WO2023061467A1 - 一种苯并呋喃衍生物的制备方法 - Google Patents

一种苯并呋喃衍生物的制备方法 Download PDF

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WO2023061467A1
WO2023061467A1 PCT/CN2022/125302 CN2022125302W WO2023061467A1 WO 2023061467 A1 WO2023061467 A1 WO 2023061467A1 CN 2022125302 W CN2022125302 W CN 2022125302W WO 2023061467 A1 WO2023061467 A1 WO 2023061467A1
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formula
pharmaceutically acceptable
compound represented
acceptable salt
compound
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PCT/CN2022/125302
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English (en)
French (fr)
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陈亚
王入志
王洋
谢婷
张磊
郭昌山
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江苏恒瑞医药股份有限公司
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Priority to MX2024004579A priority Critical patent/MX2024004579A/es
Priority to CA3234851A priority patent/CA3234851A1/en
Priority to KR1020247015921A priority patent/KR20240089711A/ko
Priority to CN202280068273.2A priority patent/CN118055928A/zh
Priority to EP22880403.5A priority patent/EP4417603A1/en
Priority to AU2022365986A priority patent/AU2022365986A1/en
Priority to JP2024522187A priority patent/JP2024537339A/ja
Priority to IL312137A priority patent/IL312137A/en
Publication of WO2023061467A1 publication Critical patent/WO2023061467A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/33—Polycyclic acids
    • C07C63/337—Polycyclic acids with carboxyl groups bound to condensed ring systems
    • C07C63/42—Polycyclic acids with carboxyl groups bound to condensed ring systems containing three or more condensed rings
    • C07C63/44—Polycyclic acids with carboxyl groups bound to condensed ring systems containing three or more condensed rings containing one carboxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/68—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings containing halogen
    • C07C63/70—Monocarboxylic acids

Definitions

  • the disclosure relates to a preparation method of benzofuran derivatives, which belongs to the field of pharmacy.
  • Lymphoma is a malignant tumor originating from the lymphatic hematopoietic system. According to the tumor cells, it is divided into two types: non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL). In Asia, 90% of patients are NHL, and the pathology is mainly They are lymphocytes, histiocytes or reticulocytes with different degrees of differentiation.
  • NHL human immunodeficiency virus
  • T cell T cell
  • NK natural killer
  • the histone methyltransferase encoded by the EZH2 gene is a catalytic component of the polycomb repressive complex 2 (PRC2).
  • PRC2 polycomb repressive complex 2
  • the level of EZH2 is abnormally elevated in cancer tissues, and the expression level of EZH2 is the highest in advanced cancer or poor prognosis.
  • overexpression of EZH2 coincides with amplification of the EZH2 gene.
  • si/shRNA experimental studies have found that reducing the expression of EZH2 in tumor cell lines can inhibit tumor cell proliferation, migration and invasion or angiogenesis, and lead to cell apoptosis.
  • EZH2 inhibitor is provided in WO2017084494A, the structure of which is shown below,
  • WO2019091450A also discloses a method for preparing the aforementioned compound.
  • the present disclosure provides a new method for preparing a pharmaceutically acceptable salt of the compound.
  • the present disclosure provides a preparation method of a compound represented by formula V or a pharmaceutically acceptable salt thereof, comprising the step of reacting the compound represented by formula VI with the compound represented by formula VII,
  • R are the same or different, each independently selected from halogen, alkyl, alkoxy, amino, nitro, hydroxyl, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, said alkyl Base, alkoxy, cycloalkyl or heterocycloalkyl are optionally substituted by one or more R A ; said R A is selected from halogen, hydroxyl, cyano, amino, nitro, alkyl, alkoxy , cycloalkyl, heterocycloalkyl;
  • R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from hydrogen, halogen, alkyl, alkoxy, amino, nitro, hydroxyl, cyano, cycloalkyl, heterocycloalkyl;
  • the alkyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by one or more R B ;
  • the R B is selected from halogen, hydroxyl, cyano, amino, nitro;
  • n is selected from 1 or 2;
  • X is selected from halogen.
