WO2020228591A1 - Preparation method for 6-substituted aminobenzofuran compound - Google Patents

Abstract

Provided in the present disclosure is a preparation method for a 6-substituted aminobenzofuran compound. Specifically, provided in the present disclosure is a preparation method for a compound represented by formula III. The method provided in the present disclosure may significantly increase the yield of a reaction, and provide the possibility of industrial production.

Description

Preparation method of 6-substituted aminobenzofuran compound

This application claims the priority of Chinese patent application 201910387881.X whose filing date is May 10, 2019. This application quotes the full text of the aforementioned Chinese patent application.

Technical field

The present disclosure relates to a preparation method of 6-substituted aminobenzofuran compounds.

Background technique

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.

The histone methyltransferase encoded by EZH2 gene is the catalytic component of polycomb inhibitory complex 2 (PRC2). Compared with normal tissues, the level of EZH2 is abnormally increased in cancer tissues, and the expression level of EZH2 is the highest in advanced cancer or poor prognosis. In some cancer types, overexpression of EZH2 occurs simultaneously with amplification of the EZH2 gene. A large number of 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.

At present, EZH2 inhibitors have entered the clinical development stage. The following is a brief list. Tazemetostat (EPZ-6438) 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 application also discloses the preparation method of the general formula compound,

Summary of the invention

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,

Wherein X is selected from fluorine, chlorine, bromine, iodine, -OS(O) ₂ alkyl, and -OS(O) ₂ aryl.

In an alternative embodiment, 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.

In the preparation method provided in the present disclosure, the structure of the biphenyl monophosphine ligand may be as shown in formula L:

Wherein 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;

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.

In an optional embodiment, 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 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _6-10 aryl and 5-10 membered heteroaryl Is substituted by one or more substituents.

In the preparation method provided in the present disclosure, the monophosphine ligand L can be selected from the following structures:

In the preparation method provided by the present disclosure, 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 .

In an alternative embodiment, the palladium catalyst is selected from Pd ₂ (dba) ₃ , Pd(dba) ₂ , and Pd(OAc) ₂ .

In an alternative embodiment, the palladium catalyst is Pd ₂ (dba) ₃ .

In an alternative embodiment, in the preparation method provided by the present disclosure, 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

Where L is as defined above.

In an alternative embodiment, the amount of the palladium catalyst in the present disclosure is 0.001-30% (calculated by mole) of the compound represented by formula Va. In the method provided in the present disclosure, 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.

In an alternative embodiment, the amount of the palladium catalyst is 0.01-20% of the compound represented by formula Va.

In an alternative embodiment, the amount of the palladium catalyst is 0.1-10% of the compound represented by formula Va.

In an alternative embodiment, the amount of ligand used in the present disclosure is 0.1-40 times (calculated in molar amount) of the amount of palladium catalyst. In this disclosure, the number of palladium atoms in the catalyst is also used when calculating the amount of ligand. 1 calculation.

In an alternative embodiment, the amount of the ligand is 2-20 times the amount of the palladium catalyst.

In an alternative embodiment, the amount of the ligand is 4-16 times the amount of the palladium catalyst.

In an alternative embodiment, 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.

In an optional embodiment, the basic substance is selected from t-BuOK, t-BuONa, LHMDS, Cs ₂ CO ₃ , K ₂ CO ₃ , diethylamine, and dicyclohexylamine.

In an alternative embodiment, the alkaline substance is selected from t-BuOK or t-BuONa.

In an alternative embodiment, 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.

In an alternative embodiment, the amount of the basic substance is 1-20 times that of the compound represented by formula Va.

In an alternative embodiment, the amount of the basic substance is 3-10 times that of the compound represented by formula Va.

In an alternative embodiment, 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.

In an alternative embodiment, the reaction is carried out in at least one solvent selected from toluene, dioxane, tetrahydrofuran, and tert-butanol.

In an alternative embodiment, the reaction is carried out in toluene.

In an alternative embodiment, in the method for preparing the compound represented by formula III provided in the present disclosure, the reaction temperature is selected from 0 to 140°C.

In an alternative embodiment, the reaction temperature is selected from 40-120°C.

In an alternative embodiment, the reaction temperature is selected from 80-110°C.

Specifically, 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.

