WO2020228591A1 - Procédé de préparation d'un composé aminobenzofurane 6-substitué - Google Patents

Procédé de préparation d'un composé aminobenzofurane 6-substitué Download PDF

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WO2020228591A1
WO2020228591A1 PCT/CN2020/089113 CN2020089113W WO2020228591A1 WO 2020228591 A1 WO2020228591 A1 WO 2020228591A1 CN 2020089113 W CN2020089113 W CN 2020089113W WO 2020228591 A1 WO2020228591 A1 WO 2020228591A1
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alkyl
aryl
formula
preparation
compound represented
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PCT/CN2020/089113
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Chinese (zh)
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张浩宇
徐超
陆伟栋
邵启云
冯君
贺峰
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN202080033176.0A priority Critical patent/CN113767096B/zh
Publication of WO2020228591A1 publication Critical patent/WO2020228591A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • 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
    • C07C63/04—Monocyclic monocarboxylic acids
    • C07C63/06—Benzoic acid
    • C07C63/10—Halides thereof
    • 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
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

Definitions

  • the present disclosure relates to a preparation method of 6-substituted aminobenzofuran compounds.
  • Lymphoma is a malignant tumor that originates from the lymphoid 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, the main pathology Lymphocytes, histiocytes or reticular cells with different degrees of differentiation. According to the natural course of NHL, they can be classified into three major clinical types, namely highly aggressive, aggressive and indolent lymphomas; according to different lymphocyte origins, they can be classified It is B cell, T cell and natural killer (NK) cell lymphoma. The main function of B cell is to secrete various antibodies to help the body resist various foreign invasions.
  • NHL non-Hodgkin’s lymphoma
  • HL Hodgkin’s lymphoma
  • the histone methyltransferase encoded by EZH2 gene is the catalytic component of polycomb inhibitory complex 2 (PRC2).
  • PRC2 polycomb inhibitory complex 2
  • EZH2 is the catalytic component of polycomb inhibitory complex 2
  • PRC2 polycomb inhibitory complex 2
  • overexpression of EZH2 occurs simultaneously with amplification of the EZH2 gene.
  • si/shRNA experimental studies have found that reducing EZH2 expression in tumor cell lines can inhibit tumor cell proliferation, migration and invasion or angiogenesis, and lead to cell apoptosis.
  • Tazemetostat developed by Eisai is used for the treatment of non-Hodgkin B-cell lymphoma. It is currently in phase II clinical phase.
  • CPI developed by Constellation -1205 is used to treat B-cell lymphoma and is currently in clinical phase I.
  • GSK-2816126 developed by GlaxoSmithKline is used to treat diffuse large B-cell lymphoma and follicular lymphoma. It is currently in clinical phase I.
  • WO2017084494A provides an EZH2 inhibitor, the structure is as follows:
  • the present disclosure provides a method for preparing the compound represented by formula III.
  • the method reacts under the action of at least one biphenyl monophosphine ligand, at least one palladium catalyst and at least one alkaline substance to obtain the compound represented by formula III
  • the method provided in the present disclosure can significantly improve the selectivity of the reaction, thereby increasing the yield, and providing the possibility for industrial production.
  • the present disclosure provides a method for preparing a compound represented by formula III, which is characterized in that the compound represented by formula IV or its salt and the compound represented by formula Va are combined with at least one biphenyl monophosphine ligand and at least one palladium catalyst and at least Under the action of an alkaline substance, the compound of formula III is obtained,
  • X is selected from fluorine, chlorine, bromine, iodine, -OS(O) 2 alkyl, and -OS(O) 2 aryl.
  • X is selected from iodine or bromine.
  • the salts of the compound represented by formula IV described in the present disclosure include, but are not limited to, hydrochloride, acetate, methanesulfonate, and hydrobromide.
  • the structure of the biphenyl monophosphine ligand may be as shown in formula L:
  • Y is selected from P(R) 2 ;
  • Z is selected from H, R, N(R) 2 , OR, SR, preferably N(R) 2 , OR;
  • R is selected from alkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, preferably alkyl, cycloalkyl, aryl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are each independently selected from alkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, Hydrogen, alkenyl, alkynyl, hydroxy, alkoxy, siloxy, amino, alkylamino, halogen, cyano, haloalkyl, hydroxyalkyl; wherein the alkyl, haloalkyl, heterocyclyl, Aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocycle Substituted by one or more substituents in the group, aryl group and heteroaryl group;
  • the ligand L When the ligand L is chiral, it can be a racemate or a separate enantiomer
  • the R in Y and the R in Z are optionally the same or different.
  • the R is selected from C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, heterocycloalkyl, C 6-10 aryl, 5-10 Member heteroaryl, preferably C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are each independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, Heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, hydrogen, alkenyl, alkynyl, hydroxyl, C 1-6 alkoxy, siloxy, amino, C 1-6 alkyl Amino, halogen, cyano, C 1-6 haloalkyl, C 1-6 hydroxyalkyl; wherein the C 1-6 alkyl, C 1-6 haloalkyl, 3-8 membered heterocyclic group, C 6 -10 aryl and 5-10 membered heteroaryl are each independently optionally selected from C 1-6 alkyl, C 1-6 haloalkyl, halogen, amino, nitro, cyano, hydroxyl, C 1-6 Alkoxy, C 1-6 halo