  • the condensing agent is selected from N,N-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 4-dimethylaminopyridine (DMAP), 4-pyrrolidinylpyridine (4-PPY), 1-hydroxybenzo Triazole (HOBT), 1-Hydroxy-7-azabenzotriazole (HOAT), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (HATU), O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU).
  • CDI N,N-carbonyldiimidazole
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbod
  • the condensing agent is selected from a combination of EDCI and HOBT.
  • the preparation method of the compound represented by formula V or a pharmaceutically acceptable salt thereof is reacted in an alkaline environment.
  • the preparation method of the compound shown in formula V or a pharmaceutically acceptable salt thereof, the substance providing an alkaline environment is selected from triethylamine, pyridine, N, N-diisopropylethylamine (DIPEA) .
  • the reaction solvent is selected from N,N-dimethylformamide (DMF) or dichloromethane.
  • the preparation method of the compound represented by formula V or a pharmaceutically acceptable salt thereof comprises compound 1 and 3-(aminomethyl)-4,6-lutidine-2(1H )-ketone reaction obtains the step of compound 2,
  • Another aspect of the present disclosure provides a method for preparing a compound represented by formula III or a pharmaceutically acceptable salt thereof, comprising the step of reacting the compound represented by formula V with the compound represented by formula IV,
  • Ring A is selected from cycloalkyl, heterocycloalkyl
  • R is selected from halogen, alkyl, alkoxy, amino, nitro, hydroxyl, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; the alkyl, alkoxy, ring Alkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted by one or more R c , said R c is selected from halogen, alkyl, alkoxy, amino, nitro, hydroxyl, cyano , cycloalkyl, heterocycloalkyl, aryl, heteroaryl;
  • n is selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and n are respectively as defined in the compound represented by formula V.
  • the compound represented by formula V reacts with the compound represented by formula IV under the action of a palladium catalyst and a phosphine ligand catalyst.
  • the palladium catalyst is bis(dibenzylideneacetone) palladium (Pd(dba) 2 ).
  • the phosphine ligand catalyst is R-(+)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (BINAP).
  • the preparation method of the compound represented by formula III or a pharmaceutically acceptable salt thereof is reacted in an alkaline environment.
  • the substance providing an alkaline environment is selected from potassium tert-butoxide (tBuOK) and/or sodium tert-butoxide (tBuONa).
  • the preparation method of the compound represented by formula III or a pharmaceutically acceptable salt thereof comprises the step of reacting compound 2 with 4-aminotetrahydropyran to obtain compound 3,
  • the present disclosure provides a method for preparing the compound represented by formula III or a pharmaceutically acceptable salt thereof, further comprising the steps in the aforementioned method for preparing the compound represented by formula V or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present disclosure provides a method for preparing a compound represented by formula I or a pharmaceutically acceptable salt thereof, comprising the step of reacting the compound represented by formula III with the compound represented by formula II,
  • R 8 is an alkyl group
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, n and m are respectively as defined in the compound represented by formula III.
  • the preparation method of the compound represented by formula I or a pharmaceutically acceptable salt thereof is reacted in a weak acid environment.
  • the weak acid environment is provided by acetic acid.
  • the preparation method of the compound represented by formula I or a pharmaceutically acceptable salt thereof, the compound represented by formula III reacts with the compound represented by formula II under the action of a reducing agent.
  • the reducing agent is selected from sodium borohydride or sodium cyanoborohydride.
  • the preparation method of the compound represented by formula I or a pharmaceutically acceptable salt thereof comprises the step of reacting compound 3 with acetaldehyde to obtain compound 4,
  • the preparation method of the compound represented by formula I or a pharmaceutically acceptable salt thereof provided in the present disclosure further includes the steps in the preparation method of the compound represented by formula V or a pharmaceutically acceptable salt thereof, And/or the steps in the preparation method of the compound represented by the aforementioned formula III or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method for preparing a compound represented by formula I or a pharmaceutically acceptable salt thereof, comprising the following steps,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, n and m are respectively as described above.