In an alternative embodiment, in the method for preparing the compound represented by formula III provided in the present disclosure, the reaction is carried out under the protection of an inert gas, and the inert gas is selected from nitrogen, argon, and helium.

In an alternative embodiment, the method for preparing the compound represented by formula III provided in the present disclosure, the reaction 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.

The compound represented by formula I provided in the present disclosure can be specifically prepared by the following route:

Detailed description of the invention

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "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-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers. More preferred is 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.

The term "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.

The term "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. When substituted, 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.

The term "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 Π electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the ring and the ring, 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. Non-limiting examples of spirocycloalkyl groups include:

The term "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 π 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. Non-limiting examples of fused cycloalkyl groups include:

The term "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 π 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. Non-limiting examples of 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. When substituted, 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.

The term "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.

The term "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 π-electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiro atoms between the ring and the ring, 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. Non-limiting examples of spiroheterocyclic groups include:

The term "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 π-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. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

The term "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 π-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. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of 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:

Wait.

The heterocyclic group may be optionally substituted or unsubstituted. When substituted, 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.

The term "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.

The term "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 π-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. When substituted, 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.

The term "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 cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl group may be optionally substituted or unsubstituted. When substituted, 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.

The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, 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.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.

The term "hydroxy" refers to the -OH group.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "oxo" refers to =O.

The term "carbonyl" refers to C=O.

The term "carboxy" refers to -C(O)OH.

The term "isocyanato" refers to -NCO.

The term "oxime group" refers to =N-OH.

The term "carboxylate group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

"Optional" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "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.

Unless stated to the contrary, the English abbreviations used in the specification and claims except for the substances represented by the structural formula have the following meanings.

Detailed ways

Hereinafter, the present disclosure will be explained in detail with reference to specific examples, so that those skilled in the art will more fully understand that the specific examples of the present disclosure are only used to illustrate the technical solutions of the present disclosure, and do not limit the present disclosure in any way.

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).

Water e2695-2489 high performance liquid chromatograph was used for HPLC measurement.

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.

Example 1

Preparation of 5-ethyl-2-(piperidin-1-ylmethyl)-6-((tetrahydro-2H-pyran-4-yl)amino)benzofuran-4-carboxylic acid

The first step: 2-ethyl-6-iodobenzoic acid

Dissolve IX (100g, 667mmol) in 1000mL N,N-dimethylformamide, stir to dissolve, add NIS (165g, 733mmol) and Pd(OAc) ₂ (3g, 13.4mmol) successively, and replace twice with argon , The temperature is raised to 100°C, and the reaction is stirred until the conversion of the raw material IX in the thin layer detection is complete, and the reaction is stopped.

Post-treatment: Pour the reaction solution into 2L water, extract with ethyl acetate (1000mL×3), combine the organic phases, concentrate to remove most of the ethyl acetate, and wash the organic phase with saturated sodium thiosulfate solution and saturated sodium chloride solution in turn , Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 184g (yellow oil) m/z[MH] ^- =275.1, ¹ H NMR (400MHz, CHLOROFORM-d) ppm: 11.85 (br.s. ,1H),7.72(d,1H),7.28(d,1H),7.07-7.14(m,1H),2.78(q,2H),1.29(t,3H), the product goes directly to the next reaction without purification .

Step 2: 3,5-Dibromo-2-ethyl-6-iodobenzoic acid

Dissolve Ⅷ (27.6g, 83mmol) in 138mL concentrated sulfuric acid, cool to 0-5℃, 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.

Post-treatment: spread diatomaceous earth on a suction filter funnel, filter the reaction solution while it is hot, and rinse the filter cake with a small amount of DMSO. Pour the filtrate slowly into 2.4L sodium chloride solution, adjust the pH to 5.5 with 2N HCl under ice-bath conditions, and solid precipitate, stir for 0.5 hours, filter, rinse the filter cake with water, collect the filter cake, and dry it in vacuum Recrystallization from isopropanol yielded 48.8 g of the title product, purity: 97.3%. m/z[M, M+2]=366,368.

The fourth step: 5-ethyl-2-(piperidin-1-ylmethyl)-6-((tetrahydro-2H-pyran-4-yl)amino)benzofuran-4-carboxylic acid

Combine V (40.8g, 110mmol), DavePhos (0.877g, 2.2mmol), Pd ₂ (dba) ₃ (0.255g, 0.278mmol), t-BuONa (54g, 560mmol) and 500mL toluene (dehydrated and deoxygenated) ) Put into the reaction flask, add tetrahydro-2H-pyran-4-amine (22.5g, 220mmol), replace with argon three times, heat the oil bath to 105-108℃, stir and react for 24 hours, and trace to the raw material Ⅴ disappeared and the reaction stopped.

