BTK vehicle is the expression of BTK in the vehicle control group.
  • BTK% BTK administration /BTK vehicle ⁇ 100 Formula (2)
  • BTK wt (Carna, Cat. No 08-180) and BTK C481S (Carna, Cat. No 08-547) were prepared as 2.5 ⁇ kinase solutions, and the substrate FAM-P2 (GL Biochem, Cat. No. 112394) was mixed with ATP ((Sigma, Cat. No. A7699-1G) was prepared as a 2.5 ⁇ substrate solution.
  • Inhibition rate% (max-conversion)/(max-min)*100.
  • Compound 1 has a significant inhibitory effect on BTK wt/C481S kinase.

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Abstract

La présente invention concerne un procédé de préparation d'un composé tel que représenté par la formule (I) et un intermédiaire de celui-ci. Le procédé est mis en œuvre dans des conditions de réaction modérées, n'implique pas de réaction à haute température et à haute pression, fait intervenir des matières premières non toxiques ou à faible toxicité, est simple à mettre en œuvre, permet d'obtenir un rendement de réaction élevé, une pureté de produit élevée, un post-traitement pratique, et une bonne reproductibilité, et est approprié pour une production industrielle.
PCT/CN2021/132332 2020-11-25 2021-11-23 Procédé de préparation d'un agent de dégradation de btk WO2022111448A1 (fr)

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