  • the preparation method of the compound represented by formula I or a pharmaceutically acceptable salt thereof provided by the present disclosure comprises the following steps:
  • Another aspect of the present disclosure provides a compound represented by formula III or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A, n and m are respectively as described above.
  • the present disclosure provides a compound represented by formula III or a pharmaceutically acceptable salt thereof, which is
  • Another aspect of the present disclosure provides a compound represented by formula V or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , n and m are respectively as described above.
  • the present disclosure provides a compound represented by formula V or a pharmaceutically acceptable salt thereof, which is
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a linear or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-hexyl, n-octyl, n-heptyl, isooctyl, decyl, undecyl, dodecyl and various branched isomers, etc.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, preferably containing 3 to 10 Carbon atoms, more preferably contain 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
  • heterocycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O ) m (where m is an integer from 0 to 2), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms Preferably contain 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contain 3 to 10 ring atoms, of which 1-4 are heteroatoms; more preferably contain 5 to 6 ring atoms; of which 1-3 One is a heteroatom.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl, etc.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated pi-electron system, such as benzene base and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxy One or more substituents in alkyl, cyano, amino, nitro, cycloalkyl and heterocyclyl.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered, e.g. furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, tetrazole Base etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, One or more substituents in hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • hydroxyl refers to a -OH group.
  • hydroxyalkyl refers to an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • the bond " in the chemical structures of the compounds described in this disclosure, the bond " "indicates that no configuration is specified, i.e. if chiral isomers exist in the chemical structure, the bond” “can be” “or” , or both “ “and” “Two configurations. In the chemical structures of the compounds described in this disclosure, the bond” " does not specify the configuration, it can be the Z configuration or the E configuration, or both configurations.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • lactam-lactim isomerization
  • An example of a lactam-lactim equilibrium is between A and B as shown below.
  • the pharmaceutically acceptable salts described in the present disclosure include but are not limited to solvates, and the solvents include but are not limited to water, methanol, ethanol, isopropanol, acetonitrile, acetone, tetrahydrofuran, ethyl acetate, n-propanol, 2 - butanone, propylene glycol monomethyl ether, n-heptane, cyclohexane, n-hexane.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • the purity or content in the present disclosure is determined by HPLC detection, and the compound characterization data is obtained by analyzing the nuclear magnetic resonance spectra; the reagents used in the present disclosure can be purchased through commercial channels.
  • the structures of the disclosed compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shift (shift R is given in the unit of 10-6 (ppm).
  • the mensuration of NMR is to use Bruker AVANCE-400 nuclear magnetic instrument, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform ( CDCl 3 ), deuterated methanol (CD 3 OD), internal standard tetramethylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS internal standard tetramethylsilane
  • MS was determined with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • HPLC HPLC
  • reaction solution was quenched with water, the aqueous phase was washed with DCM, the organic phase was discarded, and the aqueous phase was retained. Then add DCM to the aqueous phase for extraction, discard the aqueous phase and keep the organic phase.
  • Aqueous NaHSO 3 solution was added thereto, the internal temperature was raised to 30-40° C. and stirred for 1 hour, then left to separate liquids, and the organic phase was separated. Dry, filter with suction, and spin dry to obtain the crude compound of formula 3.