  • the monophosphine ligand L can be selected from the following structures:
  • the palladium catalyst can be selected from Pd 2 (dba) 3 , Pd(dba) 2 , Pd(OAc) 2 , Pd(tfa) 2 , Pd(Piv) 2 , Pd(OTf) 2.
  • Pd(PPh 3 ) 4 PdCl 2 , Pd(PPh 3 ) 2 Cl 2 , Pd(dppf)Cl 2 .
  • the palladium catalyst is selected from Pd 2 (dba) 3 , Pd(dba) 2 , and Pd(OAc) 2 .
  • the palladium catalyst is Pd 2 (dba) 3 .
  • the biphenyl monophosphine ligand L and the palladium catalyst may be in the form of a precursor catalyst.
  • the form of the precursor catalyst described in the method provided in the present disclosure includes but is not limited to the following structure
  • the amount of the palladium catalyst in the present disclosure is 0.001-30% (calculated by mole) of the compound represented by formula Va.
  • the amount of the palladium catalyst is calculated based on the amount of the palladium atoms in the catalyst. The number is calculated as 1, if the catalyst contains multiple palladium atoms, it needs to be divided by the corresponding multiple.
  • the amount of the palladium catalyst is 0.01-20% of the compound represented by formula Va.
  • the amount of the palladium catalyst is 0.1-10% of the compound represented by formula Va.
  • the amount of ligand used in the present disclosure is 0.1-40 times (calculated in molar amount) of the amount of palladium catalyst.
  • the number of palladium atoms in the catalyst is also used when calculating the amount of ligand. 1 calculation.
  • the amount of the ligand is 2-20 times the amount of the palladium catalyst.
  • the amount of the ligand is 4-16 times the amount of the palladium catalyst.
  • the present disclosure provides a method for preparing the compound represented by formula III, the alkaline substance is selected from KHCO 3 , NaHCO 3 , Na 2 CO 3 , Ba(OH) 2 , K 3 PO 4 , Cs 2 CO 3 , K 2 CO 3 , KF, CsF, KCN, NaCN, NaOH, KOH, Et 3 N, DIPEA, DABCO, NaOMe, NaOEt, t-BuOK, t-BuONa, NaH, DBU, TMG, LHMDS, NaHMDS , Sodium tert-amyloxide, n-butyl lithium.
  • the basic substance is selected from t-BuOK, t-BuONa, LHMDS, Cs 2 CO 3 , K 2 CO 3 , diethylamine, and dicyclohexylamine.
  • the alkaline substance is selected from t-BuOK or t-BuONa.
  • the amount of the basic substance in the present disclosure is 0.1-40 times (calculated by molar amount) of the compound represented by formula Va.
  • the amount of the basic substance is 1-20 times that of the compound represented by formula Va.
  • the amount of the basic substance is 3-10 times that of the compound represented by formula Va.
  • the method for preparing the compound represented by formula III provided in the present disclosure is reacted in a group selected from toluene, dioxane, tetrahydrofuran, o-xylene, tert-butyl ether, tert-butanol, tert-amyl alcohol, Ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, isopropyl ether, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, It is carried out in at least one solvent of ethyl acetate, isopropyl acetate, acetonitrile, isopropanol, ethanol, and acetone.
  • the reaction is carried out in at least one solvent selected from toluene, dioxane, tetrahydrofuran, and tert-butanol.
  • reaction is carried out in toluene.
  • the reaction temperature is selected from 0 to 140°C.
  • reaction temperature is selected from 40-120°C.
  • reaction temperature is selected from 80-110°C.
  • the preferred reaction temperature in the preparation method provided in the present disclosure may be a specific point value or interval value in the range of 80-110°C.
  • the reaction is carried out under the protection of an inert gas, and the inert gas is selected from nitrogen, argon, and helium.
  • the method for preparing the compound represented by formula III provided in the present disclosure is carried out under the protection of argon.
  • the method for preparing the compound of formula III provided in the present disclosure may further include the step of reacting the compound of formula V with tetrahydro-2H-pyran-4-amine to obtain the compound of formula III
  • the present disclosure provides a method for preparing the compound represented by formula II, which includes the step of N-ethylation of the compound represented by formula III provided by the present disclosure to obtain the compound represented by formula II
  • the present disclosure provides a method for preparing a compound represented by formula I, which comprises reacting a compound represented by formula II with 3-(aminomethyl)-4,6-lutidine-2(1H)-one hydrochloride to prepare
  • the step of obtaining the compound represented by formula I may also include the step of preparing the compound of formula III by the method provided in the present disclosure or the step of preparing the compound of formula II by the method provided in the present disclosure
  • the method for producing the compound of formula II from the compound of formula III provided in the present disclosure can be specifically referred to the preparation method of the analog disclosed in Example 1 of WO2017084494A.
  • the preparation methods from the compound represented by formula II to the compound represented by formula I provided in the present disclosure can be specifically referred to the methods for preparing amides disclosed in WO2017084494A, WO2012142513, WO2013039988, WO2015141616, WO2011140325.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing 1 to 6 carbons Atom of the alkyl group.