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. Filter while hot, adjust the pH of the filtrate to about 6 with 1N HCl solution, close to the isoelectric point, add solid sodium chloride until the solution is saturated, and extract with a mixed solvent of dichloromethane and methanol (DCM/MeOH=5:1) (400mL×3) ), combine the organic phases, dry with anhydrous sodium sulfate, filter, add 2.5 g of activated carbon to the filtrate, heat to reflux, stir for 1 hour, filter while hot, and concentrate the filtrate under reduced pressure to obtain 28 g of the compound represented by formula III (brown solid) , M/z[M+H] ⁺ =387.4, purity 83.1%, unknown impurity content 8.3%.

Example 2

V (20g, 55mmol), C-phos (480.3mg, 1.1mmol), Pd ₂ (dba) ₃ (125.8mg, 0.137mmol), t-BuONa (26.4g, 275mmol) obtained by the same method in Example 1 ) And 200mL of toluene (dehydrated and deoxygenated) were added to the reaction flask, tetrahydro-2H-pyran-4-amine (11.1g, 110mmol) was added, argon replaced three times, and the oil bath was heated to 105-108℃ , The reaction was stirred for 24 hours, the thin layer tracked until the material V disappeared, and the reaction was stopped.

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. Adjust the pH of the filtrate to about 6 with 1N HCl solution, add solid sodium chloride until the solution is saturated, extract with a mixed solvent of dichloromethane and methanol (DCM/MeOH=5:1) (200mL×3), combine the organic phases, and anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure to obtain 11 g of the compound represented by formula III (orange solid) with a purity of 95.8% and an unknown impurity content of 3.2%.

Example 3

The V (5g, 13.6mmol), DavePhos (0.85g, 2.176mmol), Pd(OAc) ₂ (0.12g, 5.4mmol), t-BuONa (6.6g, 68mmol) obtained by the same method in Example 1 Add 50mL toluene (treated by removing water and oxygen) into the reaction flask, add tetrahydro-2H-pyran-4-amine (2.8g, 27mmol), replace with argon three times, heat the oil bath to 105-108℃, and stir After reacting for 24 hours, the thin layer tracked until the raw material V disappeared, and the reaction was stopped. The same post-treatment method as in Example 2 was used to obtain 1.8 g (brown solid) of the compound represented by formula III with a purity of 69.1% and unknown impurities of 25.5%.

Example 4

N-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-ethyl-6-(ethyl(tetrahydro-2H-pyridine Preparation of pyran-4-yl)amino)-2-(piperidin-1-ylmethyl)benzofuran-4-carboxamide

5-ethyl-6-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-(piperidin-1-ylmethyl)benzofuran-4-carboxylic acid

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.

Post-treatment: Add 50 mL of saturated sodium chloride solution to the reaction solution and stir for 0.5 hours. After standing for liquid separation, the organic phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 94 mg of the product (brown solid). m/z [M+H] ⁺ =415.5.

¹ H NMR (400MHz, DMSO-d ₆ ) ppm 7.55 (s, 1H) 6.76 (s, 1H) 3.82 (d, 2H) 3.65 (s, 2H) 3.22 (t, 2H) 3.05 (q, 4H) 2.95 ( t,1H)2.46(br.s.,4H)1.66(br.s.,2H)1.44-1.56(m,6H)1.37(br.s.,2H)1.03-1.14(m,3H)0.81(t ,3H).

N-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-ethyl-6-(ethyl(tetrahydro-2H-pyridine (Pyran-4-yl)amino)-2-(piperidin-1-ylmethyl)benzofuran-4-carboxamide

In a 25mL three-necked flask, mix raw material II (50mg, 0.12mmol), 1-ethyl-3(3-dimethylpropylamine) carbodiimide (34.5mg, 0.18mmol), 1-hydroxybenzotriazole (23.67) mg, 0.18mmol), mixed with N,N-diisopropylethylamine (77.89mg, 0.6mmol), dissolved in 3mL N,N-dimethylformamide, and stirred evenly; add the raw material 3-(amino (Methyl)-4,6-lutidine-2(1H)-one hydrochloride (24.9mg, 0.13mmol), the reaction was stirred at room temperature until the thin layer tracked until the starting material point II disappeared, and the reaction was terminated. Add excess water to the reaction solution, extract with a mixed solvent of dichloromethane and methanol (V:V=8:1), combine the organic phases, wash with water, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with a dichloromethane-methanol eluent system to obtain 30.1 mg of white solid, with a yield of 47.0%.

m/z [M+H] ⁺ = 549.6.