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Abstract

一种苯并呋喃衍生物的制备方法。具体而言，涉及如式I所示的苯并呋喃衍生物的制备方法，该制备方法极大地提升了收率，具有良好的应用前景。

Description

一种苯并呋喃衍生物的制备方法
本申请要求申请日为2021年10月15日的中国专利申请2021112061010的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开涉及一种苯并呋喃衍生物的制备方法，属于制药领域。
背景技术
淋巴瘤是起源于淋巴造血系统的恶性肿瘤，根据瘤细胞分为非霍奇金淋巴瘤(NHL)和霍奇金淋巴瘤(HL)两类，在亚洲，90％患者为NHL，病理上主要是分化程度不同的淋巴细胞、组织细胞或网状细胞，根据NHL的自然病程，可以归为三大临床类型，即高度侵袭性、侵袭性和惰性淋巴瘤；根据不同的淋巴细胞起源，可以分为B细胞、T细胞和自然杀伤(natural killer，NK)细胞淋巴瘤，其中B细胞的主要职能是分泌各种抗体帮助人体抵御各种外来的侵入。
EZH2基因编码的组蛋白甲基转移酶是多梳蛋白抑制性复合体2(PRC2)的催化组分。与正常组织相比，EZH2水平在癌组织异常升高，而在癌症晚期或不良预后中，EZH2的表达水平最高。在一些癌症类型中，EZH2表达过剩与EZH2基因的扩增同时发生。大量si/shRNA实验研究发现在肿瘤细胞系中减少EZH2表达，可抑制肿瘤细胞的增殖，迁移和侵袭或血管生成，并导致细胞凋亡。
WO2017084494A中提供了一种EZH2抑制剂，结构如下所示，
Figure PCTCN2022125302-appb-000001
WO2019091450A也公开了一种前述化合物的制备方法，鉴于简化制备工艺、降低生产成本的考虑，本公开提供了一种该化合物可药用盐的新的制备方法。
发明内容
本公开提供一种式V所示化合物或其药学上可接受盐的制备方法，包括式VI所示化合物与式VII示化合物反应的步骤，
Figure PCTCN2022125302-appb-000002
其中，
R 1相同或不同，各自独立地选自卤素、烷基、烷氧基、氨基、硝基、羟基、氰基、环烷基、杂环烷基、芳基、杂芳基，所述的烷基、烷氧基、环烷基或杂环烷基任选被一个或多个R A取代；所述的R A选自卤素、羟基、氰基、氨基、硝基、烷基、烷氧基、环烷基、杂环烷基；
R 2、R 3、R 4、R 5、R 6各自独立地选自氢、卤素、烷基、烷氧基、氨基、硝基、羟基、氰基、环烷基、杂环烷基；所述的烷基、烷氧基、环烷基、杂环烷基任选被一个或多个R B取代；所述的R B选自卤素、羟基、氰基、氨基、 硝基；
n选自1或2；
X选自卤素。
可选的实施方案中，所述的式V所示化合物或其药学上可接受盐的制备方法，其中式VI所示化合物与式VII所示化合物在缩合剂作用下反应。
可选的实施方案中，所述缩合剂选自N,N-碳酰二咪唑(CDI)、二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI)、4-二甲氨基吡啶(DMAP)、4-吡咯烷基吡啶(4-PPY)、1-羟基苯并三唑(HOBT)、1-羟基-7-氮杂苯并三氮唑(HOAT)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、O-苯并三氮唑-四甲基脲六氟磷酸盐(HBTU)。
可选的实施方案中，所述缩合剂选自EDCI和HOBT的组合。
可选的实施方案中，式V所示化合物或其药学上可接受盐的制备方法，在碱性环境下反应。
可选的实施方案中，式V所示化合物或其药学上可接受盐的制备方法，提供碱性环境的物质选自三乙胺、吡啶、N，N-二异丙基乙胺(DIPEA)。
可选的实施方案中，本公开中式V所示化合物或其药学上可接受盐的制备方法，反应溶剂选自N,N-二甲基甲酰胺(DMF)或二氯甲烷。
可选的实施方案中，所述的式V所示化合物或其药学上可接受盐的制备方法，包括化合物1与3-(氨基甲基)-4,6-二甲基吡啶-2(1H)-酮反应得到化合物2的步骤，
Figure PCTCN2022125302-appb-000003
本公开另一方面提供一种式III所示化合物或其药学上可接受盐的制备方法，包括式V所示化合物与式IV所示化合物反应的步骤，
Figure PCTCN2022125302-appb-000004
其中，
环A选自环烷基、杂环烷基；
R 7选自卤素、烷基、烷氧基、氨基、硝基、羟基、氰基、环烷基、杂环烷基、芳基、杂芳基；所述的烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基任选被一个或多个R c取代，所述的R c选自卤素、烷基、烷氧基、氨基、硝基、羟基、氰基、环烷基、杂环烷基、芳基、杂芳基；
