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WO2022111449A1 - 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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Publication number
WO2022111449A1
WO2022111449A1 PCT/CN2021/132335 CN2021132335W WO2022111449A1 WO 2022111449 A1 WO2022111449 A1 WO 2022111449A1 CN 2021132335 W CN2021132335 W CN 2021132335W WO 2022111449 A1 WO2022111449 A1 WO 2022111449A1
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WO
WIPO (PCT)
Prior art keywords
acid
compound
solvents
reaction
preparation
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.)
Ceased
Application number
PCT/CN2021/132335
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English (en)
Chinese (zh)
Inventor
郭军辉
易仕旭
陈曾飞
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.)
Sichuan Haisco Pharmaceutical Co Ltd
Original Assignee
Sichuan Haisco 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 Sichuan Haisco Pharmaceutical Co Ltd filed Critical Sichuan Haisco Pharmaceutical Co Ltd
Priority to CN202180053129.7A priority Critical patent/CN116348460A/zh
Publication of WO2022111449A1 publication Critical patent/WO2022111449A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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
    • C07D403/02—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 two 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

  • PROTAC proteolysis targeting chimera
  • PROTAC proteolysis targeting chimera
  • the present invention relates to a preparation method of compound (II), which is prepared by following reaction formula (1) or formula (2),
  • 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);
  • X 1 is selected from halogen, sulfonate, sulfinate, silyl, silyloxy, alkylacyl, and boronate.
  • 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 to the reaction formula (1).
  • 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-5), which is prepared by the following reaction formula,
  • X 1 is selected from electron withdrawing groups or leaving groups
  • 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 present invention relates to a preparation method of compound (II), comprising the steps of:
  • 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
  • Reaction c) optionally add desiccant is selected from one or more in anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate or molecular sieve;
  • 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;
  • 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 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 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.
  • 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 -10°C to 40°C, preferably 0°C to 10°C;
  • the reaction solvent of reaction e) is 30°C to 120°C, preferably 30°C to 70°C, more preferably 40°C to 50°C.
  • the present invention relates to compounds 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
  • 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 its 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 , silyl, siloxy, amino, amine, alkylthio or alkanoyl.
  • Halogen means F, Cl, Br or I.
  • 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.
  • 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, HMF (hydroxymethyl furfural), crown ethers, acetonitrile, N,N-dimethylformamide, N,N-ethylformamide, N,N-dimethylacetamide, 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé inhibiteur de BTK et un procédé de préparation d'un intermédiaire de celui-ci. Selon le procédé, les conditions de réaction sont douces, aucune réaction à haute température et haute pression n'est impliquée, les matières premières sont faiblement toxiques ou non toxiques, l'opération est simple, le rendement de réaction et la pureté du produit sont élevés, le post-traitement est pratique, et la reproductibilité est bonne ; et ledit procédé est approprié pour une production industrielle.
PCT/CN2021/132335 2020-11-25 2021-11-23 Procédé de préparation d'un agent de dégradation de btk Ceased WO2022111449A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202180053129.7A CN116348460A (zh) 2020-11-25 2021-11-23 一种btk降解剂的制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011335696.5 2020-11-25
CN202011335696 2020-11-25

Publications (1)

Publication Number Publication Date
WO2022111449A1 true WO2022111449A1 (fr) 2022-06-02

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CN (1) CN116348460A (fr)
WO (1) WO2022111449A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019127008A1 (fr) * 2017-12-26 2019-07-04 清华大学 Composé de dégradation ciblée de btk et son application
CN110724143A (zh) * 2019-10-09 2020-01-24 清华大学 一种靶向btk蛋白降解化合物的制备及其在治疗自身免疫系统疾病与肿瘤中的应用
CN111372585A (zh) * 2017-11-16 2020-07-03 C4医药公司 用于靶蛋白降解的降解剂和降解决定子
CN112010858A (zh) * 2019-05-31 2020-12-01 四川海思科制药有限公司 一种btk抑制剂及其制备方法和药学上的应用
WO2020239103A1 (fr) * 2019-05-31 2020-12-03 四川海思科制药有限公司 Dérivé de cycle inhibiteur de btk, son procédé de préparation et son application pharmaceutique

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111138413B (zh) * 2018-11-01 2022-11-04 江苏豪森药业集团有限公司 一种细胞周期蛋白依赖性激酶抑制剂的制备方法及其中间体
CN111662294A (zh) * 2019-03-05 2020-09-15 上海美志医药科技有限公司 一类具有降解Btk活性的化合物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111372585A (zh) * 2017-11-16 2020-07-03 C4医药公司 用于靶蛋白降解的降解剂和降解决定子
WO2019127008A1 (fr) * 2017-12-26 2019-07-04 清华大学 Composé de dégradation ciblée de btk et son application
CN112010858A (zh) * 2019-05-31 2020-12-01 四川海思科制药有限公司 一种btk抑制剂及其制备方法和药学上的应用
WO2020239103A1 (fr) * 2019-05-31 2020-12-03 四川海思科制药有限公司 Dérivé de cycle inhibiteur de btk, son procédé de préparation et son application pharmaceutique
CN110724143A (zh) * 2019-10-09 2020-01-24 清华大学 一种靶向btk蛋白降解化合物的制备及其在治疗自身免疫系统疾病与肿瘤中的应用

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