  • 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, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • a lower alkyl group containing 1 to 6 carbon atoms non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • alkylene means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene” means -CH 2 -, "ethylene” means -(CH 2 ) 2 -, “propylene” Refers to -(CH 2 ) 3 -, "Butylene” refers to -(CH 2 ) 4 -, etc.
  • alkenyl refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl etc. Alkenyl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but none of the rings have complete conjugate ⁇ electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls, preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptyl group, etc. Cycloalkyl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • groups are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthi
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 Carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between monocyclic rings of 5 to 20 members, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (where m is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclic groups include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the rest of the ring
  • the atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples thereof include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contains 3 to 6 ring atoms, of which 1 to 2 Are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably piperidinyl, pyrrolidinyl, pyranyl, morpholinyl or Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene Base and naphthyl. Phenyl is more preferred.
  • the aryl ring may be fused on a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxy, or carboxylate.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridine Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, tetrazolyl, thienyl, pyrazolyl or pyrimidinyl, thiazolyl ; More choice pyrazolyl or thiazolyl.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or
  • the heteroaryl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • isocyanato refers to -NCO.
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four For methylsilane (TMS), the chemical shift is given in units of 10 -6 (ppm).
  • the MS is measured with FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • the known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from companies such as BEPHARM.
  • the first step 2-ethyl-6-iodobenzoic acid
  • Dissolve VIII (27.6g, 83mmol) in 138mL concentrated sulfuric acid, cool to 0-5°C, dissolve N-bromosuccinimide (19.6g, 110mmol) in trifluoroacetic acid (5mL/g), control the reaction The temperature of the liquid is 0-5°C, and the above-mentioned N-bromosuccinimide trifluoroacetic acid solution is slowly added dropwise to the reaction solution. After the addition is completed, it will naturally rise to room temperature and react for 1 hour, then slowly rise to 40°C and then add dropwise. 5mL/g N-bromosuccinimide in trifluoroacetic acid solution (14.2g, 80mmol), stop the reaction after detecting VIII ⁇ 2%.
  • Post-treatment the reaction solution was poured into 4 times volume of ice water, solids separated out, stirred at room temperature for 0.5 hours, filtered, collected the filter cake, dissolved in ethyl acetate, dried over anhydrous sodium sulfate, spin-dried to obtain the crude product, recrystallized from ethyl acetate , Vacuum drying, to obtain 29.5 g off-white solid, yield: 82%; purity 95.0%.
  • the third step 6-bromo-5-ethyl-2-(piperidin-1-ylmethyl)benzofuran-4-carboxylic acid
  • Dissolve VII (100g, 230.4mmol), cesium carbonate (187.6g, 576mmol), cuprous iodide (13.16g, 69.12mmol), deionized water (16.6g, 921.6mmol) in 800mL DMSO, and add VI (34.04) g, 276.5 mmol), replaced with argon three times, heated to 110° C., stirred for 5 hours, followed by thin layer tracking until the raw material point VII disappeared, and the reaction was terminated.
  • the fourth step 5-ethyl-2-(piperidin-1-ylmethyl)-6-((tetrahydro-2H-pyran-4-yl)amino)benzofuran-4-carboxylic acid
  • Post-treatment The reaction solution was cooled to room temperature, and a large amount of solid was precipitated. 250 mL of water and 200 mL of saturated sodium chloride solution were slowly added, and stirred to dissolve. Spread diatomaceous earth and filter to remove a small amount of black insoluble matter, and rinse the filter cake with 50 mL of water. The filtrate was allowed to stand for layering, the organic phase was separated, the aqueous phase was back-extracted with toluene (250 mL ⁇ 2), the organic phases were combined, washed with water (100 mL), the aqueous phases were combined, APDTC (201 mg) was added, and the temperature was raised to 50°C and stirred for 1 hour.
  • Post-treatment the reaction solution was cooled to room temperature, and 100 mL of water and 100 mL of saturated sodium chloride solution were slowly added, and stirred to dissolve. Spread diatomaceous earth and filter to remove a small amount of black insoluble matter. The filtrate was allowed to stand for layering, the organic phase was separated, the aqueous phase was back-extracted with toluene (200mL ⁇ 2), the organic phases were combined, washed with water (40mL), added APTDC (103mg), heated to 50°C and stirred for 1 hour, then filtered while hot.
  • APTDC 103mg
  • the raw material III 120mg, 0.31mmol was placed in a 25mL three-necked flask, 3mL of dichloromethane (DCM) was added, acetaldehyde (69mg, 1.55mmol) and acetic acid (94mg, 1.55mmol) were added under ice bath, and the reaction was stirred for 0.5 After hours, under ice bath, add sodium triacetoxyborohydride (198mg, 0.93mmol) three times (each 66mg, 1.0eq), warm up to room temperature, stir the reaction until thin layer tracking until raw material point III disappears, and terminate the reaction.
  • DCM dichloromethane