m选自0、1、2、3、4、5或6；
R 1、R 2、R 3、R 4、R 5、R 6、n分别如式V所示化合物中定义。
可选的实施方案中，式III所示化合物或其药学上可接受盐的制备方法中式V所示化合物与式IV所示化合物在钯催化剂和膦配体催化剂作用下反应。
可选的实施方案中钯催化剂为双(二亚芐基丙酮)钯(Pd(dba) 2)。
可选的实施方案中，膦配体催化剂为R-(+)-2,2'-双(二苯基膦)-1,1'-联萘(BINAP)。
可选的实施方案中，式III所示化合物或其药学上可接受盐的制备方法，在碱性环境下反应。
可选的实施方案中，式III所示化合物或其药学上可接受盐的制备方法，提供碱性环境的物质选自叔丁醇钾(tBuOK)和/或叔丁醇钠(tBuONa)。
可选的实施方案中，式III所示化合物或其药学上可接受盐的制备方法，包括化合物2与4-氨基四氢吡喃反应得到化合物3的步骤，
Figure PCTCN2022125302-appb-000005
可选的实施方案中，本公开提供式III所示化合物或其药学上可接受盐的制备方法，进一步包括前述的式V所示化合物或其药学上可接受盐的制备方法中的步骤。
本公开另一方面提供一种式I所示化合物或其药学上可接受盐的制备方法，包括式III所示化合物与式II所示化合物反应的步骤，
Figure PCTCN2022125302-appb-000006
其中，
R 8为烷基；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、环A、n及m分别如式III所示化合物中定义。
可选的实施方案中，式I所示化合物或其药学上可接受盐的制备方法在弱酸环境下反应。
可选的实施方案中，式I所示化合物或其药学上可接受盐的制备方法，所述的弱酸环境由醋酸提供。
可选的实施方案中，式I所示化合物或其药学上可接受盐的制备方法， 式III所示化合物与式II所示化合物在还原剂作用下反应。
可选的实施方案中，所述的还原剂选自硼氢化钠或氰基硼氢化钠。
可选的实施方案中，式I所示化合物或其药学上可接受盐的制备方法，包括化合物3与乙醛反应得到化合物4的步骤，
Figure PCTCN2022125302-appb-000007
可选的实施方案中，本公开提供的式I所示化合物或其药学上可接受盐的制备方法，进一步包括前述的式V所示化合物或其药学上可接受盐的制备方法中的步骤，和/或前述的式III所示化合物或其药学上可接受盐的制备方法中的步骤。
可选的实施方案中，本公开提供一种式I所示化合物或其药学上可接受盐的制备方法，包括如下步骤，
Figure PCTCN2022125302-appb-000008
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、环A、n及m分别如前所述。
可选的实施方案中，本公开提供的式I所示化合物或其药学上可接受盐 的制备方法，包含以下步骤：
Figure PCTCN2022125302-appb-000009
本公开另一方面，提供一种式III所示的化合物或其药学上可接受的盐，
Figure PCTCN2022125302-appb-000010
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、环A、n及m分别如前所述。
可选的实施方案中，本公开提供的式III所示的化合物或其药学上可接受的盐，其为
Figure PCTCN2022125302-appb-000011
本公开另一方面，提供一种式V所示的化合物或其药学上可接受的盐，
Figure PCTCN2022125302-appb-000012
其中R 1、R 2、R 3、R 4、R 5、R 6、n及m分别如前所述。
可选的实施方案中，本公开提供的式V所示的化合物或其药学上可接受的盐，其为
Figure PCTCN2022125302-appb-000013
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、正己基、正辛基、正庚基、异辛基、癸基、十一烷基、十二烷基及其各种支链异构体等。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，优选包含3至10个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“杂环烷基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至10个环原子，其中1-4是杂原子；更优选包含5至6个环原子；其中1-3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2.3.6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2022125302-appb-000014