¹ H NMR(400MHz,DMSO-d6)ppm 11.51(s,1H)8.17(t,1H)7.39(s,1H)6.47(s,1H) 5.86(s,1H)4.32(d,2H)3.83(d ,2H)3.53(s,2H)3.21(t,2H)3.04(d,2H)2.94(br.s.,1H)2.79(d,2H)2.38(br.s.,4H)2.23(s,3H) ) 2.08-2.14(m,3H)1.65(d,2H)1.44-1.56(m,6H)1.36(d,2H)1.02(t,3H)0.81(t,3H).

Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are merely examples, and various changes or modifications can be made to these embodiments without departing from the principle and essence of the present invention. modify. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims (13)

1. A method for preparing a compound represented by formula III, which comprises a compound represented by formula IV or its salt and a compound represented by formula Va in at least one biphenyl monophosphine ligand, at least one palladium catalyst and at least one basic The step of reacting to get the compound of formula III under the action of the substance,

   

   Wherein X is selected from fluorine, chlorine, bromine, iodine, -OS(O) ₂ alkyl, and -OS(O) ₂ aryl, preferably iodine and bromine.
2. The preparation method according to claim 1, wherein the structure of the phosphine ligand is shown in formula L:

   

   Wherein 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;

   When the ligand L is chiral, it is optionally a racemate or a separate enantiomer;

   The R in Y and the R in Z are optionally the same or different.
3. The preparation method according to claim 2, wherein

   R is selected from C _1-6 alkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, heterocycloalkyl, C _6-10 aryl, 5-10 membered 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 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic group, C _6-10 aryl and 5-10 membered heteroaryl Is substituted by one or more substituents.
4. The preparation method according to claim 2, wherein the L is selected from the following structures:

   

   
5. The preparation method according to claim 1, wherein the palladium catalyst is selected from the group consisting of 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 , preferably Pd ₂ (dba) ₃ , Pd(dba) ₂ , Pd(OAc) ₂ , Pd ₂ (dba) _{3 is} most preferred.
6. The preparation method according to claim 1, wherein the biphenyl monophosphine ligand and the palladium catalyst are in the form of a precursor catalyst.
7. The preparation method according to claim 6, wherein the precursor catalyst is G-I, G-II or G-III, wherein L is as defined in any one of claims 2-4

   
8. The preparation method according to any one of claims 1-7, 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-pentoxide , N-butyl lithium, preferably t-BuOK, t-BuONa, LHMDS, Cs ₂ CO ₃ , K ₂ CO ₃ , diethylamine, dicyclohexylamine, most preferably t-BuOK, t-BuONa.
9. The preparation method according to any one of claims 1-8, the reaction is 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, dimethylsulfoxide, N-methylpyrrolidone, ethyl acetate , Isopropyl acetate, acetonitrile, isopropanol, ethanol, acetone, at least one solvent, preferably the solvent is toluene, dioxane, tetrahydrofuran, tert-butanol, most preferably the solvent is toluene.
10. The preparation method according to any one of claims 1-9, wherein the reaction is carried out under the protection of an inert gas, and the inert gas is selected from the group consisting of nitrogen, argon, and helium, preferably argon.
11. The preparation method according to any one of claims 1-10, which comprises the step of reacting the compound shown in V with tetrahydro-2H-pyran-4-amine to obtain the compound shown in formula III,

    
12. A method for preparing the compound represented by formula II, which comprises the step of N-ethylation of the compound represented by formula III to obtain the compound represented by formula II. The compound represented by formula III is defined by any one of claims 1-11. Preparation method described

    
13. 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 obtain formula The step of the compound shown in I further comprises the step of preparing the compound of formula III according to any one of claims 1-11 or the step of preparing the compound of formula II according to claim 12,