Abstract

La présente invention concerne un procédé de préparation d'un composé aminobenzofurane 6-substitué. De façon spécifique, la présente invention concerne un procédé de préparation d'un composé représenté par la formule III. Le procédé selon la présente invention peut augmenter significativement le rendement d'une réaction, et permettre une production industrielle.
PCT/CN2020/089113 2019-05-10 2020-05-08 Procédé de préparation d'un composé aminobenzofurane 6-substitué WO2020228591A1 (fr)

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CN114456156A (zh) * 2020-11-09 2022-05-10 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纯化方法
WO2023030299A1 (fr) * 2021-08-30 2023-03-09 江苏恒瑞医药股份有限公司 Utilisation d'un inhibiteur d'ezh2 dans la préparation d'un médicament pour le traitement d'un lymphome à cellules t
WO2023061467A1 (fr) * 2021-10-15 2023-04-20 江苏恒瑞医药股份有限公司 Procédé de préparation d'un dérivé de benzofurane
WO2023244917A1 (fr) 2022-06-13 2023-12-21 Treeline Biosciences, Inc. Agents dégradant bcl6 hétérobifonctionnels 1,8-naphthyridin-2-one
WO2023244918A1 (fr) 2022-06-13 2023-12-21 Treeline Biosciences, Inc. Agents de dégradation bifonctionnels de quinolone bcl6

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WO2017084494A1 (fr) * 2015-11-19 2017-05-26 江苏恒瑞医药股份有限公司 Dérivé du benzofurane, son procédé de préparation et son utilisation en médecine
WO2018210302A1 (fr) * 2017-05-18 2018-11-22 江苏恒瑞医药股份有限公司 Formes cristallines du chlore libre dérivé du benzofurane et son procédé de préparation
WO2019091450A1 (fr) * 2017-11-10 2019-05-16 江苏恒瑞医药股份有限公司 Procédé de préparation d'un dérivé de benzofurane

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WO2017084494A1 (fr) * 2015-11-19 2017-05-26 江苏恒瑞医药股份有限公司 Dérivé du benzofurane, son procédé de préparation et son utilisation en médecine
WO2018210302A1 (fr) * 2017-05-18 2018-11-22 江苏恒瑞医药股份有限公司 Formes cristallines du chlore libre dérivé du benzofurane et son procédé de préparation
WO2019091450A1 (fr) * 2017-11-10 2019-05-16 江苏恒瑞医药股份有限公司 Procédé de préparation d'un dérivé de benzofurane

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114456156A (zh) * 2020-11-09 2022-05-10 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纯化方法
WO2023030299A1 (fr) * 2021-08-30 2023-03-09 江苏恒瑞医药股份有限公司 Utilisation d'un inhibiteur d'ezh2 dans la préparation d'un médicament pour le traitement d'un lymphome à cellules t
WO2023061467A1 (fr) * 2021-10-15 2023-04-20 江苏恒瑞医药股份有限公司 Procédé de préparation d'un dérivé de benzofurane
WO2023244917A1 (fr) 2022-06-13 2023-12-21 Treeline Biosciences, Inc. Agents dégradant bcl6 hétérobifonctionnels 1,8-naphthyridin-2-one
WO2023244918A1 (fr) 2022-06-13 2023-12-21 Treeline Biosciences, Inc. Agents de dégradation bifonctionnels de quinolone bcl6

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