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2022125302-appb-000015
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地任选选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基和杂环基中的一个或多个取代基所取代。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2022125302-appb-000016
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基所取代。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。术语“羟基”指-OH基团。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”指＝O。
本公开所述化合物的化学结构中，键“
Figure PCTCN2022125302-appb-000017
”表示未指定构型，即如果化学结构中存在手性异构体，键“
Figure PCTCN2022125302-appb-000018
”可以为“
Figure PCTCN2022125302-appb-000019
”或“
Figure PCTCN2022125302-appb-000020
”，或者同时包含“
Figure PCTCN2022125302-appb-000021
”和“
Figure PCTCN2022125302-appb-000022
”两种构型。本公开所述化合物的化学结构中，键“
Figure PCTCN2022125302-appb-000023
”并未指定构型，即可以为Z构型或E构型，或者同时包含两种构型。
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。
Figure PCTCN2022125302-appb-000024
本公开中的所有化合物可以被画成A型或B型。所有的互变异构形式在本公开的范围内。化合物的命名不排除任何互变异构体。
本公开所述的可药用盐包括但不限于溶剂合物，所述的溶剂包括但不限于水、甲醇、乙醇、异丙醇、乙腈、丙酮、四氢呋喃、乙酸乙酯、正丙醇、2-丁酮、丙二醇单甲醚、正庚烷、环己烷、正己烷。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确 定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。本公开所述纯度或含量通过HPLC检测确定的，化合物表征数据是通过对核磁共振图谱的解析获得；本公开所用试剂可以通过商业途径购得。
具体实施方式
以下将结合实施例更详细地解释本公开，本公开的实施例仅用于说明本公开的技术方案，本公开的实质和范围并不局限于此。
本公开化合物结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(移R以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo，型号：Finnigan LCQ advantage MAX)。
HPLC的测定使用WATER e2695-2489高效液相色谱仪。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自BEPHARM等公司。
实施例1化合物4的制备
Figure PCTCN2022125302-appb-000025
步骤1.化合物2的合成
在反应瓶中依次加入DMF 4L、式1化合物500g，DIPEA 800g，搅拌之后依次加入HOBt 335.5g，EDCI 476g，3-(氨基甲基)-4,6-二甲基吡啶-2(1H)-酮257.5g，之后补加1L DMF。加热升温至内温40℃，搅拌反应至完全，加水析出固体，打浆后甩滤，水洗，干燥后得式2化合物(580g)，收率94％。
1H NMR(400MHz,DMSO-d 6)δ11.20(s,1H),8.74(t,J＝4.8,1H),7.99(d,J＝0.4,1H),7.08(s,1H),6.26(s,1H),5.40-4.52(m,2H),4.43-4.42(m,2H),3.41-3.38(m,2H),2.97-2.92(m,2H),2.81-2.76(m,2H),2.54(t,J＝2.0,3H),2.35(s,3H),1.87-1.80(m,4H),1.69-1.65(m,1H),1.39-1.28(m,1H),1.10(t,J＝7.6,3H)ppm。
LCMS(m/z):500.36[M+H] +。
步骤2.化合物3的合成
称取Pd(dba) 2 0.46g和BINAP 2.0g，混合均匀后加入反应瓶中。再依次加入式2化合物20.0g， tBuONa 11.52g， tBuOLi 3.2g，真空-N 2置换，N 2保护下加入200mL 1,4-二氧六环，之后加入4-氨基四氢吡喃8.08g，搅拌下升温至100℃回流反应24小时至反应完全，开始后处理。
反应液加水淬灭，用DCM洗涤水相，弃去有机相，保留水相。之后向水相中加入DCM萃取，弃去水相，保留有机相。向其中加入NaHSO 3水溶液，内温升至30-40℃搅拌1小时，静置分液，分出有机相。干燥，抽滤，旋干，即得式3化合物粗品。
加入MTBE，搅拌，回流，打浆。之后加入正庚烷，降温析晶，母液甩滤，滤饼用正庚烷淋洗，干燥后得式3化合物(17.3g)，收率83％。
1H NMR(400MHz,CDCl 3)δ12.80(s,1H),7.13(t,J＝5.6,1H),6.77(s,1H),6.36(s,1H),5.93(s,1H),4.59(d,J＝6.0,2H),4.03-3.98(m,2H),3.64-3.62(m,2H),3.57-3.51(m,3H),3.45(s,2H),2.62(dd,J＝7.6,2H),2.4(s,3H),2.35(s,3H),2.09-2.06(m,5H),1.54-1.46(m,6H),1.19-1.15(m,3H),1.35-1.26(m,2H),1.19-1.15(m,3H)ppm。
LCMS(m/z):521.05[M+H] +。
步骤3.化合物4的合成
在反应瓶中加入50mL DCM，搅拌下加入式3化合物5.0g，溶解后降至0-10℃，依次加入乙醛2.11g，乙酸0.576g，下搅拌0.5小时，之后加入醋酸硼氢化钠6.31kg，N 2保护下缓慢升至25℃反应18小时至反应完全，反应液加入水，NaOH，分液，饱和碳酸氢钠洗涤，干燥，过滤，旋干。往瓶中加入甲基叔丁基醚，搅拌溶清，加热回流，滴加正庚烷，降温析晶，过滤后即得式4化合物粗品(5.0g)，收率95％。
1H NMR(400MHz,CDCl 3)δ12.98(s,1H),7.28-7.27(m,1H),7.10(t,J＝5.2,1H),6.50(s,1H),5.94(s,1H),4.61(d,J＝5.6,2H),3.94(d,J＝10.8,2H),3.51(s,2H),3.28(t,J＝10.4,2H),3.05(dd,J＝6.8,2H),2.97-2.87(m,3H),2.43-2.39(m,7H),2.17-2.10(m,3H),1.69-1.64(m,4H),1.55(s,4H),1.37(s,2H),1.05(t,J＝7.2,3H),0.87(t,J＝6.8,3H)ppm。
LCMS(m/z):549.25[M+H] +。

Claims (14)

  1. 一种式V所示化合物或其药学上可接受盐的制备方法，包括式VI所示化合物与式VII示化合物反应的步骤，
    Figure PCTCN2022125302-appb-100001
    其中，
    R 1相同或不同，各自独立地选自卤素、烷基、烷氧基、氨基、硝基、羟基、氰基、环烷基、杂环烷基、芳基、杂芳基，所述的烷基、烷氧基、环烷基或杂环烷基任选被一个或多个R A取代；所述的R A选自卤素、羟基、氰基、氨基、硝基、烷基、烷氧基、环烷基、杂环烷基；
    R 2、R 3、R 4、R 5、R 6各自独立地选自氢、卤素、烷基、烷氧基、氨基、硝基、羟基、氰基、环烷基、杂环烷基；所述的烷基、烷氧基、环烷基、杂环烷基任选被一个或多个R B取代；所述的R B选自卤素、羟基、氰基、氨基、硝基；
    n选自1或2；
    X选自卤素。
  2. 根据权利要求1所述的式V所示化合物或其药学上可接受盐的制备方法，包括化合物1与3-(氨基甲基)-4,6-二甲基吡啶-2(1H)-酮反应得到化合物2的步骤，
    Figure PCTCN2022125302-appb-100002
  3. 一种式III所示化合物或其药学上可接受盐的制备方法，包括式V所示化合物与式IV所示化合物反应的步骤，
    Figure PCTCN2022125302-appb-100003
    其中，
    环A选自环烷基、杂环烷基；
    R 7选自卤素、烷基、烷氧基、氨基、硝基、羟基、氰基、环烷基、杂环烷基、芳基、杂芳基；所述的烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基任选被一个或多个R c取代，所述的R c选自卤素、烷基、烷氧基、氨基、硝基、羟基、氰基、环烷基、杂环烷基、芳基、杂芳基；
    m选自0、1、2、3、4、5或6；
    R 1、R 2、R 3、R 4、R 5、R 6、n分别如权利要求1中所述。
  4. 根据权利要求3所述的式III所示化合物或其药学上可接受盐的制备方法，包括化合物2与4-氨基四氢吡喃反应得到化合物3的步骤，
    Figure PCTCN2022125302-appb-100004
  5. 根据权利要3-4任一项所述的式III所示化合物或其药学上可接受盐的制备方法，进一步包括权利要求1-2任一项所述的式V所示化合物或其药学上可接受盐的制备方法中的步骤。
  6. 一种式I所示化合物或其药学上可接受盐的制备方法，包括式III所示化合物与式II所示化合物反应的步骤，
    Figure PCTCN2022125302-appb-100005
    其中，
    R 8为烷基；
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、环A、n及m分别如权利要求3中所述。
  7. 根据权利要求6所述的式I所示化合物或其药学上可接受盐的制备方法，包括化合物3与乙醛反应得到化合物4的步骤，
    Figure PCTCN2022125302-appb-100006
  8. 根据权利要求6-7任一项所述的式I所示化合物或其药学上可接受盐的制备方法，进一步包括权利要求1-2任一项所述的式V所示化合物或其药学上可接受盐的制备方法中的步骤，和/或权利要求权利要求3-4任一项所述的式III所示化合物或其药学上可接受盐的制备方法中的步骤。
  9. 根据权利要求8所述的式I所示化合物或其药学上可接受盐的制备方法，包含以下步骤：
    Figure PCTCN2022125302-appb-100007
  10. 一种式III所示的化合物或其药学上可接受的盐，
    Figure PCTCN2022125302-appb-100008
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、环A、n及m分别如权利要求3中所述。
  11. 根据权利要求10所述的式III所示的化合物或其药学上可接受的盐，其为
    Figure PCTCN2022125302-appb-100009
  12. 一种式V所示的化合物或其药学上可接受的盐，
    Figure PCTCN2022125302-appb-100010
    其中R 1、R 2、R 3、R 4、R 5、R 6、n及m分别如权利要求1中所述。
  13. 根据权利要求12所述的式V所示的化合物或其药学上可接受的盐，其为
    Figure PCTCN2022125302-appb-100011
  14. 一种药物组合物，所述药物组合物含有治疗有效量的由权利要求6-9任一项所述方法制备获得式I所示化合物或其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
PCT/CN2022/125302 2021-10-15 2022-10-14 一种苯并呋喃衍生物的制备方法 WO2023061467A1 (zh)

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WO2017084494A1 (zh) 2015-11-19 2017-05-26 江苏恒瑞医药股份有限公司 苯并呋喃类衍生物、其制备方法及其在医药上的应用
WO2019091450A1 (zh) 2017-11-10 2019-05-16 江苏恒瑞医药股份有限公司 一种苯并呋喃衍生物的制备方法
CN110179796A (zh) * 2018-02-23 2019-08-30 江苏恒瑞医药股份有限公司 一种苯并呋喃类衍生物的组合物及制备方法
WO2020228591A1 (zh) * 2019-05-10 2020-11-19 江苏恒瑞医药股份有限公司 一种6-取代氨基苯并呋喃化合物的制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017084494A1 (zh) 2015-11-19 2017-05-26 江苏恒瑞医药股份有限公司 苯并呋喃类衍生物、其制备方法及其在医药上的应用
WO2019091450A1 (zh) 2017-11-10 2019-05-16 江苏恒瑞医药股份有限公司 一种苯并呋喃衍生物的制备方法
CN110179796A (zh) * 2018-02-23 2019-08-30 江苏恒瑞医药股份有限公司 一种苯并呋喃类衍生物的组合物及制备方法
WO2020228591A1 (zh) * 2019-05-10 2020-11-19 江苏恒瑞医药股份有限公司 一种6-取代氨基苯并呋喃化合物的制备方法

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